Jerrold Lerman - Neonatal Anesthesia-Springer (2023)

Jerrold
Lerman
Editor
Neonatal
Anesthesia
Second Edition
123
Neonatal Anesthesia
Jerrold Lerman
Editor
Neonatal Anesthesia
Second Edition
Editor
Jerrold Lerman
Department of Anesthesia
John R. Oishei Children’s Hospitalr
Buffalo, NY, USA
ISBN 978-3-031-25357-7 ISBN 978-3-031-25358-4 (eBook)

https://doi.org/10.1007/978-3-031-25358-4
© Springer Nature Switzerland AG 2023

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The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
I wish to thank my wife, Robin, and my children and grandchildren for their
endless support and patience in undertaking this project.
I also wish to thank Drs. Robert E. Creighton and David J. Steward for their
guidance and mentorship in shaping my academic career as a pediatric
anesthesiologist.
Finally, not a day goes by that I do not reflect on the two anesthesiologists
whose teaching, advice, influence, and mentoring set a trajectory for my
academic career in pediatric anesthesia that would not have been possible
otherwise: Drs. George Gregory and E.I. Eger II.
Thank you all.
Jerrold Lerman, MD, FRCPC, FANZCA
Foreword
The anesthesiologist … who has to spend more than a half hour in putting an infant to sleep because of
unavoidable difficulties, and who during this time makes no excuses for his slowness and resorts to no
drastic expedients to impress the onlookers or to console the impatient surgeon, is a gift beyond price to
the welfare of children who are entrusted to his care in the operating room.—Willis J. Potts, The Surgeon
and the Child, 1959
Those of us who have been privileged to practice neonatal anesthesia have indeed enjoyed
a special relationship with our surgeons. We have also had to meet the challenges of working
in one of the most demanding of anesthesia subspecialties. The technical aspects of our prac-
tice require a level of precision and attention to detail unparalleled in other areas of anesthesia
practice. Successful perioperative management of the neonate requires obsessive monitoring
and the potential for rapid and appropriate therapeutic responses based on a comprehensive
knowledge of neonatal physiology and pharmacology. The neonatal anesthesiologist assumes
a daunting responsibility, their patients are at a critical stage of development, and neonates are
in the prelude to a potential lifetime of achievements.
Neonates have been given anesthetics since 1847, but the real history of neonatal anesthesia
did not begin until halfway through the twentieth century. I started my training in pediatric
anesthesia in 1967 at a world-renowned Canadian children’s hospital. One day, I was assigned
to assist with the anesthesia for a neonate with a pre-ductal coarctation of the aorta. I was told
that the way to manage this patient was to give a large dose of d-tubocurarine (a paralytic drug)
and ventilate the lungs with oxygen. My monitors included an esophageal stethoscope, an
electrocardioscope, an oscillometer, and a rectal temperature probe. What a long way we have
come in more than 50 years!
What you are about to read is the second edition of Neonatal Anesthesia. It is most appro-
priate that a comprehensive book devoted to neonatal anesthesia should be revised at this time.
There has been a progressive and steady accumulation of knowledge related to the subject over
the past few decades. Well-designed studies have been published, which now permit an
evidence-based approach to anesthetizing the neonate. This, along with simultaneous wide-
spread advances in medical technology, has provided clinicians with new and efficient means
to improve all aspects of the neonate’s care. All of this has culminated in a rapid evolution in
the management strategies available for the neonate. The neonatal anesthesiologist can now
very safely apply a full range of modalities to optimize the perioperative cardiorespiratory and
overall physiological status, prevent pain, and contribute very significantly to the success of
the surgery.
This second edition includes four new chapters that cover fetal surgery and the EXIT pro-
cedure, extracorporeal membrane oxygenation (ECMO), neonatal resuscitation, and the very
important and somewhat controversial subject, “Do Anesthetics Harm Neonates.” The chapter
entitled “Metabolic Care” has been extensively revised to reflect the new insights and expanded
evidence on this subject, and to recognize the importance of these advances in designing the
perioperative prescription for the neonate. All of the remaining chapters have been revised and
updated to incorporate the latest developments in their fields.
vii
viii Foreword
Dr. Lerman has a very extensive personal experience as a clinical neonatal anesthesiologist,
gained in the very busy neonatal surgical service at the Hospital for Sick Children, Toronto,
and subsequently at the Oishei Children’s Hospital in Buffalo, NY. As an investigator, he has
contributed significantly to our knowledge. He has recruited an outstanding international team
of well-known contributors, each an expert in his or her field, that include neonatologists,
intensivists, and pediatric surgeons in addition to pediatric anesthesiologists, to compile this
sourcebook for the practitioner.
Department of Anaesthesia, Pharmacology and Therapeutics David J. Steward

University of British Columbia
Vancouver, BC, Canada
June 2022
Acknowledgments
We thank the authors for their excellent contributions to the first edition of Neonatal Anesthesia.
ix
Contents
1 The
History of Neonatal Anesthesia �� 1
David J. Steward
2 Physiology
and Development of the Term and Preterm Neonate�� 19
Claire Brett and David Robinowitz
3 Anesthesia
and Ancillary Drugs and the Neonate�� 99
Brian J. Anderson and Jerrold Lerman
4 The
Selection of Anesthesia Techniques for the Neonate�� 167
Nada Sabourdin, Nicolas Louvet, and Isabelle Constant
5 Airway Management �� 189
Annery G. Garcia-Marcinkiewicz, Paul A. Stricker, and John E. Fiadjoe
6 Neonatal
Ventilation Strategies and Their Practical Application�� 213
Adam Balogh and Walid Habre
7 Perioperative
Monitoring: Methods, Implementation, and Interpretation�� 227
Nicola Disma and Christian Breschan
8 Metabolic
Care of the Preterm and Term Infants, Including Control of Body
Temperature �� 257
Gianluca Bertolizio, Pablo Ingelmo, and Jerrold Lerman
9 General
and Thoracoabdominal Surgery Including Management
of Conjoined Twins�� 291
Kate Cross, Peter Carachi, and Sally Wilmshurst
10 Neurosurgery and Ophthalmology�� 347
David N. Levin and Sulpicio G. Soriano
11 Cardiac Surgery �� 359
Wanda C. Miller-Hance, Erin A. Gottlieb, and Pablo Motta
12 ECMO
for the Neonate�� 439
Omar Alibrahim and Christopher M. B. Heard
13 Anesthesia
Outside the Operating Room�� 455
Christopher M. B. Heard, Satyan Lakshminrusimha, and Jerrold Lerman
14 Fetal
Surgery and the EXIT Procedure �� 485
Marla B. Ferschl and Mark D. Rollins
15 Neonatal
Pain: Significance, Assessment, and Management �� 505
Joy M. Dawes and Richard F. Howard
xi
xii Contents
16 Regional Anesthesia for Neonates�� 529

Adrian Bosenberg
17 Anesthetic
Complications in the Neonate: Incidence, Prevention,
and Management�� 553
Mary Lyn Stein, Robert F. O’Donnell, Monica Kleinman, and Pete G. Kovatsis
18 Do
Anesthetic Drugs Harm Neonates? A Global Perspective�� 581
Tom G. Hansen, Steen W. Henneberg, and Thomas Engelhardt
19 Neonatal Resuscitation for Anesthesiologists�� 607
Satyan Lakshminrusimha and Payam Vali
20 Ethical
and Medicolegal Considerations �� 631
Mariah K. Tanious and Thomas J. Mancuso
Index�� 639
Contributors
Omar Alibrahim, MD Division of Pediatric Critical Care Medicine, Duke University

Medical Center, Durham, NC, USA
Brian J. Anderson, PhD, FANZCA, FJFICM Department of Anaesthesiology, University
of Auckland, Auckland, New Zealand
Adam Balogh, MD, PhD Unit for Anesthesiological Investigations, University of Geneva,
Geneva, Switzerland
Gianluca Bertolizio, MD, FRCPC Department of Anesthesia, Montreal Children’s Hospital,
Montreal, QC, Canada
Adrian Bosenberg, MB, ChB, FFA (SA) Department Anesthesiology and Pain Management,
Faculty Health Sciences, University Washington and Seattle Children’s Hospital, Seattle, WA, USA
Christian Breschan, MD Department of Anaesthesia, Klinikum Klagenfurt, Klagenfurt,
Austria
Claire Brett, MD Department of Anesthesia and Perioperative Care, UCSF School of
Medicine, University of California, San Francisco, CA, USA
Peter Carachi, MB, ChB, FRCA Children’s Hospital at Wales, Cardiff, UK
Isabelle Constant, MD, PhD Department of Anesthesiology and Intensive Care, Armand
Trousseau Hospital, APHP, Sorbonne University, Paris, France
Kate Cross, FRACS Great Ormond Street Hospital NHS Trust, London, UK
Joy M. Dawes, MBBS, FRCA Great Ormond Street Hospital for Children, London, UK
Nicola Disma, MD Unit for Research in Anaesthesia, Department of Paediatric Anaesthesia,
IRCCS Istituto Giannina Gaslini, Genova, Italy
Thomas Engelhardt, MD, PhD, FRCA Department of Anesthesia, Montreal, QC, Canada
Marla B. Ferschl, MD University of California San Francisco, San Francisco, CA, USA
John E. Fiadjoe, MD Department of Anesthesiology, Critical Care and Pain Medicine,
Harvard Medical School, Boston Children’s Hospital, Boston, MA, USA
Annery G. Garcia-Marcinkiewicz, MD Department of Anesthesiology and Critical Care,
The Children’s Hospital of Pennsylvania and the Perelman School of Medicine at the University
of Pennsylvania, Philadelphia, PA, USA
Erin A. Gottlieb, MD Pediatric Cardiac Anesthesiology, Dell Children’s Medical Center,
The University of Texas at Austin, Austin, TX, USA
xiii
xiv Contributors
Surgery and Perioperative Care, Dell Medical School, The University of Texas at Austin,
Austin, TX, USA
Walid Habre, MD, PhD Unit for Anesthesiological Investigations, University of Geneva,
Pediatric Anesthesia Unit, Geneva Children’s Hospital, University Hospitals of Geneva,
Geneva, Switzerland
Tom G. Hansen, MD, PhD Department of Anesthesiology and Intensive Care Medicine—
Pediatric Section, Akershus University Hospital, Lørenskog, Norway and Faculty of Medicine,
Institute of Clinical Medicine, Oslo University, Norway, Oslo, Norway
Christopher M. B. Heard, MD, FRCA Division of Pediatric Critical Care Medicine,
Departments of Pediatrics and Pediatric Anesthesiology, Oishei Children’s Hospital, Jacobs
School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
Steen W. Henneberg, MD, PhD Copenhagen University Hospital, Copenhagen, Denmark
Uppsala University, Uppsala, Sweden
Richard F. Howard, BSc, MB, ChB, FRCA, FFPM Department of Anaesthesia and Pain
Medicine, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
Pablo Ingelmo, MD Department of Anaesthesia, Montreal Children’s Hospital, Montreal,
QC, Canada
Monica Kleinman, MD Division of Critical Care Medicine, Department of Anesthesiology,
Critical Care and Pain Medicine, Boston Children’s Hospital, Harvard Medical School, Boston,
MA, USA
Pete G. Kovatsis, MD Division of Perioperative Anesthesia, Department of Anesthesiology,
MA, USA
Satyan Lakshminrusimha, MD Division of Neonatology, Department of Pediatrics, UC
Davis Children’s Hospital, Sacramento, CA, USA
Jerrold Lerman, MD, FRCPC, FANZCA Department of Anesthesiology, John R. Oishei
Children’s Hospital, Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
David N. Levin, MD, FRCPC Hospital for Sick Children and University of Toronto, Toronto,
ON, Canada
Nicolas Louvet, MD Department of Anesthesiology and Intensive Care, Armand Trousseau
Hospital, APHP, Sorbonne University, Paris, France
Thomas J. Mancuso, MD Department of Critical Care, Boston Children’s Hospital, Boston,
MA, USA
Wanda C. Miller-Hance, MD Department of Anesthesiology, Perioperative and Pain
Medicine, Arthur S. Keats Division of Pediatric Cardiovascular Anesthesiology; Department
of Pediatrics, Lillie Frank Abercrombie Division of Pediatric Cardiology, Baylor College of
Medicine and Texas Children’s Hospital, Houston, TX, USA
Pablo Motta, MD Department of Anesthesiology, Perioperative and Pain Medicine, Arthur S.
Keats Division of Pediatric Cardiovascular Anesthesiology, Baylor College of Medicine and
Texas Children’s Hospital, Houston, TX, USA
Robert F. O’Donnell, MD Division of Pediatric Anesthesia, Department of Anesthesia,
F. Edward Hebert School of Medicine, Naval Medical Center, Uniformed Services University,
Portsmouth, VA, USA
Contributors xv
David Robinowitz, MD Department of Anesthesia and Perioperative Care, UCSF School of

Medicine, UCSF Benioff Children’s Hospital, San Francisco, CA, USA
Mark D. Rollins, MD, PhD Mayo Clinic, Rochester, MN, USA
Nada Sabourdin, MD, PhD Department of Anesthesiology and Intensive Care, Armand
Trousseau Hospital, APHP, Sorbonne University, Paris, France
Sulpicio G. Soriano, MD Boston Children’s Hospital and Harvard Medical School, Boston,
MS, USA
Mary Lyn Stein, MD Division of Perioperative Anesthesia, Department of Anesthesiology,
MA, USA
David J. Steward, MBBS, FRCPC Department of Anaesthesia, Pharmacology and
Therapeutics, University of British Columbia, Vancouver, BC, Canada
Paul A. Stricker, MD Department of Anesthesiology and Critical Care, The Children’s
Hospital of Pennsylvania and the Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA, USA
Mariah K. Tanious, MD, MPH Department of Anesthesia and Perioperative Medicine,
MUSC Shawn Jenkins Children’s Hospital, Charleston, SC, USA
Payam Vali, MD Department of Pediatrics, UC Davis Children’s Hospital, Sacramento, CA,
USA
Sally Wilmshurst, MRCP, FRCA Great Ormond Street Hospital for Children, London, UK
The History of Neonatal Anesthesia
1
David J. Steward
Prelude Early Times
Operations in neonates were sometimes undertaken in the Diethyl ether was administered during operations by
years before the introduction of anesthesia. Those proce- Crawford Long in 1842, but it was the demonstration by
dures most frequently documented were imperforate anus William G. Morton in 1846 at the Massachusetts General
and harelip (cleft lip). Harelip repair was quite often success- Hospital in Boston, Massachusetts, that led to the widespread
ful, whereas imperforate anus procedures were often fol- introduction of general anesthesia. However, the benefits of
lowed by death. Many surgeons were reluctant to operate on anesthesia during surgery were not immediately or univer-
neonates and there was controversy regarding the propriety sally applied. “They don’t feel it like we do” was a saying
of these procedures [1]. In 1833, Wardrop observed that held to be true by physicians and surgeons long after 1846
“Infants are sometimes destroyed by the loss of even a small [4]. In 1847, one-third of the surgical operations on adults at
quantity of blood,” although he also reported the successful the Massachusetts General Hospital, the site of Morton’s
repair of a double harelip in an 8-day-old child and preferred demonstrations, were performed without anesthesia [4].
to operate on the infant at an early age [2]. At the same time, Anesthesia was selectively applied to those who it was
he was concerned that the emotional effects of the mother or judged felt pain more severely, i.e., white, wealthy, and espe-
nurse (i.e., “wet nurse”) observing the infant’s distress dur- cially female patients. Infants, in particular, were considered
ing the operation might alter the composition of her breast incapable of perceiving pain; indeed Dr. Abel Pierson stated
milk. This concern was then used to explain the cause of con- that “infants could sleep insensibly even while undergoing
vulsions and death, which sometimes ensued. Indeed, he surgery” [4]. Henry J. Bigelow considered that like the lower
suggested that “neither the mother nor the hired nurse should animals, the very young lacked the mental capacity to suffer
be agitated by the screams of the child or that if they be at all pain [5]. Indeed, in the case of the neonate, misunderstand-
alarmed by them the child should not be allowed to suckle ing of their perception of pain persisted well into the twenti-
until all effects of such agitation have ceased.” eth century.1
Considering our present knowledge of the adverse physi- During the second half of the nineteenth century and the
ological effects of unmodified pain on the neonate, it is not early part of the twentieth century, the decision to administer
surprising that surgery without anesthesia was often unsuc- anesthesia to a neonate to relieve the pain of surgery was
cessful. It is somewhat surprising that though poppy extract inconsistent. This is perhaps not surprising given the primi-
(opium) had long been administered to infants who were cry- tive methods that were available to administer anesthesia, the
ing with the discomforts of teething [3], there are no reports rarity of neonatal surgery, and the fact that small infants
of its use to ease the pain of surgery. could be quite easily restrained during an operation (in addi-
The introduction of general anesthesia had the potential to tion to the thought that they do not feel pain anyway!).
render operations in neonates much more acceptable to all
those who were involved (not least the patient!); however, it
As recently as 1976, a technique of “anesthesia” for ductus arteriosus
1
was to be a long time before such anesthesia was universally
ligation in preterm infants, which was totally devoid of anesthetic or
and effectively administered. analgesic agents, was reported from a large American University
Hospital in a widely respected British journal. The authors stated “No
premedication was given. Just before the procedure, if necessary, a
D. J. Steward (*) paralysing dose of suxamethonium 1 mg/kg body wt. was given. No
Department of Anaesthesia, Pharmacology and Therapeutics, other anaesthetic agent was used…We have avoided the use of anes-
University of British Columbia, Vancouver, BC, Canada thetic or analgesic agents which in our opinion are unnecessary” [6].
© Springer Nature Switzerland AG 2023 1

J. Lerman (ed.), Neonatal Anesthesia, https://doi.org/10.1007/978-3-031-25358-4_1
2 D. J. Steward
Reports of operations on “impervious rectum” [7], strangu- being established. The Hospital for Sick Children at Great
lated inguinal hernia, and even meningomyelocele [8] with- Ormond Street in London (GOS) in England opened in 1852;
out anesthesia can be found in medical journals of this era. the Hospital for Sick Children, in Toronto, Canada opened in
However, reports from this same time period can also be 1875; and Boston Children’s Hospital, in the USA, which was
found describing anesthesia that was administered to infants modeled after GOS, opened in 1882 [12]. Other European and
in the first month of life. John Snow preferred chloroform North American cities established children’s hospitals at about
and wrote in 1855 “Chloroform may be given with propriety this time. “Pediatric surgery” in these early years involved
to patients of all ages. I have exhibited it to several infants mainly orthopedic procedures, neonatal surgery was rarely
aged from ten days to three weeks” [9]. He went on to say performed, but the children’s hospitals would serve as a site
that “Chloroform acts very favourably on infants and chil- and a catalyst for the subsequent expansion of infant surgery.
dren. There has, I believe, been no death from chloroform In the late nineteenth century, progress was being made in
under the age of fifteen years.” The most commonly described the care of the sick neonate and preterm infant. It was recog-
indication for elective surgery in neonates during these years nized that the survival of small preterm infants was improved
was for correction of “harelip,” an operation that was fre- if they could be kept warm. A warm-air heated incubator was
quently performed “at the earliest period of life.”2 On developed by a French obstetrician, Stephane Tarnier, and
Saturday, July 4, 1857, an entry in the case books of John installed at the Paris Maternity Hospital. This was based on a
Snow [10] reads “Administered Chloroform at Kings College device for raising poultry, which Tarnier had seen at the zoo-
Hospital to an infant, 8 days old, previous to Mr. Fergusson logical garden [13]. The design was improved by Pierre
operating for hare-lip. The face piece was too large and the Budin, and his incubators were shown at the Berlin World
chloroform took very little effect.” Chloroform was adminis- Exhibition of 1896 by his associate Martin Couney, infants
tered on this occasion using Snow’s inhaler with a small being provided by Dr. Czerny, who was the Professor of
facepiece; the latter, however, was still too large for a neo- Pediatrics in the city. Couney later exhibited his incubators
nate. According to Snow, the use of the inhaler permitted “a in London and at the Pan-American Exposition in Buffalo,
more gradual introduction of the agent than when adminis- New York, in 1901. He also opened an exhibit at the Coney
tered on a sponge or handkerchief” [9]. Island fairground in New York City, which ran until 1943.
The alternative method was to administer chloroform to Infants in incubators were also displayed at various other
the infant using a sponge. “Mr. Greenhalgh preferred a public exhibitions and fairgrounds. The public was invited to
sponge to every other kind of apparatus. He had employed pay 25 cents to view these infants in incubators, an unlikely
the chloroform in a great number of cases, and with success: start for the specialty of neonatology. Once having been used
one of the cases was an infant, three weeks old, for an opera- in an exhibit, many incubators were later sold to hospitals.
tion for hare-lip” [11].
During the second half of the nineteenth century, neonatal
surgery was limited to superficial lesions. Abdominal sur- The Twentieth Century
gery was largely confined to the emergency management of
incarcerated inguinal hernia. Imperforate anus of the low In 1905, ethyl chloride was being used for brief procedures
type was relieved by incision, often without anesthesia. in infants as young as 5 days of age. It was administered
There were also reports of successful operations on neonates using an inhaler [12, 14, 15]:
under chloroform anesthesia for high imperforate anus. A celluloid face-piece is generally preferable since it not only
Thoracic surgery was certainly not attempted. However, dur- permits the anaesthetist to observe the patient more readily but
ing these years, great progress was achieved in basic surgical also resists the action of the vapour better than rubber. For
techniques and the prevention of infection. The concepts of infants of a few days or a few weeks old I commence by spray-
ing three cubic centimetres into the inhaler; for those of six
antisepsis and asepsis were recognized and applied. Many of months and upwards I give five cubic centimetres at once. The
the congenital lesions that would much later become the field mask is then approached to the face but not pressed against it so
of the neonatal surgeon were being recognized—though that the baby has several breaths of air and vapour mixed; it is
only as curiosities [12]. then more closely applied so as to exclude all air except that
which is already in the bag, and in a few seconds the child
It is during this time that the first books on pediatric surgery becomes unconscious. When one is sure that the anaesthesia is
were being published and special hospitals for children were deep and the surgeon has made his incision or begun the opera-
tion the mask should be removed from the face and a few breaths
of air should be given. If it is desired to continue the period of
2
Repair of cleft lip (“harelip”) today conjures up thoughts of a delicate narcosis for some time the mask should not be kept off for long
procedure with carefully planned and positioned skin flaps sutured but only raised occasionally for air. If the respiration indicates
using many fine sutures in a procedure lasting an hour or more. In the the lightening of the narcosis a few more cubic centimetres may
1850s, the repair would require 3–5 sutures and be completed within be added to the bag; on these lines the anaesthesia may be indefi-
3–5 min, at most. nitely prolonged.
1 The History of Neonatal Anesthesia 3
Abdominal surgery for infants became established around of its extent. This fortunately proved to be the case and the
the turn of the twentieth century with the introduction of sur- whole operation lasted only 12 min, notwithstanding the
gical procedures for the relief of pyloric stenosis. Originally fact that the work had to be stopped every few seconds to
managed by gastroenterostomy, the lesion was later cor- allow the infant to breathe. In order to diminish the duration
rected by pyloroplasty [16] and finally by Ramstedt’s of the operation and the amount of shock a continuous cat-
extramucosal pyloromyotomy [17]. Though most patients gut suture was used and no attempt was made to remove the
were older, some neonates were operated upon for pyloric superfluous skin” [18].
stenosis. Chloroform was the preferred anesthetic and the These then were the early days of neonatal surgery. The
need for adequate and constant levels of anesthesia was rec- treatment of major congenital anomalies would have to await
ognized. Reporting success in their cases of pyloroplasty in further progress in the perioperative and anesthesia manage-
the Lancet in 1902, Cautley and Dent stated: “Unless the ment of the infant. One major step forward was the introduc-
patient is deeply under the influence of chloroform (which tion of endotracheal anesthesia and the associated potential
certainly appears to be the best anaesthetic) there is risk of for controlling ventilation.
protrusion of the intestine and rapidity of operating becomes
a matter of great difficulty. On the other hand, in abdominal
operations on very young children deep anaesthesia, unless Endotracheal Intubation of Neonates
most carefully induced and maintained, may lead to very
sudden and alarming symptoms. Any interruption to the MacEwen introduced the concept of passing tubes through
operative procedure while in progress would be a very seri- the adult glottis into the trachea as an alternative to trache-
ous matter, for if the patient is not deeply anaesthetised there otomy in 1880 [19]. Elsberg passed intratracheal catheters
is every likelihood of his recovering sufficiently to cry or to and used these to insufflate anesthetic gases describing his
struggle. If any such event happens the intestines are likely to technique in 1909 [20]. When using an intratracheal insuffla-
protrude at once with the most astonishing suddenness and tion technique, a small catheter was utilized to leave an ade-
force. In a case recorded by Stern; both of these troubles quate route for expired gases. Indeed, common practice was
seem to have occurred. The child’s breathing stopped just to pass a second catheter through the glottis to provide a reli-
after the operation had begun; the anaesthetic was so badly able route for expiration. This prompted C Langton Hewer,
borne that it had to be discontinued while the operation was who a year later was to write the first British text on pediatric
completed; and the result was that the intestine protruded anesthesia, to state in 1924: “Endo-tracheal anaesthesia is
extensively, thus prolonging the operation and enormously contra-indicated in the following class of case:—Babies
increasing its severity” [16]. There followed a much-deserved below the age of one year. The lumen of the glottis is so
tribute to the skill of their own anesthetists: “The success of small in babies that it is practically impossible to obtain a
our cases was largely due to the extreme care and skill with catheter of such size as will permit sufficient vapour to pass
which the anaesthetic was administered, in the first case by and yet leave an adequate return airway” [21]. However, also
Dr. H. Menzies, and in the second by Dr. G. P. Shuter. The in 1924, Ivan Magill did describe an expiratory attachment
surgeon is too often inclined to absorb all the credit of a suc- for an intratracheal catheter, which was available in five
cessful operation, when a great part of it is really due to the sizes—the smallest of which would attach to a 9-French
anaesthetist” [16]. Anesthesia for infants was already recog- catheter (i.e., a 3-mm external diameter catheter) [22]. The
nized as requiring special attention to detail. expiratory attachment was essentially a tapered metal tube,
Monitoring during these early years depended on obser- which could be sited at the level of the glottis and connected
vation of the patient’s color, the pattern of ventilation, and in to a second catheter. He later reported that he had used this
older patients perhaps a finger on the pulse! Much skill must tube attachment in children under 2 years.
have been needed to maintain an airway without instrumen- In 1928, Magill was routinely using endotracheal tubes of
tation, ensure a constant level of anesthesia, and avoid car- sufficient caliber to permit to-and-fro ventilation, a method
diorespiratory depression. It is not at all surprising that the he preferred in small children and which he had first used in
mortality rate for infants was very high. However, some adults in 1920 [23]. Magill tubes were manufactured of red
amazing successes were reported with what must have been rubber and the smallest size was 00 which had an external
very challenging clinical cases. One such was the resection diameter of 4 mm, similar to that of today’s 3.5-mm ID plas-
of an extremely large teratoma from the neck of a child 3 tic tube, though the internal diameter of the Magill 00 tube
weeks old [18]. Anesthesia was induced and maintained was only 3 mm.
with chloroform on a sponge. “The element of time was In 1939, Gillespie described methods for routine tracheal
necessarily a most important point in the operation and it intubation of infants [24]. He stressed that though the advan-
was hoped that as the cyst wall was well defined it might be tages of intubation were now universally accepted, the intu-
possible to shell out the tumour throughout the greater part bation itself was more difficult in infants and, in inexperienced
4 D. J. Steward
hands, might endanger the patient. To facilitate intubation, were breathing spontaneously. However, he did stress the
he favored a nitrous oxide/oxygen mixture with ether anes- need to attempt to pass the tube “gently” [24].
thetic and added 5% of carbon dioxide to induce hyperpnea The use of endotracheal intubation in infants was not
and speed induction. When respiration was regular and auto- without problems, however, and cases of postoperative
matic, the mandible relaxed, and no trace of glottic spasm laryngeal edema and, more rarely, subglottic stenosis were
evident, intubation could be attempted. (There were, of reported. The need to use a tube, which passed easily through
course, no relaxant drugs available at this time.) He had the glottis and subglottic space and allowed a slight leak on
developed a modification of the smallest-size Chevalier pressurization of the anesthesia circuit, was, in time, recog-
Jackson laryngoscope, which was marketed under the name nized by anesthesiologists. A classic paper by Eckenhoff
“Shadwell” laryngoscope (Fig. 1.1). It was designed to be [25] in 1951 described the anatomy and dimensions of the
held with the fingers rather than in the palm of the hand “to infant larynx and stressed the need to avoid injury to the
discourage the use of force” [24]. mucosa in the region of the cricoid ring. The problems that
Gillespie noted that the epiglottis in the neonate was pro- sometimes followed intubation and the fear that these might
portionally longer than in the adult and that, with each breath, adversely affect outcomes led many surgeons, particularly in
the larynx tended to move anteriorly and out of the field of the USA, to oppose this practice for their patients. Anesthesia
vision; deepening the anesthetic to prevent this movement providers were directed to manage neonates for complex
tended to induce signs of impending cardiorespiratory fail- repairs, e.g., tracheoesophageal fistula or coarctation of the
ure. He stressed the need for gentleness and warned that any aorta, using mask anesthesia. However, the pioneers of pedi-
use of force might cause complications varying from a atric anesthesia persisted, perfected safer methods, and thus
croupy cough to acute edema of the larynx. In his own facilitated acceptance of the need for endotracheal intuba-
reported series of 70 infants under the age of 2 years, he had tion, essential if progress in neonatal surgery was to
remarkably few complications, especially in view of his continue.
statement that the largest possible tube should be passed. He Red rubber tubes were largely abandoned in favor of plas-
was concerned to not narrow the airway, as all his patients tic tubes in the 1950s. However, early plastic tubes were also
not without problems. Irritant chemical substances (organo-
tins) within the plastic material were found to be capable of
stimulating local tissue reactions that could lead to fibrosis
[26]. The establishment of routines for implantation testing
of plastic material led to improvements in endotracheal tube
composition and manufacture and a subsequent decrease in
complications.
In 1945, Cole described a new endotracheal tube for
infants. This tube had a wider proximal portion and a nar-
rower distal segment to pass through the glottis, the rationale
being that the wider portion would decrease the resistance to
airflow. In addition, it was claimed that the shoulder of the
tube would decrease the likelihood of the tube passing too far
and entering a bronchus. In fact, the resistance of the Cole
tube was found to be greater than that of a similar internal
diameter parallel-sided tube [27]. This was attributed to tur-
bulent flow within the Cole tube. More seriously, the shoul-
der on the tube was shown to cause laryngeal damage if
advanced into the glottis [28]. The Cole tube was generally
abandoned for use during anesthesia but remained in use for
neonatal resuscitation in some centers, the claim being that it
was easier for the less expert practitioner to insert.
The concept of prolonged endotracheal intubation as an
alternative to tracheostomy was presented by Bernard
Brandstater at the First European Congress of Anesthesiology
in 1962 [29]. He reported his experience with seven patients
ranging in age from the neonate to 4 years. Until that time, it
had been customary to perform a tracheostomy if infants
Fig. 1.1 The Shadwell laryngoscope required ventilator assistance [30]. The tracheostomy tubes
in general use were uncuffed and the variable leak that tion, but initially, there was a lack of universal enthusiasm
occurred via the glottis made a constant level of ventilation for using relaxant drugs in the neonate. In Europe, a pioneer-
difficult to attain—especially in patients with reduced pul- ing neonatal anesthetist, Dr. Jackson Rees, wrote in 1950 “In
monary compliance. Fortunately, the ventilators in common the newborn, as has already been shown, control of the respi-
use in North America at this time were pressure cycled (the ration is easily obtained at light levels of anaesthesia without
“Bird” Mark VIII) and this reduced the problem to some the use of relaxants: muscle relaxation does not appear to be
extent. In mid-1960s, the use of intermittent positive pres- of major importance in the production of good operating
sure ventilation (IPPV) in the therapy of newborn respiratory conditions, and the usual untoward effects of endotracheal-
distress syndrome was becoming established as was the need tube induction are not seen.(sic) On these grounds it can be
to treat respiratory insufficiency in the postoperative cardiac said that the use of relaxant drugs in anaesthesia is contrain-
patient [31]. In 1965 Reid and Tunstall reported a case of dicated in the newborn patient, and I have abandoned these
respiratory distress syndrome in a 1800-g preterm infant suc- drugs in such cases” [34].
cessfully treated by IPPV via a 2.5-mm ID nasotracheal tube In the USA, the study of Beecher and Todd published in
[32]. In the same year, McDonald and Stocks from the Royal 1954 [38] demonstrated an increased mortality associated
Children’s Hospital in Melbourne, Australia, reported a with the use of relaxant drugs—especially in those in the
larger series of infants treated with prolonged nasotracheal early years of life. Postoperative respiratory difficulties were
intubation [33]. They described the complications, including reported in infants given relaxants [39]. In 1955, Stead
post-intubation subglottic stenosis, and offered suggestions reported that the neonate was sensitive to the effects of non-
to minimize the incidence of this serious outcome. By the depolarizing neuromuscular blocking drugs but was resistant
end of the 1960s, prolonged endotracheal intubation had to the effect of the depolarizing drug succinylcholine [40].
superseded tracheostomy as the management of choice for This further supported the impression that residual curariza-
infants requiring ventilatory assistance. tion was a problem in infants. However, Rackow and
During the 1960s and 1970s, it was a very common, Salanitre in New York reported their experience with relax-
almost standard, practice to intubate the trachea while the ant drugs [41] and suggested that postoperative respiratory
infant was awake, before induction of anesthesia. This, it was depression was seen only as a result of drug overdose or with
claimed, minimized the danger of regurgitation and aspira- hypothermia; the latter was not uncommon at that time in the
tion and facilitated the rapid induction of anesthesia [34]. In smaller infants. Warming from hypothermia had been dem-
addition, if attempts at intubation failed, there was little dan- onstrated to potentiate any residual block [42]—hence, the
ger as the infant would usually maintain the airway and con- infant placed in a heated isolette to rewarm after surgery was
tinue ventilation. Awake intubation of the neonate continued at risk! This observation encouraged efforts to maintain nor-
to be widely practiced until toward the end of the twentieth mothermia during neonatal surgery (see below).
century when concerns about the physiological stress that In the 1960s, the use of neuromuscular blocking drugs in
might be imposed on the infant prompted further consider- the neonate was widely accepted, and the use of heating
ation [35]. In addition, it was demonstrated that intubation is blankets and overhead warmers to maintain normothermia
much more likely to be successful with fewer attempts and became routine. Rees wrote “Following intubation the child
less elapsed time if performed in the anesthetized infant [36]. may be saturated with nitrous oxide as rapidly as possible by
Having intubated the airway in the neonate, the scene was intermittent positive pressure ventilation, and the relaxant
set to control ventilation during anesthesia. This would facil- drug may then be administered. In this way perfect operating
itate procedures to correct intrathoracic congenital defects. conditions are obtainable, and the more potent and, therefore
In addition, it would allow the administration of neuromus- more toxic agents are eliminated from the anesthetic tech-
cular blocking drugs to provide optimal conditions for nique” [37]. This was the “Liverpool technique,” which was
abdominal surgery and reduce the need for high concentra- widely used in Britain and elsewhere. For brief procedures, it
tions of inhaled anesthetics. was not uncommon to use repeated injections of succinyl-
choline as a relaxant.
The question of the sensitivity of the neonate to
Neuromuscular Blocking Drugs d-tubocurarine (dTc) was finally resolved by Fisher in 1982
[43]. The neonatal neuromuscular junction is indeed sensi-
d-Tubocurarine was introduced into anesthesia practice in tive to the effects of dTc, but this is largely compensated by
the 1940s and succinylcholine became available in the 1950s. the increased volume of distribution of the drug in this age
Both drugs were used in neonates soon after their introduc- group [43].
6 D. J. Steward
nesthesia Circuits and Controlled

A rebreathing valves. These required only a gas flow equal to
Ventilation the minute ventilation. Ronald Stephen and Harry Slater
described their non-rebreathing valve in 1948. It incorpo-
The T-piece system was considered by many to be the anes- rated two rubber valves and was described as having very
thesia circuit of choice for the neonate. It is lightweight and low resistance to breathing and negligible dead space.
simple and has low dead space and low resistance, and ven- Controlled ventilation could be delivered by compressing the
tilation could be controlled simply by intermittently occlud- exhalation valve with a finger while compressing the reser-
ing the expiratory limb with the finger. Jackson Rees in voir bag, and the authors claimed to have used this method in
Liverpool improved on this system by adding an open-ended infants of 3 weeks for up to 90 min [45]. In 1948, Digby
bag to the end of the expiratory limb [34]. A vulcanite tap Leigh independently described a valve of very similar design,
was inserted into the open end of the bag and adjusted to which could be used in infants [46]. George Lewis modified
maintain the bag inflated but to allow escape of expired and the Leigh valve to permit controlled ventilation without the
excess gases. Manual controlled ventilation was readily need to digitally compress the exhalation valve. The Lewis/
applied with this system. However, a fresh gas flow of 2–2.5 Leigh valve incorporated a flap that would close the exhala-
times the minute ventilation was required to prevent rebreath- tion port if the reservoir bag were compressed [47].
ing of expired gases. This was wasteful of anesthetic gases, A problem with the T-piece system and with non-
which were cheap in those days, and potentially caused sig- rebreathing valves was that they delivered very dry gases to
nificant atmospheric pollution (not appreciated to be a prob- the airway. In the USA, this concern led to the development
lem until the 1970s). A modification to prevent rebreathing of circle systems modified for the neonate. The Bloomquist
with lower fresh gas flows was to use a small-sized Waters infant circle was marketed by the Foregger company and
soda lime canister on the expiratory limb for CO2 absorption, incorporated a soda lime canister. However, a laboratory
but this was generally considered less easy to apply to the study of the humidity output of this circuit concluded that it
small infant. Indeed, Leigh and Belton writing in 1950 stated offered no advantage over a humidified T-piece system and
“Use of absorption technic in the first few months of life is was more cumbersome to use [48]. The Columbia Valve was
impracticable and affords no distinct benefits to patient, sur- developed to allow a modified adult circuit to be used for
geon and anesthesiologist” [44]. infants; the valve had low resistance and a very low dead
The pattern of ventilation chosen by the Liverpool group space of 0.5 mL [49]. This valve was used in a circuit in
for infants is interesting. Dr. Jackson Rees always encour- which the fresh gases were passed through the soda lime
aged the use of rapid shallow ventilation for the neonate. He canister together with the expired gases in an effort to maxi-
admitted that this often led to hyperventilation and hypocap- mize the level of humification (Rackow H, personal commu-
nia but did not consider this to be a significant problem [37]. nication). The T-piece and its variants were almost always
In later years, he would add small concentrations of carbon used for the neonate in Britain and Canada; non-rebreathing
dioxide to the inspired gases when indicated to prevent hypo- valves and various circle absorber systems were more com-
capnia (Rees GJ, personal communication). The pattern of monly used in the USA.
ventilation used, however, did tend to limit the duration of In later years, pediatric anesthesiologists adapted various
expiration and maintain a constant positive pressure—both neonatal ventilators for operating room use. Progressive
of which acted to reverse the reduction in lung volumes that improvements in anesthesia machine design eventually
occurs during anesthesia and muscle paralysis and thus allowed small infants to be successfully managed simply by
improve gas exchange. Dr. Rees was quite gratified to read changing to a smaller-diameter set of circuit tubing.
much later of the clinical studies that defined adverse changes
in pulmonary function which accompanied infant anesthesia,
changes which his technique had tended to moderate. Monitoring
As neonatal surgery became more complex and longer
procedures were performed, the need to provide for mechan- As has been stated previously, monitoring in the early days
ical ventilation during surgery was apparent. Fortunately, by consisted of watching the chest movements, examining the
this time, progress in ventilator design made this possible. color, and perhaps feeling the pulse. Indeed, this situation
Quite simply, the Bird Mark VIII ventilator or the Ohio persisted well into the twentieth century. Writing on anesthe-
Ventimeter Ventilator could be adjusted so that they would sia for neonatal chest surgery in 1965, Bell stated “A guide to
periodically serve to occlude the expired limb of a T-piece the general clinical condition I find useful is this:
system. baby pink and pulses palpable-condition good;
As an alternative to the T-piece system, which required a baby pale, pulses palpable or baby pink, pulses not palpable-
fresh gas flow 2–3 times the minute ventilation to prevent condition satisfactory, but check ventilation and blood balance;
rebreathing, some anesthesiologists preferred to use non- baby pale, pulses not palpable—condition serious.
I do not think that cardiac stethoscopes (the heart action can beIn 1950, the monitoring of the oxygen saturation of blood
seen in thoracic operations), sphygmomanometers, pulse moni-
during anesthesia was described by a group from Montreal
tors or E.C.G. tracings contribute enough additional informa-
tion about a baby's condition to merit their use; they may be [59]. They used an earpiece, which had been developed dur-
distracting” [50]. ing World War II for the purpose of studying pilots flying at
various altitudes. The equipment they used was delicate,
I cannot say that this was the general attitude to monitor- however, and required a dedicated technician to operate it.
ing in those years, but it is a recorded opinion. Continuous monitoring of transcutaneous oxygen tension
Accounts of neonatal anesthesia prior to 1960 make little (TcpO2) in neonates was described in 1972 [60], but this was
or no mention of monitoring [34, 37, 39]. In fact, the not introduced as a routine into the neonatal nursery for sev-
technology to satisfactorily monitor blood pressure in the eral years. Though TcpO2 was capable of indicating trends,
neonate was not generally available until the late 1950s. individual readings lacked precise accuracy especially with
Palpation or auscultation distal to a blood pressure cuff was decreased skin blood flow [61]. Electrodes required frequent
noted to be very difficult in small infants. Oscillometry had attention and had to be moved periodically to prevent burns.
been used but was not uniformly reliable. Hence, it was not During anesthesia, inhaled agents were found to further
common practice to monitor the blood pressure even in interfere with the performance of the electrode and decreased
larger infants. Anesthesia records from this era commonly its accuracy, though not to a significant degree [62].
displayed only a heart rate. In an article on anesthesia for Pulse oximetry became available for clinical use in 1983
major surgery in 1950, CR Stephen displayed an anesthesia [63] and was rapidly adopted as a routine monitor during the
record for pyloromyotomy on which the only vital signs surgery and acute care of neonates; it was far easier to apply
recorded were the heart rate and respiratory rate [51]. than the TcpO2 electrode and did not require repositioning
The optimal width of the blood pressure cuff (one inch) periodically. It was now possible to continuously display the
that was required for accurate measurement in the neonate level of oxygenation throughout the perioperative period and
was determined in 1939 by direct comparison with an intra- immediately respond to any adverse changes. It was also
arterial needle [52]. However, as noted above, it was uncom- quite possible to apply two probes: one in the preductal area
monly used in anesthesia practice. Detection of pulsation and one in the postductal area. The question now arose as to
distal to the cuff most often depended upon oscillometry. To the safe level of preductal oxygen saturation to maintain in
detect the very small deflection of the oscillometer needle the preterm infant at risk for retinopathy of prematurity
was frequently highly dependent upon “the eye of faith.” (ROP). Surveys performed in recent years indicate that many
This could be very worrying during thoracic surgery or units aim to maintain SpO2 in the 85–93% range [64] and
indeed any other major procedure; this I remember well. that this does indeed decrease the incidence of serious ROP
In 1969, the use of the Doppler flow meter to monitor changes [65].
flow in the radial artery distal to a blood pressure cuff and Monitoring of end-tidal carbon dioxide as a routine pro-
reliably measure intraoperative blood pressure in infants was cedure in anesthesia care became commonplace during the
reported [53]. The battery-operated “Parks Doppler 1980s. When applied to the neonate, it became apparent that
Flowmeter” became widely available and took much of the both methods for CO2 analysis, mainstream and sidestream,
worry out of neonatal anesthesia. It could be used to measure are problematic [66]. The increase in dead space with main-
blood pressure and also served as a continuous audible moni- stream analysis may lead to rebreathing in small infants.
tor of the pulse volume, serving as an early warning of During sidestream analysis, the site of sampling, the sam-
adverse changes. pling flow rate, and length of the sampling tube proved to be
Direct intravascular measurement of the arterial pressure critical factors in obtaining accurate measurements of end-
was initially measured from the umbilical artery; however, tidal CO2.
this resulted in a relatively high incidence of serious compli-
cations (e.g., bowel infarction) and was only applicable in
the immediate neonatal period. Percutaneous cannulation of Intraoperative Temperature Control
the radial artery in neonates was described in 1975 as a safer
alternative [54, 55]. The use of the temporal artery for moni- As more prolonged surgery was being performed in neo-
toring was also suggested [56] but was later generally aban- nates, the problem of intraoperative hypothermia became
doned when it became known that cerebral embolism was recognized [67] and identified as a cause of increased mor-
associated with this technique [57]. Femoral artery lines bidity and mortality [41, 68–70]. Two of five postoperative
were also used on occasion but, in the neonatal age group, deaths in a series of 12 neonates were attributed to hypother-
the incidence of ischemic complications exceeded that with mia [68]. In another series of 67 infants, 12 patients died;
radial lines [58]. seven of these were judged due to postoperative hypothermia
8 D. J. Steward
[70]. It was noted that the decrease in body temperature was doned and the infant died 24 h later.[79] At autopsy, the
directly related to the duration of surgery and that smaller upper and lower esophagus ended blindly one and one-half
infants suffered a greater decrease. The vulnerability of the inches apart. There is no mention of an associated fistula.
small infant to heat loss as a result of the large body surface The first successful ligation of a tracheoesophageal fistula
area to weight ratio was noted [71]. At this time in the 1950s, (TEF) with anastomosis of the associated esophageal atresia
little was done to keep the neonate normothermic during sur- was reported by Haight in 1943 [80]. Local analgesia was
gery and indeed intraoperative hypothermia was considered used for the first part of the operation; open ether was added
by some to be beneficial. during the esophageal anastomosis in order to obtain optimal
An improved understanding of the adverse physiological surgical conditions. Spontaneous ventilation was maintained
effects of hypothermia came in the early 1960s. It also throughout. In Britain, Franklin described two successful
became recognized that it was much easier to keep the patient repairs of TEF with esophageal anastomosis in 1947 [81];
warm during surgery than to resort to rewarming postopera- both of these procedures were performed using infiltration of
tively. The adverse effects of cooling on oxygen consump- local anesthetic (1% procaine) to the chest wall incision line
tion [72], catecholamine levels [73], and acid/base status and no other anesthesia. During the operation “the infant was
[74] were identified. Oxygen consumption in the neonate secured prone over a rubber hot water bottle” [81].
was shown to correlate most closely with the skin to environ- As has been previously stated, in early days, many sur-
ment temperature gradient, hence the significance of the geons opposed the use of endotracheal intubation for their
“neutral thermal environment.” With this new understanding, patients. Swenson, a much respected pioneer pediatric sur-
efforts were made to maintain normothermia intraopera- geon, reported his experiences with TEF in 1943 and advo-
tively. Hot water bottles alongside the infant were recom- cated the administration of cyclopropane via a tightly applied
mended, but unfortunately, this sometimes led to burns. face mask [82]. Kennedy and Stoelting reported a series of
Heating pads for the operating room table were described by 86 cases of TEF operated upon at Indiana University Hospital
Leigh and Belton in the second edition of their book on pedi- from 1940 until 1956 [83]. Before 1948, 17 cases were man-
atric anesthesia published in 1960 [75]. Wrapping the limbs aged without intubation using a combination of local analge-
in cotton wadding and placing the infant on a warming blan- sia and open ether; the mortality rate was 88%; two patients
ket set at 40°C were advocated by RM Smith in his textbook died during surgery. After 1948, all 69 neonates underwent
in 1968. It was also found that heating blankets were more tracheal intubation, none died during surgery, and the overall
effective in maintaining normothermia in smaller infants—a mortality rate was 42%. Many factors were considered
beneficial effect of the large surface area to body mass ratio responsible for these improved results, but the role of endo-
[76]. The addition of overhead radiant heaters during prepa- tracheal intubation and tracheobronchial toilet was consid-
ration for surgery and humidification of anesthetic gases pro- ered to be very significant. General anesthesia methods
vided for what was considered optimal patient management reported by Zindler and Deming in 1953 [84] employed
in the late 1960s and 1970s [77]. In the 1990s, forced air awake endotracheal intubation to administer cyclopropane
warmers became generally available and proved very effec- via a non-rebreathing valve and controlled ventilation. They
tive in maintaining normothermia [78]. also stressed the need for frequent suctioning of the trachea.
Progressively improving results from the surgical and
anesthesia management of TEF can be followed by examin-
eonatal Anesthesia: Some Landmark
N ing the Toronto experience. A review of the results from
Procedures and Their Development 1959 to 1964 [85] shows an overall mortality rate of 36.5%,
with a rate of 57.5% for the infants who were under 2500 g
epair of Esophageal Atresia
R body weight. The predictors of mortality were prematurity,
and Tracheoesophageal Fistula the presence of associated congenital malformations (espe-
cially cardiac), and extensive pulmonary disease (i.e.,
The first operation for esophageal atresia was performed in delayed diagnosis). A subsequent review [86] of the years
London, England, by Charles Steele in 1888 [79]. The diag- 1964–1968 noted an overall mortality rate of 22%, and the
nosis was made when the infant became livid and had diffi- mortality rate for those under 2500 g had decreased to 40%.
culty breathing “after the first nourishment”; a sound could The problem of gastric distension due to gases passing
not be passed by mouth for further than 5 inches. Surgery through the fistula into the stomach was a concern for the
was performed the next day after “the infant took chloroform anesthesiologist, especially as this has been reported to cause
well.” The stomach was opened via an abdominal incision serious ventilatory embarrassment and even cardiac arrest
and an unsuccessful attempt was made to pass a gum elastic [87]. Some preferred to maintain spontaneous (perhaps gen-
catheter retrograde up the esophagus, in the hope that a sim- tly assisted) ventilation until the fistula was ligated. Other
ple membrane could be perforated. The surgery was aban- suggestions to prevent this complication included perform-
ing a preliminary gastrostomy under local analgesia [88]; patient and so that collapse of both lungs can be prevented in
those rare cases in which there is a free communication between
this was also favored by some surgeons as part of a two-stage
the two pleural cavities. In all cases of the present series, cyclo-
repair, especially in critically ill infants. Passing an endotra- propane was used and was eminently satisfactory. It is clear,
cheal tube (without a side hole) into the bronchus and with- however, that this choice depended on my good fortune in hav-
drawing it until bilateral ventilation could be heard and then ing an anesthetist who is expert in handling babies and who has
had enough initiative to devise a homemade apparatus which is
positioning the tube with the bevel facing anteriorly were
suitable for babies of the smallest size. It must be emphasized
also suggested [89]. This would direct ventilation to the that cyanosis should not be a deterrent to operation, since the
lungs and protect the fistula with the longer side of the bevel. administration of a gas containing a high percentage of oxygen
(However, the fistula is occasionally at the level of the will improve the baby's color, and the operative removal of the
abdominal viscera from the chest will also facilitate the child's
carina!) Some more complicated methods to position the
breathing efforts. It is unnecessary to use an intratracheal tube;
tube and prevent gastric distension have also been described. indeed, this is apt to be followed by troublesome edema of the
If a gastrostomy was present, it was suggested that placing larynx in the ensuing twenty-four hours. Only a tightly fitting
the gastrostomy tube under water in a beaker while advanc- mask, without an intra-tracheal tube, was used for all of the
patients reported on here. [98]
ing the endotracheal tube could indicate when the ETT was
below the fistula [90], i.e., no more bubbles! The significance
of leaks via the fistula increased as preterm infants with CDH was considered a surgical emergency [99] and
respiratory distress syndrome requiring greater airway pres- immediate operation was recommended once the diagnosis
sures presented for surgery. Karl suggested that a balloon had been made—especially if respiratory distress was pres-
catheter should be inserted into the lower esophagus via the ent. A case report from 1950 [100] demonstrated the extent
gastrostomy to control the leak [91]. Others suggested that a to which improvisation was employed to facilitate urgent
Fogarty or pulmonary artery catheter should be advanced via surgery. The child was 5 days old and in considerable respi-
a bronchoscope directly into the fistula [92]. In many units, it ratory distress and required oxygen at all times—a decision
became a routine to perform early ligation of the fistula in was made to perform immediate surgery. “Ether was the
preterm infants, thus largely avoiding the problem. anesthetic agent of choice. The equipment at hand was a
Preoperative endoscopic examination of the fistula was small open mask, an infant-sized metal oral pharyngeal air-
introduced in the 1980s [93] and became routine in some way, a rubber infant-sized mask from a Kreiselman resusci-
centers [94]. It was suggested that an exact knowledge of the tator, a socket elbow, a short corrugated tube section, a
size and site of the fistula would improve results and in addi- Peterson ether drop cup, and for a breathing bag a toy red
tion endoscopy permitted placement of balloon catheters to rubber balloon.” During the procedure, the two red rubber
occlude the lumen. Others preferred to keep things simple balloons that were available both disintegrated due to contact
and manage the airway without endoscopy [95]. with liquid ether and were replaced by rubber condoms! To
the credit of the team, the infant survived.3
In the 1950s, the association between pulmonary hypo-
Congenital Diaphragmatic Hernia plasia and CDH was reported [101]. From this time and into
the 1960s, improvements in the care and transportation [102]
Congenital diaphragmatic hernia (CDH) was described in of critically ill neonates resulted in more infants with CDH
1757 by a society of physicians in London following post- presenting for emergency surgery. Many of these who would
mortem examination of an infant who died under 2 h of age have died without surgery now died postoperatively second-
in respiratory distress [96]. Early reports of operations for ary to their pulmonary status. The high mortality rates asso-
CDH are found in the medical literature of the 1930s [97] ciated with repair CDH stimulated many investigators and
and 1940s [98], but it is significant that the neonates were all clinicians and attention turned to means to optimize pulmo-
more than 20 h of age, and some patients were much older, nary function postoperatively. These means included various
i.e., they had adequate pulmonary function to survive the patterns of controlled ventilation and measures to reduce
immediate neonatal period. In 1946, Robert Gross reported pulmonary vascular resistance (PVR) [103]. The thought
seven cases that came to surgery with ages ranging from 22 h developed that the cause of death in some cases was not sim-
to 7 years; he also recorded his preferred anesthesia tech- ple hypoplasia but potentially reversible changes in PVR
nique [98]: [103]. The standard approach to anesthesia for CDH at this
The choice of anesthetic agent and the method of its administra-
tion are important considerations, particularly in the cases of 3
The other obvious question that this case raises is whether the report-
patients in whom cyanosis and respiratory embarrassment are ing institution was the most appropriate place to be performing this
pronounced. Ether can be employed, and indeed may be given surgery. However, in 1950, the concept of regionalization of pediatric
with an open mask. It is preferable to use a closed system, so and neonatal services was undeveloped even in Europe and was largely
that a higher percentage of oxygen can be supplied to the unrecognized in North America.
10 D. J. Steward
time, no bag and mask ventilation, endotracheal intubation, wound was closed in a single layer. The anaesthesia must be
avoidance of N2O, and care to avoid large positive pressures, sufficiently deep to relax the abdominal muscles. This
was augmented by steps to control PVR if required. requires the services of a skilled anaesthetist” [110]. It was
One problem that had complicated the management of the suggested that a stomach tube should be in place to aspirate
infant with CDH was that some experienced very few prob- secretions as the bowel was reduced into the abdomen—
lems postoperatively, whereas others were desperately ill. obviously a serious concern when an open technique was
Hence, there was great interest in identifying those prognos- used.
tic factors that determined which infants would require By the 1970s, the problems of heat conservation, fluid
aggressive invasive measures. Raphaely and Downs in therapy, prevention of infection, and prolonged postopera-
Philadelphia developed a scoring system based on the preop- tive ileus were recognized and being managed [111]. Local
erative and postreduction alveolar/arterial oxygen tension analgesia infiltrated by the surgeon was still quite frequently
gradient [104]. Desmond Bohn and his colleagues in Toronto utilized “with anesthesia standby.” This led to cautions in the
suggested a system to predict the extent of pulmonary hypo- 1979 edition of the Manual of Pediatric Anesthesia [112]:
plasia based on the preoperative arterial CO2 tension and a first, to monitor how much local analgesic the surgeon
ventilatory index (mean airway pressure x ventilatory rate) injected and, second, to consider intubating the airway—to
[105]. Bohn et al. also suggested that consideration should protect it against aspiration of regurgitated stomach contents.
be given to an initial nonsurgical approach to CDH in the The introduction of endotracheal intubation and controlled
expectation that impaired pulmonary function not due to ventilation greatly facilitated general anesthesia manage-
hypoplasia might improve [105]. In the same year, 1987, ment but introduced the problem of determining whether the
another study from Toronto had shown that surgical repair of infant could tolerate the increased intra-abdominal pressure
CDH impaired rather than improved respiratory mechanics (IAP) postoperatively. Controlled ventilation could be con-
[106]. Thus, CDH management evolved from a surgical tinued postoperatively, and simple closure of the skin only
emergency into a potential complex management problem and delayed closure using Silon pouch were options.
for the neonatal intensivist, sometimes involving preopera- However, it was appreciated that increased IAP not only
tive ECMO therapy. Surgery was now performed only when impaired ventilation and circulation but also severely com-
the respiratory status was improved. promised splanchnic and renal perfusion. In 1989, Yaster
et al. suggested that the intragastric pressure (IGP) and/or
central venous pressure (CVP) should be monitored during
Abdominal Wall Defects replacement of the viscera; IGP in excess of 20 mm/Hg or
CVP increases of 4 mm/Hg are unlikely to be tolerated [113].
Reports of exomphalos (omphalocele) are found in medical By the end of the twentieth century, prenatal diagnosis
writings from the middle ages onward, but the infants gener- and progress in anesthesia management, critical care, and
ally soon died—usually of peritonitis. There are a few intravenous alimentation resulted in significantly reduced
instances where conservative treatment using antiseptic mortality and morbidity. The mortality rate for gastroschisis
preparations applied to the lesion resulted in granulation tis- was under 10% and the mortality in cases of omphalocele
sue formation and epithelialization with survival. Operative was largely dictated by the presence or absence of associated
treatment before the 1940s was usually fatal [107]. Successful malformations.
surgical treatment was reported in 1948 [108], and in 1951, a
further successful case was reported in which the anesthetic
used “was sugar and whisky administered on a small gauze Neonatal Cardiovascular Surgery
nipple” [109]. The postoperative course was complicated by
peritonitis; however, the patient recovered and was dis- Surgery of the heart and great vessels was introduced in the
charged on the 75th postoperative day. Much credit for the 1940s and 1950s, but initially, very few of the patients were
recovery was given to the use of prolonged intravenous fluid neonates. Robert Gross ligated a persistent ductus arteriosus
therapy. At this time, it was recognized that omphalocele was in a child in 1939 and launched pediatric cardiovascular sur-
often associated with other significant congenital malforma- gery. Most of his early patients were older but he did describe
tions. It was also noted that the immediate prognosis division of vascular ring in patients that included a 3-week-
depended on whether the membrane covering the viscera old infant in 1951 [114]:
was intact or ruptured; in the latter case, a fatal result was Anesthesia in all these subjects has been with a closed system,
certain [110]. In 1953, a successful case is recorded in which using ether or cyclopropane. In all cases, an intratracheal tube,
open ether was administered for anesthesia: “The bowels preferably of soft polyethylene, has been employed. Such a tube
were returned to the abdominal cavity with difficulty, and the is essential for the maintenance of an adequate airway, particu-
larly in the first four types of anomalies just described, in each cerning the long-term safety of PHCA versus continued per-
of which the trachea is markedly narrowed and an adequate
fusion [119]. There was also much debate concerning the
exchange might not be obtained until a tube is passed down
beyond the obstructed point. [114] optimal management of the pH status and other variables
(e.g., hematocrit) during cooling bypass [120].
William Mustard in Toronto operated on neonates with
preductal coarctation of the aorta in 1953 [115] with long-
term success. The anesthetic regimen was: “Induction is with Regional Analgesia
pentothal 5 mg per pound and syncurine 0.01 mg per pound
mixed together in the same syringe. Orotracheal intubation Bier popularized spinal analgesia in 1898, though Corning
is performed after succinylcholine 1 mg per 5 pounds. The had successfully used the method 15 years earlier. The use of
patient is maintained on a 50–75% nitrous oxide with oxygen spinal analgesia in a neonate 24 h old with acute intestinal
mixture, and control of ventilation is maintained by means of obstruction due to congenital hernia of the umbilical cord
frequent small doses of succinylcholine” [115]. The anesthet- was described in 1912 [121]. The method used was that of
ics were all administered by Dr. Code Smith who first Dr. Tyrell Gray, at that time medical superintendent at the
described the esophageal stethoscope [116], developed in Hospital for Sick Children, Great Ormond Street, who had
order to monitor heart and breath sounds reliably during tho- written extensively on the subject of spinal anesthesia in
racic surgery in small infants. infants and children [122]. The drug used was Stovaine
(0.012G) with glucose. Stovaine (amylocaine) was the first
synthesized local anesthetic and was widely used for spinal
Open Heart Surgery anesthesia being less toxic than cocaine. The dose used
would produce anesthesia for up to 1 h. Reports of the use of
The use of open heart surgery with cardiopulmonary bypass spinal analgesia for abdominal and perineal surgery in infants
(CPB) in neonates was initially associated with very high are found from several centers during the first half of the
mortality rates. In 1963, it was stated “It is apparent that per- twentieth century.
fusion can be performed on even the smallest infants. It is In the 1960s, an interesting series of neonates with open
equally certain that present methods of perfusion in small myelomeningocele underwent corrective surgery after direct
infants are hazardous and should be applied only in extraor- injection of local analgesic into the lesion by the surgeon
dinary circumstances” [117]. The authors reported a mortal- [123]. A solution of 1% lidocaine was used and produced
ity rate of 66% for infants of 0.2 square meters body surface anesthesia very adequate for the repair—which was always
area. The mortality was considered related to the severity of completed in less than one hour. No complications were
the CHD and to postoperative complications related to the noted and the decrease in blood pressure after the injection
“marginal status of the infant’s cardiopulmonary system” was small. The rationale for the use of this technique was
[117] There were, however, also frequent technical problems that it was less hazardous than general anesthesia adminis-
related to the small size of the patients. The problems of tered by an inexperienced anesthetist.
applying CPB to the smaller infants stimulated an interest in Spinal anesthesia for preterm neonates with inguinal her-
performing surgery under deep hypothermic circulatory nia became popular late in the twentieth century when it was
arrest (18–20 °C) using only surface cooling and rewarming suggested that postoperative respiratory complications were
[118]. The technique originated in Japan but was adopted by less common than after general anesthesia [124]. Studies
several centers in North America. Anesthesia was maintained also confirmed that the effect of a spinal block on the blood
using diethyl ether, which was thought to protect against pressure is relatively minor in small infants [125]. There was
ventricular fibrillation during the cooling phase [118]. Using also renewed interest in some centers for the use of spinal
this technique, an overall mortality rate of 42% was reported anesthesia for abdominal and even thoracic surgery.
[118]. As techniques for CPB rapidly evolved, and as flam- As has been mentioned throughout this chapter, infiltra-
mable ether was considered an unacceptable hazard by many tion of local anesthetics was often employed for the neonate.
groups, cooling of neonates on bypass became more In 1930, Denis Browne, the surgeon at Great Ormond Street
common. Hospital, described a restraint for the small infant that could
Profoundly hypothermic circulatory arrest (PHCA) was be used during local or general anesthesia (Fig. 1.2) [126].
first used in neonates in the 1960s and became widely used This was widely used in Britain for many years, and he wrote
thereafter. Intra-atrial repair was simplified in the absence of of it: “In operating on babies there are certain special diffi-
venous cannulae. However, controversy soon emerged con- culties. Owing to their light weight and powers of contortion
12 D. J. Steward
and by thoracoscopic clipping of the ductus in a preterm

infant in 1993 [128]. Regarding endoscopic abdominal sur-
gery, extramucosal pyloromyotomy was described in 1991 in
a series of 70 infants [129]. Peritoneoscopy of infants for
diagnostic purposes had been performed since 1972 [130].
The physiological effects on the neonate of abdominal dis-
tension by carbon dioxide and the problems of facilitating
intrathoracic endoscopic procedures were soon described
and discussed [131]. Very early in the twenty-first century,
thoracoscopic repair of tracheoesophageal fistula was
reported [132]. By 2014, it could be stated that many surgical
procedures for the neonate could be performed by minimally
invasive techniques [133]. Significantly, these techniques
reduce the stress of the surgical procedure and short-term
morbidity [133] and eliminate the risk of some delayed com-
plications, for example, post-thoracotomy scoliosis [134].
x Utero Intrapartum Treatment: “The EXIT

E
Procedure”
The “EXIT Procedure” was described in 1997 as a means to

maintain the newly delivered infant on the placental circula-
tion until pulmonary ventilation could be established. The
first indication for this was to provide time for the surgical
removal of tracheal clips which had been placed to stimulate
lung growth in cases of diaphragmatic hernia [135].
Subsequently, the technique has been applied to manage
Fig. 1.2 The Denis Browne crucifix infants with various congenital airway obstructive lesions.
Anesthesia management for the mother and infant was devel-
oped to ensure continued placental blood flow to the infant,
they need careful holding for greater or less time, according maximize placental gas exchange, and provide uterine relax-
to the type of anaesthetic, and their small size makes it dif- ation [136]. Most recently, the technique has been applied to
ficult for the holder to avoid the operators. In work on these permit EXIT to ECMO management of infants with poten-
cases, both as operator and anaesthetist, I have found great tially disastrous congenital cardiac anomalies.[137]
help in a simple device which holds the child firmly, prevents
chilling, and permits the use of local anaesthesia or the mini-
mum of general. It is a ‘crucifix,’ the original model of which Regionalization of Neonatal Services
was a simple T of 2-inch wood, the cross limb 18 inches long
and the main one 24 inches. As this was awkward to carry Real progress in modern neonatal surgery commenced in
and had an inauspicious look about it when taken into a pri- 1945 after World War II. In 1949, there were 58 neonatal
vate house, I devised a collapsible model in duralumin, with operations at the Hospital for Sick Children in London and
a sponge rubber padding, and this has been very satisfactory” 27 (46%) of these infants died [138]. These results and simi-
[126]. lar figures from the Alder Hey Hospital in Liverpool led
Peter Rickham to write “If in this country we are to improve
the chances of survival of children born with congenital mal-
Minimally Invasive Neonatal Surgery formations an efficient neonatal surgical service must be
organized” [138]. At this time, congenital malformations
During the final decades of the twentieth century, advances were listed as the third most common cause of neonatal death
in techniques and technology made it possible to apply mini- in the USA, but there were three centers (Boston, Philadelphia,
mally invasive/endoscopic surgery to very small infants. Chicago) where Rickham observed very good results for
Closure of persistent ductus arteriosus by inserting an intra- neonatal surgery: “Surgical management and technique dif-
vascular balloon was performed in an infant in 1979 [127] fered very little. American neonatal anesthesia was definitely
inferior to that in Liverpool, many operations being done preterm infants were conducted by Ledez and Lerman shortly
under local or ether anesthesia. The important difference was thereafter [147]. As the numbers of pediatric anesthesia sub-
the postoperative management. There were more highly specialists swelled in the last decades of the twentieth cen-
trained medical personnel and nurses in the American tury, there was a corresponding increase in research output
Hospitals providing a highly efficient round the clock and a more scientific approach to neonatal anesthesia became
service….” a reality. This did, however, require a closer evaluation of the
Mr. Rickham went on to act as a prime mover in the estab- ethics of performing studies in infants [148] and indeed the
lishment of the “first neonatal unit in the world” which opened ethics of providing anesthesia for infants.
in 1953 at the Alder Hey Children’s Hospital [139]. In the last
half of the twentieth century, regionalization of neonatal ser-
vices progressed steadily in Great Britain and in other Ethical Considerations and Infant Anesthesia
European countries. The standards for the staffing and equip-
ping of neonatal units and the organization for the transport of The suggestion that the administration of anesthesia to
patients to these units are rigidly controlled. The concentra- infants might have long-term adverse consequences has been
tion of patients in a few units ensured that the medical and raised. In the 1970s, it was suggested that the incidence of
nursing staff could gather the experience necessary to ensure asthma and respiratory allergies might be increased in chil-
optimal outcomes for their patients while providing training dren who were administered anesthesia in infancy [149]. A
for the next generation of care providers. In Canada, complex subsequent study failed to corroborate this association [150].
neonatal surgery has been largely concentrated within the Late in the twentieth century, learning disabilities were
children’s hospitals which are situated in most provinces, and described in children who had general anesthesia in infancy
thus, a similar regionalization has been achieved. [151]. However, a study in more than 1100 identical twins in
In the USA, regionalization of neonatal services and the the Netherlands demonstrated that in discordant twins (i.e.,
establishment of units to serve all regions with an associated one had an anesthetic and the other did not), the IQ values in
high volume of patients has been less consistent. There are each pair were identical in a 10-year follow-up [152].
many geographic problems involved, and there has also been Concerns were also raised by numerous neonatal animal
a desire by many smaller hospitals to have a neonatal unit studies that suggested that most general anesthetic agents are
and to provide pediatric surgical services. This has some- toxic to the developing brain [153]. Despite many studies
times led to problems with providing an adequate pediatric [154–156], it has not been proven that exposure of human
case load for credentialing purposes [140] and might indeed neonates to a well-conducted general anesthetic has signifi-
sometimes compromise results. In many states, however, cant adverse effects [157]. It has, however, been demon-
neonatal emergency transport systems have been effective in strated that inadequately treated pain during infancy results
directing a high volume of patients to regional neonatal sur- in both short-term and long-term adverse effects [158].
gical units [141]. The American Academy of Pediatrics in Repeated anesthesia may be associated with adverse neuro-
2002 formulated and published general guidelines for refer- cognitive outcomes but many perioperative factors other
ral of patients with major congenital anomalies to pediatric than the use of an anesthetic drug are present in such patients
surgical specialists [142]. [157]. Currently, the preponderance of evidence supports the
ethical path of administering anesthesia to prevent pain and
modulate the physiological responses to surgery in neonates.
Research in Neonatal Anesthesia The problem for the anesthesiologist is to communicate
these thoughts clearly to anxious parents who may have been
Before 1960 very little research was conducted, those anes- exposed to less reliable information in the media. Indeed,
thetizing infants were busy with their clinical work [143], parents have every right to be confused. In the 1980s, news-
and anesthesia methods were largely based on what had paper headlines screamed about newborn infants being sub-
worked in the experience of practitioners and their teachers. jected to surgery without effective anesthesia [159]; more
However, early investigations into the pharmacology of the recently, these same newspapers now warn that anesthesia
anesthetic drugs in the neonate were commencing. Stead in drugs may harm those same patients [160].
1955 reported the effects of neuromuscular blocking agents The future path for pediatric anesthesiology is to pursue
in the neonate [144]. Rackow and Salanitre studied the phar- the ideal of perfecting agents and techniques that will cause
macokinetics of the inhaled anesthetics in infants and the least harm and ensure the greatest benefits for our pre-
reported these in 1969 [145]. The volatile anesthetic dose cious neonatal patients. Progressively, we have been able to
requirements for the neonate were the subject of some confu- practice evidence-based neonatal anesthesia management.
sion until more precise studies in tightly controlled age The full history of neonatal anesthesia cannot yet be writ-
groups were carried out in the 1980s [146]. Similar studies in ten—but the future may be just as exciting as was the past.
14 D. J. Steward
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Physiology and Development
of the Term and Preterm Neonate 2
Claire Brett and David Robinowitz
Perinatal injury, prematurity, and/or congenital anomalies Mortality during the first year of life for late preterm
inflict profound long- and short-term physical, psychologi- infants (34–36 weeks’ gestation) is threefold greater than
cal, emotional, social, and financial stresses on survivors, for full-term infants, often related to a combination of intra-
their families, and society. Both the Annual Summary of partum events (e.g., placental and umbilical cord injury) and
Vital Statistics (2013–2014) [2] and the National Vital postnatal complications (e.g., respiratory problems, sepsis,
Statistics Reports (2017) [1] list “disorders relating to short and metabolic instability such as hypoglycemia and hypo-
gestation and low birth weight” as the second leading cause thermia) [5]. Recently, late–moderate preterm infants (32–
(~18%) of infant death, second only to congenital malforma- 36 weeks’ gestation) exhibited approximately twice the risk
tions, deformations, and chromosomal abnormalities for neurodevelopmental impairment at age 2 years, primarily
(~20%). In the United States in 2014 [2], 9.57% of the in the cognitive domain, compared with full-term neonates.
3,988,076 live births (381,659) were preterm (<37 weeks’ Male sex, socioeconomic disadvantage, and preeclampsia
gestation), 8.0% (319,046) were low birth weight (<2500 g), were identified as independent predictors of low cognitive
6.6% (263,213) were moderately low birth weight (1500– scores in this cohort [6]. The morbidity and mortality asso-
2499 g), and 1.40% (55,833) were very low birth weight ciated with late preterm infants are particularly stunning
(<1500 g). because approximately 8% of all births [3] and 75% of pre-
Although birth rates decreased 13% between 2009 and term infants are 34–36 weeks’ gestational age [4, 5]
2016, the rate of preterm birth increased from 9.57% in 2014 The management of extremely low birth weight (ELBW)
and 9.63% in 2015 to 9.85% in 2016. Of the preterm births, infants (<1000 g), especially those born near the limits of
the early preterm birth rate remained steady (2.76%) over viability (gestational age between 22 and 24 weeks), contin-
this period, whereas the late preterm rate (34–36 weeks’ ues to receive intense scrutiny, primarily because of the large
gestation) primarily accounted for the difference, increasing risk for death and adverse neurodevelopment. A prediction
from 6.82% in 2014 to 7.09% in 2016 [3]. In fact, 75% of model of survival of preterm infants developed in England
preterm infants are late preterm [4]. (East Midlands and Yorkshire regions) using gestational age,
In 2014, 56.9% of all infant deaths could be attributed to birth weight, and gender in preterm infants showed increas-
five causes: congenital malformations (20%), short gestation ing survival from 27.7% (boys) and 34.5% (girls) at 23 weeks
and low birth weight (18%), neonates affected by maternal to >99% (boys and girls) at 32 weeks [7]. Several reports
complications of pregnancy (6.8%), sudden infant death syn- noted that a decrease in short-term complications lagged
drome (6.7%), and accidents (5.0%). The etiology of neona- behind the improved survival of ELBW infants [8–11]. More
tal death (<28 days) differs from that for infants (>28 days to recently, reports note that mortality has decreased and neuro-
1 year). For example, in the neonate in 2015, sepsis, respira- developmental outcomes improved slightly, but progress has
tory distress of the newborn, neonatal hemorrhage, necrotiz- not been dramatic. For example, the Eunice Kennedy Shriver
ing enterocolitis, and birth asphyxia contributed to neonatal National Institute of Child Health and Human Development
mortality, whereas sudden infant death syndrome did not [1]. Neonatal Research Network reported that the percentage of
infants (gestational age 22–24 weeks) who survived with-
out neurodevelopmental impairment increased from 16%
(2004–2007) to 20% (2008–2011), whereas the percentage
C. Brett (*) · D. Robinowitz of infants who survived with neurodevelopmental impair-
Department of Anesthesia and Perioperative Care, UCSF School of ment did not change significantly (15%, 2003–2007; 16%,
Medicine, San Francisco, CA, USA
2008–2011). [12] Data from Japan describe the incidence of
e-mail: [email protected]; [email protected]

20 C. Brett and D. Robinowitz
death or neurodevelopmental impairment as 80%, 64%, and as intrauterine growth restriction, preterm birth, exposure to
39% in infants after 22, 23, and 24 weeks’ gestation, respec- environmental toxins, or dietary deficiency during critical
tively [13] periods of fetal development has been increasingly appreci-
Major morbidities (e.g., chronic lung disease, retinopathy ated both from epigenetic factors [32], genetics, and other
of prematurity) and direct injury to the brain (intraventricular host susceptibilities [33–35]. That is, in many cases, the ori-
hemorrhage or periventricular leukomalacia) predict death gins of asthma and COPD can be traced to fetal and early
or survival with significant neurodevelopmental impairment postnatal life [33, 35, 36]. One concept suggests that insults
[14, 15]. The incidence of poor outcomes at 18 months is during prenatal and early neonatal life (especially the first
doubled, tripled, or quintupled when 1, 2, or 3 of these mor- year) impede normal structural and functional maturation so
bidities, respectively, are encountered [15]. Infection (sepsis, that peak lung function is never achieved, exaggerating the
meningitis) seems to inflict less of an impact on outcomes normal age-related decline in lung function [33] beginning
than the three major morbidities. Intrauterine and early post- in the second to third decade of life. In part, this may evolve
natal events impact long-term survival, health, and function. secondary to greater susceptibility to infectious and environ-
Developing strategies to prevent preterm birth and devising mental toxins during infancy and childhood and continuing
interventions to treat anomalies both in utero and postnatally into adulthood.
remain strategic priorities. Thus, the “thrifty phenotype hypothesis” shifted to a
Over the last two decades, a significant epidemiology- “developmental plasticity” theory [37, 38], which captures
based literature has suggested the importance of the the effects of a wider variety of early derangements on risk
“developmental origins of health and disease.” That is, an for diseases in adulthood, including small-for-gestational-
environmental insult (e.g., over- or undernutrition, infection, age [39], large-for-gestational-age [40], and preterm infants
psychological stress) during a critical period of fetal or early [41–44]. The initial report from Barker has spawned an
postnatal development may “program” long-term physi- entire research focus and model, the “developmental origins
ologic, structural, and epigenetic changes that increase the of health and disease” [38, 45–47]. The full impact of and/or
risk for various diseases in adulthood. In his initial study, synergistic role of “the thrifty phenotype” and/or “develop-
Barker correlated increased mortality from coronary disease mental plasticity” on the well-established lifelong diagnoses
with low birth weight in a cohort from Hertfordshire, United associated with preterm birth and congenital anomalies con-
Kingdom [16]. His “thrifty phenotype hypothesis” (sur- tinues to evolve.
vival of the undernourished fetus demands that nutrition be
directed to vital organs such as the brain, resulting in insulin
resistance in other tissues such as the muscle and pancreas) Cardiovascular Function
[17, 18] provided a framework to suggest that an adverse
fetal environment (e.g., chronic placental insufficiency) elic- The Transitional Circulation
ited an adaptive response to protect critical organs such as
the brain and heart at the expense of other sites (e.g., kidney) The abrupt shift from fetal to postnatal life demands drastic
that involve long-term physiologic reprogramming [19–21]. and prompt changes in cardiopulmonary physiology. The fetal
Such reprogramming is associated with risk for hyperten- circulation is characterized by increased pulmonary vascular
sion, type II diabetes, and hyperlipidemia, which predispose resistance, decreased pulmonary blood flow (Fig. 2.1),
to the metabolic syndrome and cardiovascular disease [22– decreased systemic vascular resistance, and right-to-left blood
26]. Of note, the most significant glucose intolerance has flow through the patent ductus arteriosus and the foramen
been correlated with low birth weight combined with rapid ovale (Fig. 2.2). In utero, the return of blood to the heart is
postnatal weight gain [27, 28]. Recently, based on a cohort of derived from both the fetal and the placental circulations.
ELBW subjects from Canada (born 1977–1982), a group of Similarly, blood distributed to organs and the placenta from
adults was noted to have a fourfold increased risk of devel- the heart is derived from both ventricles. Thus, the fetal circu-
oping dysglycemia by their fourth decade of life. Increased lation is not in series as it is in the adult. Furthermore, in utero,
adiposity and reduced lean mass for height accompanied the volumetric outputs from the right and left ventricles differ.
dysglycemia [29]. Therefore, cardiac output is expressed as the combined ven-
In addition to long-term metabolic effects, restricted tricular output, the total volume ejected by the two ventricles.
intrauterine growth has been associated with a reduced num- For example, in fetal sheep, in late gestation, the right ventri-
ber of nephrons, a recognized pathway to renal failure, and cle ejects 300 mL/min/kg (or 66% of the combined ventricular
hypertension. Similar to intrauterine growth retardation, pre- output) compared with 150 mL/min/kg (or 33% of the com-
term birth is associated with an apparent arrest of nephron bined ventricular output) from the left ventricle [48]. Estimated
growth and later hypertension and insulin resistance [30, 31]. with Doppler ultrasound, the combined ventricular output in
Similarly, linking adult lung disease to perinatal insults such human fetuses is similar (range, 410–503 mL/kg/min) [49].
2 Physiology and Development of the Term and Preterm Neonate 21
60
50
Pulmonary
40
arterial
mean pressure 30
mmHg 20 SVC
10
AO
RPA
160 DA
Pulmonary 120
blood flow 80
ml/kg/min LPA
40
1.8 PA
1.6 FO LA
1.4
Pulmonary 1.2
vascular 1.0 RA
resistance .8
mmHg/ml/min/kg .6
.4
.2 LV
Birth
–7 –5 –3 –1 1 3 5 7
Weeks
RV
Fig. 2.1 The fetal circulation is characterized by high pulmonary arte-
rial mean pressure and pulmonary vascular resistance and low pulmo-
nary blood flow. At birth, the dramatic decrease in pulmonary vascular
IVC
resistance is accompanied by a parallel decrease in pulmonary arterial
blood pressure and an increase in pulmonary blood flow. Of note, the
pulmonary vascular resistance gradually decreases further over the first
6 weeks of life (from [52])
However, the distribution of the combined ventricular output

between the right and left ventricles, respectfully, differed Fig. 2.2 The fetal circulation. Desaturated blood from the superior
throughout gestation (at 20 weeks, 53% vs. 47%; 30 weeks, vena cava preferentially flows into the right ventricle, into the pulmo-
57% vs. 43%; 38 weeks, 60% vs. 40%) [50]. During the same nary artery, across the ductus arteriosus, and to the descending aorta to
periods, flow via the foramen ovale decreased from 34% the placenta. Relatively well-saturated blood from the ductus venosus
enters the inferior vena cava and preferentially crosses the foramen
(20 weeks) to 18–19% (30–40 weeks) [50]. In contrast, in ovale to the left atrium, the left ventricle, and the cerebral circulation
another study, although reporting a similar combined ventricu- (from [53])
lar output (425 mL/kg/min) in human fetuses, the value did
not vary as a function of gestation. The ratio of fetal right
(59%) to left ventricular output (41%) also remained vein to supply the right lobe, and the ductus venosus that
unchanged throughout gestation (13 weeks to term) [49]. In proceeds cephalad to join the inferior vena cava (Fig. 2.3).
the human fetus, blood flow through the ductus venosus Umbilical venous blood flowing into the inferior vena cava
decreases between mid-gestation (30% of umbilical blood via the ductus venosus is preferentially directed across the
flow) and 30 weeks (20% of umbilical flow). This flow is vari- foramen ovale into the left atrium and then the left ventricle.
able among subjects but without dramatic changes in late Thus, highly oxygenated blood exits the placenta, bypasses
pregnancy. The physiologic implication of reduced blood flow the liver, and flows directly to the myocardium and brain.
after 30 weeks’ gestation is unclear [51]. On the other hand, Desaturated blood from the superior vena cava and the
examining flow in the ductus venosus via Doppler has been abdominal vena cava enters the right atrium and ventricle
incorporated into clinical care to monitor fetal well-being and then returns to the placenta after crossing the ductus
(e.g., growth retardation, congenital heart disease, hydrops arteriosus. A variety of anatomic features of the atrial septum
fetalis) by evaluating the adequacy of placental flow, in some (e.g., crista dividens, eustachian valve) and the angle of entry
cases to determine the timing of delivery. of the ductus venosus into the inferior vena cava facilitate
The umbilical vein enters the hilum of the liver where it this preferential streaming [48].
divides into three branches: vessels that provide flow directly Pulmonary blood flow increases during mid-gestation
to the left lobe, a large arcuate branch that joins the portal (20–30 weeks) in the human fetus as pulmonary vascular
Tricuspid valve
SVC
150 days
Foramen ovale
LHV
PVR
RHV
130 days
Ductus venosus
110 days
90 days
Umbilical vein 10 15 20
IVC Po2 mm Hg
Portal vein Fig. 2.4 Response of the fetal pulmonary circulation to hypoxia (fetal
lamb). With advancing gestation, the response of the pulmonary circu-
Fig. 2.3 The fetal circulation. The blood from the umbilical vein that lation to decreasing oxygen saturation becomes more pronounced
enters the ductus venosus preferentially streams across the foramen (from Rudolph [57])
ovale to enter the left atrium and ventricle and the cerebral circulation
(from Rudolph [54])
onset of alveolar ventilation (Fig. 2.1). Simultaneously, both
systemic vascular resistance and left atrial pressure increase,
resistance decreases. In addition, the proportion of the com- eliminating the right-to-left shunting through the foramen
bined ventricular output allocated to pulmonary blood flow ovale. Bidirectional shunting through the ductus arteriosus
increases from ~13% of the combined ventricular output at may continue in the normal full-term infant during the first
mid-gestation to 25% at 30 weeks, without further change in 48 h of life. With normal transition, distinct and separate pul-
the third trimester; pulmonary vascular resistance decreases monary and systemic circulations are established.
1.5-fold [50]. These values contrast with those from the Postnatally, the marked vasoconstrictor responses of the
classic studies in lambs where pulmonary blood flow was pulmonary circulation to hypoxia persist, and pulmonary
<10% of the combined ventricular output (late gestation) vascular resistance also responds significantly to changes
and with one study in human fetuses that also noted that in pH (Fig. 2.5) [58]. In part, this reactivity may be related
in utero pulmonary blood flow was small (~11%) and did to the persistent high pulmonary vascular resistance during
not change between 13 and 41 weeks’ gestation [49]. The the first few weeks of postnatal life compared with the older
pulmonary vascular resistance of human fetuses responds infant (Fig. 2.1). The reactivity of the pulmonary vasculature
to the administration of oxygen to the mother (FIO2 = 0.60) can be striking, and, in the neonate, arterial hypoxemia or
after 31 weeks’ gestation [55]. Similar studies in fetal lambs acidosis can vasoconstrict the pulmonary arteries and induce
documented that the fetal circulation is briskly responsive pulmonary hypertension, thereby impeding forward blood
to both hyperoxia and hypoxia and that these responses are flow and, by default, forcing right-to-left shunting through
greater in late gestation (Fig. 2.4) [56]. Vasomotor control the foramen ovale and/or ductus arteriosus. This resembles
of the pulmonary circulation in utero, however, may be the normal fetal circulatory pattern and, therefore is often
disturbed in the presence of a congenital heart defect in termed persistent fetal circulation or persistent pulmonary
which oxygen delivery to the lungs may be abnormal (e.g., hypertension of the newborn (PPHN) and further exacer-
aortopulmonary transposition) thereby dramatically affect- bates the hypoxemia and acidosis. The disorder has been
ing the development of vessel morphology [57]. At birth, divided into three types: maladaptation (structurally normal
when the placenta separates, pulmonary vascular resistance but abnormally constricted vessels due to parenchymal dis-
decreases dramatically, and pulmonary blood flow increases ease such as meconium aspiration, respiratory distress syn-
in response to the rapid increase in oxygen tension and the drome, pneumonia), maldevelopment (excessive muscular
600 A wide range of therapies and agents (ventilation, vasoac-

tive agents) have been evaluated to treat PPHN, but the only
selective vasodilator of the pulmonary circulation is NO. In
500 many cases, inhaled NO induces a selective, rapid, and potent
decrease in pulmonary vascular resistance without affecting
systemic vascular resistance [63]. At low doses, toxicity is
400 minimal. Unfortunately, up to 40% of infants with PPHN do
not respond to NO. Moreover, although inhaled NO may pro-
% Increase PVR
vide short-term benefits (e.g., decreased need for ECMO), it

300 has failed to reduce mortality, duration of hospitalization, or
risk of neurodevelopmental impairment [64–67]). Similarly,
pH effects as an antioxidant and an anti-inflammation agent (in
200 7.1 animals) have been controversial [68]. Endogenous NO may
have a role in alveolar and vascular development in the imma-
ture lung [69, 70] and, as a result, may be relevant in treating
100 7.2 infants with bronchopulmonary dysplasia and other lung inju-
7.3
ries [71]. However, the production and metabolism of NO are
regulated on several levels, so that it is not surprising that its
0 7.4 clinical effectiveness in both term and preterm infants remains
controversial. For example, NO production depends on endo-
25 50 75 100 thelial nitric oxide synthetase activity (eNOS; lung eNOS is
Po2 (mmHg) type III). eNOS has both reductase and oxygenase domains.
When its substrate l-arginine is available, oxidation of NADPH
Fig. 2.5 Response of the neonatal pulmonary circulation to hypoxia and NO synthetase produces NO. On the other hand, when the
and acidosis (lamb). The breakpoint for a marked increase in pulmo- concentration of substrates or cofactors (e.g., heat shock pro-
nary vascular resistance in response to decreasing oxygen saturation is
dramatically dependent on pH (used with permission from Rudolph and
tein 90) are reduced, NOS is uncoupled, and reactive oxygen
Yuan [58]) or nitrogen species such as peroxynitrite are produced instead
of NO. In fact, oxidative stress may contribute to the devel-
opment of PPHN [72]. Similarly, the activity of soluble gua-
development in the pulmonary vessels), and underdevelop- nylate cyclase and cGMP-specific phosphodiesterase (PDE5)
ment (hypoplasia, as with congenital diaphragmatic hernia) on smooth muscle cells potentiates the effectiveness of NO
[59]. An echocardiogram is routinely performed in infants in augmenting cGMP production. PDE5 hydrolyzes cGMP,
manifesting signs and symptoms of persistent pulmonary which controls the duration and magnitude of cGMP’s effect.
hypertension to definitively exclude structural cyanotic heart Understanding the mechanisms for pulmonary vasoactiv-
disease [60]. ity should be the basis for clinical therapy. That is, oxygen,
Although the control of the pulmonary circulation, inhaled NO, and other relevant agents continue to evolve.
especially during the transition from fetal to postnatal life, Although oxygen is a potent pulmonary vasodilator, an
is complex and depends on the interaction of a variety of inspired concentration in excess of 0.50 does not increase
mediators and factors, receptors, and neurologic, endocrine, benefit [73]. Similarly, hyperoxia may induce oxidative stress
and vascular control mechanisms, nitric oxide (NO) plays a and lung injury, counteracting any benefit of oxygen-induced
critical role in mediating the vasodilating effect of oxygen vasodilation [74]. As a specific inhibitor of phosphodiester-
[61] via the (NO)-cyclic guanosine monophosphate pathway ase type 5 (PDE5), sildenafil decreases the metabolism of
[59]. Another major pathway regulating pulmonary vascular cAMP (i.e., inducing vasodilation) and has evolved as an
tone includes the prostacyclin-cyclic adenosine monophos- adjunct to treat infants who fail to respond to iNO [75–77]
phate pathway [59]. Both act by decreasing the concentra- as well as in the settings without access to iNO [78], with an
tion of intracellular calcium. Other mechanisms contribute impressive safety profile [79]. Similarly, milrinone (inhibitor
(e.g., oxygen-sensitive K+ channels in pulmonary vascular of phosphodiesterase type 3 [PDE3]) decreases the metabo-
smooth muscle) [62]. Despite the enormity of the research lism of cGMP and serves as an adjunct to iNO to synergisti-
that has been focused on this topic, no single factor has yet cally promote vasodilation [80], especially in the setting of
been identified as the primary trigger responsible for the ini- left ventricular dysfunction. Inhaled prostacyclin (PGI2) also
tiation of pulmonary vasodilatation at birth, nor is it clear targets the second major pathway (cGMP) to induce pulmo-
whether the endothelial cell or the smooth muscle cell is the nary vasodilatation, and its effectiveness seems similar to
prime target [63]. iNO [81], but more effective than oral sildenafil [76].
Distinct from both NO and prostacyclin, a molecule syn- of blood transfused correlates with the timing of clamping.
thesized by the endothelial cell, endothelin-1 (ET-1) also Up to 50% of the transfusion is complete within 1 min and
exerts critical function in pulmonary vasoactivity. Bosentan for the most part, it is completed by 5 min [85, 89].
and PGI2 target the ET-1 pathway. The role of bosentan, a Initially, “delayed clamping” and/or “milking” of the
nonselective endothelin-1 receptor antagonist (endothelin A umbilical cord simply was recognized as a safe method to
[vasoconstriction] and endothelin B [vasodilation]) remains deliver the significant placental volume of red blood cells
incompletely defined, but one trial reported that it offered no to the neonate. Although the data are inconsistent among
benefit over NO [82]. studies, delaying cord clamping until after adequate pul-
In summary, a clear and effective therapy for PPHN monary ventilation has been associated with a wide range
remains elusive, in part related to the variation of associated of improved short- and longer-term outcomes, especially in
clinical settings (i.e., intrauterine growth retardation, con- preterm infants, including decreased mortality, greater hema-
genital diaphragmatic hernia, meconium aspiration, etc.). As tocrit, and improved perinatal cardiovascular function/less
novel therapies evolve (e.g., antioxidants, soluble guanylate need for inotropes [90, 91]. Data supporting advantages such
cyclase activators, L-citrulline), the long-term outcome of as a reduced frequency of sepsis [92], necrotizing enteroco-
infants with PPHN may be redefined. litis [93], and intraventricular hemorrhage [90–92] are less
consistent. At the very least, this maneuver may promote a
more physiologic transition from fetal to extrauterine life by
he Placenta: In Utero Function and Cord
T avoiding the abrupt side effects of immediate cord clamping
Clamping at birth.
Clamping of the umbilical cord occludes both the umbili-
The fundamental and obvious role of the placenta is to ensure cal arteries (provides flow to the placenta from the descend-
the health and well-being of the fetus. Recently, this organ ing aorta of the fetus) and the umbilical veins (provides flow
has been increasingly scrutinized from additional perspec- from the placenta to the fetal heart). Clamping the umbilical
tives, such as its regulatory function both for the mother cord after ventilation has been established provides two clear
(e.g., preeclampsia) and the fetus (prematurity, intrauterine cardiovascular advantages to the neonate, especially the pre-
growth retardation). By studying regulatory genes and other term neonate [94]. First, venous return to the heart (preload)
factors associated with the intense interaction of mother and abruptly decreases by as much as 40–50% because clamp-
fetus [83] that define fetal growth, immune competence, and ing the cord occludes the umbilical vein [95, 96]. Second,
in utero cardiovascular and hormonal/endocrine function, occluding the umbilical artery eliminates the low-resistance
investigators have provided a preliminary framework for placenta and, therefore, increases the afterload to the left ven-
eventually intervening early in gestation to improve outcome tricle. This combination of decreasing preload at the same
[84]. In particular, a variety of markers released by the pla- time that afterload increases may dramatically decrease car-
centa may guide treatment and intervention during preg- diac output, challenging the neonatal myocardium during the
nancy. Development of an “organoid model” may allow an transition from the fetal environment.
in vitro system to expand our understanding of the roles of At birth, expanding and aerating the lung are the primary
this transient, but vital organ. triggers that decrease the pulmonary vascular resistance
Of more immediate clinical relevance, the timing of and increase pulmonary blood flow. This pulmonary blood
umbilical cord clamping, the event that terminates the rela- flow replaces umbilical venous return as preload to the left
tionship of the fetus with the placenta, has been the subject of ventricle. The interrelated cascade of hemodynamic events
numerous investigations, clinical trials, and meta-analyses. at birth (i.e., closure of fetal vascular shunts, increased sys-
The goals of these efforts center on optimally utilizing this temic and decreased pulmonary vascular resistances) sepa-
organ during the immediate transition from fetal to extrauter- rates the pulmonary and systemic circulations, enabling the
ine cardiovascular physiology. right ventricle output to become the sole source for pulmo-
The volume of blood available for transfusion to the neo- nary blood flow; the pulmonary blood flow becomes the
nate varies depending on the gestational age. At 20–32 weeks’ sole source of preload for the left ventricle. Thus, effective
gestation, the placenta receives approximately 33% of the ventilation (spontaneous crying or assisted support) expands
fetal combined ventricular output or 110–120 mL/kg/min the fluid-filled fetal lung, dramatically increasing pulmonary
[85]. After 32 weeks, this distribution decreases to approxi- blood flow (secondary to the dramatic decrease in pulmonary
mately 20% [86]. At birth, the blood remaining in the pla- vascular resistance), preserving filling of the left atrium and
centa may be critical to ensuring a smooth transition from left ventricular output. The interdependence of ventilation,
fetus to neonate. In the term neonate, 20–35 mL/kg remains establishing pulmonary blood flow, and timing of clamping
available to transfuse at birth [87], whereas in the preterm of the umbilical cord directly impacts care during the third
infant only 11–15 mL/kg [88] is available. Also, the volume stage of labor [95]. For example, clamping the cord before
the lungs are expanded exposes the asphyxiated, hypoxic Maternal complications/morbidity (e.g., postpartum hemor-
neonate to the added risk of an ischemic event (i.e., low car- rhage, need for transfusion) were not affected in any popu-
diac output secondary to decreased preload plus increased lation. The primary advantage for term infants centers on
systemic vascular resistance). increased hemoglobin concentration and iron stores, without
In summary, delayed clamping of the umbilical cord effects on mortality or morbidity [105].
may contribute to a more physiologic transition to post- Given the limited risks from and complications of coupled
natal physiology by maintaining preload both by transfu- with potential advantages associated with delayed umbili-
sion and allowing pulmonary blood flow to increase before cal cord clamping or “milking”, the American Academy of
eliminating umbilical venous flow. Although labor induces Pediatrics [106], the American College of Obstetricians and
the release of catecholamines, renin, and angiotensin (i.e., Gynecologists [107], the World Health Organization [108],
contractions intermittently interrupt oxygen delivery) which and the International Liaison Committee on Resuscitation
may increase SVR, clamping the cord inflicts an even more [109] have published statements recommending “enhanced
dramatic effect because of the abrupt and dramatic increase placental transfusion” [90, 110] (delayed cord clamping and/
in left ventricular afterload. The cardiovascular advantages or “milking”), noting the need for additional data about ben-
of clamping the umbilical cord after the onset of breathing efits to define clinical guidelines. A consistent concern cen-
have been widely described in both preterm [97, 98] and ters on the possible delay in initiating resuscitation, but this
term infants [99, 100]. In addition to the direct effects of the is more relevant to delayed clamping rather than to “milking”
delayed clamping of the umbilical cord, tactile stimulation of the umbilical cord. Others argue that optimizing transfu-
during the ~60-second (or longer) wait may induce infants sion may decrease the need for resuscitation [90, 91, 97].
to initiate spontaneous ventilation that stabilizes the neona- Furthermore, rather than setting a specific time or protocol,
tal circulatory transition, [91, 97, 101] which coincidently the clinical status of the neonate should dictate the approach
delays aggressive resuscitation. toward clamping the umbilical cord [95].
In spite of robust publications, the definitive benefits ver-
sus risks of delaying clamping of the umbilical cord remain
elusive. A recent Cochrane Review concluded that in pre- Myocardial Development
term infants (<37 weeks’ gestation), “increased circulating
volume improves blood pressure, reduces the need for blood Myocytes: Fetal and adult myocardia contract and relax sim-
transfusion, risk of intraventricular hemorrhage and necrotiz- ilarly. That is, with activation, the cytosolic calcium concen-
ing enterocolitis” with no effect on mortality [93]. Similarly, tration increases, inducing force generation, and as the
a systematic review of preterm infants (<32 weeks’ gestation) cytosolic calcium concentration decreases, relaxation ensues.
noted advantages to delayed cord clamping (or “milking of At all stages of maturation, the ventricle develops force
the cord”) including a reduced rate of blood transfusion and against a varying resistance or load (contraction/ejection)
intraventricular hemorrhage as well as reduced mortality followed by a period of relaxation (filling). The membranes
[90]. In contrast, the Australian Placental Transfusion Study in the adult myocardium that control calcium flux and the
of preterm infants failed to identify advantages (mortality contractile system that responds to calcium are present in the
or major morbidity) of delayed compared with immediate fetal heart; however, structures associated with the mechan-
cord clamping [102]. Similarly, the Cochrane Review, which ics of force generation (sarcomere, myofibril), those corre-
focused on the need to establish ventilation before clamp- lated with controlling calcium flux (sarcoplasmic reticulum
ing the umbilical cord concluded that “a greater body of evi- and other membrane components including receptors, chan-
dence is required … to answer the question of whether the nels, exchangers, transporters, and pumps), those related to
intervention is or is not harmful” [103]. myocardial compliance (extracellular matrix/cytoskeleton),
Finally, the most recent systematic review of preterm and sympathetic innervation undergo qualitative and quanti-
infants (18 randomized clinical trials) claims that delayed tative age-related changes. In part, age-related differences in
clamping reduced hospital mortality and the need for later cardiovascular function and responses to calcium and other
transfusion, but without a difference in major morbidities pharmacologic agents can be attributed to the developmental
(severe intraventricular hemorrhage, periventricular leukom- state of these various components of myocardial anatomy
alacia, chronic lung disease, patent ductus arteriosus, necro- and function.
tizing enterocolitis, late-onset sepsis, and severe retinopathy During fetal and neonatal development, myocytes dif-
of prematurity). Apgar scores and the need for resuscitation ferentiate markedly and increase in number and size, which
did not differ between the groups. Not unexpectedly, in some correlates with profound changes in mechanical properties
but not all studies [104], polycythemia and hyperbilirubi- and therefore contractility and performance. In the perina-
nemia were more common in infants after the transfusion tal period, the myocytes complete “terminal differentiation”
secondary to delayed clamping of the umbilical cord [91]. and lose their capacity to proliferate, as evidenced by their
transition from mono- to binucleation (a final nuclear divi- performance [114]. Similarly, changes in contractility during
sion without cellular division) [111]. Concurrently, the shape embryonic and fetal development (mouse) were related to
and size of myocytes change, gradually remodeling from a both the amount and isoform patterns of sarcomeric proteins,
spherical to a more rectangular shape by adulthood. Since focusing on myosin heavy chains and troponin (actin, myo-
shortening typically occurs along the long axis, the adult sin light chains, and tropomyosin were not studied) [117].
myocyte (dimensions of the adult vs. neonate myocyte: 150 Both the cell membrane (sarcolemma) and the intracellu-
vs. 40 μm in length; 5 vs. 25 μm in width) generates a more lar sarcoplasmic reticulum modulate the increase in cytosolic
rapid response and a larger increase in amplitude than the calcium that facilitates contraction and undergo developmen-
neonatal myocyte [112]. tal changes. In the adult, a small calcium influx via L-type
Recent studies in both human [113] and animal [111] calcium channels stimulates calcium release from the sarco-
fetuses have documented that the late gestational exponential plasmic reticulum (calcium-induced calcium release [CICR]).
cardiac growth secondary to the increase in size and number CICR depends on an intricate coupling of the L-type calcium
of myocytes correlates with an increase in both left ventricu- channel, the ryanodine receptor (RyR), and T tubules (invagi-
lar volume and active tension per unit of myocardial volume. nations of the sarcolemma) [118, 119]. Despite differences
Of possible importance in the setting of congenital heart dis- among species, CICR has been allocated a secondary role in
ease (e.g., single ventricle associated with pulmonary or aor- the generation of a myocardial contraction in the immature
tic atresia), marked differences between the development of myocardium because of limited sarcoplasmic reticulum and
the left and right ventricles have been noted, including fewer underdeveloped T tubules [120, 121]. Instead, contraction
but larger myocytes in the right ventricle [111]. relies more on the L-type calcium channels and extracellu-
Subcellular Components: In addition to the increased lar calcium (Wu 2016). Recently, attention has focused on a
number of myocytes, age-related changes in subcellular role that links the Na+–Ca+ exchanger (NCX) with the RyR
components/ultrastructure, and protein composition also to allow an age-defined reverse version of CICR [122, 123].
contribute to maturation in excitation–contraction and force These studies document that the NCX and NCX-CICR play
development in the myocardium and, therefore, cardiovas- a significant role in excitation–contraction coupling in early
cular function. Not only does the number of myocytes per developmental stages. The notable contribution of calcium
cross-sectional area increase, but the organization of the influx via reverse-mode NCX correlates with the greater
myofibrils also undergo striking age-related changes [112, expression and activity of NCX in the neonatal heart [122]. An
114]. In the immature myocardium, myofibrils appear in thin L-type calcium current mediated by CICR plays an increas-
layers, and groups of nuclei and mitochondria congregate ingly critical role as the myocardium matures, although the
chaotically in the center of the cell. In contrast, in the mature details of the molecular mechanisms remain unclear. Finally,
myocardium, long parallel rows of myofibrils alternate with in addition to RyR-gated calcium flux, inositol 1,4,5-trispho-
rows of mitochondria (and sarcoplasmic reticulum). The sphate (IP(3)-gated Ca(2+) release channels also contribute to
chaotic arrangement of mitochondria and myofibrils in the activating CICR to induce cardiac contraction [124]
immature myocardium contributes in part to the reduced Clinically relevant developmental changes are pervasive
contractility compared with the adult heart. in the developing myocardium including the sarcoplasmic
In addition to the effects of age-related changes in gross reticulum, T tubules, and various channels and regulatory
anatomy/morphology, the development of various mem- proteins. For example, the force generated by the human left
branes that control the regulation of calcium flux also exerts ventricle increases substantially between approximately 8
substantial effects on the force of myocardial contraction. For and 20 weeks’ gestation [114] but remained less than 50% of
example, during gestation, heart rate decreases but diastolic the specific force of healthy adult ventricle myofibrils [114].
filling and ventricular ejection increase [115]. Similarly, oth- Relevant to this, the volume of sarcoplasmic reticulum and
ers [116] have defined gestational age-adjusted reference its ability to pump calcium (uptake, longitudinal sarcoplas-
values for a “modified myocardial performance index” as mic reticulum; storage and release, junctional sarcoplasmic
well as contraction, relaxation, and ejection times (human reticulum) increase in utero and postnatally. Furthermore, the
fetuses, 20–38 weeks’ gestation), hypothesizing that these various subtypes of sarcoplasmic reticulum are less differen-
indices changed secondary to improved ventricular compli- tiated functionally in the immature heart. As a result, imma-
ance as the ratio of contractile to noncontractile elements ture hearts are more sensitive to calcium channel antagonists
increase and myofilaments grow; the data on performance [125], and maximal contractility depends to a greater extent
did not correlate with morphologic development. However, in on extracellular calcium that does the mature heart [126].
human fetal cardiac muscle, a change in function correlated When compared with the adult myocyte, the reduced
directly with changes in ultrastructure. Maturation of the sar- velocity and magnitude of sarcomere shortening [114] in the
comere and changes in protein isoforms (e.g., β-myosin and immature myocyte in part may be attributed to age-related
troponin I) seemed to underlie the developmental changes in changes in expression of various isoforms of contractile pro-
teins such as troponins [127]. The troponin complex, which tions of troponins are generally increased in preterm infants,
consists of three subunits (structural proteins: troponin C, although treatment with inotropes correlates with greater
I, and T) and binds to the thin filament of the myofibril, cTnT concentrations in both term and preterm neonates.
regulates activation of the interaction of actin and myosin Thus, although troponin concentrations are likely to become
(calcium-dependent) that results in force generation. Both an integral segment of evaluating perinatal injury in both
troponin I and T exist in multiple isoforms that are devel- preterm and term infants, specific prognostic and therapeutic
opmentally regulated. For example, an isoform identical to roles have not been completely defined. Nonetheless, recent
that in slow skeletal muscle (ssTnI) is expressed in embry- reports suggest that significant increases in cord troponin is
onic, fetal, and neonatal myocardium [114, 128], whereas an excellent and early predictor of the severity of hypoxic–
the cardiac isoform (cTnI) is expressed predominately in the ischemic encephalopathy (HIE) and mortality in term infants
adult myocardium. Of note, by 9 months of postnatal devel- [132]. Similarly, measuring brain natriuretic peptide is a reli-
opment, cardiac troponin I is the only detectable isoform. able test to diagnose significant structural or functional car-
The myocardial expression of the slow skeletal muscle in diovascular disease but should be considered an adjunctive
terms of the cardiac isoforms of troponin I may be of particu- marker, not a stand-alone test [132, 133].
lar importance in the immature myocardium since this has
been correlated with the relative resistance of the immature
heart to acidosis [129]. The response of the immature myo- yocardial Compliance: Extracellular Matrix/
M
cardium to sympathetic stimulation is similarly correlated Cytoskeleton
with the expression of slow skeletal troponin I. Cardiac,
but not slow skeletal muscle, troponin is phosphorylated in The cytoskeleton includes the contractile proteins and titan
response to β-stimulation, which may correlate with the dif- (a large protein that extends over half the span of the sarco-
ference in diastolic function noted in the neonate [130]. This mere) as well as microfilaments, intermediate fibers, and
phosphorylation decreases the sensitivity to calcium, facili- microtubules. This intricate complex provides the structural
tating diastolic relaxation. framework for intracellular and extracellular communication
TnT isoforms vary among species and stages of devel- that allows the contractile movement of the individual sarco-
opment. The human cardiac muscle contains four isoforms meres to be translated into effective systolic contraction and
of TnT (cTnT 1–4); cTnT1 expression peaks in the fetus, diastolic relaxation. That is, the cytoskeleton provides the
whereas only cTnT3 is expressed in the adult. Calcium sen- system for mechanical signaling. Examining the general
sitivity has been correlated with the shift in the expression appearance of the immature sarcomere provides an overview
of the troponin T isoform [127]. The expression of specific of the dramatic changes in organization that occur during
isoforms of troponin T has been correlated with the respon- early development. In the immature myocyte, A and I bands
siveness of myofilaments to calcium. are more irregular, M bands are absent, and Z bands vary in
Although cardiac troponins are routinely used to evalu- width. Several of the proteins and microfilaments, intermedi-
ate and monitor cardiac injury in children and adults, only ate fibers, and microtubules develop postnatally, which is
recently has their importance in the intensive care nursery critical in mediating a range of activities such as cell growth,
been recognized [131]. Troponins are typically bound to the migration, and adhesion as well as signaling for remodeling
thin filament of the myofibril, but with acute injury to the in response to the adaptation of the transitional circulation at
myocardium, bound troponin is released from damaged tis- birth [48]. For example, desmin, a protein that links Z bands
sues, first appearing in blood after 2–4 h and persisting for of myofibrils, improves the connection of myofibrils with
up to 21 days. The range of normal concentrations of the mitochondria facilitating the mechanics of contraction. The
isoforms of troponin in the neonate has been reported for expression of various isoforms of collagen (amount and
both cTnT and cTnI. The concentrations of troponins in cord types) that improve the resting load and passive state of the
blood samples vary as a function of gender, mode of deliv- myocardium undergo developmental changes. For example,
ery, and assay. Both cTnT and cTnI increase after asphyxia- the type I isoform correlates more tightly with developing
associated myocardial injury, although the variability in rigidity, whereas the type III isoform contributes to elasticity,
the responses among studies is notable. As in children and and the relative proportion of these two correlates with myo-
adults, laboratory evidence of injury is often an adjunct to cardial compliance. As the collagen network becomes pro-
other assessments (e.g., echocardiogram) of cardiac func- gressively more organized with maturation, the population of
tion. For example, asphyxiated neonates have greater con- type III isoform increases, eventually equaling or exceeding
centrations of cTnT than normal-term infants that correlate that of type I [134]. That is, the ratio of isoforms (I:III) is
with echocardiographic evidence of myocardial dysfunc- increased in preterm and term infants, a level that persists
tion. Nonetheless, in many cases, cardiac output is similar in until at least age 6 years, but then decreases thereafter to ~0.5
asphyxiated and non-asphyxiated neonates. The concentra- by adulthood [134].
Adrenergic Function The early postnatal hours of the preterm infant are often con-
sidered one of the most unstable periods, often characterized
The sympathetic nervous system modulates cell growth and by “low systemic flow” [146]. At less than 30 weeks’ gesta-
differentiation, as well as the distribution of and sensitivity to tional age, the ductus arteriosus often fails to close, systemic
calcium. Of note, the increased concentration of and pulmonary vascular resistances are high relative to the
α-adrenoreceptors in the early postnatal period may be criti- placental circulation, and often the cardiac output does not
cal in stimulating left ventricular growth [135]. For example, increase dramatically in the first 24 or more postnatal hours.
α-2A adenoceptors affect growth by stimulating actin organi- Although the Frank–Starling relationship (increasing pre-
zation (cytoskeleton) [136]; α-1A receptors seem to mediate load increases stroke volume, up to a point) exists, the imma-
inotropic activity [137, 138], not hypertrophy. Several studies ture myocardium renders this population more vulnerable to
(mice, rabbits) report a developmental increase (i.e., as gesta- cardiovascular instability, especially during the transition
tion advances) in the density of β-adenoceptors [139, 140], from fetal to extrauterine life. At the same time, because of
but other studies suggest that although the receptors increase the unique physiology of the ELBW infant, assessing or
with development, “specific activity” decreases [141]. measuring cardiac output and establishing “normal” values
Recently, the expression of β1-adenoceptors was documented for systemic blood pressure and heart rate become compli-
to be reduced in the preterm heart (pig) and unaffected by cated; defining hypotension becomes difficult (see below)
maternal glucocorticoids [142]. On the other hand, α-1A [147]. Consequently, diagnostic and therapeutic regimens in
receptors (quantity of mRNA) did not differ in preterm com- the intensive care nursery cannot be established based on
pared with term ventricles. Finally, the activity of adenylate clear-cut, abundant, evidence-based data.
cyclase, an important enzyme involved in the intracellular At any developmental stage, ventricular function is gov-
transmission of β-stimulation, increases in parallel with the erned by the same factors: preload, afterload, contractility,
increase in catecholamine concentrations [141, 481]. Of note, and heart rate. However, the ability to compensate for per-
glucocorticoids delivered to the mother to promote in utero turbations in these factors is limited in the neonate, espe-
lung maturation may play a significant role in adrenergic cially in ELBW infants. In the preterm infant (i.e., in some
receptor expression and subsequent neonatal cardiac function cases, a mid-gestation fetus), the immature myocardium
[143, 144], but other studies report conflicting data [142]. and the peripheral circulation present significant disadvan-
Although incompletely elucidated, the role of the cardiac tages when, at birth, the low-resistance placenta is abruptly
opioid system in regulating the myocardial function seems replaced with the high-resistance pulmonary and systemic
especially relevant to the development of the sympathetic vascular beds, and interventions such as positive pressure
and parasympathetic innervation of the neonatal heart. For ventilation and inotropic support are introduced. The pre-
example, in one report enhanced expression of δ-opioid term infant may also be dramatically sensitive to changes in
receptors paralleled the maturation of parasympathetic, sym- heart rate. Marked variability in the quantity of blood flow-
pathetic, and sensory innervation of the heart, suggesting ing across the foramen ovale and ductus arteriosus adds to
that the cardiac opioid system may regulate aspects of neo- the complexity of monitoring the cardiovascular function of
natal heart function [145]. the preterm infant.
Thus, in general, the increase in the network of adrenergic The relationship between blood pressure, cardiac out-
fibers innervating the myocardium induces widespread devel- put, and systemic vascular resistance is constant throughout
opment and expression of the various contractile systems life: BP = CO X SVR. That is, pressure and flow are not
(e.g., the expression of the contractile proteins, the efficiency equal but are related via resistance (SVR). Thus, flow to an
of the calcium channel, expression of the myosin ATPase organ may increase, decrease, or remain constant over a wide
isoforms). On the other hand, the controversial and variable range of blood pressures depending on changes in resistance.
data about the expression and function of neonatal adrener- Although the normal ranges for blood pressure correlate
gic receptors imply that specific inotropic support to maintain with gestational age [148, 149], the definition of hypoten-
cardiovascular stability in the neonate, especially the preterm sion remains elusive [150]. Because a mean arterial pressure
infant, remains imperfect. In many cases, a trial of a variety of <30 mmHg for more than 1 h (measured on the first day of
traditional and newer agents constitutes the routine approach life, beginning at 5 h) has been associated with intracranial
to bedside care, especially in the preterm infant. lesions [151] and/or adverse neurodevelopmental outcome
[152] or reduced cerebral blood flow (CBF) [153], many set
a breakpoint for hypotension at 30 mmHg in preterm infants.
The Preterm Infant However, others hold that the normal mean arterial blood
pressure is <30 mmHg in the most preterm infants during
The typical changes of the transitional circulation are blurred the first 3 postnatal days (Fig. 2.6) [154]. And others suggest
in the setting of the very low birth weight (VLBW, <1500 g) that a mean blood pressure that is less than the gestational
and extremely low birth weight (ELBW, <1000 g) infant. age correlates with the 10th percentile for blood pressure
60 50
Mean blood pressure (mm Hg)

Mean blood pressure (mm Hg)
≥ 37 weeks 40
50
33–36 weeks 30
40 27–32 weeks
20
23–26 weeks
30
10
20 0
0 50 100 150
0 12 24 36 48 60 72
SVC flow (ml/kg/min)
Age (h)
Fig. 2.7 Ultrasound-measured flow in the superior vena cava has been
Fig. 2.6 Mean blood pressure in neonates predicted lower limit (initial validated as an estimate of CBF. Note the lack of correlation of SVC
72 h of life) (from Nuntnarumit et al. [154]) flow with simultaneously measured mean arterial blood flow (from
Kluckow and Evans [172])
[155, 156], and this constitutes a definition of hypotension. A

recent study in ELBW infants noted that arterial blood pres- of this measurement [169]. In these studies, mean arterial
sure reached a nadir during the initial 5 h after birth, increas- pressure correlated poorly with superior vena cava flow
ing steadily afterward at a rate of 0.2 mmHg/h [157]. (Fig. 2.7). Similarly, others noted that during the first 48 h
Although studies have reported an association between of life, blood pressure did not correlate with the volume of
hypotension and intraventricular hemorrhage [158, 159], a blood flow in the descending aorta, superior vena cava, or
clear cause-and-effect relationship remains controversial left or right ventricle [167]. If a relationship between blood
(see Autoregulation). That is, aggressive treatment of “hypo- pressure and blood flow in the superior vena cava existed
tension” has not been shown in prospective studies to affect at some time points, it would most accurately be labeled as
specific indices of cardiac function [160], morbidity or mor- being “inverse, as reported in earlier studies” [170]. Of inter-
tality [147], or long-term outcome [161–164]. And, unfortu- est, neither dopamine nor dobutamine increased contractility
nately, identifying links between a specific inotropic agent, when introduced in response to reduced superior vena cava
change in CBF, and outcome remains at best an estimate. blood flow [171].
No study “has shown any improvement in any meaningful Measuring superior vena cava flow (and other flows)
clinical outcome, short or long term, in response to a specific may improve the accuracy of ensuring adequate oxygen and
inotrope” [150, 165]. nutrient delivery, especially to the brain, and monitoring the
Thus, the variability in “normal” for blood pressure and effectiveness of therapy. For example, superior vena cava
heart rate among infants of the same gestational and/or post- flow has been correlated with both the incidence of peri-
natal age creates a dilemma in the setting of clinical care, ventricular hemorrhage and neurodevelopmental outcomes
especially in the commonly unstable setting of the operating [152, 172]. This method of “functional echocardiography”
room. Furthermore, without access to reliable measures of is evolving as a more common bedside monitor [156, 173–
perfusion to critical organs (i.e., the brain), devising precise 175]. When combined with algorithms derived from near-
guidelines for treating “hypotension” in the neonate is virtu- infrared spectroscopy (NIRS), “optimal blood pressure” may
ally impossible. eventually guide clinical therapy that reliably preserves CBF
Several investigators [150, 166, 167] have proposed a (see Autoregulation).
novel approach to monitor CBF in the setting of the tran- However, at present, given our inability to easily and
sitional circulation of the preterm infant, especially in the accurately measure the cardiac output and organ-specific
first few postnatal days. Recognizing that neither blood pres- blood flow (e.g., CBF) in the neonate (Fig. 2.7), systemic
sure [166, 167] nor capillary refill time [168] reliably cor- blood pressure and heart rate, bedside echocardiography, and
relate with left ventricular output in the preterm infant, the metabolic indices including blood gases/lactate/electrolytes
flow in the superior vena cava has been measured to esti- and trends in clinical status remain the primary parameters to
mate systemic blood flow to the brain (and upper body). track cardiovascular homeostasis in the neonate, especially
Measuring blood flow of the superior vena cava eliminates the ELBW infant [156]. Coupled with the intense variabil-
the need to consider the influence of shunting via either ity and unpredictability of blood pressure and response to
the ductus arteriosus or the foramen ovale on the accuracy vasopressors, the physiology of the neonate requires man-
aging patients individually with meticulous reassessment. exchangers, and enzymes. Over the first months of life, myo-
Even investigators who reported the relevance of superior cardial contractility gradually increases, which maintains
vena cava flow remain focused on rational clinical care cardiac output over wider ranges of preload and afterload.
based on commonly available cardiovascular indices [165], Similarly, the increase in contractile proteins and the shift
with repeated reassessment to guide and modify manage- in expression to various isoforms, the development of sarco-
ment. As always, a parameter such as blood pressure must plasmic reticulum and T tubules, and adrenergic innervation
be interpreted within the wider context of other clinical and all contribute to complex changes in force development, cal-
diagnostic data. For example, even if superior vena cava flow cium recruitment, and transport that prime the myocardium
was measured, these data might be correlated with MRI and for a more powerful response to stress and increased oxygen
clinical status to fine-tune therapies. demands.
Clinical Significance and Summary Central Nervous System Function
The neonate has the highest cardiac output per body weight Discussing the central nervous system after the cardiovascular
of all age groups (~300 cc/kg/min). This increased resting function is intentional since the physiologic vulnerability of
cardiac output limits the neonate’s ability to respond to an the immature brain is inextricably linked to age-related hemo-
increased oxygen demand or to adapt to wide variations in dynamic function. Circulatory immaturity undoubtedly plays
preload or afterload. That is, the neonate cannot readily com- a fundamental role in perinatal brain injury. Hemodynamic
pensate for inadequate blood flow if the preload becomes instability is common in the neonatal period (especially in the
inadequate or if afterload increases, or if heart rate, or con- preterm infant) and has been implicated in ischemic and hem-
tractility wanes. For example, the non-distensible heart has orrhagic brain injury in both term and preterm infants.
limited capacity to increase stroke volume to augment car- Unfortunately, cerebrovascular injury has been linked to life-
diac output in response to increasing preload [176, 177]. long dysfunction including motor disorders, learning/develop-
Although volume loading in the immature ventricle increases mental delays, seizures, and secondary complications (e.g.,
cardiac output, the effect is attenuated compared with the from chronic lung disease secondary to recurrent aspiration
response at older ages. Similarly, the immature myocardium pneumonia). Minimizing or preventing neurologic complica-
poorly tolerates increases in afterload compared with that at tions from perinatal injury requires a complete understanding
older ages. The increased content of collagen and high ratio of the cellular and molecular mechanisms of the responses of
of types I:III collagen may account for the relative noncom- the developing brain to asphyxia, hypoxia, and/or inflamma-
pliance of the neonatal heart. These factors are all magnified tion. To date, such mechanisms have not been definitively
in the setting of the ELBW infant where blood flow across mapped, and the extent and nature of the initial injury does not
the foramen ovale and ductus arteriosus varies markedly invariably predict long-term outcomes.
over short periods. Finally, since the normal heart rate in the The general pattern of injury to the developing brain
neonate is high, increasing the heart rate may not further involves an initial insult from hypoxia, inflammation, and/
increase the cardiac output, but decreasing the heart rate may or ischemia followed by secondary damage from reperfu-
dramatically decrease the cardiac output. Some propose that sion that results in excitotoxicity and release of a host of
the resting myocardium in the neonate exists at a greater cytokines [179]. Recently, Volpe introduced the concept of
level of “β-adrenergic tone” than does the child and adult. As “panencephalopathy” [180] and “encephalopathy of prema-
this β-adrenergic tone wanes over the first weeks to months turity” [181–183] to emphasize that the initial white and gray
after birth, adrenergic stimulation may elicit a greater matter injury incurred by the preterm infant is not simply a
increase in cardiac performance [178]. simple loss of tissue. That is, injury to the immature brain
The fetus (i.e., ELBW infant) and neonate may have significantly impairs subsequent development by disrupting
impaired ventricular function secondary to a decreased “connectivity.” Volpe emphasizes that “neonatal brain injury
number of myofibrils, decreased sympathetic innerva- and its subsequent clinical and anatomic consequences must
tion, decreased β-adrenoceptor concentration, immaturity be viewed as an amalgam of destructive and developmental
of the sarcoplasmic reticulum structurally and functionally disturbances.” Kinney asserted that the term “encephalopa-
maturation-specific mechanisms for calcium uptake, release thy of prematurity” implies that “the constellation of cogni-
and storage, and specific spectra of expression of various tive, motor and emotional impairment in long-term survivors
isoforms of contractile/noncontractile proteins, channels, of prematurity reflects the particular patterns of white and
gray matter damage in combination with arrested develop- magnum, aqueductal stenosis and associated hydrocephalus
mental programs—patterns that depend upon the severity, can develop. Severe anomalies may cause apnea, vocal cord
timing, and chronicity of the injury as well as individual paralysis, and/or central and obstructive ventilatory distur-
confounding factors” [184]. bances and require early correction [187]. Of significance, as
many as 20% of infants with myelomeningocele have sleep-
disordered breathing [188].
ormal Development of the Central Nervous
N Agenesis of the corpus callosum and septum pellucidum
System is often associated with abnormal neuronal migration and
significant clinical abnormalities. Agenesis of the corpus cal-
The two primary structures of embryogenesis of the brain losum is usually associated with a syndrome (e.g., Aicardi
that develop early in gestation are the neural tube (future or Andermann syndrome) or a chromosomal [11, 14, 16,
brain and spinal cord) by 3–4 weeks and the prosencephalon 18, 21] abnormality. As many as 80% of children without a
(future forebrain) by 2–3 months [185]. Early neural tube corpus callosum have other brain anomalies, as well as non-
anomalies are dramatic and often fatal: anencephaly, cranio- CNS malformations [189, 190]. Partial agenesis of the brain
rachischisis totalis, myeloschisis, and encephalocele. probably occurs later in development and is associated with
Similarly, severe prosencephalic anomalies (holoprosen- clinical syndromes with migrational and structural disor-
cephalies) are often fatal, especially when associated with ders. Agenesis of the septum pellucidum is never an isolated
chromosomal abnormalities (e.g., trisomy 13–15, trisomy/ lesion, often occurring in conjunction with optic nerve hypo-
ring/deletion 18). kpo6 plasia (septo-optic dysplasia).
As a less severe form of abnormal neural tube closure, During the third trimester, cortical gray and white mat-
lesions of spina bifida (incidence 3–7 per 10,000 births) are ter volumes increase four- to fivefold [182, 183], second-
clinically important because affected infants frequently sur- ary to growth and differentiation of dendrites and axons,
vive and have lifelong problems. The four primary types of the proliferation of glia, synaptogenesis, and myelination
spina bifida are categorized according to the severity of the (Fig. 2.8) [191]. The proliferation in the cerebellum is even
defect [185]. In spina bifida occulta, the divided vertebral more rapid than the cerebral cortex and is characterized by
arch, the spinal cord, and the meninges are covered with intense migration of various populations of cells (Fig. 2.9)
skin. Hair often protrudes from the skin overlying the defect, [192–194]. In parallel with the intense growth of the paren-
forming a sacral dimple. In spina bifida cystica, neural tissue chyma, the vascular network of the late gestation brain also
and its coverings protrude through the incompletely formed develops rapidly. The long and short penetrators lengthen
vertebral arch as a cystic-like structure. In meningocele, and arborize, decreasing border/end zone blood flow.
the neural tube lies in its normal position, but the meninges
protrude through the defect; skin usually covers this lesion.
In the fourth type, the myelomeningocele, both the spinal Human Brain Growth
cord and the meninges protrude, often without skin. These
100
lesions can occur at any level of the spine. Hydrocephalus,
90
which commonly accompanies myelomeningocele (in 60%
80
of those with occipital, cervical, thoracic, or sacral lesions
% Full-term Brain
70
and in about 90% of those with thoracolumbar, lumbar, and/
or lumbosacral lesions) [186], is often not evident before 60
Weight
the meningomyelocele is closed because cerebrospinal 50

fluid leaks through the open lesion and decompresses the 40
ventricles. 30
Arnold–Chiari malformation, an abnormality of the hind- 20
brain, occurs in most patients with myelomeningocele. The 10
medulla oblongata is flattened and elongated and, along 0
with the fourth ventricle, protrudes into the spinal canal 18 20 22 24 26 28 30 32 34 36 38 40
through the foramen magnum. The downward position of Gestational Age (wks)
the medulla elongates the lower pons and upper medulla
Fig. 2.8 Growth of the human brain over the second half of gestation
and may compress brain stem nuclei and cranial nerves. as a function of % of the weight for the full-term infant. The 34-week
If the cerebellar tonsils are displaced through the foramen gestation brain is only 65% of its weight at term (from Kinney [191])
95th% uniquely vulnerable to injury in the preterm infant [199, 201,

125
202]. Furthermore, the detailed anatomy of injury identified
via MRI may be combined with the known selective vulner-
100 50th% ability of various cell populations to estimate, first, the pat-
3D Cerebellar volume
terns of defective “connectivity” in brain development that

% of 40 weeks
75 develop after the injury and, second, to correlate these pat-

5th% terns with the clinical outcome identified during long-term
50
follow-up [199, 200].
Patterns of injury common to preterm and term infants
involve various excitatory mediators. For example, although
25
glutamate plays a critical role in the proliferation, differen-
tiation, and migration of developing cells, excessive release
0 of this molecule in the setting of a hypoxic–ischemic injury
20 25 30 35 40
contributes to a state of “excitotoxicity” that is associated
Gestational age (weeks)
with cell death. When glutamate receptors (N-methyl-d-
Fig. 2.9 Growth of the human cerebellum (5th, 50th, 95th percentile) aspartic acid [NMDA], alpha-3-amino-hydroxy-5methyl-4-
during the last half of gestation as a function of % of the volume for the isoxazole propionic acid [AMPA], kainate) are excessively
full-term infant. The 34-week gestation brain is only 65% of its volume stimulated (especially certain subtypes), intracellular cal-
at term (from Volpe [195])
cium accumulates and activates caspase-3, which leads to
abnormal apoptosis. The NMDA receptor predominantly
mediates this activity, and one subunit (NR2B) that pre-
Age-Related Patterns of Injury dominates early in gestation mediates slower deactivation,
resulting in prolonged action compared with other subunits
In addition to the overall intense growth of the brain in late [203]. In addition to excitotoxicity, oxidative stress seems
gestation, specific transient cell types define the unique sus- fundamental to the widespread injury to the brain of the neo-
ceptibility of the developing brain to ischemia, inflamma- nate, especially the VLBW infant. When the production of
tion, excitotoxicity, and free radical injury. That is, various toxic free radicals exceeds the availability of antioxidants to
populations of cells are critical in forming pathways in the neutralize the excessive level, the imbalance leads to disrup-
central nervous system and, at the same time, are exquisitely tion of fundamental cellular structures (e.g., DNA, lipids,
sensitive to injury. This selective vulnerability of specific and proteins). Preterm infants are especially prone to oxi-
populations of cells at different developmental stages (24– dative stress secondary to exposure to events that predis-
28 weeks vs. 28–32 weeks vs. 32–37 weeks vs. term) leads pose to this condition (i.e., hyperoxia, hypoxia, ischemia/
to predictable patterns of injury and associated pathology reperfusion, infection/inflammation, blood transfusion/iron
[196]. Thus, the specific characteristics of an insult and tis- load) in the presence of limited antioxidant capacity (e.g.,
sue combine with gestational age resulting in unique cellular vitamins A, C, and E, catalase, glutathione peroxidase, Mg
vulnerability that defines pathology and associated clinical and Cu superoxide dismutase) [203–205]. Although a spe-
outcome. Three examples have received prominent attention cific mechanism for injury is elusive, painful and stressful
by experts in neonatal neuropathology (see Vulnerable Cell procedures encountered during neonatal intensive care have
Populations). been associated with disturbances in brain growth and matu-
In general, the preterm infant, especially VLBW infants, ration [201, 206]. Most complications of prematurity (e.g.,
is considered to be the infant most vulnerable to white matter retinopathy of prematurity, bronchopulmonary dysplasia,
injury, whereas the term infant is most vulnerable to injury necrotizing enterocolitis, intraventricular hemorrhage, peri-
in the deep gray nuclei (e.g., basal ganglia and thalamus). ventricular leukomalacia, diffuse white matter injury, punc-
However, advanced MRI (e.g., high-resolution MRI, spec- tate white matter lesions) have been linked to oxidative stress
troscopic imaging, diffusion tensor imaging) has expanded [207]. Consistent with this, Saugstad suggested the term “the
our understanding of brain development leading to the oxygen radical disease of neonatology” [208]. On the other
“blurring” of this “gray-white” dichotomy of the response hand, while harmful in excess, low or moderate concentra-
to injury in the term versus preterm infant [197]. For exam- tions of reactive oxygen species and reactive nitrogen species
ple, periventricular white matter in preterm infants is selec- are critical factors in various processes such as maturation of
tively vulnerable to ischemia during hypotension [198]. But, cellular structures and host defenses.
increasingly, white matter injury has been recognized in term Of interest, areas of the brain expressing NMDA receptors
infants, and gray matter injury has been identified in pre- also express neuronal (nNOS) and inducible nitric oxide syn-
term infants [180, 199–201]. Finally, the cerebellum seems thase (iNOS) [209]. While endothelial nitric oxide (eNOS)
mediates cerebral vasodilatation, excessive nitric oxide medi- after birth [216]. Although the subplate diminishes after
ated by iNOS in response to hypoxia–ischemia generates reac- 34 weeks’ gestation and a distinct subplate zone is not distin-
tive nitrogen species (free radicals). The excess oxygen and guishable 6 months after birth [217], subplate neurons con-
nitrogen free radicals generated in response to hypoxia–isch- tinue to develop postnatally, populate the adult gyral white
emia or to free iron (Fenton reaction generates the hydroxyl matter [218], and are referred to as “interstitial white matter
radical when hydrogen peroxide encounters free iron) [210, cells” [217, 219]. As one expert noted, “transient populations
211] associated with hemorrhage deplete endogenous anti- of cortical neurons generate such great interest because they
oxidant systems, damaging cell membranes and resulting in are the link between developing and mature cortical cir-
cell death. Oxidative stress seems to enhance excitotoxicity cuits”; subplate neurons have been investigated as links to
via regulatory effects on glutamate receptors [212]. psychiatric disorders and brain abnormalities, including epi-
Therapy with antioxidants (caffeine, an adenosine inhibi- lepsy, autism, bipolar disorder, and schizophrenia and vari-
tor; melatonin, free radical scavenger, pro-myelination func- ous developmental abnormalities secondary to migrational
tion; recombinant human insulin-growth factor 1, stimulates disorders [217, 220]. Finally, hypoxic–ischemic injury to the
growth and differentiation) has been proposed, but clinical subplate zone either in utero or in preterm infants may pre-
studies remain in early stages [204, 208]. Also, erythropoi- dispose to these disorders as well as cognitive problems in
etin has been shown to provide neuroregeneration in the later life. For example, injury to a vulnerable subpopulation
setting of hyperoxia-induced brain injury (rat), implying a of neurons (granular neurons) in the white matter and sub-
possible therapeutic role in the preterm infant [213]. plate region of humans in the setting of periventricular leu-
komalacia supports an association between insults at certain
critical phases of development and later neurodevelopmental
Vulnerable Cell Populations: The Preterm and cognitive dysfunction [221].
Infant In summary, by expressing various neurotransmitters and
growth factors, this subplate zone orchestrates the migration
Two unique cell types (subplate neurons and pre- of cells from the germinal neuroepithelium to distant sites
oligodendrocytes) with marked sensitivity to hypoxia–isch- (e.g., corpus callosum, basal ganglia, thalamus) and initi-
emia populate the white matter of mid-gestation fetuses and ates formation of synapses [217, 220]. These neurons have
express glutamate receptors. The subplate neurons located in abundant receptors for excitatory amino acids (e.g., gluta-
the subcortical white matter first appear at ~10 weeks’ gesta- mate) that are critical modulators for normal development,
tion and peak in number between 24 and 32 weeks [203, but hypoxia–ischemia may stimulate excessive release of
214], when the subplate zone is 4–5 times thicker than the these modulators, excitotoxicity, and white matter injury.
cortical plate. The subplate serves as a waiting zone for cells In vitro studies have documented the relative sensitivity of
and thalamocortical axons until their final ultimate location subplate neurons to glutamate compared with other corti-
in the cortex is defined [215]. That is, postmitotic cortical cal cells [222]. Damage to the subplate may disrupt axon
neurons migrate through the subplate along “radial glial development in vital sites such as thalamocortical areas,
guides” on their way to the cortical plate. As noted by impeding critical innervation and interaction, interrupting
Kostović, “the subplate becomes the thickest and most volu- feedback between the cortex and thalamus, and leading to
minous transient compartment of the human fetal cerebral long-term functional consequences. Interfering with the con-
wall between 15 and 35 weeks gestation and represents the nectivity among various distant structures during a period of
major site of synaptogenesis and neuronal maturation and critical brain development has been postulated to correlate
differentiation. Before 24 weeks, the subplate is the major with deficits identified in the ex-premature in the specific
site of synaptogenesis in the fetal brain. Between 28 and areas of behavior, cognition, and other complicated higher
34 weeks’ gestation, this region remains at the peak of its cortical functions (e.g., executive function) [193, 223–226].
development because of continuous growth and relocation of Thus, the subplate neurons are a transient cell population
massive corticocortical pathways; this period is also charac- that mediates essential thalamocortical development.
terized by extensive growth of fetal white matter, further for- Before myelination and during the time of peak vulner-
mation of cortical convolutions, and exponentially increasing ability to white matter injury (23–32 weeks) (see “Cerebral
synaptogenesis” [216]. Damage to the subplate in the pre- White Matter Injury”), the late oligodendrocyte progenitors
term infant during the “waiting period” when thalamocorti- (pre-oligodendrocytes) are the predominant cells that populate
cal fibers are rapidly accumulating (~22 weeks) and during the subcortical white matter. While mature oligodendrocytes
relocation into the cortical plate (~24–28 weeks) may lead to are relatively resistant, pre-oligodendrocytes are especially
abnormal cerebral development. That is, the subplate func- susceptible to injury from oxidative and excitotoxic stress
tions as a “waiting compartment” for cortico-cortical affer- and, when injured, fail to reach full maturation, resulting in
ents until birth and even as a “mini-waiting compartment” diffuse hypomyelination and axonal disruption. Thus, injury
to progenitors inhibits their maturation, allowing the per- infections, seizures, and hemodynamic instability, all inter-
sistence of a population of cells that exhibit excitotoxicity acting to produce the outcome.
as well as fail to generate mature oligodendrocytes that are
capable of myelination [201, 227].
Finally, microglia are concentrated in the cortical white Vulnerable Cell Populations: The Term Infant
matter during the third trimester but decline rapidly after
37 weeks of gestation [228]. Recently described as “‘gate- The term infant experiences hypoxia–ischemia from several
keepers’ of a healthy brain microenvironment and cell–cell clinical sources (placental injury [e.g., abruption, infarct],
communications under physiological conditions” [228], birth trauma, umbilical cord prolapse/compression) that are
microglia exert a broad range of functions during normal distinct from those that commonly injure the preterm infant
development (immune surveillance, vasculogenesis, neuro- (e.g., infection/inflammation). In general, hypoxic–ischemic
genesis, myelination, network connectivity). To fulfill such insults in the term infant primarily target the deep gray
varied roles, these cells display a range of morphological nuclei, especially the basal ganglia. As in the preterm infant,
and ultrastructural phenotypes. On the other hand, abnor- the selective vulnerability is linked to overexpression of cer-
mal activation of these cells secondary to infection/inflam- tain glutamate receptors (especially NMDA) and various
mation precipitates the release of cytokine and glutamate, subunits (e.g., NR2B > NR2A). In the basal ganglia, these
producing reactive oxygen and nitrogen species [201, 211, receptors coexist with an abundant population of neurons
229, 230]. Because stimulation of microglia isolated from that express nNOS, thus creating a site of increased suscepti-
embryonic and neonatal brains is associated with a greater bility to injury. Additionally, free radicals generated from
release of cytokines [229], preterm infants may be complete hypoxia–ischemia as well as from reactions with free iron
increased risk for injury secondary to microglia-mediated (the Fenton reaction produces the hydroxyl radical when
cytotoxic effects during infection/inflammation. Of note, hydrogen peroxide reacts with free iron) generated after
microglial activation and release of excess cytokines after hemorrhage may lead to oxidative damage [234].
immune stimulation in the developing brain may not only Contrary to the traditional belief that injury recognized
induce inflammation but also directly affect neurotransmis- at birth is often associated with chronic in utero events (e.g.,
sion [228]. Such injury and/or immune stimuli have been infection/inflammation), most neonatal encephalopathy is
reported to stimulate innate immunity via Toll-like receptors secondary to insults at or near birth [235–237] and evolves
(TLRs). Although mediating TLR2 expression during nor- over the first few weeks (or months) of postnatal life. Since
mal postnatal brain development and pathologic conditions, such injury is relatively acute but does evolve, neuroprotec-
microglia mediate excessive release of proinflammatory tive therapy may be critically relevant for improving long-
cytokines that may be associated with long-term pathology, term outcomes. In 2010, the International Liaison Committee
such as white and gray matter injury [231]. These cells also on Resuscitation (ILCOR) published guidelines that term
play a role in the response to ischemic insults associated with infants with signs of moderate or severe perinatal asphyxia
stroke [230]. Currently, the complex role of microglia both should receive therapeutic hypothermia [109]. All western
in normal development and in the emergence of neurologic countries now have therapeutic hypothermia as a “stan-
outcomes after perinatal insults has yet to be fully elucidated. dard of care” after moderate and severe perinatal asphyxia
Thus, after the neural tube and the prosencephalon are [238–240]. Currently, servo-controlled whole-body cooling
established, the central nervous system primarily develops (rather than head cooling) is preferred to provide stable tem-
by proliferation and migration. Neurons proliferate from peratures, while less labor-intensive to apply. Cooling should
ventricular and subventricular regions at every level of the start within 6 h of birth, and core temperature is maintained
developing nervous system. From the second to the fourth at 33.5°C for 72 h (rectal temperature), followed by rewarm-
month of gestation, most proliferating cells are neurons. ing at a rate of 0.5°C/h [238]. Cooling at a lower temperature
From the fifth month of gestation to adulthood, glia are pri- and/or for more prolonged periods has not been proven ben-
marily proliferating. Interruption of migration (e.g., from the eficial. Hypothermia has been feasible in late preterm infants
subplate), abnormal activation (e.g., microglia), and/or fail- (gestational age 34–36 weeks), but caution is critical in the
ure of proliferation/maturation (e.g., pre-oligodendrocytes) setting of sepsis or bleeding.
are key factors underlying the pathophysiology of injury to The significant physiologic effects of cooling demand that
the immature brain. clinical experts adhere to strict guidelines and m onitoring
The risk of white matter injury and the associated neuro- protocols during therapeutic hypothermia. For example, as
developmental abnormalities increase with systemic illness expected with decreasing metabolic rate, therapeutic hypo-
such as chronic lung disease [232] and necrotizing entero- thermia (decreasing core temperature to a few degrees)
colitis [233]. Moreover, the critical care of neonates is com- reduces heart rate and cardiac output (e.g., 7% decrease per
plex, including pharmacologic therapy, ventilatory support, °C below 37°C). Of note, the unique physiology of calcium
metabolism in the neonatal heart must be considered (see Although widely recognized as a hematopoietic growth
Myocardial Development, Subcellular Components) when factor, EPO’s broad effects as antiapoptotic, antioxidative,
interpreting measurements such as blood pressure and car- and anti-inflammatory led to proposals for a role as a neu-
diac output. Similarly, the production of carbon dioxide roprotective agent in the setting of neonatal HIE [247]. Of
decreases ~3–4% per °C, predisposing to hyperventilation note, the increased permeability of the blood–brain bar-
in the setting of mechanical ventilatory support (alkalosis rier in the context of HIE allows this factor to gain access
may decrease CBF and predispose to seizures). Although to the central nervous system, compared with limited entry
these changes are predictable, and even “physiologic,” into this protected environment during normal physiology.
hypothermia also blunts the response to inotropic agents Larger doses than those used to treat anemia (250 μ/kg)
and exaggerates α- compared to β-effects. At the same time, have been evaluated in multiple clinical trials (e.g., often
vasoconstriction increases hydrostatic pressure, leading 500–1000 μ/kg or greater) for a variety of total doses. In the
to extravasation of intravascular fluid, possibly decreasing setting of HIE, EPO induces a variety of mechanisms associ-
venous return. Finally, diverse effects on coagulation and ated with neuroprotection (e.g., increased expression of EPO
leukocyte function may predispose to bleeding and infection receptors in the central nervous system, increasing produc-
[241]. At the same time, the multisystem derangements asso- tion of nitric oxide, inhibited release and increased uptake of
ciated with asphyxia (i.e., myocardial depression, pulmonary glutamate, inactivation of caspase enzymes, upregulation of
insults [e.g., meconium aspiration, hemorrhage, pulmonary enzymes that scavenge oxygen radicals, downregulation of
hypertension], renal and hepatic dysfunction [e.g., drug proinflammatory cytokines, activation of vascular endothe-
metabolism], metabolic instability [e.g., hypoglycemia]) lial growth factor, etc.) [247]. Repeatedly, infants exposed to
add to the complexity of supportive care during therapeutic EPO (alone or in addition to therapeutic hypothermia) had
hypothermia [242, 243]. improved neurodevelopmental outcome (usually evaluated
Despite evidence for its effectiveness, hypothermia yields at 12–24 months’ postnatal age), as measured by reduced
only modest benefits and is unlikely to be a panacea for death/disability, decreased risk for cerebral palsy, reduced
preventing long-term complications associated with neona- incidence of “breakthrough” seizures/reduced number of
tal encephalopathy. The results of the TOBY (Total Body infants treated with anticonvulsants, decreased incidence of
Hypothermia for Neonatal Encephalopathy) trial reported abnormalities/injury on MRI [247]. Nonetheless, published
the following (cooled vs. not cooled): IQ >85–77% versus studies have been limited in size and scope, so that EPO has
63% (P = 0.05); cerebral palsy, 21% versus 36% (P = 0.03); not yet been adopted at a routine clinical therapy for HIE;
and without neurologic abnormalities, 45% versus 28% (RR robust data attest to safety. Recently, experts have reported
1.60) [244]. Similarly, a Cochrane review of therapeutic the effectiveness of EPO as a prophylactic neuroprotective
hypothermia in neonates with HIE concluded that although agent in very low birth weight infants [248]. Ongoing larger
beneficial (number needed to benefit 11 and 8, respectively), phase III clinical trials aim to establish the efficacy of this
the effect on mortality or major disability was small, with a agent for neonatal HIE, both in term and preterm infants.
reduction from 61% to 46% [240]. At the same time, the US Magnesium exerts diverse regulatory actions on neu-
National Institute of Child Health and Human Development rons and at neuromuscular junctions, but effects on the
(NICHD) study reported that the primary outcome of death NMDA receptor defines its proposed role in the setting of
or an IQ <70, which had been significantly less at 18 to neuroprotection [249]. Although the mechanism for inhibit-
22 months of age in those treated (47% vs. 62%), no longer ing neuroexcitation has not been established and data are
differed significantly at 6–7 years of age. Of note, at follow- controversial, studies repeatedly explore the role of mag-
up, the incidence of moderate or severe disability (35% vs. nesium in interfering with the rapid influx of calcium that
38%) was similar between the two groups [245]. accompanies hypoxic–ischemic insults and that initiates a
Thus, with significant risks and imperfect progress on secondary cascade of injury. Furthermore, magnesium has
improving outcomes, rather than relying on a single modal- been allocated anti-inflammatory roles in various pathways
ity such as therapeutic hypothermia, many suggest that a (e.g., nuclear factor-κB). Although a recent meta-analysis
multipronged approach to perinatal neuroprotection/rescue concluded that antenatal magnesium reduced the risk for
will be essential to improving outcomes [210]. That is, after cerebral palsy and other motor dysfunction [250], the out-
moderate to severe HIE, ~50% of neonates will die or incur come at school age failed to confirm benefits in motor or
long-term developmental problems. Various strategies have cognitive performance, or in behavior [251]. Also, recent
been reported, including erythropoietin (EPO), melatonin, reports [252], including a Cochrane meta-analysis con-
N-acetyl cysteine, inhaled xenon or argon, allopurinol, and cluded: “there is currently insufficient evidence to assess
magnesium [242, 246, 247]. Of these, EPO has achieved the efficacy and safety of magnesium sulfate when admin-
major attention, especially as an adjunct to therapeutic istered to women for neuroprotection of the term fetus”
hypothermia. [253]. Similar results were noted in other studies. Despite
these disappointing results, clinical guidelines recommend neurodevelopmental abnormalities [259], including behav-
prenatal magnesium as a neuroprotective agent, focusing on ioral, cognitive, social/attention, and motor disorders.
decreasing the incidence of cerebral palsy at early follow-up Although a broad range of factors (e.g., genetic, environ-
[249, 254]. Of note, the incidence of cerebellar hemorrhage mental, in utero insults, pre- and postoperative events) have
was reduced among very low birth weight infants exposed been associated with these findings recently, the focus has
to prenatal magnesium [255]. shifted from documenting brain injuries associated with sur-
Xenon, a gas that crosses the placenta and the blood– gery to analyzing antenatal and preoperative factors govern-
brain barrier, is a candidate agent for neuroprotection by ing altered brain maturation in congenital heart disease,
binding to N-methyl-D-aspartate (NMDA) glutamate recep- especially complex cyanotic lesions [260, 261]. A recent
tors to inhibit apoptosis in the setting of neuroexcitation comprehensive review of the main findings on prenatal MRI
encountered with HIE. Although preliminary results from associated with various congenital heart lesions (aortopul-
the TOBY-Xe Trial are encouraging [256], the clinical rel- monary transposition, hypoplastic heart disease, tetralogy of
evance of this agent has not been established. Similar to Fallot, single ventricle) noted that the abnormalities reflected
xenon, preliminary data for melatonin imply a role for neu- delayed development of the brain (e.g., ventriculomegaly,
roprotection. As an endogenous “neurohormone,” melato- extra-axial CSF spaces, lower brain volumes). Furthermore,
nin imparts antioxidant effects by scavenging free radicals, markers of cerebral metabolism and measurements of micro-
stimulating various antioxidative enzymes (e.g., glutathione structure also reflected developmental delay. Of note, fetuses
reductase, superoxide dismutase), and inducing activities with lesions associated with impaired oxygen delivery to the
of calcium-binding proteins [246]. Recently, a limited trial brain (hypoplastic left heart syndrome, critical aortic steno-
in newborns with HIE noted decreased seizures and white sis, interrupted aortic arch, and aortopulmonary transposi-
matter abnormalities on MRI, with improved survival with- tion) had more dramatic evidence of delay in brain maturation
out developmental abnormalities (at 6 months) [257]. From compared with the fetus with sufficient CBF. In addition to
the perspective of low risk and the option for both pre- and evidence for delayed brain maturation, the most common
postnatal delivery, melatonin offers notable advantages for lesions included punctate white matter injury, periventricular
neuroprotection. Other agents (e.g., N-acetylcysteine, allo- leukomalacia, and stroke [262]. Many studies using a variety
purinol, biotin) and therapies (stem cells) have gained atten- of tools (e.g., NIRS, cerebral oximetry, EEG) have docu-
tion and are under ongoing evaluation [246, 258]. mented abnormal cerebral oxygenation in complex congeni-
Advanced MRI techniques have identified two primary tal heart disease, but the correlation with neurodevelopmental
patterns of injury in the term infant [182, 197, 234]. First, outcomes is inconsistent [260]. Thus, in the setting of com-
a watershed pattern involves the vascular border/end zones plex congenital heart disease, the concept that hypoxic–isch-
of the white matter that may extend into the cortical gray emic injury and dysmaturation in utero coupled with a high
matter after a severe insult. In general, watershed lesions are risk of acquired brain injury postnatally combine to increase
more often associated with cognitive than motor disorders. the risk for short- and long-term adverse neurologic out-
Second, the basal nuclei (basal ganglia/thalamus) pattern comes [263].
involves the deep gray nuclei that may extend throughout the Similar to fetal MRIs, preoperative postnatal MRI in
cortex after a severe insult. That is, this pattern often includes neonates with complex congenital heart disease (e.g., single
diffuse cortical injury. At presentation, these neonates have ventricle, aortopulmonary transposition) has documented
had more severe clinical abnormalities including intensive maturational abnormalities. The impaired brain development
resuscitation, severe encephalopathy, and seizures. In gen- (“cortical dysmaturation”) and metabolism of the brain of
eral, these lesions are typically associated with more severe the fetus and neonate with complex congenital heart disease
cognitive and motor disabilities than in the watershed pattern. resemble findings in the preterm infant. This immature status
However, even when one pattern predominates, the damage of the brain may predispose these infants to similar vulnera-
is common in the other domain [236]. Thus, the spectrum of bility to white matter/subplate injury as that seen with prema-
deficits on follow-up correlates with the pattern of injury on turity (see Vulnerable Cell Populations: The Preterm Infant)
MRI, rather than simply the severity of the lesion. [264–267]. However, the patterns of structural and meta-
bolic abnormalities in congenital heart disease also include
features distinguishable from prematurity and white matter
Congenital Heart Disease injury [260, 268]. That is, although white matter defects are
the most common injury associated with congenital heart
Two decades ago, the dramatic impact of complex congenital disease, the distribution of white matter injury differs from
heart disease on neurodevelopment was reported. That is, that seen in the preterm neonate [269], and white matter
50% of neonates with congenital heart disease have micro- injury fails to completely explain the neuropathology asso-
cephaly and neurologic deficits that correlate with long-term ciated with complex lesions (e.g., decrease brain volumes,
abnormal gyrification, abnormalities in microstructure/con- Similar to the preterm infant, the neurodevelopmental
nectivity) [270]. For example, reduced total and gray matter outcome of the term infant with complex congenital heart
volumes have been noted in fetuses with tetralogy of Fallot disease reflects a complex interaction between a focal brain
between 20 and 34 weeks’ gestation [271]. In another report, injury (e.g., white matter injury) and its profound effects on
reduced subcortical gray matter volume in term patients with subsequent brain development [275]. Although the specific
complex heart disease was associated with “poor behav- mechanism for the in utero delay in development is unclear,
ioral state regulation” [261]. Finally, using quantitative MRI disturbances in the fetal circulation with decreased deliv-
and magnetic resonance spectroscopy, detailed associations ery of oxygen and other metabolites to the brain may play a
between subcortical morphology (i.e., thalamus and cerebel- fundamental role [48, 276]. Consistent with this hypothesis,
lum) and white matter metabolism revealed distinct regional infants diagnosed with complex heart disease prenatally had
patterns of metabolic deficits (i.e., glutamate, citrate, n-acetyl improved outcomes compared with those who were diag-
aspartate, lactate, citrate) when preterm control infants were nosed postnatally [277]. That is, delivery of high-level inten-
compared with term and preterm infants with complex heart sive cardiac care preoperatively correlates closely with a fetal
disease [268]. For example, reduced cerebellar volume was diagnosis, thereby improving the likelihood of cardiovascu-
associated with reduced glutamine metabolism in the preterm lar stability. Similarly, acquired postoperative periventricular
and term groups with congenital heart disease, but not in the leukomalacia in infants with hypoplastic left heart syndrome
preterm control group. Such studies advance the understand- correlated with the time to surgery after birth [278], implying
ing of the complexity of gray and white matter abnormalities that the risk for injury may increase with prolonged expo-
in the context of metabolism of the brain in neonates with sure to the disturbed postnatal cerebral hemodynamics and/
complex congenital heart disease. From another viewpoint, or metabolism associated with this critical lesion [279].
after documenting aspects of normal patterns of migration Finally, although complex cyanotic heart disease confers
from the subventricular zone (piglet model), investigators a particularly high risk of developmental delay, neurologic
compared the effects of chronic hypoxia on this process and abnormalities commonly evolve in children with either acya-
compared the findings with autopsy specimens from infants notic or cyanotic lesions, especially in those who require sur-
with complex congenital heart disease. Of particular signifi- gical intervention in the first few days of life [280].
cance, a drastic depletion of neuroblasts within the subven-
tricular zone was noted in both groups [270], implying that
chronic hypoxia may be a fundamental mechanism for the Summary
injury in patients with complex congenital heart disease.
Thus, although conventional brain magnetic resonance That the brain of the 34-week gestation fetus weighs only
imaging documents preoperative injury in the multiple 65% of that of a term infant (Fig. 2.8) [191] implies dramatic
domains, including ischemic infarcts, white matter injury, development during the last month of normal fetal life.
and other insults in up to 50% of infants with congenital Overlap in the pathophysiology of lesions common in the
heart lesions that require surgery in the neonatal period, preterm infant (periventricular leukomalacia [PVL] and ger-
quantitative imagining and spectroscopy are critical to minal matrix–intraventricular hemorrhage [GM-IVH]) with
advance the goal of correlating metabolic mechanisms with those most common in the term infant (HIE, arterial stroke)
the structural injury. Also, quantitative MRI techniques con- is not surprising. In part, the overlap can be explained by
tribute to knowledge about the timeline of brain injury. For responses to injury in the setting of selective vulnerability of
example, a recent report focused on the “DTI tract-based the immature/newborn brain coupled with disturbances in
spatial” technique applied to infants with complex lesions, the regulation of CBF.
advancing the possibility of tracking injury with sequen-
tial imaging to attempt to document an evolving injury and
predict neurodevelopmental outcome [272]. Diffusion ten- Autoregulation of Cerebral Blood Flow
sor imaging (DTI) has been broadly applied to monitor the
development of white matter microstructure, especially in Cerebral autoregulation accounts for a constant CBF over a
the setting of dysmaturation of the immature brain. The tech- wide range of systemic blood pressure (in adults, between
nique applies the “properties of water molecules as a win- mean arterial pressures 60 and 150 mmHg) [281]. Such a
dow into regional axonal density and white matter integrity” phenomenon implies that changes in perfusion pressure
[273]. Specifically, fractional anisotropy (FA) reflects axonal elicit vasoconstriction and vasodilation to maintain a stable
density and integrity of white matter (increases with matura- blood flow. Various vasoactive factors have been linked to
tion), and mean diffusivity (MD) measures the diffusion of local regulation of CBF (e.g., hydrogen ions, potassium,
water molecules (decreases with maturation) [274]. adenosine, prostaglandins, osmolarity, and calcium) [210].
The term “pressure passive” refers to the disruption of auto- integration of a secondary source of information such as
regulation so that changes in blood pressure alter CBF. In EEG, will allow for personalized blood pressure manage-
neonates, especially the very low birth weight infant, ment, avoiding overtreatment of ‘hypotension’ in infants
pressure-passive CBF is common [282–284] and has been with intact autoregulation and enhancing recognition of poor
identified as a critical risk factor for central nervous system cerebrovascular health in infants with ‘normal’ blood pres-
injury and the subsequent adverse neurodevelopment [285, sures” [290].
286]. That is, even if intact, the range for autoregulation in Although normal blood pressure increases markedly dur-
normal fetal/preterm and term animals and humans is nar- ing the third trimester, defining “hypotension” has remained
rower compared with their more mature counterparts. controversial, especially in the first day to week of life [148,
With rapidly evolving noninvasive monitoring, experts 149, 291–294], when parameters that influence blood pres-
have proposed a variety of systems to monitor autoregula- sure (e.g., afterload, preload, contractility, adrenergic func-
tory function. For example, correlating cerebral oxygenation tion, and other factors) tend to be variable, unpredictable,
(via near-infrared spectroscopy [NIRS]) with arterial pres- and impossible to measure directly [295]. Furthermore, the
sure, investigators noted that autoregulation and “cerebral criteria for treating “hypotension” remain elusive [296–
reactivity” improve over the first 4 postnatal days and served 298]. Antihypotensive therapy has neither improved out-
to predict death/severe intraventricular hemorrhage [287]. comes [299] nor been detrimental [300]. As gestational age
Recently, using a combination of transcranial Doppler tech- decreases, the normal blood pressure in preterm infants is
niques and intra-arterial blood pressure monitoring in pre- close to the lower limit of autoregulation [293, 301, 302].
term infants, experts reported that the regulation of systolic As a result, if the arterial blood pressure increases abruptly
cerebral blood flow velocity by autoregulation improved and/or rapidly, the fragile vessels in the immature brain may
dramatically between 23 and 33 weeks’ gestational age rupture (see Germinal Matrix–Intraventricular Hemorrhage).
[288]. The maturation of autoregulation appears to track the Similarly, hypoxia–ischemia may develop with hypotension.
increase in the muscularis layers of the cerebral arteries and Thus, the CBF of the preterm infant seems to be vulnerable
arterioles during the third trimester [285, 288]. Similarly, to both hypo- and hypertension.
the concept of a “cerebrovascular critical closing pressure” Greisen posited that in critically ill neonates, cerebral
(i.e., the arterial blood pressure at which blood flow to the autoregulation should be considered “imperfect,” not simply
brain ceases) in the setting of immature autoregulation in the present or absent or “all or nothing.” That is, the flat part of
preterm infant has been proposed as relevant to determining the autoregulatory plateau is not horizontal but upward slop-
“effective cerebral perfusion” (i.e., arterial blood pressure ing. The slope of this part of the curve defines the degree of
minus the critical closing pressure). Similar to autoregula- disturbance in the autoregulation (Fig. 2.10) [303]. Although
tion, critical closing pressure increases with gestational age the limits of the autoregulatory plateau have not been defined
(1.4 mmHg/week, between 23 and 31 weeks) [289]. The with certainty, the range in the term infant is ~25–50 mmHg
clinical implication is that cerebral under-perfusion may (mean arterial pressure), but less and narrower in the preterm
accompany hypotension. Although this measurement would infant. Similarly, postnatal age and other factors affect the
be challenging to apply routinely in the clinical setting, the range and the limits of autoregulation [210]. To complicate
developmental pattern of critical closing pressure adds to the matters, metabolic abnormalities common in the neonates
understanding of mechanisms of injury in the preterm infant. (e.g., hypoxia, hypercarbia) impact cerebral autoregulation
Of more relevance to the clinical setting, near-infrared [301, 304–306]. For example, the series of reports by Lou
spectroscopy (NIRS) has been widely adapted to measure documented a reduced CBF in the neonate (i.e., 20 mL/100
cerebral hemodynamics and oxygenation, including estimat- g/min), and in various clinical settings, cerebral flow changed
ing CBF. A novel adaptation of this technique to quantify in response to blood pressure (i.e., disturbed autoregulation)
autoregulation involves correlating cerebral blood volume (or [301, 305].
cerebral oxygenation) and mean arterial pressure to identify In the immature human (spontaneously breathing or
the “optimal mean arterial blood pressure” in each patient at after 48 h in the mechanically ventilated), with intact
a specific time point (e.g., in settings such as cardiopulmo- autoregulation, the response of CBF to changes in carbon
nary bypass and after hypoxic–ischemic injury) [285]. For dioxide (4% change for each 1 mmHg in PaCO2) is more
example, loss of autoregulation is implied when blood pres- robust than to changes in blood pressure (1% change for each
sure and cerebral blood volume correlate. Although these 1 mmHg in pressure) [307, 308]. However, such responses are
algorithms have not achieved everyday clinical relevance, not predictable when autoregulation is markedly impaired,
“a bedside monitor capable of demonstrating the function such as in severely asphyxiated infants [309], in response to
(dysfunction) of the autoregulatory system, aided with the seizures [310], and, to a less degree, in mechanically venti-
Cerebral White Matter Injury
The risk for white matter injury is increased in very low birth
weight infants (<1500 g), in that 10–15% develop motor
deficits (cerebral palsy), and 25–50% may display cognitive,
Cerebral blood flow
attentional, behavioral, or socialization problems. Thus,

white matter injury in the preterm infant implies long-term
motor and cognitive disabilities. The patterns of injuries now
include neurons and axons as well as white matter [201, 319,
320].
Recently, the term “white matter injury” (WMI) was
proposed to supplant “periventricular leukomalacia (PVL)”
[321], since necrosis (“leukomalacia”) is absent in the
predominate variety of this lesion. That is, on the basis of
neuropathological studies, cerebral WMI can be stratified
Arterial blood pressure
into four categories, including three levels of PVL based
Fig. 2.10 Theoretical concept of autoregulation in the neonate. The on severity: necrosis with macroscopic cysts (>5 mm) with
flat section of the heavy line represents intact autoregulation, where loss of all cellular elements (“leukomalacia”), focal necrosis
CBF changes minimally over a range of arterial blood pressure. Below with macroscopic but small (2–3 mm) lesions (i.e., punctate
the knee of this curve, CBF decreases as blood pressure decreases.
white matter lesions [PWMLs]), and focal necrosis with
Similarly, above the flat part of the curve, CBF increases as blood pres-
sure increases. Greisen suggests that the flat part of the autoregulatory microscopic (<1 mm) lesions not visible on conventional
plateau may never be horizontal and the shape of the curve may change MRI. Finally, the least severe lesion, without “leukomala-
in various clinical scenarios. The degree of the tilt may be the critical cia,” includes diffuse white matter gliosis (DWMG) but no
clinical factor. He suggests that autoregulation should not be simply
focal necrosis [211, 321].
considered “present” or “absent” but instead should be approached as
quantifiable (from Greisen [303]) The cystic lesions that typically develop in the deep, peri-
ventricular white matter consist of macroscopic necrosis,
which eventually evolves into cysts that are easily imaged
lated preterm infants especially in the first day of life [311, on cranial ultrasound, but only in <5% of VLBW infants.
312]. Similarly, routine maneuvers for supportive care in the The diffuse, non-cystic component of PVL (PWML) is gen-
NICU (e.g., suctioning, administering surfactant) have been erally identified in the more central periventricular white
associated with disturbed autoregulation [313, 314]. matter, comprises ~15–25% of WMI, and consists of focal,
Although impossible to accurately predict and although microscopic necrosis not readily identified on cranial ultra-
responses to changes in PaCO2 vary with gestational and sound; 95% of WMI is identifiable on early MRI [211, 322–
postnatal age, neurologic injury, systemic illness, and meta- 326]. With advanced MRI techniques, DWMG has been
bolic derangement, both hypo- and hypercarbia should be identified in as many as 50% of ELBW infants [321, 322].
considered to have potentially dramatic effects on CBF Unfortunately, neuropathologic data cannot be definitively
[315]. In fact, in the neonate, both hypercarbia and hypo- correlated with neuroradiologic studies.
carbia have been associated with severe neurologic insults On MRI, cysts or PWMLs can be readily visualized,
[316, 317]. Hypercarbia in the neonate directly inhibits probably representing the more severe categories of PVL. A
cerebral autoregulation in preterm infants (500–1500 g) third category of abnormality has been noted via diffusion-
[316]. Similarly, within various developmentally distinct based MRI and includes “excessive high signal intensity
ranges, both hypoxemia and hypoglycemia directly increase diffuse signal abnormality, increased apparent diffusion
CBF [318]. coefficient, and decreased anisotropy” [324]. This abnormal-
Thus, common therapeutic maneuvers (mechanical ity may occur in isolation but also accompanies the cystic
ventilation, airway suctioning), metabolic derangements WMI as well as PWML. Whether this lesion represents WMI
(hypoglycemia, hypercarbia, hypocarbia, hypoxia, hypo-/ with gliosis but no necrosis and/or microscopic necrosis is
hypernatremia, and hypocalcemia), the presence of a patent unclear. With advances in neuroimaging, this spectrum of
ductus arteriosus, and other insults (seizures, sepsis) may WMI may be more clearly defined and more closely aligned
dramatically affect the neonate’s ability to compensate for with neuropathology.
derangements in either hemodynamic or cerebrovascular Of importance, the timing of MRI impacts the reported
status. Developing a reliable and simple system to measure incidence of various types of WMI. As cysts evolve into
CBF seems critical to enhance care to the preterm infant. gliotic scars, size diminishes [327]. Similarly, PWMLs vis-
ible at early postnatal scans often are not apparent on term 3.0 mL/100 g/min [211]. In the neonatal puppy, the decrease
equivalent scans [325, 328]. In contrast, the diffuse high- in CBF as a result of hypotension differed among various
intensity signal increases with postnatal age. For example, in regions of the brain, but the white matter was most vulnerable
one report, the incidence of diffuse white matter abnormali- [335]. In addition to the substantial incidence of hypotension
ties increased with postnatal age, from 21% to 53% and 79% in the preterm infant in the setting of the transitional circula-
between the first postnatal week and term equivalent [329]. tion during the first 48 h after birth, disturbed autoregulation
Whether this diffuse lesion correlates with outcome remains (see Autoregulation of Cerebral Blood Flow) augments the
controversial [330], but quantitative analyses imply that cog- risk for injury from either over- or under-perfusion.
nitive function may be correlated [331]. Although hypoxia and/or ischemia stimulates the release
Although white matter injury has been identified in pre- of proinflammatory cytokines, a robust relationship between
term infants for decades, associated gray matter develop- infection (e.g., production of cytokines/free radicals) and
mental abnormalities have been increasingly recognized over WMI remains elusive. Nonetheless, a clear-cut maturation-
the last two decades as quantitative MRI techniques have dependent susceptibility of pre-oligodendrocytes to free radi-
evolved. Volumetric analyses have documented neuronal/ cal injury (both reactive oxygen species and reactive nitrogen
axonal disease most commonly in the thalamus, basal gan- species) in the presence of iron and decreased antioxidant
glia, cerebral cortex, and cerebellum. These lesions appear mechanisms has been documented [204, 211, 326] and asso-
on MRIs performed as early as term equivalent and persist ciated with axonal hypomyelination (see Vulnerable Cell
to adulthood [180, 224]. Although the focal, cystic, necrotic Populations: The Preterm Infant). Finally, a novel hypoth-
lesions of WMI seem to correlate with motor deficits, only esis suggests that “mitochondrial dysfunction” evolves from
a more extensive insult can account for the widespread neu- such stresses during periods of rapid development, resulting
rologic insults of the ex-ELBW infant. The non-cystic com- in “arrested cellular differentiation and proliferation” and
ponent of white matter injury may account for the cognitive impaired development, allowing a unifying hypothesis for
deficits of ex-premature infants, although the attention defi- injury in both the brain and the lung [336].
cits and behavior/socialization abnormalities are more likely Thus, the evolution of WMI seems to be multifactorial
related to the associated axonal/gray matter injury. Of note, [319], involving complex interactions of immature cardio-
in a recent autopsy study, damage to the thalamus was iden- vascular, neurologic, and immunologic (and other) factors
tified in ~60% of infants with PVL who died early in life often in the presence of infection (e.g., neonatal sepsis) or
[332]. The authors note that the thalamus likely mediates chronic inflammation (e.g., chorioamnionitis), consistent
cognition via connectivity with the entire cerebral cortex so with the “multiple-hit hypothesis” for WMI in the preterm
that neuronal loss in the thalamus may be a strategic site for infant (e.g., immaturity, fetal growth restriction, mechanical
cognitive dysfunction in preterm survivors with WMI. Volpe ventilation, surgery for NEC, male gender) [337]. Hence,
emphasizes that the ultimate clinical outcome from this “pan- vulnerability increases with exposure to multiple risk fac-
encephalopathy of prematurity” (i.e., white and gray matter tors. From the viewpoint of possible treatment, erythro-
injury) evolves not only from the primary injury (e.g., white poietin does enhance oligodendrogenesis and the survival
matter injury) but possibly more importantly from the proof oligodendrocytes (see Vulnerable Cell Populations: The
found abnormalities in subsequent development [182, 183]. Preterm Infant). Other possible treatments including growth
The vulnerability of the immature brain to white matter factors (e.g., epidermal growth factor) and mesenchymal
injury is attributed to a combination of insults: ischemia/ stem cells have received attention for possible therapeutic
disturbed autoregulation and/or infection/inflammation. The roles, although their mechanisms have not been established
border/end zones of the immature cerebral circulation, with [338]. Lastly, a novel therapy in the early stages of evalu-
incomplete development of both long and short penetrators ation centers on drug-based myelin-enhancing strategies,
into the white matter, are inherently at risk for ischemia [333]. such as clemastine, a compound that promotes myelination
The deep focal necrotic lesions of PVL are identified in the in patients with multiple sclerosis [339].
end zones of the long penetrating vessels from the middle
cerebral artery. Furthermore, the extremely low blood flow in
the white matter especially in the first 1–2 days of life adds Germinal Matrix–Intraventricular
to the vulnerability of this region of the brain [334]. Global Hemorrhage
CBF is ~15 mL/100 g/min at this age (compared with the
human adult, 45–50 mL/100 g/min). Of importance, flow to The etiologies of intracranial hemorrhage in the term infant
white and gray matter can vary significantly. In one study, generally include trauma, coagulation abnormalities, ana-
blood flow to white matter was only 17% of that to the basal tomic anomalies (aneurysm, arteriovenous malformation),
ganglia/thalamus [334]. Specifically, blood flow to the white and perinatal asphyxia. Overall, the most common etiology
matter is ~25% of that to the cortex, ranging between 1.6 and of intraventricular hemorrhage, the germinal matrix–intra-
ventricular hemorrhage (GM-IVH), predominantly occurs in the incidence declined since the 1980s, with improved sur-
the preterm infant, with incidence and severity increasing vival of the ELBW, the absolute number of cases remains
with decreasing gestational age [196]. The persistent signifi- high [347]. In this recent meta-analysis, the incidence in all
cance of this lesion centers on long-term consequences, as infants <1500 g ranged between 25% and 30% but as great
50–75% of infants develop cerebral palsy, developmental as 45% in those <1000 g.
abnormalities, and/or hydrocephalus [340]. Thus, the mes- Although substantial in infants with PVHI (~50%), in
sage in a recent publication remains notable: “Germinal early studies, grade I–II bleeds did not seem to affect mortal-
Matrix—Intraventricular Haemorrhage: still a very impor- ity in preterm infants [348]. A recent meta-analysis (infants
tant brain lesion in premature infants!”) [341]. <34 weeks’ gestation) describes a greater odds of death or
Initially, GM-IVH was divided into categories that cor- moderate to severe neurodevelopmental impairment associ-
related with the severity, extent of the initial injury, and the ated with mild IVH, with greater odds in those with severe
clinical outcome. The lesions were classified based on data IVH [347]. Thus, increasing severity of IVH may be asso-
from computerized tomography [342]. In this context, grade ciated with adverse long-term neurodevelopmental out-
I refers to a subependymal hemorrhage with minimal or no comes, but mild IVH alone may impact outcomes compared
IVH (i.e., restricted to the germinal matrix) and grade II with infants without IVH. Of note, while severe neurologic
implies an IVH into a lateral ventricle without distention. sequelae are rare in near-term infants with uncomplicated
Grade III IVH includes enlargement of the ventricles by grade I or II IVH, developmental functioning [344] is abnor-
intraventricular blood. In this classification, a grade IV hem- mal, and gray matter volumes are 16% less than predicted
orrhage involves ventricular dilatation and hemorrhage into based on MRI [349]. In ELBW infants, data for outcome
the parenchyma of the brain. after low-grade IVH are controversial [350]. For example,
After correlating the severity of the GM-IVH with the while some recent reports document increased rates of neu-
extent of hemorrhage in the lateral ventricle on the parasag- rosensory impairment, developmental delay, cerebral palsy,
ittal cranial ultrasound, the grading system was revised. In deafness at 2–3 years [351], and long-term neurodevelop-
grade I, the hemorrhage is limited to the germinal matrix, ment impairment [352], some experts continue to contend
and ventricular enlargement is less than 10%. In grade II, that low-grade hemorrhage is benign [353]. Finally, similar
10–50% of the ventricle is filled with blood. In grade III, to earlier reports, recent data (infants <27 weeks’ gesta-
more than 50% of the ventricle is involved, usually with tion) from the Eunice Kennedy Shriver National Institute of
enlargement of the lateral ventricles. Grade IV was elimi- Child Health and Human Development Neonatal Research
nated, and instead, the term periventricular hemorrhagic Network noted that, compared with neonates with normal
infarction (PVHI) was introduced to describe an echo den- cranial ultrasounds, nonhemorrhagic ventriculomegaly (i.e.,
sity of the periventricular parenchyma secondary to hem- no GM-IVH) was associated with a two- to threefold greater
orrhage [343]; this lesion is distinct from GM-IVH. Thus, odds of abnormal neurodevelopment, cognitive impairment,
in the former classification, intraparenchymal lesions were moderate to severe cerebral palsy, and death or neurodevel-
labeled grade IV GM-IVH, hypothesizing that the IVH had opmental impairment (but not death alone) [354].
extended from the ventricle laterally into the white matter. Because WMI is more accurately assessed via MRI,
The latter classification emphasizes that the pathophysiology data based solely on ultrasound may be difficult to corre-
of PVHI is a hemorrhagic venous infarction (see below), not late definitively with outcome [355]. In contrast to GM-IVH,
simply a massive GM-IVH. However, many experts continue PVHI often is a devastating lesion [351]. For example, in
to refer to a PVHI as grade IV IVH. Based on three factors, one report, two-thirds of survivors of PVHI had motor
PVHI is stratified further according to severity: size (local- delays, and one-half had cognitive impairment, with visual
ized vs. extensive), unilateral versus bilateral, and evidence field abnormalities in one-third and epilepsy in 20%. After
of midline shift [343, 344]. a PVHI, 90% of infants have poor neurodevelopmental out-
Overall, the incidence of GM-IVH has remained remark- come [356]. Similarly, a recent analysis noted moderate-to-
ably stable over the last two decades [340], ranging from 7% severe neurosensory impairment in ~40% of grade III and
to 23% [345], but in ELBW, it may occur as frequently as grade IV (PVHI) hemorrhage [351]. Finally, posthemor-
30% (750–1,000 g) to 40% (501–750 g) [8]. In this same rhagic hydrocephalus severe enough to require a ventricu-
large cohort of the NICHD Neonatal Research Network, lar–peritoneal shunt is associated with severe neurocognitive
in 2000–2002, the incidence of severe IVH (grade III) and impairment in early childhood in 78% of those with grade III
PVHI was 16% and 24%, respectively. In another cohort, lesions and 92% in those with a PVHI [345].
the overall incidence of GM-IVH decreased from 42% At least in part, the pathophysiology of GM-IVH is related
(1982–1989) and 22% (1990–1999) to 22% between 2000 to the structure of the immature brain. The anatomy of the
and 2002. The incidence of severe GM-IVH also decreased germinal matrix, the site of bleeding in this lesion (usually
from 15% to 2% [346]. From another perspective, although between the caudate nucleus and the thalamus at the level of
the foramen of Monro) [343], also contributes to the greater free radicals that are generated during hypoxic–ischemic
risk for hemorrhage in the preterm neonate. Proliferating injury. Ideally, antioxidant systems (e.g., superoxide dis-
ventricular and subventricular areas of the germinal matrix mutase; glutathione peroxidase; catalase; vitamins A, C,
(most prominent at the head of the caudate nucleus) produce and E; beta carotenes; glutathione) are robust and redun-
neuroblasts (cerebral precursors for both gray and white dant to effectively scavenge free radicals. However, when
matter) and glioblasts primarily between 10 and 20 weeks excess free radicals are generated, stores of antioxidants are
(but as late as 36 weeks). Reflecting on the great metabolic depleted. In that setting, the downstream effect is cell mem-
demand associated with rapid angiogenesis, the germinal brane damage, increased intracellular calcium, and even-
matrix is densely cellular and vascularized. But the region tually cell death. The neonatal brain encounters increased
is gelatinous, with poor support for the vascular network. risk for injury secondary to the combination of high oxygen
That is, sparse support of microvessels with astrocyte end consumption coupled with a reduced concentration of anti-
feet, decreased number of pericytes, reduced fibronectin, and oxidant systems [212].
immature tight junctions define the intrinsic vulnerability of Coincident with the often-tumultuous events characteriz-
the germinal matrix [340]. The gelatinous nature of the area ing the transitional circulation including the large incidence
gradually decreases with increasing age, with maximum vol- of hemodynamic instability over the first few days of life,
ume at 25 weeks but being barely present in term infants. 50% of GM-IVHs are diagnosed by day 1 and 90% by day
This dense vascular network arises from the middle and 4 [357]. The large incidence of pressure-passive CBF cor-
anterior cerebral and anterior choroidal arteries that enter relates with GM-IVH (see Autoregulation of Cerebral Blood
into a bed of immature, large, irregular capillary-like ves- Flow) [358]. In the presence of pressure-passive flow and
sels and eventually drain into the deep venous system from because both the periventricular white matter and the ger-
the brain. The specific vulnerability of the immature neuro- minal matrix lie within arterial end zones, both areas are
vasculature to GM-IVH correlates with the delayed devel- at great risk for ischemia during periods of decreased cere-
opment of the venous drainage compared with the arterial bral perfusion and for rupture during periods of increased
system. The immature veins are thin-walled with a branching flow. Reperfusion after ischemia may contribute to excito-
pattern predisposed to collapse. Because the superficial veins toxic injury [359]. Thus, in the presence of disturbed auto-
are underdeveloped, most cerebral venous drainage depends regulation, noxious stimuli (e.g., airway suctioning, painful
on the deep venous system that drains the germinal matrix procedures such as surgery), commonly associated clinical
and most of the white matter. problems (severe respiratory distress syndrome, pneumotho-
The veins join, forming the terminal vein, which makes rax, seizures, patent ductus arteriosus, infection), rapid deliv-
a “U-turn” near the head of the caudate nucleus to join the ery of intravenous fluids, and metabolic disturbances (e.g.,
vein of Galen. Thus, the “terminal vein” courses within the hypoglycemia, hypoxia, and hypercarbia) [306] may pre-
germinal matrix and makes an abrupt change in course at cipitate an acute increase in arterial and/or venous pressures
the common site of GM-IVH. Because of this unique anat- that may contribute to a GM-ICH. In the opposite direc-
omy, a large GM-IVH may obstruct the terminal vein, lead- tion, hypotension from a variety of insults (e.g., asphyxia,
ing to venous distension, ischemia, and rupture, producing a anesthetic agents, sepsis, hypocarbia) may cause alternating
PVHI. Thus, PVHI either accompanies or follows but never cycles of decreased CBF and reperfusion. Finally, positive
precedes a large GM-IVH and, if the GM-IVH is bilateral, pressure ventilation or pneumothorax can abruptly increase
the PVHI is always ipsilateral to the side of the larger hemor- central venous pressure, impeding cerebral venous drain-
rhage [343]. age, possibly increasing the risk for venous hemorrhage. Of
The primary site of bleeding in the preterm brain is interest, no events during pregnancy have been definitively
the junction of the veins and capillaries, rather than at the linked to postnatal GM-IVH [360, 361]. Finally, the rela-
junction of the arteries/arterioles and capillaries. Between tionship between inadequate function of various mechanisms
24 and 28 weeks’ gestation, the germinal matrix is most of coagulation to GM-IVH remains of interest but poorly
prominent at the body of the caudate nucleus and between defined [362].
28 and 32 weeks resides at the level of the head of the cau- Thus, although WMI (e.g., nonhemorrhagic, symmetri-
date, involuting by ~36 weeks’ gestation [343, 357]. When cal) and GM-IVH (hemorrhagic, nonsymmetrical) are
hemorrhage extends from the germinal matrix into the characterized by distinct pathophysiology, the underlying
ventricles, blood spreads throughout the ventricular sys- etiologies overlap and are related to the combination of
tem possibly causing arachnoiditis and obstructive hydro- immature cardio- and cerebrovascular function in the pres-
cephalus. The free iron that is released from hemoglobin ence of vulnerable anatomy and age-specific metabolic
may produce hydroxyl free radicals (Fenton reaction; see requirements. Not surprisingly, WMI and GM-IVH are com-
Age-Related Patterns of Injury) [234], in addition to other monly identified on the same MRI.
Cerebellar Injury tiple remote tropic transneuronal interactions” [195]. For

example, unilateral PVHI may be associated not only with
In addition to the pervasive neuronal/axonal disturbances an expected loss of ipsilateral cerebral volume but also with
involving the cerebral cortex, thalamus, and basal ganglia of loss of contralateral cerebellar volume; similarly, unilateral
neonates secondary to PVL and GM-ICH, the cerebellum cerebellar hemorrhage is associated not only with decreased
has recently been identified as highly vulnerable to injury. ipsilateral cerebellar volume but also with decreased con-
“From 24 weeks to 40 weeks of gestation, the cerebellum tralateral cerebral volumes. Bilateral primary injury in the
undergoes a rate of growth nearly unparalleled elsewhere in cerebrum is associated with secondary bilateral injury in the
the brain” (Fig. 2.9). The surface area of the cerebellar cortex cerebellum and vice versa. Similarly, the development of the
increases more than 30-fold during this period [195]. Of par- pons is associated with cerebellar injury, perhaps secondary
ticular relevance to the preterm infant, cerebellar develop- to degeneration of pontocerebellar tracts [367]. Volpe sug-
ment accelerates between 20 and 30 weeks of gestation. gests, “an intact reverberating circuit between cerebrum and
As with other neurologic injuries in the neonate, the inci- cerebellum and vice versa may be especially critical for nor-
dence of insults to the cerebellum is inversely related to gesta- mal growth during this critical phase of development” [195].
tional age and can be attributed to two etiologies: destructive Recently, the development of the microstructure of the cer-
(hemorrhage/infarction) and impaired development. For ebellum is disturbed in preterm infants at term equivalent age
example, the incidence of hemorrhage varies with the type (<32 weeks’ gestation) compared with healthy term infants
and protocols for imaging, ranging from 9% to 19% (vari- [372], but the clinical correlate is unclear. Consistent with
ous ultrasound-based imaging with or without MRI) [363] other studies [373], some experts note that preterm birth
and, more recently, 37% (MRI) [254]. Similar to GM-IVH, more significantly reflects brain injury and comorbidities
cerebellar hemorrhage is usually unilateral, with 77% associ- rather than simply gestational age [273].
ated with supratentorial lesions (mostly white matter injury) In the setting of impaired cerebellar development, long-
[195]. In contrast, in a cohort of <33-week gestation infants, term outcome includes deficits in executive functions,
cerebellar hemorrhage was more common than WMI, not visual–spatial functions, and language [374]. Others have
directly associated with WMI, and more common in the most documented disturbances in expressive language and social-
immature infants [364]. Pathophysiologically, this injury ization [375]. The complex role of the cerebellum extends
remains incompletely defined. beyond motor function, as this area of the brain provides
Impaired cerebrovascular autoregulation predictably integral effects for cognitive and emotional development.
contributes to the pathogenesis. For example, in a group of Cerebellar injury is associated with significant neuromotor
ex-ELBW infants with cerebral palsy, 64% (32/50 patients) and intellectual deficits, as well as learning, language, and
had parenchymal cerebellar loss which coexisted with cystic social behavior deficits. That is, cerebellar injury can result
PVL and/or cerebral white matter loss [365] or IVH [366], in cognitive and affective disturbances, including socializa-
suggesting a common etiology (i.e., ischemia, infection/ tion difficulties and some positive autism findings [376].
inflammation) [367]. Of note, the germinal matrix is pres- Finally, a “cognitive–affective disorder” (executive, visual–
ent in the cerebellum in the roof of the fourth ventricle and spatial, linguistic, affective deficits) has been described in
has been referred to as a “secondary germinal matrix” [368]. older children and adults with cerebellar injury [377, 378].
Destructive lesions can be confined to the cerebellum, and Thus, abnormalities in cerebellar developmental may cause
infants can be asymptomatic until delayed development is cognitive, language, and socio-affective abnormalities in the
noted months to years after birth [369]. In those with severe ex-premature infant.
destructive injuries, the impact on function can be signifi-
cant, including spastic–ataxic–dyskinetic cerebral palsy,
severe cognitive deficits, microcephaly, and epilepsy [370]. Clinical Significance and Summary
In other cases, MRIs reveal cerebellar underdevelop-
ment (unilateral or bilateral symmetric deficits in cerebellar Many characteristics of the immature neurologic system pre-
volumes) without destructive lesions [371] but in associa- dispose the neonate to injury in the predictably labile intra-
tion with supratentorial lesions (i.e., PVL and/or GM-IVH). operative period. Disturbed autoregulation combined with
Injury to granular cells (e.g., secondary to injury from free vulnerable populations of cells in the setting of labile hemo-
iron after hemorrhage) [371] is significant not only because dynamic and respiratory status in the perinatal period with-
of decreasing this population of cells but also because of out a reliable system for monitoring cerebral perfusion
disturbing the excitatory input to other cells (e.g., Purkinje demands that neonatal anesthesiologists focus on defining
cells) that disrupts the development of the intricate cerebellar “normal” preoperatively for each infant and attempting to
circuitry [195]. The association of cerebellar underdevelop- maintain that status intraoperatively. Although easy to rec-
ment with supratentorial lesions suggests the role of “mul- ommend, avoiding wide fluctuations in blood pressure,
PaCO2, and PaO2 is almost impossible, especially in the Knowledge of the sequence of developmental events can
intraoperative setting when cardiorespiratory instability is inform estimates of the timing of congenital malformations
common. Hemorrhage often requires rapid infusions of crys- [380] that result from fetal–maternal factors (e.g., oligohy-
talloid and colloid, which can inflict neurologic injury in the dramnios), genetics, or developmental insults [381].
setting of disturbed autoregulation and fragile vasculature. Development of the lung includes a tightly regulated, com-
NIRS may eventually function as a trend monitor, but cur- plex, interactive process involving epithelium, mesenchyme,
rently, artifacts are notoriously common. and endothelium. Recently, investigators have increasingly
recognized that the differentiating alveolar epithelial cell
is regulated by the simultaneously differentiating capillary
The Pulmonary System endothelial. This has led to a newly identified process, “angi-
ocrine signaling,” that refers to an “endothelial, cell-driven
Moving from fetal to postnatal life requires an abrupt and active paracrine function of blood vessels on organ devel-
dramatic transition from complete dependency on the pla- opment and regeneration mediated by the organ- specific
centa for gas exchange to air-filled, perfused lungs within microvasculature.” That is, pulmonary endothelial–epithelial
seconds after birth. For preterm or asphyxiated infants or in interactions govern pulmonary development, and “regenera-
the setting of anomalies associated with cardiorespiratory tion is driven by growth factors derived from blood vessels
dysfunction (e.g., congenital diaphragmatic hernia, tracheo- that trigger epithelial differentiation.” Growth factors from
esophageal fistula, some types of congenital heart disease), blood vessels induce epithelial differentiation and, therefore,
the superimposed effects of surgery, inhalational anesthetics development and, at other times, regeneration [382].
and other medications, positive pressure ventilation, and Intense investigations into the molecular basis of devel-
infection add to the critical short-term challenge of achieving opment have ventured into the closely related topic of
postnatal physiologic stability without incurring long-term “regeneration.” The capacity and function of various pro-
morbidity. genitors in the postnatal lung, especially in the setting of
injury, are central to the concept of “outcome” after critical
events such as preterm birth. Understanding the complex
Embryology pathways during development is central to the question of
“whether the pathways that govern the differentiation of
Based on morphology, the development of the pulmonary these progenitors during development are reactivated upon
system includes five morphologically and biochemically injury.” Such data contribute to innovative targeting to treat
defined (but somewhat overlapping) stages (embryonic, pseu- preterm infants and those with congenital anomalies and
doglandular, canalicular, saccular, alveolar) [379] (Fig. 2.11). pulmonary dysfunction [383].
Fig. 2.11 Stages of normal

Fetal stage Lung structure
lung development with the
airway structure developing Trachea 24 days
within each stage (from
Extrapulmonary 28 days
Kotecha [381]) Embryonic
Main Bronchus
0-7 weeks
Bronchi 4-12 weeks
8-13 generations
P seudoglandular Bronchioli 12-16 weeks

7-17 weeks 3-10 generations
Terminal Bronchiolus 16-17 weeks

1 generation
Canalicular Respirtory bronchioli 18-25 weeks
17-27 weeks 1 generation
Acinus
Alveolar ducts 25 wk-1yr

Saccular/Alveolar
2-3 generations
28 weeks–term
Alveoli 30 wk-2-3yr
1 generation
pleura ie 1000/acinus
he Embryonic Stage (0–7 Weeks’

T stage of lung growth can alter bronchial growth patterns,
Gestational Age) producing lesions characterized by poor lung growth (pul-
monary hypoplasia), sequestration lesions, and congenital
At 3–4 weeks’ gestational age, the laryngotracheal grove pulmonary airway malformations (formerly, cystic adeno-
first appears as a ventral diverticulum from the primitive matoid malformation) [380].
foregut, lined by epithelial cells of endodermal origin [380]. During this critical period of lung growth, the muscu-
During the embryonic stage, the large airways first appear as lotendinous, dome-shaped diaphragm develops, which, in
epithelial cells from the foregut that eventually invade the addition to becoming the primary muscle of respiration,
mesenchyme to form the trachea. This structure then under- serves to separate the pleural and peritoneal cavities and
goes a series of branching events [384], requiring the interac- promote pulmonary growth [389]. At the end of the third
tion of epithelial and mesenchymal cells [385]. By the fifth week of gestation, the diaphragm consists of a collection of
week of gestation, the branching has advanced to the level of mesodermal tissue, the septum transversum, which separates
lobar and segmental bronchi [384], so that five pulmonary the pleural–pericardial cavity from the peritoneal cavity. Of
lobes have been formed. By the end of the embryonic stage, note, pleural–peritoneal canals allow limited but persistent
the 18 major lobules are easily recognized [386]. Although communication between these two cavities [389, 390]. The
the airway epithelium resembles that of the esophagus at this septum transversum migrates downward from the level of
stage, throughout development, differentiation, and matura- the occipital and upper cervical somites (C3) to the level of
tion, the primitive endodermal cells produce the population the thoracic somites by the sixth week of gestation and L1
of epithelial cells that characterize the adult lung [384]. by the eighth week [389]. During the descent, the neural tis-
During the embryonic stage, the pulmonary vasculature sue of C3–C5 origin penetrates the mesoderm and eventually
develops in parallel with the airways. At 4 weeks’ gestational develops into the phrenic nerve. At approximately this time,
age, endothelial cell precursors around the developing lung the right and left pleuroperitoneal membranes close the com-
bud eventually form endothelial tubes that continuously munication between pleural and peritoneal cavities [389]. As
coalesce to form the intrapulmonary arteries [387]. elucidated in murine models, muscle precursor cells migrate
Congenital malformations associated with events during the laterally to form the lip of the primitive diaphragm and then
embryonic stage involve the large airways and/or whole sec- radiate throughout the developing diaphragm accompanied
tions of the lungs and include pulmonary agenesis, ectopic by new branches of the phrenic nerve [390].
lobes, lobar cysts, agenesis, malformation, stenosis, or mala- Congenital diaphragmatic hernia (CDH) results from the
cia and vascular malformations [380]. failure of complete separation of the pleural and peritoneal
cavities. At 10–12 weeks’ gestation, before the bowel returns
to the abdominal cavity from the amnion (where it resides
seudoglandular Stage (7–17 Weeks’
P in early gestation), closure of the diaphragm is complete. If
Gestational Age) the separation of two body cavities is incomplete, the bowel
enters the chest, the path of least resistance. However, the
The most rapid branching of the airways occurs during the bowel then occupies space needed for lung growth. A pos-
pseudoglandular stage. As the epithelial cells divide, the sur- terolateral CDH (Bochdalek hernia) results from failure of
rounding mass of gland-like mesenchyme [381, 384] regu- closure of the pleural–peritoneal membranes, accounts for
lates the branching. The mesenchyme inhibits branching in 95% of diaphragmatic hernias (approximately 1/2,000–
the trachea but induces branching in the bronchi [388]. By 1/4,000 live births) [391, 392], is usually unilateral (78% on
14 weeks’ gestational age, 70% of the airways present at the left, 20% on the right, 2% bilateral) [391], and often is
birth have formed, and by 17 weeks, the conducting airways, associated with significant ipsilateral pulmonary hypoplasia
terminal bronchioles, and primitive acini are completely as well as abnormal development of the contralateral lung
established [381]. In parallel with the development of the air- [393]. In addition to abnormal lung development, other
ways during the pseudoglandular stage, the vascular struc- anomalies not directly related to the hernia often accompany
tures branch rapidly leading to the formation of the this lesion (e.g., congenital heart disease, central nervous
pulmonary arteries and veins, which, along with the airways, system anomalies) [391]. The etiology of CDH is not clear,
are derived from mesenchymal tissue [380, 387]. Further dif- but genetic associations have been noted (e.g., chromosomal
ferentiation of the pseudostratified epithelium of the airway aneuploidy) [394] (for a review, see [395]).
involves its progressive replacement with columnar cells Intrauterine exposure to teratogens affecting the retinoic
proximally and cuboidal cells distally. Between 11 and acid enzyme pathway induces CDH through malformation
16 weeks’ gestation, ciliated epithelium appears and airway of the primordial nonmuscular diaphragmatic tissue as early
mucus is first synthesized [384]. The cuboidal cells eventu- as the fifth to seventh weeks of gestation via a cascade of
ally mature into type II pneumocytes. Insults during this events that leads to failure of closure of the posterolateral
walls in later gestation [390, 396]. Of note, experiments in that store and release surfactant lipids and proteins [399]. At
transgenic mice caused hypoplastic lung development with- term, the total number of alveoli in the healthy infant is only
out causing CDH, prompting investigators to conclude that 20–50 million [386], increasing to adult numbers of more
CDH is a primary event [397, 398]. than 300 million per lung, by 2–3 years of age [400, 401].
Developmental abnormalities during the alveolar phase can
result in respiratory distress syndrome, chronic lung disease
Canalicular Stage (17–27 Weeks) (see below), and dysplasia of the acini or alveolar capillaries
[380]. Although rare, several genetic disorders can also
During the canalicular stage, the distal airways develop into adversely affect lung development, such as mutations in the
primary acini, consisting of respiratory bronchioles, alveolar surfactant protein system [386].
ducts, and rudimentary alveoli. The surrounding capillaries The molecular basis of the control of lung development
develop in parallel [386]. These represent the first units of is incompletely understood, but involves simultaneous,
gas exchange. interrelated, reciprocal molecular signaling pathways in the
Epithelial cells differentiate into types I and II pneumo- airway and the blood vessels, under the regulation of vari-
cytes, with type I cells incorporated into the first alveolar– ous transcription and growth factors [380, 382, 383] (e.g.,
capillary barrier. Surfactant can be detected at approximately vascular endothelial growth factor [VEGF] and fibroblast
24 weeks with active production beginning at 26–28 weeks. growth factors). The surrounding mesenchyme appears to
After 26 weeks’ gestation, respiratory saccules lie in close direct the developing epithelial cells, and the mesenchy-
contact with pulmonary capillaries, increasing the likelihood mal–epithelium interactions seem to be essential for normal
of adequate gas exchange essential for extrauterine viability. development [386]. Similarly, the interaction of differenti-
Before this developmental age, gas exchange may be com- ating alveolar epithelial cells with capillary endothelium
promised because of inadequate surface area and function of plays a critical role. A vascular plexus can be identified as
the lung parenchyma and/or vasculature [379]. For example, soon as the first lung buds arise from the foregut endoderm
survival after birth during the canalicular stage, in part, is [382]. During the alveolar phase, the formation of vascular
determined by surfactant deficiency (respiratory distress networks requires alveolarization but the reverse is also true.
syndrome) (see Respiratory Distress Syndrome, below). That is, inhibition of VEGF leads to lung hypoplasia [402].
Although delivery of exogenous surfactant can improve neo- Of note, hypoxia has been identified as the primary trigger
natal lung function, subsequent insults associated with sup- of this late-stage lung development (epithelial branching)
portive care of the preterm infant (e.g., supplemental oxygen, mainly via the VEGF (and other angiogenic factors) and
mechanical ventilation, infection) often result in pulmonary HIF-2α and HIF-1α (hypoxia-inducible factors) in stimulat-
hypoplasia or acinar dysplasia [380] and later bronchopul- ing angiogenesis [403, 404].
monary dysplasia. A variety of mechanical factors affect lung growth in
utero and postnatally [33, 380]. For example, in animal
models, inadequate fetal lung fluid secondary to a defi-
Saccular Phase (28–36 Weeks’ Gestation) ciency of amniotic fluid can induce pulmonary hypoplasia
[405, 406]. In humans, pulmonary hypoplasia is prominent
An increase in the surface area of gas exchange is the major in the oligohydramnios sequence (“Potter’s syndrome”)
feature of the saccular phase of lung growth [380]. The associated with low urine output secondary to renal dysgen-
peripheral areas of the lung enlarge, as the acini dilate and esis [407]. Similarly, oligohydramnios secondary to chronic
the acinar walls thin. Gas exchange is further facilitated as leakage of amniotic fluid can interfere with lung develop-
type II pneumocytes increasingly differentiate into type I ment [408]. Finally, the role of maintaining adequate lung
cells and capillaries develop in close approximation [386]. volume with fluid in promoting lung growth and develop-
ment during the canalicular and saccular stages is the basis
of various fetal therapeutic interventions (e.g., in utero tra-
lveolar Phase (36 Weeks’ Gestation Until
A cheal occlusion) intended to induce lung growth in the pres-
~2–3 Years) ence of CDH [380, 409].
Detectable by 10 weeks’ gestation, fetal breathing may
During the alveolar phase, the surface area for gas exchange contribute to maintaining sufficient lung volume and, there-
increases as alveoli septate and increase in number, a process fore, growth of the lung, possibly by activating stretch-
that continues through the third year of life [381, 387]. Type mediated release of growth factors [380]. That is, “the
II pneumocytes proliferate and become prominent after primary function of fetal breathing is to provide intermittent
34–36 weeks of gestation. The key feature of type II pneu- stretch for structural development of the lung” [410]. When
mocytes is eosinophilic lamellar bodies, specialized vesicles fetal breathing is ablated in animals, lung growth decreases
[411, 412]. Decreased fetal breathing movements may [33, 425, 432]. Defining the pathophysiology of postnatal
underlie the pulmonary hypoplasia associated with some lung growth, especially after in utero and/or neonatal injury
neurologic disorders, abdominal wall defects, and in utero remains an “evolving database.” Over the last 10–20 years,
exposure to certain substances (e.g., chronic exposure to the definition of BPD and long-term outcomes associated
diazepam and, possibly, maternal smoking) [413]. Although with prematurity have changed [433–435]. Nonetheless,
lesions occupying the intrathoracic space (e.g., CDH, con- with no dramatic decrease in the incidence of bronchopul-
genital airway malformations) and skeletal defects involv- monary dysplasia as the survival of those at the edge of via-
ing the thorax can impede lung development secondary to bility increases, morbidity among ELBW infants, especially
obvious mechanical effects, these anomalies may also impair those less than 25 weeks’ gestation, remains significant [419,
fetal breathing, which may exacerbate the primary effect of 435–439]. Of note, the reactive airways associated with pre-
the space-occupying lesion [413]. maturity differs from that associated with “asthma” [440].
Oxidative stress has also been implicated in disorders of
lung growth (see Oxygen Therapy, below). Other physio-
Postnatal Development of the Lung logic events associated with prematurity, such as patent duc-
tus arteriosus and immune dysfunction, are also associated
Postnatal development of the lung focuses on completing the with growth disorders [381]. Probably of more importance,
alveolar stage [414] to achieve maturation of both the airway postnatal nutrition (e.g., breastfeeding) and a wide variety
and microvascular. Of importance, alveolar–capillary micro- of environmental toxins (e.g., smoke, air pollutants, alco-
architecture transforms from double to single capillary net- hol, vitamins) contribute to the overall prognosis for normal
works [415], and the adult number of alveoli (300–600 million) growth and development [33, 441]. Of interest, in preterm
is established. Although the most dramatic structural processes infants, rapid weight gain in early infancy has been associ-
take place in utero and during the first 1–3 years of postnatal ated with an increased risk for asthma [442].
life, recent studies suggest that the bronchioles and alveoli Because of the recurring theme of “inflammation” as
continue to grow in size, number, and complexity beyond ado- a fundamental mechanism for the increasing risk of BPD,
lescence into young adulthood [416–418]. Of importance, pat- therapy with corticosteroids has had a chaotic history in the
terns of postnatal lung development seem to be linked to in context of the ELBW infant. The role of early (<8 days) [443]
utero and neonatal events. For example, although maximal and late (>7 days) [444] treatment including different sys-
lung volume is generally achieved by 22 years (30-fold temic drugs and various modes of delivery has been repeat-
increase in lung volume and 20-fold in gas-exchanging sur- edly tested, but a clear consensus remains elusive [445]. The
face area compared to values at term birth), infants with abnor- conflict is that, although anti-inflammatory, these agents also
mal function secondary to in utero events, prematurity, or disturb development both in the lung [36, 380] and the brain
neonatal insults may never achieve this “normal” peak. Also, [446], but the disturbances vary with the agent and timing
this same group may have a more rapid decline than what nor- of postnatal treatment. For example, early systemic dexa-
mally occurs during the third decade [419, 420]. That is, lung methasone was associated with abnormal neurodevelopment
function seems to follow a similar centile over time, tracking but early low-dose hydrocortisone was not [443]. That is,
from newborn to adulthood [33, 420–423]. Recent studies hydrocortisone decreased mortality and reduced rates of pat-
noted that the pattern of wheezing and lung function do not ent ductus arteriosus and death/bronchopulmonary dysplasia
change noticeably in children who develop “asthma-like” without long-term complications. In contrast, the trials ini-
symptoms by 3–6 years of life [420]. Thus, prematurity and/or tiating late treatment were associated with a benefit-to-risk
other insults (e.g., infection, anomalies) can severely impact ratio that did not support intervention. Instead, the authors
the growth of both alveoli and vasculature with lifelong conse- recommend reserving this for the clinical scenario of infants
quences [33, 36, 381, 419, 424–426]. who fail to wean from mechanical ventilatory support but to
Although in utero infection (e.g., chorioamnionitis) and minimize the dose and duration of treatment [444]. Similarly,
markers of lung inflammation have been associated with other investigators suggest tailoring treatment by following a
an increased incidence of lung injury characterized by poor model that predicts risk for BPD [431]. Consistent with these
development [427, 428], the data to establish a direct link data, the American Academy of Pediatrics recommends that
between preterm birth and/or injury remain controversial [33, “early hydrocortisone treatment may be beneficial in a
429, 430]. Similarly, exposure to oxygen seems to increase specific population of patients; however, there is insuffi-
the risk for BPD [425], but as an independent factor, its role cient evidence to recommend its use for all infants at risk
is small compared with the impact of gestational age [431]. of BPD… existing data are insufficient to make a recom-
On the other hand, although a lifesaving therapy, mechani- mendation regarding treatment with high-dose hydro-
cal ventilation appears to impair normal lung development, cortisone” [447]. The academy reaffirmed this statement in
resulting in abnormal vascularization and alveolarization 2014.
Recent reports [448, 449] and reviews [450–452] of the broader group of preterm infants. Similarly, some suggest
effectiveness in decreasing BPD after inhaled steroids have that screening should be conducted both early and later in
revived interest in these agents in establishing an effective the course of the ICN stay since the timeline for develop-
but low-risk intervention to prevent BPD (see Respiratory ing seems to extend beyond the early postnatal period [461].
Distress Syndrome). Although not endorsed for routine ther- Despite the substantial morbidity, the natural history of
apy, intra-airway delivery may offer benefits while avoiding infants with BPD associated with pulmonary hypertension
the significant negative side effects on growth associated often is resolved within the first year of life. However, the
with other modes of administration, but these data are not prognosis for those with persistent pulmonary hypertension
yet established [445]. is not favorable [462].
Maternal smoking has been linked to long-standing respi- Although research in neonatal clinical care must focus on
ratory disorders during infancy, beginning with its associa- preventing prematurity and lung injury, until that is achieved,
tion with intrauterine growth restriction/low birth weight. the short-term goal remains to minimize the long-term mor-
These respiratory problems may improve in later childhood, bidity of prematurity and its associated lung injury exacer-
but also are likely to persist into adulthood, becoming appar- bated by critical therapies, such as mechanical ventilation
ent as normal aging decreases lung function [453–455]. Both and supplemental oxygen [383, 419, 466–469]. Also critical
prenatal and postnatal secondhand exposures to smoke are is a clearer understanding of the impact of “developmental
linked to structural changes in the developing lung, with origins of adult disease” to allow intervening in early postna-
altered airway geometry and size (smaller lung with fewer, tal development before irreversible injury. With data support-
larger alveoli and low capillary density) [456], increased ing a link between neonatal and later pulmonary function,
wheezing [457] with respiratory infections, as well as vari- systems to streamline the transition from pediatric to adult
able decreases in forced expiratory flows, possible increases care remain underdeveloped but deserve scrutiny, since the
in airway responsiveness and bronchospasm, and increased innate function as well as effects secondary to injury inflicts
airway resistance (see [453] for a review). This correlation lifelong functional deficits [420, 421, 423, 440, 470, 471].
of an impaired capacity for gas exchange predicting reduced
exercise tolerance in later life and a more rapid rate of decline
in pulmonary function is consistent with the “developmental Airway Anatomy
origins of adult disease” [441, 458]. At least in part, the sus-
ceptibility to the effects of smoking may be related to various Neonatal airway anatomy differs from that of the adult with
genetic variants (CYP1A1, GSTT1) [33]. significant implications for the anesthesiologist (see Chap.
Similar to the close relationship of the parenchyma and 5). With a relatively large head and prominent occiput, both
blood vessel during normal development, the pulmonary flexion and hyperextension of the neck may obstruct the
vasculature is co-injured postnatally secondary to prema- small, compliant airway (i.e., easily compressible) [472].
turity and its associated treatment (i.e., oxygen, ventilatory Moreover, this anatomy implies that the infant maintains a
support). Preterm infants with BPD have increased pulmo- natural “sniffing position.” This eliminates the need to place
nary arterial and venous smooth muscle, and infants born a support under the occiput to facilitate tracheal intubation.
before 27 weeks’ gestation age often develop hypoplasia and Finally, the tongue of the neonate is large relative to the size
dysplasia of the alveolar capillaries [387]. Although in retro- of the mouth, which may predispose to obstruction of the
spective studies the incidence of pulmonary hypertension in upper airway during mask ventilation and difficulty in
infants with BPD ranged from 14% to 38%, a recent meta- retracting it during laryngoscopy and tracheal intubation.
analysis documented an incidence of 20–25% among ELBW Infants have traditionally been described as “obligate
infants. Pulmonary hypertension seems to track the severity nasal breathers” because of difficulty maintaining adequate
of BPD [459]. The pathophysiology of these co-dependent ventilation when the nasal passageways are obstructed sec-
disorders seems to center on the effects of an incompletely ondary to congenital anomalies (e.g., bilateral choanal atre-
defined inflammatory insult [460, 461]. The correlation of sia), with inflammation or infection of the airways, which
BPD with pulmonary hypertension is not surprising; the produce mucosal edema or secretions, and after certain ther-
associated high morbidity and mortality have been docu- apeutic maneuvers (e.g., placement of an NG tube). Of note,
mented [462]. the nasal airway may account for as much as 50% of total
Recent guidelines recommend routine screening of airway resistance. An alternative descriptor, “preferential
patients with BPD for pulmonary hypertension with echocar- nasal breathers,” has been proposed, since many neonates
diogram [463, 464], but the diagnostic criteria and treatment with obstructed nasal passages can transition to oral breath-
regimens remain incompletely defined but recently updated ing, a process involving activation of the levator veli palatini
[465]. Of note, some infants develop pulmonary hyperten- and musculus uvulae [473]. Nonetheless, in the setting of
sion without BPD, so that screening may be indicated for a nasal airway obstruction, oxygen desaturation may occur,
and—even after a successful transition to mouth breathing— predisposes the neonate to upper airway obstruction. With
respiratory failure due to fatigue may follow [474]. Of note, less cartilage, smooth muscle, and contractile elements, the
obstruction of the nose can exaggerate resistance to airflow trachea is more compliant but with greater resistance to flow
and interfere with sucking–swallowing responses that may [480]. Because of a lack of development of the fascia that
increase the risk for aspiration [475]. Airflow via the nose stabilizes the neck and immaturity of control of the upper
also offers a kind of “trophic” flow of sensory input so that airway muscles that stabilize the pharynx, the upper airway
interfering with this stimulation may impact olfactory devel- of the preterm infant is especially prone to collapse [481].
opment. The local effects in the development of structure and If the same volume of gas that passes through the narrow
function of the upper airway may accompany nasal obstruc- upper airway per unit time flows through the millions of alve-
tion [475]. oli in the distal lungs at the same time, then the gas flow in the
At all ages, the activities of the closely aligned structures upper airway must be very rapid or turbulent. In contrast, the
of the upper airway (the tongue, pharynx, epiglottis) must slower flow of gas farther down the airways, from the fifth
integrate to allow coordinated eating/swallowing and breath- bronchial division to the alveoli, where the cross-sectional
ing. The neonate faces unique challenges in coordinating area has increased, becomes laminar. The airway resistance
these activities because sucking, swallowing, and breath- to flow, R, in the upper airways (where flow is turbulent) is
ing occur simultaneously so often. For example, the more inversely proportional to r5. In contrast, the R in the lower
cephalad location of the larynx forces the epiglottis adjacent airways where flow is laminar is described by Poiseuille’s
to the soft palate facilitating nasal breathing during sucking. law: R ∝ (ηL)/r4, where η is the viscosity, L is the length, and
Over the first year, the infant converts to primarily oral from r is the radius of the airway. Although R is proportional to
primarily nasal breathing, as the oral cavity enlarges and the the length of the airway, it is exquisitely sensitive to changes
larynx descends, as the neck elongates with growth. in the radius of the airway, such that a small decrease in the
The larynx of the neonate differs from that of children radius markedly increases R to airflow. Notably, in the cri-
and adults. Based on observations of castings of cadaveric coid ring region of the upper airway, decreasing the radius
airways, the shape of the newborn larynx has been tradition- of the airway by half (e.g., airway edema with infection or
ally referred to as “funnel-shaped,” becoming more cylindri- trauma) increases the baseline airway resistance to the fifth
cal (i.e., adultlike) with growth. However, reports of in vivo power or 3600% (increasing work of breathing dramatically,
imaging have noted that the neonatal larynx is cylindrical, which can result in fatigue and respiratory failure in the pre-
similar to those of adults [476–478]. Also similar to adults, term infant).
the glottic opening (true vocal cords) in sedated infants The lower airways are compliant and can readily collapse,
appears to be the narrowest part of the juvenile upper airway, increasing airway resistance, decreasing peak airflows, and
but the cricoid remains functionally the narrowest part of the increasing work of breathing. Wheezing may be audible but
airway. The confusion may be attributed to the failure to gate may or may not be associated with actual bronchospasm. Not
the MRI to the respiratory phase when the glottis was filmed. surprising, since wheezing in the neonate is associated with
While the circumferentially rigid ring of the cricoid cartilage many causes other than bronchospasm, response to broncho-
is unyielding, the vocal cords can be opened gently, from the dilators is unpredictable [482].
at-rest position, to accommodate rigid structures, like a tra-
cheal tube [476]. In the neonate, the anterior larynx is more
caudal than the posterior larynx, resulting in an elliptical natomy of Chest Wall and Mechanics
A
shape to the inlet – narrower in the transverse plane than in of Breathing
the anterior–posterior dimension [477, 478]. Forcing a tight-
fitting, circular tracheal tube through the subglottis can cause The chest wall, which consists of the rib cage, abdomen
excessive pressure to the mucosa in the anterior–posterior (despite the term “chest wall”), and associated musculature,
axis, resulting in mucosal ischemia, subglottic edema, short- functions both as the respiratory pump and framework for
or long-term stridor, and airway scarring or stenosis [476]. the respiratory system. When compared with older children
Other characteristics of the neonatal airway must be and adults, the respiratory pump is less efficient in the neo-
considered during tracheal intubation [479]. The neonate’s nate due to anatomic, mechanical, and histologic factors
neck is relatively short and the larynx located more cepha- [483]. The geometry of the pliable rib cage is more horizon-
lad (C3–C4) (of note, the larynx is more superior, not more tal compared with the angulated structure in the adult, poten-
“anterior”) compared with that in the adult (C4–C6). The tially limiting the outward and cephalad expansion of the
narrow epiglottis may be omega- or U-shaped and difficult thoracic cavity during inspiration [484] (Fig. 2.12). Finally,
to elevate directly with a laryngoscope blade. The relatively unlike the dome shape of the adult, the diaphragm of the neo-
large tongue, soft submandibular structures that are prone nate is flattened and inserts into the chest wall at an angle
to compression by a ventilator’s fingers or cricoid pressure, that results in a lower range of displacement.
Ribs pally the diaphragm, can be characterized in terms of pre-

Sternum
load, afterload, and intrinsic properties of the fibers. The
susceptibility of the neonatal diaphragm and intercostal mus-
Spine cles to respiratory fatigue often is logically attributed to the
Abdomen
relative paucity of type I cells [493]. That is, type I muscle
cells are characterized by slow cycling, aerobic metabolism,
Thoracic cross section
and resistance to fatigue and seem well suited for respiratory
cycling. The preterm infant diaphragm may have less than
10% type I cells; by term, the proportion increases to ~25–
Spine 30%, and through late infancy, the population of type I cells
increases to the adult proportion of ~55% [493]. However,
Rib directly correlating these data to “fatigue” is controversial.
Although the total cross-sectional area of all fiber types is
Sternum
small, some suggest that fatigue resistance is greater in the
neonate compared with older infants [494]. That is, when
other aspects of structure (e.g., myosin heavy-chain isoform
Fig. 2.12 Observed changes in configuration and cross-sectional
shape of the thorax from infancy to early childhood. Upper panel: [MHC] expression, MHC protein content) and specific func-
infantile and adult rib cage configurations. Lower panel: how rib growth tion (e.g., maximum specific force, twitch contraction times)
at costochondral junctions and posterior rib angles could explain the were considered, the neonatal diaphragm was regarded to be
observed changes in the cross-sectional shape of the thorax (from
more resistant to fatigue [495].
Openshaw et al. [484])
Developmental expression of distinct myosin heavy-chain
isoforms with less energy demands may protect the neona-
Resting lung volume (VR) results from the net effects tal diaphragm from fatigue by decreasing energy demands
of the outward elastic properties of the chest wall and the [495, 496]. In a study of the diaphragm of the lamb over an
inward elastic properties of the lungs. With the inward elas- extended developmental period (mid-gestation to 2 months
tance of the lungs being much greater than the outward elas- postnatal), the susceptibility to fatigue decreased in late fetal
tance of the chest wall in neonates, the compliance of the life but reached its apex at approximately 1 week after full-
cartilaginous chest wall (CCW) is much greater than that of term delivery, a finding that may be due to this experimental
the less pliable lungs (CL). Therefore, the properties of the model of fatigue, in which maximal isometric contractions
less-compliant lungs primarily determine the overall com- were induced in diaphragm isolates—contractions that are
pliance of the neonatal respiratory system (CRS) [485]. The more forceful at term, such that the term diaphragm muscles
CCW/CL ratio summarizes these relationships. The large were performing more work before becoming fatigued [497].
CCW/CL ratio of the neonate signifies the dominance of In the last two weeks before term, as fetal breathing became
inward forces [486–488] and, therefore, predicts small rest- more regular and episodic, the specific force increased two-
ing lung volumes [488]. fold. The improved maximum specific force correlated with
Further, the compliant chest wall deforms inward dur- the increase in MHC content. Similar to earlier studies, the
ing spontaneous inspiration, creating inefficient chest wall increase in MHC 1 content correlated with an increase in
motion, significantly decreasing the mechanical efficiency oxidative capacity. Alternately, the in vitro changes in resis-
of inspiration. Thus, distortion of the chest wall wastes tance to fatigue must be considered along with the intrinsic
energy [485, 489, 490]. As the chest wall matures and stiff- properties of the developing diaphragm, including decreased
ens (contemporaneously with the onset of the demands of diaphragmatic thickness and less effective force–frequency,
upright posture), CCW decreases to approximately CL [485], length–tension, and force–velocity functions [498] that may
perhaps mediated through mineralization of the rib cage and/ increase the risk of respiratory failure [495].
or increased chest wall muscle tone, as suggested by studies The concept of susceptibility to diaphragmatic fatigue
in lambs [487, 491]. is complex, and in addition to the developmental effects on
The respiratory muscles change in conformation, molecu- maturation, this muscle may be affected by the physiologic
lar biology, and function during development. During gesta- environment, including hormonal influence (e.g., cortisol,
tion, trained by fetal breathing, the respiratory muscles can thyroid) and oxidative state (e.g., nutritional status, sepsis,
power respiration at the time of term birth, although with a acidosis). The respiratory pump may fail to produce suffi-
limited reserve [492]. The respiratory pump in the neonate cient work to maintain homeostasis, secondary to the intrinsic
does not tolerate a large respiratory load compared with the properties of the muscles of respiration or from unfavorable
adult, and thus, it is predisposed to failure [483, 484]. As alterations in preload or afterload [499]. Conditions that
with other muscle systems, the respiratory muscles, princi- affect intrinsic muscle function include metabolic derange-
ments (e.g., electrolyte disturbances), hypoxemia, shock inward recoil of the lung and outward elasticity of the chest
[499], and maturation [500]. Hyper-expansion of the lungs wall. In neonates, the transpulmonary (intrapleural) pressure
due to air trapping alters preload. Inherent inefficient chest at rest is 0 cmH2O, compared with −5 cmH2O in adults
wall mechanics (see above), increased upper airway resis- [504]. With a compliant chest wall, lung volumes at end
tance (due to airway size and propensity to collapse), and expiration during tidal breathing in the neonate approach
changes in lung compliance due to respiratory distress syn- FRC, creating a significant risk of small airway collapse
drome, pulmonary edema, and other lung disease increase [505], atelectasis, ventilation–perfusion mismatch, and
afterload (i.e., work of breathing). The central and periph- hypoxemia. To compensate and to preserve FRC dynami-
eral nervous system components that control the respiratory cally, neonates adopt several strategies: shortening exhala-
pump can also contribute to respiratory failure (see Control tion via rapid respiratory rates [506, 507], “laryngeal
of Respiration, below). Respiratory failure in the neonate can braking” (auto-PEEP mediated by the dynamic partial clo-
present with respiratory distress (e.g., tachypnea, retractions, sure of the glottis) [492, 506], the tonic activity of intercostal
use of accessory muscles), hypercapnia/respiratory acidosis, muscles to stabilize the chest wall [492], and, when lung vol-
hypoxemia, and/or apnea. In addition to appropriate inter- umes are reduced, grunting [508].
ventions (e.g., supplemental oxygen, mechanical ventila- Depending on these dynamic alterations of exhalation
tory support including continuous positive airway pressure, to expand the end-expiratory volume above FRC in the set-
nutrition), methylxanthines, such as caffeine (see Apnea ting of limited respiratory reserve, the neonate is at risk for
of Prematurity), are sometimes introduced to improve dia- ventilatory failure from conditions that increase respiratory
phragmatic function [501, 502]. work or impair neural control of respiration, including gen-
Consistent with the concept that infants with respira- eral anesthesia (with or without neuromuscular blockade),
tory distress, especially preterm neonates, encounter a large rapid eye movement (REM) sleep [483, 509, 510], systemic
“respiratory load” that is reflected in impaired muscle relax- infection, and shock. In addition to its effects on intercostal
ation, experts have reported an index to clinically measure muscle function that contribute to paradoxical, inefficient
impairment of the respiratory muscles. That is, the time respiratory movement, central nervous depression relaxes the
constant of respiratory muscle relaxation τ (tau) correlates muscles of the upper airway increasing airway resistance and
with the risk for respiratory failure associated with muscular respiratory work. Decreased FRC and the ensuing atelecta-
dysfunction [503]. For example, both maturity (gestational sis inflict further demands on the diaphragm, as the reduced
age) and infection directly affect τ. Similarly, these inves- lung compliance increases the work of breathing, and energy
tigators applied this measurement to preterm infants whose is required to re-recruit alveoli [488]. By decreasing lung
airways were intubated during a trial of spontaneous breath- compliance, increasing airway resistance (e.g., from airway
ing (SBT) to predict outcome after extubation. Infants with edema), and/or decreasing diaphragmatic function, acute
slower relaxation (larger τ) and larger τ at the end of the SBT lung disease exacerbates the effects of anesthesia, sleep, and
compared with the value at the start [503] predictably failed common disorders (e.g., infection) and anomalies (e.g., pul-
extubation. On the other hand, infants who were successfully monary hypoplasia). Continuous airway distending pressure
extubated had a reduced baseline τ that decreased during the (e.g., CPAP) [511] will maintain FRC and mechanical effi-
SBT. The authors emphasize that predicting the infants who ciency during anesthesia and sleep in the setting of lung or
would be extubated successfully can be easily calculated other diseases, including prematurity. Positive pressure ven-
using the systems routinely available on mechanical ventila- tilation can maintain and restore FRC, especially with PEEP
tors. Similarly, this index has been applied to define opti- (see Chap. 6, Neonatal Ventilation). A technique rarely used
mal CPAP in neonates with intubated airways [500]. But, today is the application of external negative extrathoracic
even if this index were adopted as another routine criteria for pressure (−14 to −18 cmH2O), which increases FRC in pre-
extubation or to guide ventilatory management, these studies term neonates [512].
imply that, in addition to the other factors, impaired muscle In the fetus, a closed larynx traps liquid in the lung and
relaxation may also predispose the neonate to respiratory this applies pressure to expand the lungs, a stimulus for
failure. growth and development [513]. However, this scenario is
irrelevant after birth. The complicated process of transition-
ing from fetal to extrauterine gas exchange demands a highly
Functional Residual Capacity regulated sequence of liquid clearance and establishing the
FRC. Although the volume of lung fluid immediately before
The quantity of gas remaining in the lungs in passive (i.e., birth approximates FRC, the amount of liquid in the lungs at
with no activity of respiratory muscles) conditions is termed birth varies, in part, depending on timing and mode of deliv-
the functional residual capacity (FRC). The magnitude of the ery (e.g., vaginal vs. cesarean section) [514]. Combining a
FRC results from the net effect of the competing forces of compliant chest wall, high compression forces during late-
stage labor, and increased abdominal pressure (flexion of the note, especially in the preterm infant, a closed larynx may
trunk with vertex presentation), high intrathoracic pressure contribute to the failure of PPV [521].
during vaginal birth contributes to clearance of airway fluids. Recently, CPAP rather than PPV has been recommended
However, this process is more complicated than the so-called as the optimal ventilatory support for the neonate, reflecting
vaginal squeeze [514, 515]. Documented with time-lapsed the hypothesis that stimulating and sustaining spontaneous
phase-contrast X-ray imaging during birth (rabbits), liq- ventilation avoids the injury to both lungs and brain, espe-
uid moves into surrounding interstitium during inspiration, cially in the preterm infant. For example, PPV has been asso-
increasing the FRC with each breath in an amount equal ciated with initiating an inflammatory cascade, a common
to the volume of liquid exiting [514]. That is, hydrostatic pathway for multiorgan injury [522]. Specifically, both the
pressure drives the clearance of liquid and simultaneously overall rate of intraventricular hemorrhage (IVH) and rate of
establishing the FRC [516]. By lung ultrasound in healthy severe IVH (27%) was greater (51%) in those ELBW infants
neonates, aeration of the lung and at least partial clearance treated with a large tidal volume (>6 mL/kg) compared with
of liquid was documented during the first minutes after birth the rates (13%, 6%) in those who received <6 mL/kg [523].
with complete liquid clearance typically achieved within the However, guidelines for the ideal strategy in the delivery
first 4 h after birth ([517]. Postnatally, the transepithelial room (e.g., optimal pressure), delivery devices, and monitor-
pressure associated with inspiration continues to clear liquid ing systems (e.g., end-tidal CO2 as evidence of the degree
and maintain FRC. However, various expiratory maneuvers of aeration) continue to evolve [519]. Finally, although
(braking maneuvers, grunting, crying) contribute by restrict- some experts [514] recommend prolonged inspiratory times
ing the loss of gas volume between breaths. Furthermore, (sustained inspiration) to help clear fluid from the lungs in
after the FRC has been established, epithelial sodium chan- neonates and to avoid mechanical ventilation, the effective-
nels function to prevent liquid from reentering the airway ness of this intervention has not been definitively established
during expiration [518]. Finally, by effects on surface tension [524, 525]. Furthermore, the duration of and the pressure
at air/liquid interfaces, surfactant plays a role in establishing for this maneuver have not been defined. After aerating the
FRC (see Surfactant). lungs, subsequent strategies should focus on gas exchange
Of relevance and critical to supportive care during resus- rather than the clearance of lung fluid.
citation, FRC increased in a steplike pattern but only during
inspiration [519, 520]. As a result, standards for resuscitation
have been modified to emphasize the initial critical role of Pulmonary Function Testing
clearing liquid from the lung by applying inspiratory pres-
sure [100, 520]. However, especially in the preterm infant, Some techniques for pulmonary function testing (PFT) in
positive pressure ventilation (PPV) via a mask is challenging adults have been adapted to neonates and young infants.
and often ineffective secondary to low tidal volumes (poor Equipment to measure PFTs in neonates must address the
mask fit, airway obstruction, poor pulmonary compliance, smaller tidal volumes and dead space without sacrificing pre-
nonsynchronous with spontaneous effort) or, at other times, cision or increasing resistance to airflow. Additional chal-
injurious because of large tidal volumes produced with high lenges include the need to sedate the infants and a paucity of
pressure (may be more relevant via a tracheal tube) [519]. Of normal reference data as a function of age (Table 2.1) and for
Table 2.1 Typical values of lung function in healthy individuals (from [528])
Parameter Preterm infant Neonate 1 year 7 years Adult
Body weight (kg) 1 3 10 25 70
Crown–heel length (cm) 35 50 75 120 175
Respiratory rate (min−1) 60 45 30 20 15
Tidal volume (mL) 7 21 70 180 500
Anatomic dead space (mL) 3 6 20 50 150
Maximal flow at FRC (mL s−1) 80 150 300 – –
FRC (mL) 25 85 250 750 2100
Lung compliance (mL kPa−1) 15 50 150 500 2100
Airway resistance (kPa L−1 s) 8 4 1.5 0.4 0.2
Specific compliance (kPa–1) 0.6 0.6 0.6 0.7 0.8
Specific conductance (s–1 kPa–1) 5 2.9 2.7 2.7 2.3
Divide compliance and specific compliance by 10 to obtain values in cmH2O, multiply resistance by 10 to obtain values as cmH2O L−1 s; divide
specific conductance by 10 to obtain values in s−1 cmH2O−1
various disease states. The techniques adapted to neonates ing) than does the adult. This phenomenon is exaggerated in
and young infants include whole-body plethysmography, gas the setting of lung disease [541, 542].
dilution, and occlusion techniques, esophageal manometry, In the neonate, large alveolar ventilation and constant
weighted spirometry, and interrupter techniques (for reviews, FRC compared with adults lead to a smaller FRC “buffer”
see [526–529]). During studies of pulmonary function, tubes, [543]. However, changes in inspiratory gas composition
such as nasogastric tubes, should be placed in the smaller (e.g., oxygen, anesthetic gases) will be reflected in changes
nostril to permit maximum flow via the larger passageway in the alveolar and plasma gas concentrations more rapidly.
[530].
Static volumes and capacities (e.g., FRC and tidal volume
[Vt]) are generally similar to adult values when normalized Pulmonary Surfactant
for body mass. Anatomic dead space as a proportion of tidal
volume is similar in the neonate and adult (i.e., about 25% of Endogenous pulmonary surface-active agent, or “pulmonary
Vt). Although the additional dead space introduced by air- surfactant,” provides multidimensional functions in main-
way devices (e.g., LMA) may be negligible in the adult, this taining lung volumes and modulating innate host defenses.
effect is more significant in the neonate, given their smaller This foamy, bubble-producing substance is a complex aggre-
anatomic dead space. Closing capacity in the infant (~35 gation of macromolecules that reduces alveolar surface ten-
mL/kg) can exceed FRC (~30 mL/kg), leading to airway closure. sion, decreases the tendency of alveolar units to become
Alveolar surface area (VA) is 2.8 m2 at birth, increasing atelectatic, and increases pulmonary compliance [544, 545].
to 75 m2 in adults. This increase is related linearly to the Surfactant is an emulsion of lipids (~90%), proteins (~10%),
body surface area [531]. However, since the metabolic rate and carbohydrates [546]. Although most lipids are phospho-
and consumption of oxygen (VO2) per body mass is greater lipids (PLs) including the phosphatidylcholines (PCs) such
in the infant compared with the adult, the ratio of VA to as dipalmitoylphosphatidylcholine (DPPC), which com-
VO2 is reduced, increasing the infant’s risk for impaired gas prises 40–45% (by mass) of mammalian surfactant [547],
exchange, especially in the setting of underlying disorders surfactant also includes other phospholipids as well as unsat-
that limit VA, such as pulmonary hypoplasia. Ventilation– urated phosphatidylcholine, phosphatidylglycerol, choles-
perfusion (V–Q) mismatch (i.e., alveolar collapse leading terol, and other neutral lipids [548]. A heterogeneous mixture
to intrapulmonary shunting) commonly causes hypoxia of lipids is necessary to convey the necessary properties of
and shunting that can be quantified by noting the difference rapid spreading over the alveolar (water phase) surface and
between alveolar and arterial oxygen tension (which can also resistance to compression [549]. A generation of synthetic
reflect diffusion failure). surfactants have been developed and these agents may even-
V–Q mismatching is exaggerated in infants with lung tually replace the animal-derived preparations [550].
disease [532]. Alveolar ventilation (V-dot A) in neonates Type II pneumocytes serve several critical functions in
(~136–168 mL/kg/min) is approximately 2–3 times that of alveoli. For example, these cells serve as the progenitors
adults (~60 mL/kg/min) [533–535] reflecting the greater of type I pneumocytes (the major population of the alveo-
metabolic demand for oxygen (VO2) (6–10 mL/kg/min vs. lar epithelium) that repair the epithelium after injury. Type
~3.5 mL/kg/min for the resting adult) and greater production II pneumocytes also produce the lipid and proteins [399,
of CO2. Increased oxygen demand coupled with atelectasis 551] needed to produce surfactant that is stored within
and intrapulmonary shunting explains the rapid development characteristic organelles termed lamellar bodies. Surfactant
of hypoxemia with apnea (within ~30 s) [536], a finding with is then released as tubular myelin by merocrine secretion,
significant implications during induction of anesthesia (e.g., in response to stimulation such as β-agonists or stretch of
rapid sequence induction in the presence of a “full stomach”). the lung, eventually forming a monolayer over the alveolar
Minute ventilation increases with either a greater Vt or surface, reducing surface tension at the alveolar air–water
respiratory frequency (ƒ) or both. For a given alveolar ven- interface [547]. Thus, the various configurations of surfac-
tilation, the optimal ƒ and Vt minimizes the expenditure of tant exist (i.e., tubular myelin, droplets, and the monolayer
energy [537, 538]. Although Vt per body mass in the neonate film) each supporting specific functions including spread-
approximates that of adults, the normal respiratory rate is ing throughout the alveoli, forming a monolayer, acting as
greater in the neonate (30–60 breaths/min) compared with reserve surfactant when the monolayer is disrupted (e.g.,
the adult (18–22 breaths/min). That is, the work of breath- by oxidation), resisting compression during exhalation, and
ing to achieve adequate minute ventilation in the healthy rapid reabsorption [552]. The local environment (such as the
neonate is minimized at this increased respiratory rate [504, changing physical forces during the respiratory cycle and
539, 540]. Despite this strategy, the neonate (especially the calcium concentration) and the composition of various phos-
preterm infant) expends a larger portion of total body oxygen pholipids and surfactant-associated proteins (SPs) that com-
consumption on ventilation (i.e., the oxygen cost of breath- pose a particular surfactant molecule [399, 547] influence the
phases of surfactant. Thus, a complex pathway of highly reg- [547]. In the macro perspective, alveolar and airway collapse
ulated recycling or degradation (by alveolar macrophages) are counteracted by the outwardly acting elastic recoil of the
has evolved to allow for the energy- and substrate-intensive lung and chest wall, as well as the active respiratory control
activity of this critical molecule [399]. Approximately 85% mechanisms described above.
of the components of surfactant are recycled via reuptake In addition to its role in decreasing surface tension at
into type II pneumocytes [553–556]. the air–liquid interface, surfactant functions in a variety of
At approximately 20 weeks’ gestation, mechanical forces inflammatory and immune pathways. For example, lipo-
related to fetal breathing stimulate the expression of genes polysaccharide, interleukin-1, TNF-α, and prostaglandins
that code for the production of surfactant [557]. However, (especially PGE2) are released during chorioamnionitis.
without medical intervention, the quantity of surfactant is Being within the amniotic cavity, inflammatory molecules
reliably sufficient to support spontaneous ventilation only have access to the fetal airway (i.e., during fetal breathing
after 32 weeks’ gestation. In some preterm infants (most movements) and are known to induce synthesis and release
commonly, <32 weeks’ gestational age), inadequate surfac- of surfactant. Of note, this may explain the lung maturity
tant production manifests as respiratory distress syndrome that often accompanies preterm birth associated with cho-
(see below). Concentrations of saturated phosphatidylcho- rioamnionitis. At the same time, various components of sur-
line, phosphatidylglycerol, SP-A, and SP-B increase during factant modulate and suppress inflammatory events within
gestation. The ratio of two components of surfactant (lecithin alveoli. Finally, in normal pregnancies, surfactant proteins
to sphingomyelin, the L:S ratio) in amniotic fluid estimates (SP-A and SP-D) have been reported to promote the onset of
fetal lung maturity. This ratio provides prognostic informa- labor [564]. Thus, the interrelationship of surfactant secre-
tion on the fetus’ expected pulmonary status. An L:S ratio tion and onset of labor, in the setting of superimposed effects
>2.0 is associated with a reduced risk of RDS, whereas a of inflammatory stimuli, creates a complex and unpredict-
ratio <2.0 is associated with an increased risk of RDS [558]. able environment for the fetus.
Surface tension as modeled as a sphere is described by Distinct functions have been identified for the surfactant
Laplace’s law P = 2γ/r, where P is the intra-alveolar pres- proteins (SP-A, SP-B, SP-C, and SP-D) [565, 566]. That is,
sure or “collapse pressure” of the alveolus (i.e., the pressure the small hydrophobic proteins SP-B and SP-C interact with
necessary to counteract the contracting molecular forces pro- the surfactant lipids to reduce surface tension and stabilize sur-
duced at the air/fluid interface—the inward force acting to factant when exposed to the changing mechanical forces of
shorten the radius of the sphere, promoting collapse) [559]. the respiratory cycle [567]. With lipids, these two proteins are
This law states that the distending pressure is proportional to packaged with lamellar bodies that are then secreted into the
the surface tension (γ) and inversely related to the radius of alveoli. SP-A and SP-D are hydrophilic oligomers, members
the alveolus (r). During inspiration, alveolar radii generally of the collectin family of host defense proteins, that play a role
increase due to forces generated by the respiratory pump, and in the innate immune response to microbial challenge by bind-
therefore, collapse pressure tends to decrease. At the end of ing microorganisms and modulating leukocyte functions such
expiration, significant distending pressure would be needed as chemotaxis, cytokine function, and phagocytosis. SP-A and
to prevent alveolar collapse without the effects of surfactant. SP-D include recognition domains that facilitate immune cell
In films lining the alveolus, surfactant can produce large sur- recognition that coat infectious agents to enhance phagocy-
face pressures, decreasing the contracting force of surface tosis. Not only important for the innate immune system of
tension. When alveoli are large, the surfactant monolayer the lung, in mouse models, these proteins modulate alveolar
is spread thinly over the alveolus, and because of the large macrophage activity. As the most abundant of the SPs, SP-A
radius, the effect of surfactant is not critical [560]. When facilitates the formation of aqueous surfactant aggregates,
alveoli are small (e.g., during exhalation), surfactant is com- including tubular myelin. SP-D is not directly involved in the
pressed, further reducing surface tension in the setting of a biophysical properties of lung surfactant but may play a role in
small radius. Thus, surfactant acts to buffer surface tension surfactant reuptake and recycling [546, 568].
over a large range of alveolar sizes. Thus, although the proteins overlap in function, “each
However, alveoli do not operate in isolation and, instead, surfactant protein has distinct roles in surfactant homeostasis
are organized into groups of acini [561]. The lung paren- and/or innate defense. The defense activity involves facilitat-
chyma, including the alveoli themselves, directly influences ing alveolar macrophages in antibacterial activity and mini-
adjacent airways through traction [562]. At large lung vol- mizing inflammation to impede injury such as fibrosis. The
umes, such as those induced by positive pressure ventilation, integration of seemly diverse biological processes that are
the alveolar surface area to lung volume ratio is independent critical for pulmonary homeostasis” allows close regulation
of surface tension (dependent instead on tissue interactions) of interrelated processes. For example, the genes governing
[563]. In this case, the beneficial effect of surfactant therapy homeostasis of surfactant share common transcription factor
may be masked by the artificially augmented lung volumes binding sites with several innate host defense proteins [569].
Hereditary defects in the structure or the metabolism cycle Respiratory Distress Syndrome (RDS)
of surfactant can lead to fatal or chronic lung disease, such
as protein alveolar proteinosis [399]. Mutations in the genes Neonatal respiratory distress syndrome (RDS), also known
encoding SP-B (SFTPB), SP-C (SRTPB-C), or the surfactant as hyaline membrane disease, results from insufficient sur-
lipid transporter protein (ABCA3) disrupt production and factant production most often associated with prematurity
packaging of surfactant. Several distinct SFTPB mutations but can occur when surfactant release or synthesis is delayed,
have been identified in infants with neonatal respiratory fail- as with infants of diabetic mothers, or with secondary inacti-
ure or diffuse interstitial lung disease in neonates or children vation of surfactant, as in meconium aspiration syndrome. In
(i.e., neonatal or congenital pulmonary alveolar proteino- the setting of prematurity, the risk for RDS correlates
sis, infantile desquamative interstitial pneumonia, chronic inversely with gestational age with an incidence of approxi-
pneumonitis of infancy, nonspecific interstitial pneumonia), mately 5% in infants >34 weeks’ gestational age, approxi-
as well as the usual interstitial pneumonia in older children mately 30% in those between 30 and 33 weeks, and at least
and adolescents [551]. Some mutations in the gene encoding 60% in those <28 weeks [566].
SP-C may present as chronic interstitial lung disease in older The clinical features of untreated RDS result from poor
infants, children, and adults [551, 570]. Because mutations lung compliance, increased work of breathing, loss of FRC,
are recessive, infants who are deficient in SP-B may have a V–Q mismatch, poor gas exchange, right-to-left shunting via
family history of perinatal respiratory failure. More uncom- the ductus arteriosus and/or patent foramen ovale, and lung
monly, less severe mutations affect the production of SP-B injury from barotrauma and volutrauma, oxidative injury, and
in infants with chronic lung disease. In general, without lung inflammation [573]. Neonates with RDS typically present
transplantation, SFTPB-related lung disease is fatal in the with tachypnea or apnea, retractions, grunting, hypoxemia,
first months of life [551]. and respiratory and metabolic acidosis. The typical appear-
Mutations in ABCA3 are the most common cause of ance of RDS on the chest radiograph is a diffuse pattern of
hereditary respiratory failure in neonates. Mutations are reticulogranular (“ground-glass”) opacities and air bron-
associated with abnormal lipid transport and “processing” of chograms representing air-filled large airways surrounded
SP-B and SP-C. Patients present with congenital pulmonary by atelectatic alveoli [574]. Symptoms tend to worsen for
alveolar proteinosis or infantile diffuse interstitial proteino- several days after birth, followed by improved respiratory
sis, both usually fatal without transplant. Thus, this mutation function as endogenous surfactant production increases.
resembles those associated with SFTPB in terms of onset and The infant with RDS is at risk of complications associated
clinical course. Rarely, ABCA3 mutations are identified in with positive pressure ventilation (e.g., chronic lung disease,
older infants, children, and adolescents with chronic inter- pneumothorax, pneumonia), comorbidities (e.g., sepsis), and
stitial lung disease [551]. Finally, GM-CSF signaling plays prematurity (e.g., injuries to other organ systems including
a critical function in modulating alveolar macrophages in the brain [see CNS]). Since effective surfactant function is
their role in uptake and catabolism of both surfactant lipids critical to establishing a gas-filled FRC during the first few
and proteins. Because mutations in GM-CSF impair alveo- breaths after birth, RDS usually presents in the early postna-
lar macrophage differentiation, clearance of surfactant lipids tal period.
and proteins may decrease. Pulmonary alveolar proteinosis The beneficial effects to the fetal lung of antenatal deliv-
associated with mutations in the GM-CSF receptors results ery of corticosteroids to the mother was documented almost
from the accumulation of surfactant lipids and proteins. 50 years ago but has only been widely incorporated into
Therapy with a surfactant has been extensively evaluated standard practice over the last two decades. Treating the pre-
and shown to significantly decrease neonatal and infant mor- term fetus in utero by administering betamethasone to the
tality in preterm neonates with RDS [548]. Clinical trials to mother accelerates the maturation of the lung and increases
evaluate surfactant began in the 1960s, but its effectiveness the production and release of surfactant [575]. The standard
as a treatment was established only after the introduction of regimen consists of two doses of 12 mg of betamethasone
“natural” preparations of the compound in the 1970s–1980s. given IM 24 hours apart or four doses of 6 mg of dexametha-
Natural surfactants (lipid extractions that only contain SP-B sone given IM 12 hours apart, within 7 days of delivery, for
and SP-C) for patient care are derived from bovine and por- fetuses of 24–34 weeks’ gestational age [576]. Of note, this
cine lungs [571, 572]. As well, multiple generations of syn- longstanding regimen has been associated with reduced rates
thetic surfactants have been developed, but mimicking the of neonatal death, RDS, intraventricular hemorrhage, necro-
complexity of natural preparations has been challenging. tizing enterocolitis, duration of mechanical ventilation, and
More recently, third-generation synthetic surfactants with duration of oxygen therapy [577, 578].
SP-B and SP-C as well as DPPC and palmitoyloleoylphos- In addition to routine delivery of antenatal steroids, the
phatidylglycerol may offer more promise [550, 572]. If clini- development of exogenous surfactant, either synthetic or
cally effective, such agents may be more cost-effective. derived from animals, has revolutionized the treatment and
outcome of RDS [571, 577], including the severity of asso- administration (LISA), includes placing a thin catheter into
ciated pulmonary complications such as BPD. Commonly, the trachea with the aid of Magill forceps under direct laryn-
transient hypoxemia may follow the bolus delivery of sur- goscopy. A similar procedure (minimally invasive surfactant
factant. Less often, delivery may obstruct the tracheal tube therapy [MIST]) includes a rigid adult vascular catheter (e.g.,
and result in pulmonary hemorrhage or inadvertent volu- 16-G Angiocath) to eliminate the need for Magill forceps
trauma (after compliance has improved) [566]. Guidelines [585]. An LMA can serve as a noninvasive tool to deliver
have been revised repeatedly since surfactant was introduced surfactant. Recent meta-analyses combining the different tri-
into clinical care ([571, 579–583]. Currently, CPAP (no one als with these methods document reduced incidence of BPD
modality for delivery has been identified as superior) is intro- and/or death [572], but to date, the ideal strategy to deliver
duced early in the delivery room to avoid intubation and the surfactant noninvasively has not been pinpointed.
potentially injurious effects of positive pressure ventilation Because of the undisputed critical role of inflammation in
without routinely administering surfactant. the pathogenesis of BPD, corticosteroids have been exten-
In summary, the following represents the current approach sively explored in this setting. Recently, to avoid the toxic-
to supportive care for the preterm neonate with increased risk ity of systemic delivery, inhaled steroids (beclomethasone,
for RDS: budesonide, fluticasone, flunisolide, and dexamethasone)
have been reported to reduce the incidence of BPD [583, 588].
• Initiating CPAP early with subsequent selective surfac- Some suggest that intratracheal delivery of steroids prevents
tant administration in extremely preterm infants (e.g., BPD [449, 548, 583]. This strategy has not been adopted as
neonates <30 weeks’ gestation requiring mechanical ven- a routine treatment. The relevance of postnatal systemic cor-
tilation) results in reduced rates of BPD/death when com- ticosteroids in managing or preventing BPD remains contro-
pared with treatment with prophylactic surfactant therapy versial, with Cochrane reviews recommending that adverse
[581–583]. Thus, the American Academy of Pediatrics effects outweigh benefits, especially for dexamethasone (see
[581] and the European guidelines on surfactant adminis- Postnatal Development of the Lung) [443, 444]. However, a
tration [582] recommend stabilizing infants with CPAP recent trial with low-dose hydrocortisone documented less
and, only if necessary, administering surfactant as early BPD without neurodevelopmental insults at follow-up at 2
rescue therapy, but preferably within 2–3 h after birth. years [589, 590]. Outcomes were improved in the subset of
• Specifically, recent studies focused on the protocol of pro- those born at 24–25 weeks’ gestation [591]. On the other
phylactic surfactant treatment with prompt extubation hand, a recent report concluded that hydrocortisone deliv-
(intubate–surfactant–extubate [INSURE]) did not iden- ered between 7 and 14 days did not improve the outcome of
tify a benefit of prophylactic surfactant with INSURE “death or BPS” at 36 weeks’ postmenstrual age [592]. The
over CPAP. That is, using surfactant selectively versus relevance of systemic corticosteroids to the preterm infant,
prophylactically is associated with decreasing BPD and/ especially ELBW infants, continues to evolve, but in general,
or death. is reserved for those who remain dependent on mechanical
• Antenatal corticosteroids are recommended for women ventilatory support after several weeks [444].
with preterm labor at <34 weeks’ gestation. Observational Despite advances in nursery care over the past sev-
studies suggest that antenatal corticosteroids may eral decades, approximately 20% of infants with RDS will
decrease mortality in those <26 weeks’ gestation. The develop chronic lung disease, specifically bronchopulmo-
optimal treatment provides an interval of more than 24 h nary dysplasia (BPD), characterized by the persistent need
and less than 7 days after the start of steroid treatment to for oxygen at 28 days of life [593], with grading BPD at
birth. 36 weeks’ gestation (for infants born <32 weeks’ gesta-
• Although the safety and efficacy of repeating courses of tion). Furthermore, the incidence of oxygen dependence at
antenatal steroids remain controversial, beneficial effects 36 weeks has not declined, and lung function in childhood
on lung function of the preterm infant have been reported has not improved over time [443]. Of long-term significance,
[584]. pulmonary hypertension remains common and, at times, per-
• Thus, delivery of antenatal corticosteroids augments the sistent in this population (see Postnatal Development of the
beneficial effects of routine continuous positive airway Lung) [594].
pressure (CPAP) in the delivery room, also contributing to BPD in the age of surfactant therapy differs from classic
eliminating routine prophylactic surfactant therapy [548]. or “old” BPD, which was common in relatively mature pre-
term infants who had been subjected to high levels of posi-
Recently, less invasive modes for the delivery of surfac- tive pressure ventilation and oxygen therapy [595, 596]. Old
tant have been increasingly incorporated into clinical care BPD is characterized by alternating sites of hyperinflation
to avoid even a short period of positive pressure ventilation (presumably areas of lung with normal compliance exposed
[548, 572, 585–587]. For example, less invasive surfactant to positive pressure ventilation) and atelectasis, extensive
fibrotic areas, and severe epithelial and endothelial lesions mal development in utero, compared with postnatal life, the
[597]. “New” BPD develops in infants treated with more expected environment is one of physiologic hypoxia, extend-
current therapy for RDS (e.g., “gentle ventilation”), is most ing from the nearly anoxic conditions of the zygote to late
commonly seen in ELBW infants, and has pathologic find- gestation when the PaO2 reaches 20–30 mmHg. Embryonic
ings that differ from those in “old” BPD, including enlarged, stem cells grow and differentiate more efficiently at oxygen
simplified alveoli, with some interstitial thickening [598]. tension of ~10–15 mmHg (compared with 25 mmHg) [610].
New BPD appears to be a developmental disorder that results Hence, despite the “hypoxic” milieu, growth and develop-
in disrupted lung growth associated with factors other than a ment continue at faster rates than at any other period in a
deficiency of surfactant [599, 600]. Although neonates with lifetime.
new BPD may have a more benign pulmonary presentation Humans have evolved mechanisms to tightly regulate
in the ICN, many develop a non-asthmatic obstructive air- oxygen levels, at both the macro (carotid body reflexes) and
way disease as infants or children, which has the potential to cellular/mitochondrial levels [609]. Experts refer to HIF-1
complicate ventilatory support, later anesthetic care, and the as the “master regulator” of adaptive responses to hypoxia
postoperative course [443, 595, 596, 601]. Although the long- at the cellular level [610]. This protein complex governs
term prognosis of new BPD has not been completely defined, a range of responses to hypoxia including the shift from
the early disruption in normal lung growth and development aerobic to anaerobic metabolism [611, 612]. Specifically, in
may predispose to decreased respiratory reserve that may part via HIF-1, prolonged hypoxia elicits angiogenesis via
lie dormant until later life, becoming apparent when added regulation of growth factors such as vascular endothelial
to the expected decline in lung function associated with the growth factors (VEGFs), erythropoietin, placental growth
aging process, smoking, or other respiratory insults [421, factor, and angiopoietins [610]. Thus, HIF-1 maintains a
423, 470, 601–605]. Finally, the impact of pulmonary hyper- pervasive role in the activation of gene products impor-
tension contributes to the morbidity and mortality of BPD tant for angiogenesis, stem cell proliferation, and CNS and
(see Postnatal Development of the Lung). pulmonary alveolar development (via the closely related
HIF-2α) [609]. Exposure to oxygen decreases HIF activ-
ity, affecting developmental signaling, and, in that way,
Oxygen Toxicity impacting the unique growth trajectory of the preterm neo-
nate developing ex utero [609]. Of relevance, at birth, the
Although an essential metabolic substrate for human life, infant’s oxygen tension rapidly increases. Of particular
oxygen can be toxic by creating reactive oxygen species concern, even when the FIO2 is maintained at 0.21, in the
(ROS) [606]. ROS act as second messengers and transcrip- ELBW infant (23–26 weeks’ gestation is a mid-gestation
tion factors important in growth and development, critical fetus), values for oxygen saturation exceed those in utero
for immune function, and serving to regulate vascular beds and may reach extreme levels at higher inspired oxygen
including the ductus arteriosus [607]. For example, ROS concentrations. That is, the increase in the peripartum pO2
modulate mitochondrial function, the expression of several occurs during a period of critical growth for the preterm
stress proteins, and the production of regulatory T cells infant which, as an in utero fetus, would have continued to
[608]. However, exposure to ROS can also be harmful, lead- develop in a “hypoxic” milieu.
ing to the release of mitochondrial cytochrome C and other The effect of oxygen on the pathogenesis of retinopathy
apoptotic factors, degrading signal transduction, directly of prematurity (ROP) has long been recognized since this
altering proteins and impairing protein synthesis, modifying disorder often is associated with obvious impaired visual
nucleic acids including injury to DNA bases and strands, and acuity. Although factors other than hyperoxia contribute
affecting cell growth and development. In the central ner- to both the development and severity of ROP, the role of
vous system, ROS seem to modulate aspects of “synaptic oxygen has been linked to the effects of changes induced
plasticity,” but excessive exposure is associated with neuro- in VEGF and other growth factors in the developing retina.
toxicity [608]. Several mechanisms (thiol compounds such In addition to toxicity in the retina, potentially deleterious
as thioredoxin and glutathione, uric acid, bilirubin, anti- effects of oxygen have been noted in other organ systems
oxyenzymes) maintain reduction–oxidation homeostasis after only a brief exposure (e.g., during neonatal resuscita-
[606, 607]. Other molecules (superoxide dismutase, cata- tion). In multiple systematic reviews, resuscitation with an
lase) serve to maintain the physiologic balance by scaveng- FIO2 of 1.0 was associated with oxidative stress in animals
ing excess ROS. [613–616] and humans [617]; neurologic injury in animals
Eukaryotic life has evolved mechanisms to manage [618] and humans [619]; inflammation in the lung, heart, and
hypoxic but not hyperoxic environments, as the atmospheric brain in animals [620–622]; increased pulmonary vascular
concentration of oxygen throughout evolution has been simi- resistance/pulmonary hypertension in human neonates [623]
lar to or less than the current concentration [609]. During nor- and smooth muscle reactivity in animals [624]; kidney and
cardiac cellular injury in humans [625]; and increased neo- O2 concentration should be rapidly increased” (even as high
natal mortality [619, 626, 627]. as an FIO2 of 1.0) to attain a rapid return of spontaneous cir-
Neonatal resuscitation has changed radically over the past culation [633]. Recent updates remain consistent with these
decade as international and national associations have revised general recommendations [634–636].
guidelines to reflect the mounting evidence of toxicity asso- The incidence of ROP and lung injury in preterm neonates
ciated with excessive oxygen administration. Currently, rec- who receive supplemental oxygen titrated to oxygen satura-
ognizing the critical role of establishing adequate ventilation tions <93% are less than those whose oxygen saturation is
in the transition to extrauterine life, pre-ductal pulse oxim- maintained at saturations 95–98% [637, 638]. However, the
etry guides the delivery of supplemental oxygen to avoid recommendations for supplemental O2 guided by pulse oxim-
hyperoxia [109, 628, 629]. For the first 5–10 min of life, the etry remain controversial for preterm neonates, especially
hemoglobin oxygen saturation of the healthy term neonate for those who are extremely low birth weight. Although data
is frequently <90% (Fig. 2.13). Specifically, oxygen satura- from the Neonatal Oxygenation Prospective Meta-analysis
tion in term neonates commonly increases to approximately (NeOProM) have been analyzed repeatedly and provide a
70%, 80%, 90%, and 95% at 1, 3, 5, and 10 min, respec- preliminary framework for supplemental O2 targets in this
tively, after birth. For preterm neonates, oxygen saturation fragile group, definitive guidelines remain elusive.
values are approximately 60%, 75%, 85%, and 95% at 1, 3, The NeOProM collaboration included 4911 infants
5, and 10 min, respectively [630]. However, a recent report [639] across five separate, randomized, prospective, trials:
noted that preterm neonates who require respiratory support the Benefits of Oxygen Saturation Targeting (BOOST) in
do not reliably increase oxygen saturation and heart rate as New Zealand; BOOST II in the United Kingdom; BOOST
quickly as do spontaneously breathing preterm neonates who II in Australia; the Surfactant, Positive Pressure, and Pulse
do not require respiratory support [631]. To establish rational Oximetry Randomized Trial (SUPPORT) in the United
clinical care, these patterns need to be clarified. States; and the Canadian Oxygen Trial (COT) [639–642].
In response to identifying the toxicity associated with The infants in this study were <28 weeks’ gestational age,
hyperoxia, initial ventilatory support for the term neonate enrolled within 24 h of birth, randomized to a target of a
should include an FIO2 of 0.21. However, it has been sug- reduced (85–89%) or a greater (91–95%) range of oxygen
gested that “in newborns with severe circulatory arrest saturation, and enrolled until 36 weeks’ postmenstrual age.
(Apgar <1 at 1 min), the HR response to the first ventilations Although the protocols were designed to be consistent among
even before obtaining a reliable reading from the pulse oxim- the centers, differences in collecting additional secondary
eter should determine the level of inspired O2. When HR outcomes and the methods for assessing disability became
does not increase despite adequate ventilation, the inspired apparent (e.g., Bayley Scales of Infant Development [BSID]
II vs. BSID III). Interestingly, oxygen saturation frequently
deviated outside of the two specified ranges and the distri-
* bution of oxygen saturation between the two groups over-
*
100
lapped. Finally, interpreting the results was complicated by
*
* an artifact in the calibration hardware (BOOST II and COT)
* that was identified during the active phase of data collection.
90 This artifact exaggerated the difficulty of achieving compli-
ance with the defined saturation targets and forced research-
80 ers to apply several analyses to the dataset. Experts continue
SpO2 (%)
to debate the optimal approach to analyze these data [643].

Nonetheless, experts have reached a moderate consen-
70 Pre-ductal
sus on several aspects of these trials. Specifically, although
Post-ductal
no differences in the primary composite outcome (death or
60 severe disability at 18–24 months of age) were identified, the
outcome of the subset of “death” and the secondary outcome
of NEC were greater and the incidence of severe ROP less
50
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 in the group who were targeted to the lower range of oxy-
Minutes after birth gen saturation. Severe ROP that required treatment occurred
more frequently in the group targeted for the higher SpO2. Of
Fig. 2.13 Pre- and post-ductal SpO2 levels in healthy term infants dur- concern, a recent letter noted, “this finding was inconsistent
ing the first 15 min after birth (median; IQR). Post-ductal SpO2 levels
were significantly less than pre-ductal SpO2 levels at 3, 4, 5, 10, and among studies, and a systematic review of 5 recent random-
15 min. *P ≤ 0.05. Pre-ductal SpO2 measured on the right hand; post- ized trials (the NeOProM collaboration) rated the quality of
ductal on one foot (from Mariani et al. [632] lung early SpO2) evidence for this outcome as low” [644].
Also of concern, a study from Australia reported that the Thus, the ideal oxygen saturation to target in the preterm
rate of severe ROP more than doubled after changing the tar- neonate has not been authoritatively confirmed. Furthermore,
get for oxygen saturation from 88–93% to 91–95% [645]. some experts question whether oxygen tension or oxygen
The concept of maintaining oxygen saturation within a spe- saturation provides a more reliable guide for oxygen satura-
cific range to reliably balance the risks and benefits remains tion. For example, oxygen saturation of 85–95% in the first
challenging. As Cummings notes, “it is physiologically week of life represents a PO2 of 29–67 mmHg [651]. The
implausible for a single SpO2 target range to be ‘optimal’ AAP Clinical Report concluded that “the ideal SpO2 range
for all preterm infants, or even for a single preterm infant for extremely low birth weight infants remains unknown”
across the duration of an NICU stay. Neonates undergo [652]. Some recommend setting the upper and lower satura-
dramatic developmental changes during the first weeks of tion alarms to 95% and 89%, respectively [639], although
life…significantly alter(ing) the physiology of the transfer the reliability of this recommendation is poor and maintain-
of oxygen to tissue at any given SpO2” [640]. In at least one ing compliance with a target rarely is possible for extended
study, the principle of setting the target for oxygen saturation periods. The development of automated devices may offer
based on gestational and postnatal age was associated with more robust and reliable systems to avoid both hyperoxia
a smaller rate of severe ROP without increased mortality and hypoxemia compared with manual control [653–655].
[646]. Finally, a recent analysis of a subset of patients in the
SUPPORT cohort noted that SGA infants in the group target-
ing the lower range of oxygen saturation had the least median Control of Ventilation
saturation and a greater incidence of intermittent hypoxemia
(compared with AGA in the same group), which was associ- A recent summary of the basic pathway for generating a reg-
ated with greater mortality [647]. The authors raise the topic ular, sustained breathing pattern includes the following
of select susceptibility to oxygen toxicity in ELBW infants framework (simplified). The so-called central pattern
who are SGA, suggesting that saturation >92% might be generator within the ventral brain stem produces the respira-
appropriate in this subset. tory rhythm. That is, a group of interneurons in the medulla
The practical bedside exercise of maintaining a narrow (the pre-Botzinger complex) initiates inspiration and then
range of oxygen saturation remains difficult and challenging. projects to various premotor inspiratory neurons within the
Although targeting an oxygen saturation between 85% and ventral respiratory group. Finally, these neurons project to
89% may not be justified (based on data from NeOProM) the motoneurons of the diaphragm and external intercostals
and may result in episodes of severe hypoxemia, aggressively as well as to upper airway muscles and the tongue [656].
responding to a brief decrease to this range could result in Expiration is generated via a separate system within the
repeated episodes of hyperoxia. Similarly, targeting an oxy- brain stem. These respiratory-related neurons in the brain
gen saturation of 95% may be associated with prolonged peri- stem may regulate peripheral mechano- and chemoreceptors.
ods of “overshoot” and prolonged hyperoxia. The challenge Thus, the complex system for stable and responsive respira-
of maintaining the oxygen saturation within a narrow range tion requires a balance of excitatory and inhibitory input
in the setting of unstable cardiorespiratory status at times is from higher brain centers, mechanoreceptors (lungs, upper
impossible, leading some to refer to oxygen targeting as “an airway), peripheral chemoreceptors (carotid body), central
illusion” [648]. That is, the sickest infants spend significant chemoreceptors (ventral medulla), and, finally the integrity
time outside the targeted range of oxygen saturation, result- of response from the diaphragm, chest wall, and upper air-
ing in significant periods of hypoxemia, hyperoxia, and/or way. Input from the mechanoreceptor in the lung and the
wide fluctuations across a wide range of oxygen saturation peripheral chemoreceptors has been reported to provide a
[649]. Similarly, in a study that targeted oxygen saturations greater regulatory role in the neonate compared with older
between 88% and 92% in preterm neonates with CPAP, com- infants [410].
pliance was achieved only 31% of the time. Infants encoun- In the setting of the preterm infant, immaturity at a variety
tered an average of 48 episodes of hyperoxia (SpO2 >98%) of levels within this complicated and highly regulated net-
and 9 of hypoxia (SpO2 <80%). FIO2 was adjusted an average work for controlling ventilation (the central nervous system,
of 25 times per day [650]. Even in the setting of a prospective peripheral chemoreceptors, and target tissues [lung, larynx,
trial (NeOProM), the proportion of time outside the target respiratory muscles]) may interact to explain neonatal apnea
range while on supplemental oxygen ranged from 8.2% to and bradycardia [657] as well as postoperative apnea [658].
27.4% (<85%) and 8.1% to 22.4% (>95%), with significant Although the regulation of respiration begins in fetal life,
overlap between the groups [639]. Another expert reported control matures significantly postnatally. For example, fetal
that infants were only within the target range about 50% of breathing plays a critical role in lung growth and training
the time [640]. of the respiratory pump (see Alveolar Phase), but in utero
this activity is not essential for gas exchange. Although some day 22-23
aspects of fetal respiratory behavior persist postnatally, the a day 5
100
responses of the healthy term neonate to hypoxia and hyper-
carbia and other respiratory stimuli differ markedly from
the rudimentary behavior of the fetus [659]. In early ges- 80
tation, fetal breathing is continuous and under control of
% change VE
the spinal cord; as development progresses, fetal breathing 60
is controlled more centrally and, by the third trimester, is a
complex behavior that varies with the stage of sleep (e.g., 40
in fetal lambs, breathing is impeded during non-REM sleep
by inhibitory nuclei at the level of the brain stem) [659, 20
660]. In fetal sheep, hypercapnia stimulates and hypocap-
nia depresses the depth of fetal breathing [661–663]. Similar
0
responses are present in the human fetus after 24 weeks’
gestation, but at 24–26 weeks the response is less than after b 60
28 weeks [664]. Thus, the fetus responds to the CO2 tension
qualitatively similar to the adult, although quantitative dif- 50
ferences are apparent.
In contrast to adults, hypoxemia decreases fetal breathing. 40
% change VT
One hypothesis suggests that in the setting of limited access
30
to oxygen, the fetus eliminates respiratory effort to decrease
oxygen consumption when “breathing” does not contribute
20
to gas exchange [659], but this is probably an overly simplis-
tic analysis since the effect of hypoxia on fetal breathing is 10
necessarily transitory as prolonged inhibition of fetal breath-
ing would impair lung development [665]. Both decreased 0
breathing and gasping are signs of fetal distress, are a com- c 240
ponent of the obstetrical “biophysical profile,” and correlate
with abnormal fetal well-being [666–668]. After delivery, 220
inhibition of breathing movements is life-threatening and
must be reversed as the neonate depends on pulmonary gas 200
(breaths/min)
Frequency
exchange for survival. The exact mechanism by which these

pathways are reversed is unknown [659]. 180
Although more mature than in utero, the neonate’s
responses to hypercapnia, hypoxemia, and afferent stimu- 160
lation remain impaired, especially for preterm infants. The
140
immature, central-chemoreceptor-mediated hypercapnic
ventilatory response has a relatively flat slope in the neona- 120
tal period; with increased postnatal and gestational age, the 0 1 2 3 4 5
slope increases toward adult values [669]. In animal studies, Duration of CO2 exposure (minutes)
the immature ventilatory response to CO2 is reflected in the
failure to increase respiratory rate, although both immature Fig. 2.14 Lung response to CO2: effect of 5-min exposure to 5% CO2
and mature animals increase tidal volume in response to on V E (a), tidal volume (VT) (b), and frequency (c) at 5 and 22–23 days
of age in unrestrained rats. Effect of 5-min exposure to 5% CO2 on V E
hypercarbia [670] (see Fig. 2.14). The origin of the dimin-
(a), tidal volume (VT) (b), and frequency (c) at 5 and 22–23 days of age
ished response to hypercapnia in the preterm infant has been in unrestrained rats. Values are means ± SE. Hypercapnia caused a sig-
attributed to dysfunction of the central nervous system [659]. nificantly greater increase in V E at 22–23 days compared with 5 days.
However, preterm infants with a history of apnea exhibit a Percent increase in VT was similar at the two ages. Frequency decreased
significantly from baseline at 5 days, whereas it increased significantly
blunted ventilatory response curve to CO2 with a slope that
from baseline at 22–23 days (used with permission from Abu-Shaweesh
is even less than that exhibited by similar preterm infants et al. [670])
without apnea [671–673].
The ventilatory response to hypoxia also is immature in
the preterm infant. When hypoxic, preterm, and term infants for 1–2 min. Adults and term infants older than 2–3 weeks
less than 1 week of age initially increase minute ventilation sustain this pattern. However, preterm neonates and term
infants less than a week old exhibit a biphasic response to normoxic environment. Of possible relevance to the preterm
hypoxia. That is, the initial increase in ventilation (phase 1 infant, chronic hyperoxia may impair the development of the
or augmentation phase) is followed by a decline (phase 2 normal response of the carotid body (not central chemore-
or depressive phase) to or below baseline; this phenomenon ceptors) to hypercapnia, implying a diminished capacity of
is termed “hypoxic ventilatory depression” (HVD) [659, this protective response. However, clinical relevance to the
674–677]. Phase 1 is likely mediated by peripheral chemo- human has not been established.
receptors located in the carotid body as denervation of these The sensory neurons in the airway mediate the mechani-
structures abolishes the reflex [675]. The initial response cal signals that have a critical role in the control of respi-
includes increased tidal volume and respiratory rate, followed ration. However, these reflexes mediated by afferents in the
by a gradual decrease in the respiratory rate. In the second airway, lungs, and chest wall that regulate ventilation are
phase of HVD in preterm infants, the increased tidal volume immature in the preterm and young infant. For example, in
is preserved, but the respiratory rate decreases, resulting in preterm infants, mechanical or chemical stimulation of the
a net decrease in minute ventilation [678]. In other species larynx decreases ventilation and, in extreme cases, produces
(sheep, rats, cats), the depressive phase is associated with a apnea [686]. Based on data from animals, the mechanism
greater decrease in the tidal volume than the respiratory rate, is associated with superior laryngeal nerve stimulation of
but with more severe hypoxia, tidal volume may decrease as inhibitory pathways leading to either decreased respiratory
much or more than respiratory rate [676]. Across species, the center activity or enhanced CNS inhibition/expiratory path-
augmentation phase is less in the early postnatal period com- ways [687, 688]. In part, the vagal receptor system medi-
pared with baseline minute ventilation, and the depressive ates the complex process of establishing breathing during the
phase declines with advancing postnatal age [676]. Thus, the transition from fetal to extrauterine life as well as maintain-
magnitude of HVD correlates with the degree and duration ing effective ventilation in the neonatal period [689]. That is
of hypoxia and maturity. after denervation of the intrathoracic vagal nerve (newborn
The mechanism of HVD is not fully elucidated [676] but lambs), dysfunction of the surfactant system, and absence of
mechanisms within the central nervous system seem to be vagally mediated volume input resulted in respiratory failure
critical [679, 680]. For example, lesions in the pons diminish [690]. More recently, a molecular mechanism underlying the
or abolish HVD in fetal lambs [681]. Other sites (medulla control of ventilation (in mice) at the level of airway sensory
and midbrain) may also contribute [682]. Release of vari- neurons has focused on the role of Piezo2, a mechanically
ous neuromodulators also have been implicated in this cen- activated ion channel. Newborn animals who lack this chan-
tral response to hypoxia, including adenosine, serotonin, nel develop respiratory distress and die. Required to estab-
prostaglandins [683], endorphins, GABA, platelet-derived lish effective ventilation at birth as well as maintain normal
growth factor, and an imbalance between neurokinin-1 and breathing in adults, this channel serves as a “stretch sensor”
mu-opioid receptors, as pharmacologic modulation of these that seems to have a role throughout life [691].
substances also resolves HVD [659, 684]. Depression of A respiratory control mechanism most relevant in the
metabolic rate and changes in blood flow may also contribute neonatal period, especially in preterm infants [692], the
[680]. Further support for the central origin of HVD includes Hering–Breuer inflation reflex consists of inhibition of ven-
the finding that in near-term infants, hypoxia shifts the CO2 tilation by lung inflation, is mediated by the slowly adapt-
response curve to the right and decreases the slope (i.e., ing pulmonary stretch receptors (SARs), disappears during
hypoxia blunts the CNS response to hypercapnia) [685]. REM sleep, and fades during the first few weeks of life. The
In summary, the transition from a biphasic to a sustained Hering–Breuer reflex may stabilize ventilation even with
hyperventilation in response to hypoxia is complex and changing elastic loads [693]. The strength of the reflex has
may be related to increased activity of N-methyl-d-aspartate been noted to increase during active (REM) compared with
(NMDA) receptors (recruit excitatory signaling pathways quiet sleep [694] and in the prone position [695]. In part, this
that mediate sustained hyperventilation) and decreased input may contribute to the reported improved oxygenation and
from platelet-derived growth factor (PDGF) (recruits signal- pulmonary mechanics associated with this positioning.
ing that reduce NMDA activity) [680]. Chronic exposure A closely related phenomenon, the paradoxical reflex of
to hyperoxia (in rats) may also affect the development of Head, occurs when lung inflation triggers a large inspiratory
the peripheral chemoreceptor response [683]. That is, after effort resulting in a large lung volume and provides a rare
chronic hyperoxia during the first 2 weeks of postnatal life, example of a physiologic positive feedback mechanism. The
return to a normoxia was associated hypoventilation primar- reflex is accompanied by tonic inspiratory contractions [696,
ily because of decreased sensitivity of the carotid body to 697], which can be elicited in neonates via a forced inhala-
hypercapnia and blunting of the hypoxic ventilatory response, tional maneuver with positive pressure [698], and is medi-
but without phase 2 of this response. Carotid body sensitiv- ated by the rapidly adapting stretch receptors (RARs) (also
ity to CO2 seemed to recover within 7 days after return to a responsible for so-called Hering–Breuer deflation reflex in
which rapid deflation of the lungs stimulates inspiration). up to 30 s may be observed in healthy term babies. Thus, the
The paradoxical reflex of Head may play a role in establish- clinical consequences (desaturation and bradycardia) in the
ing the FRC during the transition from fetal life [698] and/or context of gestational/postnatal age rather than simply the
maintaining the lung volume in the setting of the compliant duration of apnea may be more relevant to long-term risk
chest wall of the neonate [699]. and, in that context, contribute to developing guidelines for
initiating and discontinuing treatment as well as monitoring
after discharge from the intensive care nursery.
Apnea of the Newborn Apnea is classified according to the mechanism of dys-
function: obstructive (no airflow associated with respiratory
The immaturity of respiratory control (e.g., reduced sen- effort; usually obstruction is at the pharyngeal level), central
sitivity to CO2 and hypoxia) and the mechanical proper- (no respiratory effort without obstruction), and—the most
ties of the respiratory system in the neonate (e.g., small common—mixed apnea, with features of both obstruction
airways, compliant chest wall) predispose to disorders of and pauses in the respiratory effort [687]. The incidence of
breathing, such as apnea. That is, immaturity of both the recurrent apnea increases as the gestational age decreases;
autonomic and central nervous systems as well as periph- 100% of infants <28 weeks’ gestational age, 54% at
eral and central chemoreceptors fail to accurately regulate 30–31 weeks, 15% at 32–34 weeks, and 7% at 34–35 weeks.
respiratory muscles and the upper airway. Finally, sepa- By 40 weeks’ postmenstrual age, 98% of infants no lon-
rate from imperfect neural input, a compliant chest wall ger experience apnea [704]. Of note, apnea persists beyond
and upper airway tend to collapse also leading to airway 38 weeks’ postmenstrual age more commonly in infants born
obstruction/apnea. Because of greater maturity of both the at 24–26 weeks’ gestation and in those who develop BPD. In
central nervous and respiratory systems, the term infant is most cases, episodes of severe apnea (requiring intervention)
physiologically equipped to adapt to postnatal life, Thus, decrease in frequency earlier than less severe apnea (i.e.,
apnea in the term infant should be considered pathologic spontaneously resolves) [705].
and deserves a detailed evaluation to identify a specific eti- Apnea may be accompanied by bradycardia (so-called
ology. For example, apnea in the term infant is more likely As and Bs)—with or without hemoglobin desaturation,
to imply a significant underlying condition such as brain suggesting that a common pathway (e.g., vagal inhibition)
disorders (e.g., hemorrhage, stroke, trauma, malformations, may contribute to both phenomena [687]. With hemoglobin
seizures, congenital central hypoventilation), metabolic desaturation, direct carotid body effects may lead to further
instability (e.g., glucose, calcium, sodium, temperature), bradycardia; the net result is decreased oxygen delivery
inherited errors in metabolism, lesions that predispose to (Fig. 2.15). The common thread of inflammation/oxidative
airway obstruction (e.g., craniofacial anomalies, upper stress that characterizes the diverse abnormalities associated
airway anomalies, masses/tumors), anemia, or infection. with prematurity (e.g., sepsis, intracerebral hemorrhage,
Although these pathologies also apply to and are relevant anemia, patent ductus arteriosus, neurologic abnormalities,
when evaluating the preterm infant, apnea of prematurity airway anomalies, and other systemic illness) has been pro-
(AOP) deserves additional analysis. posed to play a modulating role in AOP. The chronic inter-
One expert refers to apnea of prematurity (AOP) as a
developmental disorder, since at birth, especially in the
extremely low birth weight infant, the central and periph- Decreased respiratory drive
eral mechanisms for control of ventilation remain oriented
to fetal life, when breathing is characterized by frequent
pauses. These imperfect regulatory mechanisms coupled Apnea,
hypoventilation
with the immature parenchyma and vascular bed of the lung
in the setting of a compliant chest wall create the “perfect Increased
storm” for AOP [410]. vagal tone
The definition of apnea of prematurity varies, but com-
monly the disorder refers to a pause in breathing for greater Decreased O2
delivery
than 20 s or shorter pauses accompanied by clinical evidence
Bradycardia Desaturation
of hypoxia such as cyanosis or bradycardia [700, 701]. This
well-accepted definition is not evidence-based [702] and a Carotid
body
consensus statement for a clinically significant event based
on the duration of a pause in respiration has not been devel-
Fig. 2.15 A schematic representation of the sequence of events
oped [703]. For example, apneic events <20 s in duration can whereby apnea (or hypoventilation) results in various combinations of
lead to clinical signs of hypoxia; conversely, apneic events desaturation and bradycardia (from Martin and Abu-Shaweesh [687])
mittent hypoxia (CIH) that frequently accompanies AOP, not (see Control of Ventilation) is thought to be mediated in the
the respiratory pauses per se, has been linked to significant pons, with significant modulation via adenosine receptors.
complications, including prolonged respiratory support, a Because of its long half-life, absence of side effects
greater incidence of ROP, delayed onset of oral feeds, and (tachycardia, dysrhythmias), and lack of need for monitor-
a greater risk for abnormal neurodevelopmental outcome ing with drug levels, caffeine has evolved as the preferred
[410, 706]. Infants with BPD have been reported to have a agent (usually, 20 mg/kg loading dose, 5–10 mg/kg/day
greater incidence of AOP [706]. Recently, systemic or local maintenance). The Caffeine for Apnea of Prematurity (CAP)
inflammation has been reported to upregulate inflamma- randomized controlled trial (and other studies) established a
tory gene expression in the central nervous system (in the broad experience, defined a safety profile, and documented
rat), inducing vagally mediated responses associated with improved short-term outcomes (e.g., decreased duration of
apnea and CIH [410, 707]. Finally, recent studies suggest respiratory support, reduced frequency of BPD, less fre-
that epigenetic mechanisms (e.g., DNA methylation) associ- quent use of corticosteroids, and increased survival without
ated with CIH in the newborn (rat) contribute to the altered neurodevelopmental disability at 21 months). However, caf-
sensitivity of the carotid body. Of significance, this neonatal feine therapy did not significantly reduce the combined rate
“reprogramming” is associated with autonomic dysfunction of academic, motor, and behavioral impairments at 5 and
in adulthood. For example, adults who encountered apnea of 11 years of age, but was associated with a reduced risk of
prematurity exhibit a greater incidence of sleep-disordered motor impairment [711–713]. Despite these data, long-term
breathing [708, 709]. cellular and molecular effects of caffeine on brain develop-
End expiratory lung volume (FRC) contributes to pre- ment in the setting of prematurity are unknown [714]. For
venting prompt and severe desaturation in response to apnea. example, gestational age and dose of caffeine may affect
However, the compliant chest wall and pulmonary insuf- the balance of detrimental versus beneficial effects on the
ficiency commonly encountered by the preterm infant can brain. Although some have advocated prophylactic dosing,
decrease FRC. Activating chest wall muscles contributes especially in those <28 weeks’ gestational age, the optimal
to maintaining FRC by maintaining chest wall stability. timing for initiating therapy has not been identified [714,
However, the sleep pattern of preterm infants includes >80% 715]. For infants >28 weeks’ gestation not requiring venti-
in active sleep when chest wall muscle activity is inhibited latory support, one approach is to initiate caffeine only if
[410], interfering with the stability of the FRC. Because apnea develops [701].
the prone position stabilizes the chest wall (see Control of A recent review and meta-analysis noted (observational
Ventilation), sleep in this position may stabilize FRC and, studies, low quality of evidence) a significant benefit of early
therefore oxygen saturation, especially in patients with BPD (less than 3 days of age) treatment in decreasing the risk for
[410, 710]. As evidenced by the critical role of FRC in allow- BPD [716]. Similarly, at follow-up at 11 years (CAP study),
ing oxygen uptake to continue in the setting of apnea (i.e., expiratory flow rates in those treated with caffeine were
prevent/delay desaturation), the decrease in FRC during greater than in the control group. That is, the FVC was less
apnea has been shown to correlate inversely with the rate than the fifth percentile in fewer children (11%) in the caf-
of desaturation. That is, the greater loss of FRC mirrors the feine group compared with those in the placebo group (28%)
rapidity of desaturation. Thus, the preterm infant is predis- [717]. Although some recommended larger doses of caffeine,
posed to a small FRC which increases the risk for severe no clear advantages for the larger dose have been identified
desaturation in response to apnea [410]. Finally, titrating [718]. Caffeine should be discontinued when the infant no
supplemental oxygen in extremely low birth weight infants longer demonstrates clinically significant apnea/bradycar-
to achieve oxygen saturation of 85–95% to avoid hyperoxia dia and is weaned from positive pressure for 5–7 days or at
(see Oxygen Toxicity) may augment the risk for CIH in this 33–34 weeks’ PMA, whichever came first [701, 719].
fragile group. AOP should be differentiated from other breathing pat-
In conjunction with nasal continuous positive airway terns of the neonate. For example, periodic breathing is a
pressure (4–6 cm H2O), caffeine has evolved as the primary common physiologic pattern that includes short pauses in
pharmacologic agent to treat apnea of prematurity. Although respiration interspersed with high-frequency ventilation.
known to have a multitude of CNS effects, the role of caf- This pattern has been attributed to discoordination in the
feine (and other xanthines) in inhibiting adenosine receptors feedback control mechanisms of the respiratory control cen-
seems to be most relevant to treating apnea of prematurity. ter and generally resolves by one month of age in the term
By blocking inhibitory A1 and A2A receptors, caffeine pro- neonate [720, 721].
duces excitatory neural output, manifested clinically by Apnea associated with anesthesia and surgery in the pre-
increased minute ventilation, improved carbon dioxide sen- term, term, and ex-premature infant remains a controversial
sitivity, decreased periodic breathing, and decreased hypoxic topic with “more questions than answers” [722]. During
hypoventilation. Of note, hypoxic ventilatory depression the past 30 years, little new evidence has emerged regard-
ing the optimal timing of surgery, anesthetic agents, and tance, a history of BPD and NEC also increased the risk.
predictors for perioperative complications in ex-premature Specifically, in the absence of comorbidities, no patients in
infants [723]. The “historical risk” for perioperative apnea the older group encountered apnea [730].
in ex-preterm infants ranges from 5 to 49% [658, 724–726]. Preventing postanesthetic apnea depends on identifying
However, more recently, a randomized controlled trial who should be monitored postoperatively, but these risks
reported the overall incidence of apnea (0–12 h) was similar are not clearly defined. Some recommend that ex-premature
in ex-premature infants less than 60 weeks’ postconceptional infants <60 weeks’ postconceptional age be monitored for
age who underwent inguinal hernia repair under regional respiration and hemodynamics after anesthesia until they are
anesthesia (3%) compared with a group who received gen- at least 12 h apnea-free (see [729] for proposed algorithms).
eral anesthesia (4%). Of note, the incidence of early apnea Others suggest that those <46 weeks be observed for at least
(0–30 min) was greater in the general anesthesia group (3%) 12 h, with individualized care defined by associated comor-
compared with the regional anesthesia group (1%) [727]. bidities for those between 46 and 60 weeks [729]. These
This study confirmed that, although the incidence is low, authors also recommend administering caffeine (10 mg/kg)
life-threatening apnea occurs in both the PACU and later. IV. Others suggest overnight monitoring for patients born
Finally, these data are consistent with a Cochrane review <37 weeks’ gestation who are <50 weeks’ PCA. Although
from 2003 that found insufficient evidence to recommend the risks of gestational and PCA for perioperative apnea are
regional anesthetics in place of general anesthesia [728], well established, consensus for postoperative monitoring
despite hypotheses that regional and neuraxial anesthetics remains elusive.
may obviate postoperative apnea [729] in the ex-premature.
Apnea secondary to anesthesia may be related to inhi-
bition of central respiratory centers, decreased respiratory Hepatic Function
pump efficiency, and impaired V–Q matching. Factors
that are associated with an increased risk for postoperative Although the liver plays a critical role in fetal metabolism,
apnea include postconceptional and gestational age, history the placenta and maternal liver manage a significant propor-
of apnea, anemia (commonly seen in the former preterm tion of hepatic function in utero, providing a steady supply of
infant), neurologic disease (e.g., history of intraventricular glucose and other substrates. Throughout gestation, it is
hemorrhage), chronic lung disease, and an increased oxy- notable that the lower limit of glucose concentration is
gen requirement [658, 729]. Postanesthetic apnea has been approximately 54 mg/dL [731]. In response to either hyper-
commonly evaluated in the setting of inguinal herniorrha- glycemia (e.g., infant of a diabetic mother) or hypoglycemia
phy since inguinal hernias are more common in preterm (e.g., intrauterine growth restriction), the fetus can induce or
infants and are commonly repaired before hospital discharge suppress hepatic glucose and/or insulin production. Although
to avoid the risk of incarceration [724]. Recently, delaying the enzymes for gluconeogenesis are present by the third
surgical intervention to offset the risks for apnea as well as month of gestation, gluconeogenesis is not active in the nor-
the surgical complications associated with early repair (e.g., mal fetal liver. A variety of hepatic enzymes important for
recurrence, damage to adjacent structures such as the tes- gluconeogenesis (e.g., glucose-6-phosphatase) develop rap-
tis) has been proposed [722]. This author reports, “despite idly after birth [732, 733]. In the immediate postnatal period,
the frequency of inguinal hernia repair in preterm infants, the neonatal liver must assume the same metabolic roles per-
this issue remains unstudied in a high-quality manner. A formed by the adult liver, a process largely completed within
large, multicenter randomized trial is currently underway to hours. Understanding the differences between fetal and neo-
address the effect of timing on the short-term and long-term natal versus adult hepatic physiology is a requisite for pro-
safety and efficacy of IH repair in this population.” viding optimal care to the neonate.
Although most experts have emphasized the critical rel-
evance of gestational and postconceptional age in analyzing
risk for perioperative risk, comorbidities also deserve scru- Anatomy
tiny. For example, a recent study compared the incidence of
postoperative apnea in infants <45 weeks’ postconceptional The liver’s unique architecture and cellular composition
age with those between 45 and 60 weeks. Consistent with reflects its central role in metabolism and clearance, as well
recent reports, the overall risk of postoperative apnea was as hemostasis, hormonal regulation, and biosynthesis. In
2.5% but 4.7% in group <45 weeks’ PCA. Consistent with postnatal life, the liver has dual blood supplies. The hepatic
other data, postconceptional age inflicts the most significant artery provides richly oxygenated, arterial blood to the liver.
risk for perioperative cardiorespiratory complications; all The portal vein delivers a variety of substances from the
infants who required tracheal intubation and mechanical ven- digestive tract, including digested food products (e.g., free
tilation were <45 weeks’ PCA. However, of critical impor- fatty acids, amino acids, glucose), as well as large proteins,
gut-derived hormones (e.g., glucagon), microorganisms, and tive tissue. Meanwhile, the precursors of the hepatic and por-
immune cells and signaling molecules [734]. The canaliculi tal venous systems are formed from the yolk sack [740].
are a network of tubules, joined by tight junctions, that Populations of cholangiocytes further differentiate into the
coalesce to form ducts, through which bile is actively intrahepatic and extrahepatic portions of the biliary tree. A
secreted and, under positive pressure, flows from the biliary variety of transcription factors have been identified in the
tree into the small intestines [735]. From mid-gestation, two morphogenesis pathway of the biliary tree [736, 738, 739].
types of epithelial cells populate the liver: hepatocytes and The common bile duct first appears as a connection
cholangiocytes (biliary epithelial cells). Hepatocytes are between the hepatic bud and duodenum, and the gallblad-
arranged in “cords” that are one cell thick with a basal der and cystic duct emerge as outgrowths. For the first three
domain adjacent to sinusoidal endothelial cells to exchange months of gestation, the extrahepatic bile ducts are occluded
nutrients and metabolites with blood. The apical lumen with endodermal cells. That is, biliary atresia, intrahepatic
includes the bile canaliculus, into which bile is secreted. bile duct paucity, and autoimmune diseases, including pri-
Cholangiocytes establish a typical epithelial polar structure mary biliary cirrhosis and primary sclerosing cholangitis,
to form intrahepatic bile duct tubules to connect the bile can- have been linked to a genetic abnormality affecting devel-
aliculi to the duodenum (via hepatic and common bile ducts) opment and maintenance of the biliary system. Similarly,
to drain bile secreted by hepatocytes. During this process, interrupting the formation of patent intrahepatic bile ducts
cholangiocytes adjust the composition of the bile (e.g., also can present as liver failure during infancy. For exam-
secrete chloride and bicarbonate and/or secrete or absorb ple, biliary atresia can develop if these ducts do not recan-
water) [736]. On a macro scale, the hepatocytes are simulta- nulate, sometimes leading to liver failure as early as in the
neously in physical communication with the blood (hepatic first months of postnatal life (see Biliary Atresia, below).
artery/portal vein) and gut (canaliculi). These cells function Alagille syndrome is characterized by a paucity of intra-
as regulators of processes that span the gut, the bloodstream, lobular bile ducts as well as cardiovascular, ocular, vascu-
and—in fetuses—the placenta. Disruption of these activities lar, and vertebral anomalies [741]. A genetic association in
(e.g., with sepsis) can lead to cholestasis, hepatocyte injury, Alagille syndrome involves Jag-1 and the NOTCH signal-
and giant cell hepatitis [734]. In their unique milieu, hepato- ing pathway, which has been found to regulate the formation
cytes take on many critical physiologic functions including of intrahepatic ducts in mice [736, 742–745]. Disruption of
processing absorbed nutrients (glucose, amino acids, lipids); other signaling pathways have been associated with a variety
responding to gut hormones; clearing endogenous (e.g., of hepatic disorders such as alpha-1 antitrypsin deficiency,
damaged hemoglobin) and exogenous substances (e.g., cystic fibrosis, Gilbert’s disease, Dubin–Johnson syndrome,
drugs) from the blood, sometimes via the biliary tree; detoxi- and Zellweger syndrome [734].
fying bilirubin and ammonia; producing various serum pro- In the human, bilirubin can be detected by approxi-
teins; and forming bile. mately 14 weeks’ gestational age. In contrast to postnatal
life, the placenta removes most bilirubin in utero, with fetal
hepatic–biliary pathways eliminating only a small amount
In Utero Development (see Jaundice and Hyperbilirubinemia below). The human
placenta permits bidirectional transit of unconjugated bili-
The characteristic histologic features of the heterogeneous rubin [746]. In animal models, the placenta efficiently clears
liver parenchyma—including sinusoids and canaliculi bilirubin from the umbilical artery [747] and the amniotic
secured by tight junctions with hepatocytes straddling the fluid [748].
spaces between—are formed by a set of complex processes, Beginning at 5–6 weeks of gestation and through the
including apoptosis, morphogenic signaling, proliferation, second trimester, the liver enlarges 40-fold to assume the
and polarization of hepatocytes, involving cells from many primary role of hematopoiesis [749]. In mid-gestation,
embryologic tissue types [734]. At approximately the third to the liver contains more hematopoietic cells than hepato-
fourth week of gestation, the hepatic diverticulum arises cytes. Recently, the time course of hematopoiesis in the
from endodermal epithelia of the posterior foregut. These human liver was reported, confirming patterns of devel-
primitive pre-hepatocytes fold into mesodermal mesenchy- opment and morphology similar to that documented in
mal cells of the diaphragm forming a mixed population of murine models and earlier studies in humans [750]. That
cells of endodermal and mesodermal origin [737]. Under the is, although no clear hematopoiesis could be identified
control of a host of transcription factors, endodermal stem during the first 10 weeks, cells consistent with pluripo-
cells differentiate into progenitor cells which then are com- tent hematopoietic stem cells (perhaps migrating from
mitted to becoming either bile ducts or hepatocytes [734, the yolk sac?) were localized in the lumen of sinusoids.
738, 739], while mesodermal cells form blood vessels, Between 10 and 12 weeks’ gestation, hematopoietic cells
Kupffer cells, sinusoidal endothelium, and fibrous, connec- occupied roughly 20–30% of the hepatic parenchyma;
between 13 and 22 weeks, peak activity is associated When the umbilical cord is clamped, the liver no longer
with these cells occupying 70% of the parenchyma. In receives nutrient and oxygen-rich blood from the placenta.
general, the erythropoietic lineage quantitatively domi- Instead, the portal vein becomes the primary source for nutri-
nates every stage, especially between 13 and 22 weeks’ ents from the gut, and the hepatic artery provides arterial
gestation. Later, between 23 and 39 weeks, cells of the blood with significantly greater oxygen content. After meals,
erythropoietic line were at least three times greater than the portal venous flow increases, providing twice the blood
those of the myelomonocytic line. Finally, although pres- flow of the hepatic artery. The ductus venosus functionally
ent, megakaryopoiesis is a minor segment of the hemato- closes over the first two postnatal weeks [757]. The neonatal
poietic activity in the liver throughout gestation. Between liver comprises 4% of the body weight compared with only
23 and 39 weeks, hematopoiesis involuted to occupy 2% in the adult, reflecting its critical function during this
approximately 30% of the parenchyma. Thus, by the third period [734]. Consistent with this, 25% of the cardiac output
trimester, the bone marrow emerges as the principal site in the neonate is directed to the liver.
of blood cell production, but extramedullary hematopoi-
esis continues in the liver until after birth [749].
By the end of the first month of human gestation, primi- Early Postnatal Hepatic Function: Synthesis
tive hepatocyte function (protein synthesis and secretion) can
be detected [751, 752]. In early fetal life, the major circulat- Throughout gestation, the normal lower limit of glucose con-
ing protein is α-fetoprotein. At approximately two to three centration is approximately 54 mg/dL [731]. However, with-
months of gestation, albumin synthesis can be detected, and out a continuous supply of maternal substrates from the
adult serum concentrations are achieved by term. Glycogen umbilical vein, the newborn must maintain glucose homeo-
synthesis starts by the tenth week of gestation, and by stasis from sources of digested food, glycogenolysis, and
12 weeks, bile is secreted at a rate approximately 50–60% of gluconeogenesis. Until feeding is established, glycogen that
the level of adults [734]. has been stored mainly in the liver and heart during the third
trimester breaks down into glucose under the control of two
hormones: glucagon and catecholamines. Stress during
Early Postnatal Hepatic Function: Anatomy delivery or as a result of illness can accelerate the depletion
of glycogen stores, which may lead to hypoglycemia. Of
Throughout gestation, the fetus receives nutrients from the note, deprived of glycogen that is synthesized and stored
placenta via the umbilical vein, regulated by complex active during late gestation, preterm infants are particularly predis-
and selective transport mechanisms for sugars, amino acids, posed to hypoglycemia. Also, primarily secondary to greater
fats, and molecules [753]. Before birth, the liver receives metabolic requirements from the brain [758], glucose con-
approximately 50% of umbilical venous blood, with the sumption per body mass is greater in the preterm infant com-
remainder shunting through the ductus venous to flow pared with the term. Similarly, small- and large-for-gestational
directly into the inferior vena cava and the right atrium. This age neonates incur greater risks for hypoglycemia, second-
shunt serves to stream oxygen-rich blood from the ductus ary to decreased stores (SGA), and unreliable glucose
venosus directly from the right atrium through the foramen metabolism. Although key enzymes are expressed in the
ovale into the left-sided circulation and brain (Fig. 2.2). fetus, gluconeogenesis may not be active during fetal life.
Hypoxia and reduced umbilical venous return induce a redis- However, within 4–6 h of birth, gluconeogenesis plays an
tribution of flow away from the hepatic microcirculation to important role in glucose homeostasis [733] even in preterm
the ductus venosus and, therefore, to the left atrium (i.e., infants [759].
increased flow to the brain and other vital organs). Thus, the Neonates who cannot tolerate adequate enteral caloric
fetal liver plays a major role in determining venous return to substrates must receive exogenous glucose support, often
the heart and in regulating the distribution of oxygen and intravenously, to prevent hypoglycemia (see Chap. 8). Setting
energy substrates [754]. The liver receives variable amounts guidelines to evaluate and treat “hypoglycemia” has been
of the oxygen-rich blood flow, with most of the blood flow challenging. For example, based on a mathematical analysis,
directed to the left lobe. Fifty percent of the blood flow to the a level >47 mg/dL was posited as a necessary threshold to
right lobe arises from the umbilical vein and the remaining prevent adverse neurologic events [760]. Despite emphasiz-
50% from the portal circulation [755] (Fig. 2.3). As the per- ing that confounding factors prohibited establishing a defi-
cent of umbilical flow shunted through the ductus venosus nite causal relationship, this number (<47 mg/dL) remains
decreases as gestation advances (i.e., 40% at 20 weeks to the commonly quoted threshold of neonatal hypoglycemia
15% at term), the percent of flow to the liver increases (i.e., [731]. However, 47 mg/dL is not a “magic” number for treat-
50% at 20 weeks to 85% at term), primarily to the right lobe ing neonatal hypoglycemia [761]. Because of conflicting
[756]. data, experts admitted that: “We are not much closer today
to understanding the long-term neurodevelopmental conse- Amino acids via the portal circulation and plasma pro-
quence of hypoglycemia for these patients, and at what glu- teins via the hepatic artery are transported to the liver either
cose concentrations to become concerned” [762]. Similarly, to be degraded via the urea cycle or to serve as a substrate
Adamkin recently acknowledged, “A consistent definition for liver-derived plasma proteins. These liver-derived pro-
for neonatal hypoglycemia in the first 48 h of life continues teins include most circulating proteins with the major excep-
to elude us” [763]. tion of immunoglobulin [734]. Malnutrition or liver disease
Because clinically managing hypoglycemia must include may be manifested by reduced concentrations of circulating
the context (e.g., persistently low level in an asymptomatic proteins (e.g., albumin or ceruloplasmin). Conversely, acute
infant versus a single low value in a high-risk infant, such as inflammation decreases the efficiency of hepatic update and
an infant of a diabetic mother or SGA infant), the American metabolism of proteins that lead to increased concentrations
Academy of Pediatrics has established somewhat complex of certain circulating proteins (e.g., fibrinogen, an acute
guidelines for high- versus low-risk infants in the first 24 h phase reactant). Healthy preterm infants often have a rela-
of life, focusing on <4 h (25–40 mg/dL) and 4–24 h (35–45 tive hypoalbuminemia, which results from decreased amino
mg/dL) after birth [764]. If a neonate requires intravenous acid intake or albumin losses (renal, gut, or increased perme-
glucose, the goal is to maintain the blood level >45 mg/ ability [third spacing]), rather than an inability of the liver to
dL. In contrast to the American Academy of Pediatrics, the synthesize large amounts of albumin [753]. Abnormal hypo-
guidelines from the Pediatric Endocrine Society focus more albuminemia can lead to or result from edema (i.e., third
on hypoglycemia beyond the immediate neonatal period and spacing), ascites, and congestive heart failure.
recommend mean glucose levels of 55–65 mg/dL during the After a meal (or during parenteral nutrition), the hepa-
first 48 h after birth. The levels should increase so that by tocytes regulate the metabolism of free fatty acids allowing
72–96 h, the value should approximate those of older chil- their deposition as triglycerides in the liver or as adipose
dren and adults (>70 mg/dL). tissue. During fasting, these energy-rich molecules are con-
Because blood glucose concentrations as low as 30 verted to ketones and used for energy by neurons and other
mg/dL are common in normal neonates at 1–2 h, are usually cells. A lack of ketone production is associated with a poten-
transient, and are characteristic of mammalian adaptation tially fatal defect in metabolic pathways (e.g., deficiency of
from intrauterine to extrauterine life, some authors classify long-chain 3-hydroxyacyl dehydrogenase, an enzyme impor-
this as “physiologic glucose homeostasis” [765]. Because of tant in fat oxidation) [768, 769].
the variability in blood glucose levels over the first 3 days,
based on a meta-analysis of published reports, some have
defined “normal” glucose levels in normal term infants as a arly Postnatal Hepatic Function:
E
function of narrow ranges of postnatal age. That is, at 1 to 2, Metabolism
3 to 23, 24 to 47, and 48 to 72 h of age, the lower threshold
(<5th percentile) was reported as 28, 40, 41, and 48 mg/dL, The bile transport enzymatic system is activated when the
respectively [766]. liver transitions to the primary organ for bile elimination.
In summary, the AAP guidelines should be followed when Bile includes bilirubin (the end product of heme degrada-
managing high-risk symptomatic infants during the first 24 tion) and the detergent-like bile acids (amphipathic sterol
postnatal hours [767]. For infants between 24 and 48 h of molecules synthesized from cholesterol). In addition to
age, the concentration of glucose should be maintained at serving as important molecular building blocks for a vari-
>45 mg/dL. No evidence exists to modify these guidelines ety of synthetic pathways, bile acids play an essential role
for infants undergoing surgery and anesthesia, especially if in lipid digestion by emulsifying partially digested fat
glucose monitoring is available intraoperatively. droplets, adsorbing lipid-soluble vitamins (A, D, E, and K),
The term as well as the preterm neonate responds to and activating key endogenous digestive enzymes as well
increased concentrations of circulating glucose by releas- as breast milk lipase (also known as bile salt-stimulated
ing insulin, which promotes the uptake of glucose either for lipase) [770].
immediate energy or for storage (as triglycerides or glyco- The enterohepatic circulation provides a critical mecha-
gen). Of importance, abruptly decreasing or discontinuing nism for conserving bile. Approximately 95% of bile acids
an exogenous source of glucose (e.g., discontinuing intra- secreted into the intestine are reabsorbed via the portal
venous alimentation, separation from the placental delivery venous circulation and taken up by hepatocytes via sev-
of high glucose concentrations during gestational diabetes, eral specific bile acid transporter proteins [771]. Although
prolonged NPO period without an intravenous source of glu- bile acid production may be detected as early as 14 weeks
cose) increases the risk for hypoglycemia. Other risk factors of gestation [772], production is immature in the neonate,
for hypoglycemia include liver dysfunction (e.g., shock or especially the preterm infant, increasing the risk for bile-
sepsis) and inborn errors of metabolism. deficiency-associated steatorrhea (“diarrhea of infancy”),
vitamin deficiency, and caloric malnutrition (see Jaundice importance, the genes that regulate the production of these
and Hyperbilirubinemia, below). proteins undergo developmental expression [777, 778, 785–
After birth, hepatic enzyme activity increases rapidly. For 787]. For example, although highly functional in utero, the
example, while levels in cord blood [773] and in neonates activity of CYP3A7 rapidly diminishes by birth. In contrast,
are normally increased (mean values, 3.8–4.6 mmol/L) [774, CYP3A4 is expressed minimally in utero, whereas by six
775], the concentration of lactate typically decreases to near- months of age, activity increases to approximately 50% of
adult values within 24 h postnatally (mean 2.08 vs. 1.8 upper adult levels [777]. Phase II reactions also follow age-related
limit adult norm) [775]. Persistently increased serum lactate patterns. For example, glucuronidation (UGT2B7) of mor-
concentrations suggest increased production (poor perfusion phine does not reach adult rates until 2–6 months of age
and anaerobic metabolism), hepatic dysfunction, or mito- [787]. Another example includes human hepatic UGT2B15
chondrial metabolic defect [776]. that is expressed only late in gestation and maturation con-
In part, the variability in drug disposition in the neonate tinues postnatally [788].
can be attributed to the maturation of drug-metabolizing sys- The immaturity of these pathways is associated with two
tems and membrane transporter proteins. The ontogeny of clinically significant phenomena. First, the developing liver
these proteins is classified into three groups: high expression may be exposed to the toxic effects of large concentrations of
during gestation with low to no expression after 1 year of compounds that cannot be excreted [789]. Second, to avoid
age (e.g., phase I metabolizing enzymes such as CYP3A7 side effects of high serum concentrations, age-related dosing
and phase II metabolizing enzymes, sulfotransferase), stable may be required for drugs that are inefficiently cleared by
expression of the protein (e.g., CYP3A5 and SULT1A1), the immature liver (e.g., certain muscle relaxants and opi-
and low expression during gestation but increasing postna- oids [790–793], midazolam [794], caffeine and theophylline
tally [777]. The third category is probably the most common [795], and propofol [796]). Finally, variability in CYP2D6,
pattern, including enzymes such as CYP1A2, CYP2C19, which is responsible for the metabolism of as many as 25% of
CYP2E1, and CYP3A4 [777]. commonly used drugs (e.g. antiemetics, β-blockers, opioids)
A tremendous effort has focused on establishing the has prompted classifying individuals as ultra-, extensive,
patterns of development in the hepatic drug-metabolizing intermediate, and poor metabolizers [797].
enzymes (phase I [oxidation–reduction reactions and hydro-
lysis], phase II [conjugation with glucuronic acid and other
substances], and phase III [excretion from the liver/biliary arly Postnatal Hepatic Function: Common
E
system] reactions) critical for biotransformation and detoxi- Neonatal Hepatic Disorders
fication of exogenous substances and xenobiotics (e.g., medi- and Hemorrhagic Disease of the Newborn
cations) [777–779] (see Chap. 3). In contrast, the critical role
of drug transporters has only recently emerged and remains At birth, the liver rapidly increases the production of circu-
in the early stages of investigation [780, 781]. A recent report lating proteins of the coagulation cascade (except factor
focused on the organic anion transporters that function in VIII, which achieves adult levels within a few days).
the uptake of a wide range of molecules into a variety of Although synthesized in the hepatocytes, the vitamin K
organs, including the liver (e.g., OATP1B1 and OATP1B3). (koagulation) carboxylation-dependent factors (II, VII, IX,
Substrates for these two transporters of the OATP family and X) depend on the maturation of the digestive system to
include bile salts, thyroid hormone, and methotrexate and achieve normal function. The bacteria that colonize the gut
angiotensin II receptor antagonists [782]. after initiation of enteral feeds are an important source of
The cytochrome P450 system mediates phase I reactions vitamin K. Until the microflora are mature and the absorp-
and is variably induced at birth [783]. In addition to the tion of fat-soluble vitamins is robust, quantities of vitamin
enormous variability in developmental expression of these K may be insufficient to prevent pathologic bleeding (e.g.,
proteins, genetic (e.g., sex, polymorphisms) and nongenetic intracranial hemorrhage) [798]. For this reason, current
host (e.g., age, disease) and environmental factors (e.g., drug guidelines (in the United States) recommend that healthy
exposure) combine so that “every individual possesses his/ neonates receive 0.5–1 mg of parenteral (intramuscular)
her own unique CYP profile with important implication for vitamin K shortly after birth, which significantly decreases
drug treatment” [784]. Of particular relevance to the anes- the risk of both early and late bleeding secondary to vitamin
thesiologist are the drug-metabolizing CYPs (CYP1, A1/A2; K deficiency [799]. Otherwise, healthy infants do not require
CYP2, A6/B6/C8/C9/C19/D6/E1/J2; CYP3, A4/A5) that further supplementation, and vitamin K deficiency after
account for >95% of drug metabolism in adults [784]. Of 6 weeks is rare [734] in the absence of conditions that
impact its synthesis (such as antibiotic therapy affecting gut glucuronic acid and the organic anion transporter (OATP2)
flora) or absorption of fat-soluble vitamins (such as liver [809]. Furthermore, uptake into the liver is less efficient,
disease, including hepatitis and alpha-1-antitrypsin defi- in part due to low levels of ligandin, a hepatocyte cytosol
ciency) [800, 801]. binding protein [810]. Glutathione S-transferase contrib-
utes to the intracellular binding of bilirubin. Although low
at birth, concentrations of this enzyme reach adult levels
arly Postnatal Hepatic Function: Common
E 1–2 weeks after birth. In the hepatocyte, lipophilic bili-
Neonatal Hepatic Disorders, Jaundice, rubin is transformed into a polar, water-soluble substance
and Hyperbilirubinemia that is suitable for excretion in urine (conjugated or direct
bilirubin) by conjugation with one or two glucuronic acid
Neonatal jaundice refers to the easily visible cutaneous molecules, a reaction catalyzed by uridine 5′-diphosphate
yellow- orange color that accompanies excess bilirubin glucuronosyltransferase 1 (UGT1A1). The activity of this
deposits in the skin (total serum bilirubin levels >~5 mg/dL enzyme is diminished in neonates, increasing to adult levels
[85 micromol/L]) [802]. Increased serum concentrations of postnatally [811]. That is, the expression of isoenzymes of
unconjugated bilirubin (which indirectly reacts with diazo UGT1A1 is developmentally regulated; activity is 0.1% of
reagents in the laboratory and, therefore, termed indirect) adult levels at 17–30 weeks of gestation and 1% of adult
that is visually detectable occurs in approximately 65% values between 30 and 40 weeks of gestation, and adult lev-
[803] to 85% [804] of all normal infants during the first week els are attained by 14 weeks of postnatal life. Unconjugated
of life as a normal and transient phenomenon. Cephalocaudal bilirubin induces hepatic UGT1A1 activity, independent of
progression of jaundice is associated with, but is not a reli- the gestational age [812].
able measure of, absolute bilirubin levels. For example, The sterile gut of the neonate lacks the bacteria-medi-
when the bilirubin concentrations are approximately 5 mg/ ated conversion of bilirubin to urobilinogen. As a result,
dL, jaundice is generally most apparent in the face, but as the conjugated bilirubin remains in the lumen, where it can
serum concentrations increase, jaundice appears in the skin be de-conjugated, in a reaction catalyzed by the enzyme
of the thorax and abdomen, but in a quantitatively unpredict- β-glucuronidase. This unconjugated bilirubin can be
able manner. Without jaundice, pathologically increased reabsorbed via the enterohepatic circulation, further decreas-
concentrations of bilirubin can be excluded [805, 806]. ing the efficiency of bilirubin excretion.
The so-called physiologic jaundice of the newborn (gen- The enterohepatic system in the neonate should “catch
erally less than 12 mg/dL) results from the normal hepatic up” with the increased load of bilirubin and decreased
immaturity during the transition from fetal to extrauterine clearance within the first 2 postnatal weeks so that biliru-
life. Of primary significance, because of two inherent char- bin concentrations can decrease to adult values by that time.
acteristics of fetal hemoglobin, neonates encounter a large Differentiating physiologic from pathologic concentrations
burden of bilirubin. That is, a relatively large red blood of bilirubin presents a challenge as the range of “normal”
cell (RBC) mass coupled with a shortened erythrocyte life varies among racial groups, with breastfeeding versus bottle-
associated with fetal hemoglobin predisposes the newborn feeding, and other epidemiologic factors. Bilirubin concen-
to hyperbilirubinemia. Further, the large quantity of biliru- trations are dynamic, and an absolute blood concentration
bin stored in meconium may be reabsorbed into the portal that differentiates physiologic from pathologic is difficult
circulation (i.e., enterohepatic circulation) and hepatocytes, to pinpoint [813]. Mechanisms for the production of and a
especially if elimination of stool is limited secondary to differential diagnosis of neonatal hyperbilirubinemia vary
intestinal anomalies (e.g., bowel atresia and/or obstruction) from anatomic, metabolic, and genetic etiologies to exag-
or dysfunction (e.g., ileus with sepsis or necrotizing entero- gerated normal physiology (Table 2.2). Because the placenta
colitis) [807, 808]. Jaundice should be considered abnormal efficiently clears bilirubin, some conditions that are associ-
if it [804]: ated with pathologic jaundice such as hemolysis may not be
immediately jaundiced at birth. However, by 12–48 h after
• Presents in the first 36 h of life birth, the production of the same bilirubin that occurred in
• Persists beyond 10 days of life utero may result in jaundice.
• Increases to >12 mg/dL Jaundice associated with breastfeeding (breast milk jaun-
• Includes direct (conjugated) bilirubin >2 mg/dL and dice) is a benign, self-limited condition. Although a single
>30% of total bilirubin specific cause has not been identified, substances (e.g.,
β-glucuronidase) in mature breast milk that promote entero-
Finally, immature processes in the liver contribute to the hepatic uptake of bilirubin have been implicated [814–816].
substantial risk for neonatal indirect hyperbilirubinemia. This entity must be distinguished from jaundice due to “not
Uptake of bilirubin into hepatocytes for conjugation requires enough breastfeeding,” which is characterized by poor feed-
Table 2.2 Mechanisms of newborn jaundice (from [802]) the most common cause of chronic end-stage liver in liver
Physiologic jaundice in the newborn disease in children [818, 821]. Recently, the Japanese liver
Catabolism of heme transplant society reported excellent long-term survival of
From breakdown of fetal erythrocytes the graft at 1, 5, 10, 15 and 20 years after a living-related
From myoglobin, cytochromes, catalase liver transplant after Kasai (90.5%, 90.4%, 84.6%, 82.0%,
Decreased uptake into and excretion from liver cells and 79.9%). In Japan, living-related liver transplant was pos-
Low neonatal concentration of ligandin, the intracellular-binding
sible even in patients weighing less than 5 kg with early liver
protein
Low neonatal activity of uridine diphosphate failure after a Kasai operation using a “reduced left lateral
glucuronosyltransferase (UD-PGT) segments.” To facilitate the success of this early interven-
Nonphysiologic jaundice tion, effort was focused on increasing the donor pool, which
Increased heme catabolism decreased the mortality associated with a prolonged waiting
Congenital hemolytic anemias (e.g., glucose-6-phosphate list [822]. Although primary liver transplant for this disor-
dehydrogenase deficiency, spherocytosis)
der is rare, a recent report noted that “the Kasai operation
Immunologically mediated hemolysis (e.g., rhesus and ABO
incompatibility) has the greatest failure rate in its stated objective than any
Extravasation of blood (bruising, fractures, intracranial other operation in pediatric surgery. Failure to achieve any
hemorrhages) improvement in jaundice occurs in over 30% of all cases,
Decreased bilirubin conjugation and excretion even in the best of hands, and transplantation or listing for
Genetic defects in UDGPT (e.g., Crigler–Najjar, Arias type 2, transplantation occurs in over half the children with type
Gilbert)
II and III BA by one year of age in countries where liver
Hepatic and biliary disease (e.g., neonatal hepatitis, intra- and
extrahepatic biliary atresia)
transplantation is readily available.” The author suggests that
Increased enterohepatic circulation of bilirubin primary liver transplant may offer advantages, proposing a
Decreased bowel passage (e.g., intestinal atresias, necrotizing “multi-institutional effort that is aimed at sparing more than
enterocolitis, fasting, inadequate nutrition [breastfeeding a third of children who derive no benefit from the Kasai pro-
jaundice]) cedure from a futile procedure” [823]. Thus, jaundice at the
Increased deconjugation of bilirubin in the bowel (e.g., breast one-month pediatric evaluation should prompt consideration
milk jaundice)
of hepatic disease, including biliary atresia and other chol-
angiopathies, and possibly referral to a pediatric gastroenter-
ing, infrequent stools, and poor weight gain. Although a ologist and/or liver transplant center.
similar pattern of inadequate oral intake can develop dur- Liver dysfunction (e.g., conjugated [direct] hyperbiliru-
ing feeding with formula, association with breastfeeding binemia) or injury frequently accompanies hemodynamic
requires careful assessment of maternal factors and tech- insults associated with hypoxia, ischemia, sepsis, or primary
niques of feeding. To avoid dehydration and worsening of liver infection. In such cases, increased serum concentrations
hyperbilirubinemia, adequate enteral feeding must be estab- of liver enzymes reflect hepatocyte injury. Of importance,
lished or alternative hydration delivered (e.g., intravenous hepatocyte injury impairs synthetic function, manifested by
fluid) until the cause of inadequate oral intake is identified reduced serum albumin concentration and/or abnormal coag-
and eliminated [817]. ulation function (i.e., prolonged prothrombin time, decreased
Abnormalities in the enzymes of conjugation, anatomic fibrinogen levels) [824–827]. Fulminant liver failure may
malformations of the biliary system (e.g., biliary atresia), result from gram-negative (e.g., Escherichia coli) or menin-
and obstructive processes (e.g., neonatal obstructive fibro- gococcal bacteremia or viral infections (e.g., herpes simplex,
sclerosing cholangiopathy) [818, 819] impair biliary func- adenovirus, or echovirus) [828, 829]. With prompt restora-
tion, often leading to jaundice in the first months of life. tion of perfusion or effective treatment of infection, transam-
Prolonged (e.g., 2–3 weeks) and/or severe hyperbilirubine- inase levels (so-called liver function tests) usually decrease,
mia, development of progressive direct hyperbilirubinemia, but hyperbilirubinemia may persist for weeks [734].
and/or other signs of hepatic dysfunction (e.g., hepato- Neonatal cholestasis commonly is associated with liver
megaly, acholic stools, failure to thrive) demand meticulous injury during parenteral nutrition, and, in this setting,
evaluation to establish a definitive diagnosis. For example, increased conjugated bilirubin is associated with significant
without surgical intervention for biliary atresia (the Kasai morbidity [830, 831]. Preterm infants are more vulnerable to
procedure: resection of fibrotic extrahepatic biliary system liver injuries for a multitude of reasons, including a greater
and creation of a hepatoportoenterostomy) within several incidence of episodes of ischemia and hypoxia, of gastro-
months after diagnosis dramatically increases the likelihood intestinal and systemic infections due to immaturity of the
for infantile liver transplantation [820]. Of note, even after gut epithelium, and of requiring parenteral nutrition [734,
a timely Kasai, end-stage biliary cirrhosis eventually devel- 832]. Exaggerated immune responses to inflammatory trig-
ops in 70–80% of patients, so that biliary atresia remains gers such as lipopolysaccharide associated with decreased
T-cell-mediated immune modulation may also predispose and subthalamic nuclei), and even death [841, 842] follow
the neonate to hepatic injury during systemic infection [833]. this injury. The MRI of an infant with kernicterus mirrors
In addition to its roles as a marker of liver disease, the distinct regional nature of bilirubin-induced neuropathol-
hyperbilirubinemia can directly injure neural tissue, result- ogy, including abnormal bilateral, symmetric, high-intensity
ing in a neuropathologic syndrome known as kernicterus, signals in the globus pallidus and subthalamic nuclei and on
the pathologic term that describes the autopsy finding of occasion the internal capsule and thalamus. These structural
yellow-stained deep brain nuclei but sparing the neocortex. findings are equally apparent in both preterm and term neo-
That is, although hyperbilirubinemia is usually a benign, nates with neurologic consequences secondary to hyperbili-
transitional process in newborns, bilirubin-induced neuro- rubinemia [843].
logic damage (BIND) persists as a devastating complica- Chronic bilirubin encephalopathy (classic kernicterus) is
tion of severe hyperbilirubinemia [804, 834, 835]. Because characterized by a tetrad of clinical signs of varying sever-
experts apply the term “BIND” inconsistently, the litera- ity: movement disorders (athetosis, dystonia, spasticity, and
ture categorizing the neurologic complications of hyper- hypotonia), auditory neuropathy, oculomotor impairments,
bilirubinemia is inconsistent and confusing. For example, and dental enamel hypoplasia of the permanent teeth [841].
in some cases, BIND includes the entire spectrum of acute Although the precise cellular and molecular schema of injury
and chronic injury, both mild and severe [804, 836]. Acute has not been completely defined, the injury involves inflam-
bilirubin encephalopathy (ABE) specifically refers to neuro- matory insults and neuro-excitotoxicity [804, 843]. On the
logic abnormalities during the first few postnatal weeks. If other hand, the role of inflammation in this injury is complex.
untreated, ABE progresses to a chronic permanent disorder, For example, recently, a pathway has been described that
kernicterus. In other cases, experts reserve the term “BIND” implies that bilirubin-induced proinflammatory responses
for a subtle, less severe type of injury without the findings can paradoxically be neuroprotective, in part secondary to
of classical kernicterus. In this schema, BIND includes antioxidant effects [844, 845].
abnormalities of sensory integration, central auditory pro- The blood–brain barrier limits the entry of water-solu-
cessing, coordination, and muscle tone [837, 838]. Recently, ble, conjugated bilirubin as well as bilirubin that is bound
Le Pichon confronted this dilemma with a detailed proposal to albumin [846, 847]. Therefore, in addition to increased
to adopt consistent classification of the subsets of injury concentrations of bilirubin (i.e., unconjugated, lipophilic
and establish standard diagnostic criteria for “kernicterus form), hypoalbuminemia increases the risk of kernicterus.
spectrum disorders,” including defining and scoring sever- Furthermore, insults that impair the function of the blood–
ity, tailoring treatment, and describing short- and long-term brain barrier (e.g., hypoxia, respiratory acidosis, hypother-
outcome [839]. mia, sepsis, trauma, and prematurity) predispose to primary
In the early stage (1–3 days), ABE includes an acute central nervous system injury from hyperbilirubinemia
encephalopathy with nonspecific signs (lethargy, poor feed- because of increased access of this molecule to the brain
ing, abnormal tone, a high-pitched cry). As the disorder [848–851]. Thus, overall, when the level of bilirubin over-
progresses to an intermediate phase (4–6 days), symptoms whelms neuroprotective mechanisms, brain damage ensues.
include opisthotonos/retrocollis, seizures, and even coma. But, in addition to the actual level of unbound bilirubin,
Hypotonia, active deep-tendon reflexes, and delayed motor the risk of brain injury reflects a wide range of events and
skills predominate during the first year. Later phases include complex interactions, including the duration of exposure,
profound movement disorders including dystonia and ath- permeability of the blood–brain barrier, the intrinsic vulner-
etosis, choreoathetoid cerebral palsy with tremor, ballismus, ability of the brain (e.g., gestational and postnatal age, aci-
gaze (usually upward) abnormalities, sensorineural hearing dosis, inflammation, sepsis), and the response to aggressive
loss, or auditory neuropathy, and, in some cases, cognitive treatment. Neurons undergoing differentiation at the time of
delays [840]. This chronic phase of bilirubin neurotoxicity exposure to bilirubin may be most susceptible to bilirubin’s
correlates with the pathology in the central nervous system apoptosis-inducing effects [804]. The greater risk for neuro-
secondary to the deposition of bilirubin in the globus pal- toxicity in preterm infants is exacerbated by a high incidence
lidus, subthalamic nucleus, midbrain/pontine/ brain stem of concurrent disease (e.g., sepsis, respiratory acidosis),
nuclei (especially related to visuomotor function), hippo- nutritional deficits (e.g., hypoalbuminemia), and frequent
campal neurons, diencephalon, central and peripheral audi- drug therapy (i.e., hepatic dysfunction, competition for bind-
tory pathways, and cerebellar cells. In other infants, a more ing to albumin and other serum proteins) [836].
restricted injury including less severe neural hearing deficits By increasing the risk of hemolysis, various genetic
(auditory dyssynchrony or neuropathy) and minor fine or enzyme deficiencies (e.g., glucose-6-phosphate dehy-
gross motor deficits is associated with localized injury to drogenase deficiency, a hereditary condition prevalent in
neural pathways. Changes in EEG and auditory brain stem African-Americans) [852] are also associated with neonatal
responses, and abnormalities on MRI (e.g., globus pallidus hyperbilirubinemia. Reduced UDP-glucuronosyltransferase
(UD-PGT) activity can also increase the concentration of (i.e., when to initiate phototherapy, how long to continue,
unconjugated bilirubin, especially in the setting of prema- indications for exchange transfusion) should be based on
turity, sepsis, or certain defects in hemoglobin and biliary several variables including the trend in the absolute concen-
metabolism. With an incidence of ~1%, Gilbert disease is tration, the rapidity of the increase in bilirubin concentration
characterized by slightly decreased activity of UD-PGT, but (e.g., the trend in the concentration from hour to hour), and
with activity markedly impaired during physiologic stress the predicted risk (e.g., gestational and postnatal age, ongo-
such as infection or neonatal asphyxia [853]. In contrast, ing hemolysis, current medical status [acidosis, sepsis]) to
Crigler–Najjar syndrome has decreased (type II) or absent allow more accurate and effective treatment [862]. In par-
(type I) UD-PGT activity secondary to a variety of mutations ticular, depending on gestational age, preterm infants require
[854, 855], which, if untreated, leads to unconjugated hyper- scrutiny and individualized analysis due to the higher risk
bilirubinemia and irreversible neurologic injury [856]. Other of neurologic injury at lower bilirubin levels in the setting
genetic and environmental factors (such as UDP-GT1A1 of unstable and variable status and therapies. Because of
polymorphisms) may either increase the risk of kernicterus limited evidence-based data, recommendations for the man-
in the presence of relatively low bilirubin concentrations or, agement of hyperbilirubinemia in preterm infants evolved
in some cases, protect from kernicterus despite hyperbiliru- from a consensus-based process with patient-specific con-
binemia [857–861]. siderations [836, 845, 867]. These references are relevant for
The guidelines from the American Academy of Pediatrics perioperative care.
for the management of hyperbilirubinemia in the term and Phototherapy was first demonstrated to attenuate the
near-term neonate stress prevention of kernicterus through serum concentration of bilirubin in 1958 [869] and then
primary prevention (i.e., establishing appropriate nutrition to became an accepted treatment in the United States in the late
decrease enterohepatic recirculation of bilirubin), secondary 1960s [870]. Phototherapy effectively decreases the serum
prevention (i.e., early detection of high-risk infants includ- concentration of bilirubin by converting lipophilic bilirubin
ing screening of bilirubin levels) (Fig. 2.16), and following to more soluble, structural isomers (lumirubin), or configura-
specific protocols to initiate therapies such as phototherapy tional isomers, facilitating the excretion in a non-conjugation-
and exchange transfusion [862–864]. Compared with term dependent process [849, 871–874]. By rapidly converting
infants, preterm and late preterm infants are at greater risk bilirubin to the more polar photo isomers, phototherapy may
of kernicterus, even at lower concentrations of bilirubin decrease bilirubin-associated central nervous system injury.
[845, 865, 866]. For example, “low-bilirubin kernicterus” is That is, phototherapy may be effective by producing photo
a refractory cause of bilirubin neurotoxicity in the preterm isomers that inflict less direct neural toxicity, decreasing the
infant. Hypoalbuminemia is common in preterm infants and transit of the more polar bilirubin photoproducts across the
is a consistent finding in low-bilirubin kernicterus. At the blood–brain barrier, or by changing the proportion of free
same time, preterm infants fail to demonstrate classic neu- bilirubin to total bilirubin [875, 876]. Instead of exposure to
romotor signs of bilirubin toxicity. The only clinical mani- sunlight, artificial light of modern phototherapy is designed
festation may be recurrent apnea [843]. Treatment protocols to expose the infant to light with a wavelength of 450 nm
Fig. 2.16 Nomogram used to 25 428

designate risk in 2840 well
neonates at 36 or more weeks’
gestational age with birth
weight of 2000 g or more or 20 342
35 or more weeks’ gestational 95 th%ile
High Risk Zone
Serum Bilirubin (mg/dl)
age and birth weight of

ne
2500 g or more based on the k Zo
15 t e Ris 257
hour-specific serum bilirubin ia
med ne
nter
µmol/L
values. Note that this I k Zo

Hig
h
t e Ris
nomogram is for predicting dia
rme
likelihood of a subsequent 10 w Inte 171
bilirubin level exceeding the Lo
95th percentile—not to Low Risk Zone
represent the natural history
of neonatal 5 85
hyperbilirubinemia (from
[862]; citing Bhutani et al.
[868])
0 0
0 12 24 36 48 60 72 84 96 108 120 132 144
Postnatal Age (hours)
(blue) to avoid overheating [877]. Overall, the goal is to out of the brain. That is, the active transport of bilirubin from
reduce the risk of kernicterus by decreasing the total con- the brain into the blood may diminish injury, but acidemia
centration of bilirubin to less than that historically associated may inhibit this activity [887]. Similarly, the severity of the
with kernicterus (~20 mg/dL [340 micromol/L] for healthy injury depends on both the duration and concentration of
term babies). Phototherapy may also be used to bridge to unbound bilirubin in the vulnerable developing brain, since
liver transplantation in Crigler–Najjar type I [878]. Finally, the immature brain may be particularly at risk for apoptosis
phenobarbital can be used to induce UD-PGT activity in the and necrosis, especially in the presence of infection or other
setting of insufficiency (e.g., in Crigler–Najjar type II). stressors [841].
With the improvements in phototherapy, the need for The neonatal anesthesiologist must appreciate that the
exchange transfusion for neonatal jaundice (first found to be critically ill neonate who is at high risk for hemodynamic
effective in 1951) [879] has all but disappeared [849, 880]. and respiratory instability and associated respiratory or
If an exchange transfusion is required, one or two central metabolic acidosis, hypoalbuminemia, and liver dysfunction
venous catheters are placed, and small aliquots of blood are may at the same time incur increased risk for bilirubin neuro-
removed and then replaced with a mixture of donor (and toxicity. Hepatic dysfunction and immaturity may disrupt the
bilirubin-free) RBCs and plasma (or albumin). Infusion of normal metabolism of drugs including commonly used anes-
albumin before the exchange transfusion may increase the thetic agents (e.g., muscle relaxants). Finally, hemostasis
amount of bilirubin removed during the procedure [881]. In must be meticulously evaluated preoperatively and aggres-
addition to decreasing the bilirubin concentrations, exchange sively monitored and treated intraoperatively.
transfusion may reduce circulating antibody concentrations
during ongoing hemolysis. Severe complications in approxi-
mately 2% of patients undergoing exchange transfusion Renal Function (also See Chap. 8
[882] include problems associated with central line place-
ment (thrombosis, bleeding) and necrotizing enterocoli- In utero, the placenta maintains fetal metabolic and electro-
tis [883], electrolyte disturbances, and thrombocytopenia. lyte homeostasis. Permanent kidneys appear during the
Currently, exchange transfusions are recommended only to fifth week of gestation and nephrons during the eighth
treat acute bilirubin encephalopathy or hyperbilirubinemia week, initially in the juxtamedullary region and cortex. A
resistant to phototherapy. Levels of total serum bilirubin at complex interaction of genes (e.g., Wilms’ tumor gene 1
which exchange is recommended vary with associated risk [WT1] and growth factors [neurotrophic factor {GDNF}])
factors (e.g., isoimmune hemolytic disease, G6PD defi- orchestrates this process [888, 889]. By 20 weeks’ gesta-
ciency, signs of sepsis or asphyxia, gestational and postnatal tion, one-third of the full complement of nephrons has
age, and the bilirubin–albumin ratio) [862]. developed [890]. By 35–36 weeks’ gestation, the number
of nephrons equals that of the normal young adult [891].
When the full complement of nephrons is reached, the kid-
Clinical Significance and Summary neys mature by increasing both glomerular and tubular
size; no new nephrons/glomeruli develop. Infants born pre-
Immature and/or abnormal hepatic function in the neonate maturely develop new nephrons until about 34–35 weeks
presents several challenges in the setting of anesthesia and postconceptional age. More than 60% of nephrons form
surgery. Some medications (e.g., ceftriaxone, furosemide, during the third trimester [892]. Vascular growth and devel-
and oxacillin, but not methicillin) compete with bilirubin for opment parallel nephrogenesis.
albumin-binding sites. If displaced from albumin, the pro- The degree of renal immaturity in preterm infants is
portion of unbound or “free” bilirubin concentration inversely proportional to the gestational age. Nephrogenesis
increases, exaggerating the risk for neurotoxicity from this stops at 40 days after birth [893]. In some cases, this event
molecule crossing the blood–brain barrier [884, 885]. Of results in a low endowment of nephrons and consequent
note, in some cases, a preservative or other additive to a phar- hypertension and endothelial dysfunction [21, 26, 894], an
macologic preparation rather than the drug itself may dis- example of the phenomenon of “Developmental Origins of
place bilirubin from albumin (e.g., the sodium benzoate in Adult Disease” (see Introduction). In addition to interrupt-
intravenous diazepam) [886]. ing normal organogenesis of the kidney and its vascular bed,
Acidemia exaggerates bilirubin neurotoxicity primar- prematurity and intrauterine growth restriction both inflict
ily by its effects on bilirubin solubility and the decreased negative effects on postnatal renal growth [30, 31, 895].
binding of protonated bilirubin to albumin [848, 849, 887]. The number of nephrons varies by up to fivefold among
Neurologic injury associated with a given level of bilirubin mature, healthy term infants. The number of nephrons per
may vary as a function of the effectiveness of protective kidney averages approximately 1 million but ranges from
mechanisms that determine the relative transport into and about 300,000 to over 2 million [896]. Infants born at term
with a smaller-normal endowment of nephrons are at greater term [909, 910] and peaks at approximately 3 months of age
risk for systemic hypertension and other cardiovascular and [911]. During the first 3–7 days of extrauterine life, healthy
renal diseases as are preterm infants [19, 897]. Both genetic term infants lose about 5–10% of their body weight, primar-
and environmental factors may account for the reduced num- ily through contraction of the extracellular water space; pre-
ber of nephrons [30, 31, 898]. Chromosomal anomalies, copy term infants <1500 g may lose 10–15% of body weight
number variants, and monogenic abnormalities combine to [911]. Transepidermal fluid loss is related to gestational age
account for 30–50% of congenital abnormalities of the kid- and can be as much as 60–100 mL/kg/day in ELBW infants.
ney and urinary tract [899]. Mutations in HNF1B, the gene Over the first 5 days of life, fluid losses decrease dramati-
encoding hepatocyte nuclear factor 1β, are the most com- cally (from 45 to about 19 g/m2/h) in infants at 25–27 weeks’
monly identified genetic cause of renal malformations [900, gestation [912]. During the first few postnatal days, naked
901]. Of note, HNF1B-associated disorders extend beyond preterm infants lose up to 15 times more water through evap-
the kidney (e.g., genital tract anomalies, pancreatic hypopla- oration than naked term infants [913]. Naked VLBW infants
sia, abnormal liver function) [902]. A polymorphism of the may lose up to 10% of their body weight through evapora-
RET gene is associated with a decreased number of nephrons tion during the first 24 h of life. Although decreasing over the
[903, 904] and a common variant Pax2 with smaller kidneys first postnatal weeks, the transepidermal water loss of an ex-
at birth [905]. Interaction between HNF1B and Pax2 may 24-week gestation infant is twice that of a term infant at
be crucial to the normal development of the kidney and uri- 28 days [914].
nary tract, with mutations associated with multi-cystic and/ At least in part, the “contraction” of the extracellular
or hypoplastic kidneys [906]. Finally, environmental factors compartment has been linked to atrial natriuretic peptide, a
(intrauterine growth restriction, hyperglycemia, exposure to hormone produced in and released from the myocardium in
cocaine or alcohol) contribute to abnormal renal and urinary response to stretch of the atrium. Increased left atrial pres-
tract development [899]. Specific maternal medications such sure associated with increased pulmonary blood flow at birth
as angiotensin-converting enzyme inhibitors or angiotensin triggers the release of atrial natriuretic peptide [915].
receptor blockers, glucocorticoids, and anti-seizure medica-
tion (and others) have been associated with renal agenesis
and anomalies [899]. Finally, oxidative injury during the GFR and Blood Flow
neonatal period has been associated with decreased capillary
density and fewer nephrons in adult rats [907]. Fetal and neonatal renal function is characterized by reduced
Urine is first formed by 10 weeks’ gestation, and produc- renal blood flow, glomerular filtration rate (GFR), solid
tion increases from about 2–5 mL/h at 20 weeks’ gestation excretion, and concentrating capacity. In part, renal blood
to 10–12 mL/h at 30 weeks, 12–16 mL/h at 35 weeks, and flow is reduced in utero because of increased renal vascular
35–50 mL/h at 40 weeks’ gestation [908]. The fetal kid- resistance. After birth, renal blood flow improves markedly
neys produce large volumes of hypotonic urine essential to due to increased arterial blood pressure and decreased renal
maintain normal amniotic fluid volumes, especially after vascular resistance, which allow more of the cardiac out-
18 weeks’ gestation. In turn, large volumes of fetal urine are put to flow to the kidneys (2–4% in utero, 10% at 1 week
necessary for normal pulmonary development. For example, of age, 25% in the adult). Renal blood flow is about 20
oliguria resulting in oligohydramnios is associated with spe- mL/min/1.73 m2 at 30 weeks, 45 mL/min/1.73 m2 at 35 weeks,
cific facies, clubfeet, limb contractures, and, in severe cases, 80 mL/kg/1.7 m2 at term, 250 mL/min/1.73 m2 at 8 days, and
pulmonary hypoplasia (Potter’s sequence/oligohydramnios 770 mL/min/1.73 m2 at 5 months of age [916]. Similarly,
sequence). GFR increases rapidly in utero as the number of nephrons
increases. Because growth of the fetal kidney begins deep in
the medulla, the juxtamedullary nephrons are more mature
evelopmental Changes in Distribution
D than other nephrons at birth and have greater tubular length
of Total Body Water than outer and inner cortical nephrons. Since the glomeruli
are distributed uniformly, a “tubular–glomerular” imbalance
At 16 weeks’ gestation, the total body water accounts for exists, which allows less efficient reabsorption of substrates
94% of the fetus’ weight; at 32 weeks’ gestation, 82%; and presented to the proximal tubules of the neonate.
at term, approximately 75%. The size of the extracellular The GFR in preterm infants is a function of both gesta-
compartment decreases from 65% at 16 weeks to about 60% tional and postnatal age. During the first 24 h of extrauter-
at 24–25 weeks’ gestation and then to about 45–50% at term, ine life, the GFR of infants born before 25 weeks’ gestation
decreasing to approximately 30% at 6 months and then 20% may be as low as 2 mL/min/1.73 m2. Infants born between
by adolescence. At the same time the intracellular compart- 25 and 28 weeks’ gestation have a GFR of 10–13 mL/
ment increases from 34% in early gestation to 40–50% at min/1.73 m2 and those born after 34 weeks’ gestation, 20–25
mL/min/1.73 m2, which is similar to that of full-term infants with both gestational and postnatal age. The components of
[917]. Although GFR increases at a slower rate in ELBW microvascular filtration at the level of the glomerulus vary
infants, all neonates without acquired renal insufficiency with maturation. That is, the rate of filtration increases as
double GFR by two weeks of age and triple the value by the number of nephrons increases up to 36 weeks’ gesta-
three months of age. Thereafter, GFR increases more slowly. tion, so that the preterm infant has an additional variable that
A multicenter study from France reported GFR measured in contributes to the effective GFR. Therefore, while establish-
infants of 27–31 weeks’ gestation over the first month of life ing clinical criteria for other biomarkers, investigators have
[918]. Although the precise values in GFR (mL/min/1.73 m2) generated a variety of innovative formulae to estimate GFR
varied from previous studies, the general trend for increase (based on creatinine) in the neonate and young infant [924].
is similar and reflects an approximate doubling over the first Of clinical importance, estimating the clearance of drugs
month, between day 7 and day 28 of life (day 7, 18.5 ± 12.6; that depend on the kidneys for elimination may be challenging
day 14, 20.6 ± 13.1; day 21, 22.2 ± 11.7; day 28, 26.2 ± 19.6). in the neonate. Because renal function is immature, the serum
The increase correlates inversely with gestational age. concentrations and half-lives of drugs often differ from values
Adult values for GFR are reached by 12–24 months of in adults, particularly during the first weeks to months of post-
age. Due to rapid renal maturation after birth, a 3-week-old, natal life of the preterm infant. Given the unique aspects of
ex-27-week gestation infant may have significantly more neonatal physiology, various formulae that calculate the “esti-
mature renal function than a normal 6-h-old term infant. The mated” GFR may underestimate the GFR in this age group.
kidney matures in response to “demand” (separation from Thus, methods to evaluate renal function in the neonate are
the placenta plus solute exposure). That is, renal filtration evolving beyond estimating “creatinine clearance.”
and concentrating ability increase when the kidneys are Although creatinine is freely filtered in the glomerulus, not
exposed to a substrate [919]. metabolized, and not protein-bound, the secretion of this mol-
At birth, serum creatinine reflects maternal values ecule in various disease states (e.g., AKI) at any age, or, in the
since this molecule is freely exchanged via the placenta. case of the neonate, reabsorption in the renal tubules, estimat-
Furthermore, the placenta, not the fetal kidney, regulates ing GFR based on serum creatinine and various formulae may
metabolic stability in utero. Serum creatinine in the neo- over- (secretion) or underestimate (reabsorption) the “true”
nate is greater than that of normal 1–2-week-old term infant GFR. Creatinine is a standard but not ideal marker of GFR,
(0.4 mg/dL), reflecting both placental transfer to the fetus especially in the neonate. Furthermore, because the level is
from the mother and reabsorption via immature renal tubules stable until 25–50% of renal function is lost, serum creatinine
[894, 920] especially in the preterm infant. For at least does not predict nor reflect early acute kidney injury (AKI)
3 days after birth, the serum creatinine in the neonate cor- [924]. Finally, hepatic function, muscle mass/catabolism, and
relates with maternal values [921]. For the first 4 weeks of fluid status influence creatinine clearance, particularly in the
life, the serum creatinine in preterm infants exceeds that in neonate. Recently, experts [20, 921, 924–926] propose that
term infants [922]. Interestingly, the serum creatinine at birth markers, such as cystatin C (CysC), beta-trace protein (BTP),
in infants born before 27 weeks was the same as those born urine neutrophil gelatinase-associated lipocalin (NGAL), and
at 31–32 weeks’ gestation, increased in all groups over the others may more reliably define GFR and detect kidney injury
first 3 days of life, and then gradually decreased to <0.5 mg/ as well as predict clearance of some drugs. A panel of bio-
dL [923]. However, the maximum serum creatinine concen- markers may eventually provide the most accurate system for
tration reported was greater and occurred later (day 3.5 vs. diagnosing and evaluating AKI in the neonate and beyond.
day 1) in the most immature neonates. Creatinine clearance CysC is a low-molecular-weight endogenous protein that
increased in all groups but increased more slowly in the <27- is filtered by the glomeruli, and levels are independent of
week gestation infants. muscle mass, age, and sex. Recently, in both term and pre-
The variability in GFR and creatinine clearance, as a func- term infants, a formula incorporating serum CysC has been
tion of gestational and postnatal age, implies that estimating developed to accurately estimate GFR [927]. To improve
GFR by tracking the serum concentration of creatinine may reliability, some methods and novel formulae incorporate
be unreliable; the degree and duration of an increase in the body surface area and total kidney volume (determined by
serum creatinine depend on the degree of prematurity. That ultrasound) [924]. However, the analytical methods to mea-
is, creatinine is reabsorbed in the immature tubules for at sure this biomarker to assess renal function are evolving
least three weeks after birth, but at the same time, the lower and currently remain expensive. Some suggest that combin-
mass of nephrons, fluid loss/shifts, and the neonatal cardio- ing data for creatinine and CysC may fine-tune diagnostic
vascular transition (e.g., cardiac output, blood pressure, renal criteria for renal function and improve criteria for AKI in
blood flow), especially the ELBW, add to the variability of infants. Currently, although BTP may offer advantages as a
this marker in the first weeks of life. The normal range of marker to estimate GFR, tools for clinical analysis remain
the serum concentration of creatinine is wide and varies experimental.
Because serum creatinine estimates GFR, not renal injury, The membrane proteins (transporters) that salvage amino
the level fails to increase for days after an insult, so that the acids, glucose, bicarbonate, and phosphate from the glo-
effort to mainstream novel biomarkers is urgent in the setting merular filtrate are located on the apical membrane of the
of predicting, diagnosing, and treating acute kidney injury proximal tubule and are “active” transporters (i.e., requir-
(AKI). In the neonate, this will demand defining developing energy to move substrates across the membrane against
mentally dependent (gestational age, postnatal age) stan- their concentration gradient). The simultaneous movement
dards as well as developing the specific analytical framework of sodium down its electrochemical gradient generates the
for easy measurement. One report suggests that CysC levels energy for the transport of the substrate against its concen-
are independent of gestational age, birth weight, and gender tration gradient. For example, glucose and amino acids are
[928], but these data must be validated. For now, guidelines cotransported with sodium across the apical membrane.
for defining and evaluating AKI in clinical practice are tied Other substrates are counter-transported (e.g., H+ and
to serum creatinine and urine output, with recent efforts to sodium) with sodium moving in the direction opposite to
standardize definitions and stratify risk and severity (pedi- that of the substrate (i.e., exchange mechanism). The sodium
atric RIFLE [risk, injury, failure, loss, and end-stage renal gradient then must be reestablished, which is mediated by
disease], and AKIN [Acute Kidney Injury Network]) specifi- the activity of the Na+–K+-ATPase pump. This metabolic
cally in the neonate [929]. role of the Na+–K+-ATPase pump in maintaining the sodium
gradient for all eukaryotic cells is critical. Located on the
basolateral membrane, the activity of this enzyme accounts
Renal Tubular Function for approximately 70% of renal oxygen consumption.
Extracellular fluid volume, water balance, and sodium and

other electrolyte concentrations are interrelated and undergo Development of Sodium-Driven Transport
significant change postnatally. In addition to the dramatic Function
development in the number of nephrons, glomerular function,
and renal blood flow, the renal tubules mature throughout fetal Tubular reabsorption of water and solutes must match the
and postnatal life. Of note, tubular immaturity accounts for fourfold increase in GFR over the first 2 years of life. That is,
inefficient salvage of essential substrates (e.g., glucose, amino “if there was no increase in solute and water reabsorption
acids). The metabolic demands of rapid growth and/or ill- that parallels the increase in glomerular filtration, the neo-
nesses coupled with immature renal function complicate man- nate would become volume-depleted with a minor develop-
aging fluids and providing nutritional support to the newborn. mental increase in glomerular filtration rate” [930]. That is,
Similar to other epithelia, renal tubular cells are polar- when the filtered load of sodium increases with greater GFR,
ized. That is, specific, unique channels, transporters, and resorption must similarly increase to avoid dehydration and
other proteins populate the apical (facing the urine) versus the loss of electrolytes. This correlation between GFR and
the basolateral membrane (facing the blood), which provides transport, glomerulotubular balance, persists throughout life
the mechanism for net movement of solutes both from the so that tubular transport parallels changes in GFR (e.g., in
lumen to the capillary (reabsorption) and vice versa (secre- response to extracellular fluid volume). The proximal tubule
tion). This distribution of proteins to each membrane defines reabsorbs most of the solutes from the isotonic glomerular
the anatomically and functionally distinct sections of the filtrate (all amino acids and glucose, 80% of bicarbonate, and
renal tubules and allows the kidney to salvage most sub- approximately 70% of the “chloride”) [930], mostly via
strates from the glomerular filtrate in the proximal tubule sodium- dependent transport. These active transport pro-
and fine-tune water and solute content in the more distal cesses are linked to the extracellular-to-intracellular gradient
segments. For example, although sodium is absorbed along maintained by Na+–K+-ATPase.
the entire system, the proximal tubules reabsorb 60–80% of After birth, thyroid hormone and corticosteroids seem to
filtered sodium and water. As well, glucose, phosphate, and induce the developmental increase in function of sodium-
most amino acids are salvaged primarily along the proximal driven transport, both by quantitative effects and by changes
tubule. The loops of Henle, the distal tubules, and the col- in isoform expression [930]. For example, the activity of the
lecting tubules concentrate urine and secrete potassium. An apical sodium–hydrogen exchanger (NHE) increases dramati-
additional 10–15% of filtered sodium is absorbed in the dis- cally in the first 24 h after birth and then more slowly during
tal (aldosterone responsive) and collecting tubules (antidi- postnatal life. This protein acidifies the urine while function-
uretic hormone determines water permeability). The amount ing to mediate the bulk of transepithelial sodium reabsorption.
of sodium in fluid presented to the distal tubules depends, [915]. At the same time, reabsorption of sodium in the proxi-
in part, on the efficiency of the transport mechanisms of the mal tubules increases 5–10-fold as Na+–K+-ATPase activity
proximal tubule. [931] increases, in part secondary to developmental changes
in its regulatory β-subunit. That is, the fetal β2 isoform (which For example, the reduced serum concentration of bicar-
is present in both the apical and the basolateral membranes) bonate in the neonate (12–16 mEq/L in ELBW infants and
is downregulated after birth, and β1 is upregulated and tar- 18–20 mEq/L in 30- to 35-week gestation infants com-
geted only to the basolateral membrane [932]. The functional, pared with 20–22 mEq/L in term infants and 25–28 mEq/L
mature enzyme consists of a heterodimer of α1 and β1 sub- in adults) [937] develops secondary to the urinary loss of
units. Glucocorticoid hormones increase mRNA for both bicarbonate, primarily in the proximal tubule, which leads to
subunits of this enzyme, and prenatal administration of beta- urine with an alkaline pH and a mild serum metabolic aci-
methasone to the mother in preterm labor to induce maturation dosis. The Na+/H+ antiporter (NHE) plays a major role in
of the lungs may also mature renal function. Finally, matura- secreting protons in exchange for bicarbonate and undergoes
tional increases in sodium reabsorption have been identified in dramatic developmental changes. Although at least six dif-
the thick ascending loop (reabsorbs 25% of filtered sodium), ferent isoforms have been identified, NHE-3 (present in the
linked to developmental changes in both the apical Na+-K+- proximal tubule and the thick ascending loop) is responsi-
2Cl- (NCKK2) and basolateral NCKK1cotransporters [915]. ble for ~90% of bicarbonate reabsorption as renal function
The proximal tubule increases its capacity for absorp- matures postnatally, compared with ~60% in the perinatal
tion with advancing gestational age. Five percent of the period [938]. Both glucocorticoids [939] and thyroid hor-
filtered sodium is excreted in the urine of <30-week gesta- mone [940] facilitate the maturation of this transporter. Age-
tion infants, but only 0.2% is excreted in term infants [933]. related differences in NHE may contribute to differences in
However, fractional excretion (FENa) decreases over the first the acid–base balance among newborns and older children/
month. For example, in <28-week gestation infants, although adults. Hydrogen is actively secreted, and the secreted ion
FENa was >6% on day three of life, the value was 4% at the reacts with bicarbonate to produce carbonic acid and carbon
end of the first week and 2% by 1 month [934]. Hypoxia, dioxide. These substances enter the tubular cells through the
respiratory distress, and hyperbilirubinemia may increase action of carbonic anhydrase. In addition to age-related dys-
fractional sodium excretion. In general, the urinary sodium function of NHE, carbonic anhydrase function may also be
loss in the preterm infant (e.g., 2-week-old, 23-week gesta- immature.
tion infant) may be as high as 8 mEq/kg/day, a value that Glucose is reabsorbed in the proximal tubule via the
exceeds the commonly recommended nutritional require- sodium–glucose cotransporter (SGLT-2), and, similar to
ment of 2–4 mEq/kg/day [915]. Since sodium is critical for other carrier-mediated transporters, developmental changes
growth and development, vigorous repletion is critical in have been documented [941]. In preterm infants, tubular
ELBW infants. reabsorption is decreased so that glucosuria is common.
Neonates concentrate urine to a more limited degree The tubular reabsorption of glucose and the transport maxi-
than adults (245–450 mOsm/L in preterm infants vs. mum (Tm) (150 mg/dL in term neonates compared with 180
600–800 mOsm/L in term infants vs. 1200–1400 mOsm/L mg/dL in older children and adults) are both decreased in
in adults). Similarly, neonates >35 weeks’ gestation can the neonate. Preterm infants less than 34 weeks’ gestation
dilute their urine to adult levels (~50 mOsm/L) and infants have a greater fractional excretion of glucose and a reduced
<35 weeks’ gestation to about 70 mOsm/L [935], but neither maximal reabsorption compared to full-term infants [942].
can excrete a water load as rapidly as the older child. That Finally, calcium absorption occurs in the proximal tubules
is, the maximum urinary osmolality attained after a dose of of the kidneys, primarily by passive diffusion, but the large
DDAVP was only ~520 mOsm/kg in 30–35-week gestation renal loss of sodium increases calcium excretion. Sick neo-
infants and 570 mOsm/kg in 4–6-week-old infants born at nates, especially preterm neonates, require supplemental
term. A 6-month-old child concentrates urine to 1300– intravenous calcium to maintain normal ionized calcium
1400 mOsm/kg after a dose of DDAVP [917]. The majority concentrations.
of infants 6–12 months of life remain unable to maximally Serum potassium concentrations that exceed 5.0 mmol/L
concentrate their urine. are relatively common in the neonate, particularly in preterm
The limit in concentrating capacity of the immature kid- infants with a mild metabolic acidosis. Non-oliguric hyper-
ney is not related to the absence of arginine vasopressin kalemia (serum potassium >6.5 mmol/L in the absence of
(antidiuretic hormone [ADH]). In fact, at birth ADH levels renal failure) is characterized by a rapid increase in the serum
are increased in both preterm and term infants, but decrease potassium during the first one to three days after birth and
rapidly postnatally (see Renin–Angiotensin System) [936]. develops frequently in ELBW infants. In contrast to older
The immature corticomedullary osmotic gradient and low infants, children, and adults, this hyperkalemia is not sec-
GFR may contribute to the limited ability to both maximally ondary to abnormal potassium excretion or excessive intake,
dilute and concentrate urine. but instead seems to result from rapid shifts of potassium
The concentration of serum electrolytes in the neonate, from intra- to extracellular compartments [943, 944] and is
especially the preterm, reflects renal tubular immaturity. associated with abnormal Na+–K+-ATPase activity in eryth-
rocytes [945]. As in older children and adults, the treatment to aldosterone probably reflects the increased expression of
of hyperkalemia includes insulin/glucose, calcium/bicar- the mineralocorticoid receptor and associated mediators.
bonate, diuretics, albuterol, peritoneal dialysis, and binding In a recent study in neonates born at <33 weeks’ gestation,
resins. In neonates, exchange transfusion should also be con- 33–36 weeks, and term, aldosterone secretion was reduced
sidered [944]. in the two groups of preterm infants (serum levels correlated
directly with gestational age), and sodium wasting correlated
inversely with gestational age. However, in contrast to term
Renin–Angiotensin System and moderately preterm infants who exhibited insensitivity,
the very preterm infants (<33 weeks’ gestation) exhibited
Hormonal control of neonatal fluid and electrolyte homeo- a transitory sensitivity to aldosterone; resistance developed
stasis is complex and, in some ways, unique compared with over the first month. The clinical relevance of these data to
the older child and adult. The renin–angiotensin–aldosterone the very preterm infants is unclear [954].
system exerts a particularly central role in maintaining Prostaglandins play a role in maintaining GFR and renal
homeostasis of sodium and other electrolytes. Renin has blood flow, primarily by counterbalancing the vasoconstric-
been identified as early as 17 weeks’ gestation, and plasma tive effects of the renin–angiotensin system. The excretion of
renin activity (PRA) is inversely correlated with gestational PGE2 and prostacyclin metabolites is fivefold greater in the
age (60 mg/mL/h at 30 weeks; 10–20 mg/mL/h at term) preterm compared with the term infant and 20-fold greater
[946] but remains at least threefold greater in the neonate than that of the older child [955]. Of importance, the renal
than in the adult [947, 948]. The substantial PRA is associ- failure associated with indomethacin given to close a patent
ated with increased serum aldosterone (see below) compared ductus arteriosus has been correlated with the vasoconstric-
with adults [949]. Also, hypoxia [950] and hypovolemia tion induced by the inhibition of prostoglandins.
[951] increase renin and angiotensin II levels. However, The concentration of plasma vasopressin (antidiuretic
although angiotensin II may moderate a variety of renal hormone [ADH]) is greater in neonates than later in life,
hemodynamic effects, the tubular function of the neonate especially after vaginal delivery [956], and is considered
seems insensitive to this molecule [915]. responsible, in part, for the reduced urine output during the
Inherited renal tubular dysgenesis (absence or poor devel- first 24 h of life. Vasopressin may lead to the contraction of
opment of proximal tubules and associated anuria, leading the extracellular volume immediately after birth and may
to oligohydramnios and the Potter sequence), usually a fatal contribute to the indomethacin-induced renal failure in pre-
disorder, has been linked to mutations in the genes encoding term infants. Hypoxia, atelectasis, intraventricular hemor-
the components of the renin–angiotensin system (angioten- rhage, and BPD increase urine ADH concentrations in both
sinogen, renin, angiotensin-converting enzyme, or angioten- preterm and term infants [957].
sin II receptor type 1). Similar outcomes are associated with
secondary renal tubular dysgenesis [952]. Thus, although the
specific role of the plasma renin activity in utero is not com- Clinical Significance and Summary
pletely defined, the donor twin of severe twin-to-twin trans-
fusion syndrome, congenital hemochromatosis, exposure to Managing fluids and electrolytes in the neonate demands an
renin–angiotensin inhibitors, or administering angiotensin- in-depth knowledge of renal developmental physiology,
converting enzyme (ACE) inhibitors to mothers has been especially related to sodium and water excretion and glu-
associated with anuria–oligohydramnios, pulmonary hypo- cose homeostasis. Analyzing ongoing requirements for
plasia, growth retardation, and renal tubular dysplasia in the sodium, potassium, calcium, and glucose is essential preop-
fetus [953]. eratively to estimate maintenance fluid delivery, as well as
Although the fetus has access to aldosterone both from to predict an approach to intraoperative losses and to assess
the mother and from the fetal adrenal, the fetal kidney is the need for monitoring laboratory values during surgery. In
less responsive to this hormone than after birth. Aldosterone the setting of cardiorespiratory and central nervous system
concentrations are directly related to gestational age, being immaturity and vulnerability, normalizing intravascular vol-
greater in the preterm infant than in the adults. Nonetheless, ume and serum electrolytes preoperatively may enhance
the neonate is considered “aldosterone resistant” based on intraoperative stability. Although intraoperative events often
the greater urinary sodium loss despite large concentrations demand rapid infusion of crystalloid and/or colloid, maxi-
of aldosterone. Since aldosterone activates the mineralocor- mizing preoperative stability can only contribute to mini-
ticoid receptor to initiate sodium reabsorption and potassium mizing wide fluctuations in cardiovascular parameters
excretion, the finding of ineffective expression of this fac- perioperatively.
tor provides a framework for the “pseudohypoaldosteron- Providing a warm, humidified environment and inspired
ism” in the neonate. The gradual maturation of the tubules gases intraoperatively and minimizing transepidermal fluid
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Anesthesia and Ancillary Drugs
and the Neonate 3
Brian J. Anderson and Jerrold Lerman
Introduction its effects in the neonate have increased considerably in the

past few years, PK-PD interactions for many drugs remain
Neonates are a heterogeneous population characterized by a poorly understood. Clinical studies in neonates present mul-
limited weight or size range. They are the group of children tiple challenges and difficulties, of which ethical issues, the
from birth 28 days of postnatal life and include both preterm perceived high vulnerability, technical difficulties, lack of
(i.e., born before 37 weeks gestational age) and term neo- self-assessment, immaturity, and the need for specific for-
nates. In practice, the word “neonate” extends to former pre- mulations are salient examples. However, recent progress
term neonates. Consequently, postmenstrual age (PMA) may has improved the feasibility and the clinical relevance of
range from extreme preterm birth at 22 weeks up to 50 weeks such studies in neonates. Models have been developed to
PMA, while weight may range from 0.5 to 5 kg. Age, size, handle extensive between-individual variability in PK and
comorbidity, coadministration of drugs, and genetic poly- PD parameter estimates and to formulate dose estimation
morphisms contribute to the extensive interindividual phar- [4]. Also, population-based modeling tools have helped to
macokinetic (PK) and pharmacodynamic (PD) variabilities quantify the pharmacodynamics [5].
in this population. These phenomena distinguish neonates as Two major considerations that influence drug action in
a specific population with major pharmacological differ- children that are unimportant in adults are growth and matu-
ences from their older counterparts. Although the general ration. How these factors interact is not necessarily transpar-
principles of clinical pharmacology also apply to neonates, ent from simple clinical observations, because they correlate
their characteristics warrant a tailored approach. History pro- very closely. Drug elimination may increase with weight,
vides us with evidence of the deleterious effects of failure to height, age, body surface area, and creatinine clearance. One
account for the pharmacological differences of this age approach is to standardize for size before incorporating a
group including chloramphenicol (gray baby syndrome) and factor for maturation and organ function [6]. By adopting
benzyl alcohol (gasping syndrome) in neonates. As well, such an approach, one may directly compare pharmacoki-
bupivacaine toxicity in those receiving long-term epidural netic variables in neonates with those in older children and
infusions [1, 2] and acute fentanyl tolerance [3] are two adults to determine appropriate drug dosing [7, 8].
examples in anesthesia practice of side effects in neonates.
Effective and safe pharmacotherapy depends upon an
understanding of the clinical PK and PD properties of the isentangling Pharmacokinetic Covariates
D
drugs employed. Besides age-dependent differences in PK in Neonates
and PD, differences in adverse effects should also be con-
sidered. Although the available data on drug disposition and Size
Allometry is a term used to describe the nonlinear relation-

ship between size and function. This nonlinear relationship
B. J. Anderson (*)
Department of Anaesthesiology, University of Auckland, is expressed as
Auckland, New Zealand
y a BodyMass PWR ,
e-mail: [email protected]
J. Lerman where y is the variable of interest (e.g., basal metabolic rate
Department of Anesthesiology, John R. Oishei Children’s Hospital, (BMR)), a is the allometric coefficient, and PWR is the allo-
Jacobs School of Medicine and Biomedical Sciences,
metric exponent. The value of PWR has been the subject of
Buffalo, NY, USA

100 B. J. Anderson and J. Lerman
much debate. BMR is the most common physiological vari- time-related variables scale predictably within and between
able investigated, although camps are divided over its PWR species with weight (W) exponents (PWR) of 3/4, 1 and 1/4,
value; 2/3 (i.e., body surface area) or 3/4. respectively [12].
In all species studied to date including humans, the rela- These exponents have applicability to pharmacokinetic
tionship between the log of the BMR and the log of body parameters such as clearance (CL, a physiological process),
weight is a straight line with a slope of 3/4 (Fig. 3.1). Fractal volume (V, a structural variable), and half-time (T1/2, a time-
geometry mathematically explains this phenomenon [10, related variable) [12]. The factor for size (Fsize) for total
11]. The 3/4 power law for metabolic rates was derived drug clearance may be expected to scale with a power of 3/4:
from a general model that describes how essential materi-

3/ 4
als are transported through space-filled fractal networks of Fsize W
70
branching tubes. A great many physiological, structural, and
The weight-based clearance of the analgesic drug trama-
dol is similar in several mammalian species with human allo-
105 metric prediction (Fig. 3.2).
“homeotherms” at 39°C
Metabolic rate (W)
1
Maturation
10–5 “poikilotherms” at 20°C
Allometry alone is insufficient to predict clearance in neo-
nates and infants from adult estimates [13–15]. (Fig. 3.3)
10–10 unicells at 20°C
The addition of a model that describes maturation is required
[17]. The sigmoid hyperbolic or Hill model [18] is useful for
10–15 describing this maturation process (MF):
10–15 10–9 10–3 103 109
Body mass (kg)
PMA Hill
MF Hill
Fig. 3.1 A comparison of the temperature-standardized relation for TM 50 PMA Hill
whole-organism metabolic rate as a function of body mass. The “allo-
metric 3/4 power model” fits for unicells, poikilotherms and homeo-
therms, uncorrected for temperature, are also shown. From Gillooly JF The TM50 describes the maturation half-time, while the
et al. Effects of size and temperature on metabolic rate. (Gillooly JF et Hill coefficient relates to the slope of this maturation profile.
al. Effects of size and temperature on metabolic rate. (Science 2001; There may be asymmetry about the point of inflection, and
293: 2248–2251, with permission)
Fig. 3.2 Weight-predicted 1000

tramadol total clearance (CLP
total) compared to human CLP Total
allometric prediction using a
Human
3/4 power exponent (solid
line). From Holford S. J Rat
100
Pharmacol Clin Toxicol
Cat
2014;1:1023, with permission
Dog
Clearance L/h
Dog
10
Goat
Horse
Donkey
0.1
0.1 1 10 100 1000
Weight kg
3 Anesthesia and Ancillary Drugs and the Neonate 101
the addition of an extra parameter describing this asymme- and sustained through to adulthood (e.g., plasma esterases
try can be used to provide extra flexibility for this empirical that clear remifentanil [24]; and (iii) immature at birth [25].
function [19]. Transition from the intrauterine to the extrauterine envi-
Maturation of clearance begins before birth, suggesting ronment is associated with major changes in blood flow.
that PMA would be a better predictor of drug elimination There may also be an environmental trigger for the expres-
than postnatal age (PNA). The fetus is capable of metaboliz- sion of some metabolic enzyme activities that result in a
ing drugs. Hepatic drug metabolism activity appears as early slight increase in the maturation rate above that predicted
as 9 to 22 weeks’ gestation when fetal liver enzyme activity by PMA at birth (Fig. 3.4) [16, 26]. Many biotransformation
may vary from 2% to 36% of adult activity [20–22]. These reactions, especially those involving certain forms of cyto-
pathways then mature at different rates. Microsomal enzyme chrome P-450, are inducible before birth through maternal
activity can be classified into three groups: (i) mature at exposure to drugs, cigarette smoke, or other inducing agents.
birth but decreasing with age (e.g., CYP3A7 responsible for Postnatally, biotransformation reactions may be induced
methadone clearance in neonates [23]; (ii) mature at birth through drug exposure and may be slowed by hypoxia/
Fig. 3.3 Size and maturation ¾ Allometry alone ¾ Allometry + maturation

explain much of propofol explains 67% of CL variability explains 80% of CL variability
variability. Original data from
Ref 15. Plots show median 10
10
and 90% intervals (solid and
dashed lines). The 90%
prediction intervals for
observations (lines with 1 1
symbols) and predictions
(lines) with 95% confidence
CL L/min
CL L/min
intervals for prediction 0.1 0.1
percentiles (gray shaded
areas) are shown. From
Anderson BJ, Holford
NHG. Pediatr Anesth 2011; 0.01 0.01
21 (3): 222–237, with
permission [16]
0.001 0.001
1 10 102 1 10 102
Kg Kg
Fig. 3.4 Change in 100%

glomerular filtration rate
(GFR) associated with
maturation and birth at
40 weeks PMA. The 80%
maturation profile determined
using PMA is shown as a
black line. The effect of
adding postnatal age (PNA) is 60%
shown as a grey line.
% Adult
Maturation is slower than

anticipated before birth when
PNA is unaccounted for and 40%
there is a slight increase of
clearance maturation after
birth. From Anderson BJ,
Holford NHG. Pediatr Anesth
20%
2011; 21 (3): 222–237, with
permission [16]
0%
–26 0 26 52 78 104
PNA weeks
asphyxia, organ damage, and illness. Postnatal changes in 40

hepatic blood flow, protein binding, and/or biliary function 35 Term neonate
Concentration (mg/L)
may also alter drug elimination. 30 1 year
5 years
25
20
Organ Function 15
10
Changes associated with normal growth and development 5
can be distinguished from pathological changes in organ 0
0 2 4 6 8 10 12 14
function (OF) [6]. Pharmacokinetic parameters (P) can be
Time (hours)
described in an individual as the product of size (Fsize), mat-
uration (MF), and organ function (OF) influences, where Fig. 3.5 Simulated mean predicted time-concentration profiles for a
Pstd is the value in a standard size adult without pathological term neonate, a 1-year-old infant, and a 5-year old child given
changes in organ function [6]: paracetamol elixir. The time to peak concentration is delayed in neo-
nates due to slow gastric emptying and reduced clearance (from
P Pstd Fsize MF OF Anderson BJ et al. Anesthesiology 2002; 96:1336–45) [32]
Organ function is typically depressed in the presence

of disease. It may, however, also be increased by drugs. absorption in neonates than in adults undergoing cardiac
Phenobarbitone, a drug commonly given to neonates suffering catheter study or radiological sedation. However, the interin-
from seizures, can induce enzyme activity of several enzyme dividual variability in absorption and relative bioavailability
systems responsible for clearance [27]: CYP1A2, CYP2C9, may be more extensive compared with oral administration,
CYP2C19, CYP3A4, and UDP- glucuronosyltransferase rendering rectal administration less suitable for repeated
(UGT) [28–30]. Phenobarbitone can increase the clearance administration [35].
of bilirubin in neonates through UGT induction [27], and of The relatively greater skin surface area to body weight,
ketamine in older children [31], although no effect on ket- increased cutaneous perfusion, and thinner stratum corneum
amine in neonates has been reported. in neonates increase systemic exposure of topical drugs
(e.g., corticosteroids, local anesthetic creams, antiseptics).
Neonates have a greater tendency to form methemoglobin
Neonatal Pharmacokinetic Differences because of reduced methemoglobin reductase activity com-
pared with older children. Furthermore, fetal hemoglobin
Absorption is more readily oxidized compared with adult hemoglobin.
Combined with an increased transcutaneous absorption,
Anesthetic drugs are mainly administered through the intra- these have resulted in a reluctance to reapply topical local
venous and inhalational routes, although premedication and anesthetics such as EMLA® (lidocaine-prilocaine) cream to
postoperative pain relief are commonly administered enter- neonates in this age group [36]. Similarly, cutaneous applica-
ally. Drug absorption after oral administration in neonates is tion of iodine antiseptics in neonates may result in transient
slower than in children due to delayed gastric emptying in hypothyroidism.
the former (Fig. 3.5). Transgastric absorption may not reach Drug administration and absorption through the nasal
adult rates until 6–8 months PNA [33, 34]. Congenital mal- route in young children has become popular [37], but
formations (e.g., duodenal atresia), coadministration of remains problematic in neonates. The recommended vol-
drugs (e.g., opioids), and disease characteristics (e.g., necro- ume for delivery is 0.3 mL/kg in adults but only 0.1 mL/kg
tizing enterocolitis) may further affect the variability in drug in small children and even less in neonates. This volume is
absorption. Delayed gastric emptying and reduced clearance easily exceeded for many commercially prepared drugs and
may dictate reduced doses and frequency of repeated drugs. spill over into the pharynx and ultimately to the gastrointes-
For example, a mean steady-state target concentration of tinal tract. An unknown fraction of the given dose will have
paracetamol greater than 10 mg/L at trough can be achieved delayed absorption and reduced bioavailability as a conse-
by an oral dose of 25 mg/kg/day in preterm neonates at quence of this gastrointestinal absorption.
30 weeks, 45 mg/kg/day at 34 weeks, and 60 mg/kg/day at The delivery of inhalational anesthetics is determined
40 weeks PMA [32]. Because gastric emptying is slow in primarily by the alveolar ventilation to functional residual
preterm neonates, dosing may only be required twice daily capacity (FRC) ratio. This ratio in neonates is greater than
[32]. In contrast, the rectal administration of some drugs that in adults, primarily due to the increased metabolic
(e.g., thiopentone, methohexitone) results in more rapid demand for oxygen in neonates, which drives an increase in
alveolar ventilation. Consequently, the alveolar to inspired Distribution

fractions, and, therefore, the blood to inspired partial pres-
sure of inhalational anesthetics, reach equilibration more Distribution describes the movement from systemic circula-
rapidly in neonates than in older children and adults [38]. tion into various body compartments, tissues, and cells.
The greater cardiac output and the greater fraction of the car- Distribution is influenced by body composition, protein
diac output distributed to vessel rich tissues (i.e., a clearance binding, hemodynamics (e.g., regional blood flow), and
factor) and the reduced tissue/blood solubilities (i.e., a vol- membrane permeability. Disease processes may also impact
ume factor) further contribute to the more rapid wash-in of on the distribution of drugs.
inhalational anesthetics in early life [39, 40].
Disease characteristics may also contribute to the vari- Body Composition
ability in the absorption of inhalational anesthetics. Right- Total body water and extracellular fluid (ECF) [41] decrease
to-left shunts affect the wash-in of inhalational anesthetics throughout gestation, the neonatal period, and childhood
to a greater extent than left-to-right shunts. Induction of (Fig. 3.6), whereas the percent of body weight contributed by
anesthesia may be slowed by right-to-left shunting of blood fat increases from 3% in a 1.5-kg preterm neonate to 12% in
in neonates suffering cyanotic congenital cardiac disease a full-term neonate and then doubles by 4–5 months
or intrapulmonary (right-to-left) conditions. This slowing PNA. These changes in the body composition substantively
is greatest with the least soluble anesthetics (e.g., nitrous affect the volumes of distribution (Vd) of drugs. Polar drugs
oxide (N2O), desflurane and to a lesser extent, sevoflurane). such as depolarizing and nondepolarizing neuromuscular-
Left-to-right shunts usually have minimal impact on uptake, blocking drugs (NMBDs) distribute rapidly into the ECF but
because the increase in cardiac output maintains systemic tis- enter cells more slowly. Consequently, the initial doses of
sue perfusion at normal levels in the absence of heart failure. these drugs in neonates are greater than in children or adults.
Fig. 3.6 Body water 100

compartment changes during
growth [41]
% Body water compartments
Total body water

80 Extracellular water
Intracellular water
Per cent of body weight
60
40
20
0
Adults
0 3 6 9 0 3 6 9 1 3 5 7 9 11 13 15
Lunar months months years
Age
The Vd of lipid-soluble drugs in neonates may also be The increase in total bupivacaine is attributable in part to an
increased. At steady state, the Vd of fentanyl in neonates is increase in AAG. This increase in total bupivacaine, com-
5.9 (SD 1.5) L/kg compared with 1.6 (SD 0.3) L/kg in adults bined with reports of seizures in infants with epidural infu-
[42]. This may explain the reduced frequency of respiratory sions of bupivacaine, has led to recommendations to stop the
depression after large doses of fentanyl, 10 μg/kg, in full- epidural infusion at 24 h or change the local anesthetic used.
term neonates. However, high-dose therapy (50 μg/kg fen- However, it is the concentration of unbound bupivacaine that
tanyl) results in a prolonged effect in neonates due to the confers its CNS effects and this, in turn, is determined by the
reduced clearance. In the case of propofol, the decreased clearance of the unbound bupivacaine. Clearance, the pivotal
plasma concentration after induction of anesthesia has been variable in the elimination of unbound bupivacaine, is
attributed to redistribution rather than rapid clearance. reduced in neonates. Furthermore, clearance shows large
Neonates have less body fat and muscle content than older interindividual variability, which means that unbound bupi-
children; hence, less propofol is apportioned to these “deep” vacaine concentrations may increase steadily in some indi-
compartments. As a result, redistribution of propofol in the viduals with very low clearance. The lack of knowledge of
neonate is attenuated. Thus, repeat doses of propofol may the clearance of bupivacaine in each neonate precludes pro-
accumulate in blood and brain tissue, the latter leading to nouncing a safe duration of epidural infusions of bupivacaine
delayed awakening. for all neonates [47].
Plasma concentrations of albumin are least in preterm
Plasma Proteins neonates but increase steadily, approximating adult values by
Albumin and alpha-1 acid glycoprotein (AAG) concentra- 5 months of PNA. Binding capacity approaches adult values
tions are reduced in neonates, albeit with a broad range by 1 year of age. Furthermore, free fatty acids and unconju-
(0.32–0.92 g/L), but reach adult concentrations by 6 months gated bilirubin compete with acidic drugs (e.g., ibuprofen,
of age (Fig. 3.7) [43, 44]. AAG is an acute phase reactant that ceftriaxone) for albumin binding. The induction dose of thio-
increases after surgical stress. This increases the total plasma pentone in neonates is less than it is in children. This may
concentrations for low to intermediate extraction drugs such be related to the decreased binding of thiopentone to plasma
as bupivacaine that bind to AAG [45]. The concentration of albumin; 13% of the drug is unbound in neonates compared
unbound bupivacaine, however, will not change, because the with 7% in adults [48].
clearance of unbound bupivacaine depends only on the
intrinsic metabolizing capacity of the liver. Any increase in egional Blood Flows
R
unbound concentrations during long-term epidural infusion, The initial phase of distribution reflects the magnitude of
for example, is attributable to a reduced clearance rather than regional blood flow. Consequently, the brain, heart, and liver,
a decrease in the AAG concentration [46]. Total bupivacaine which receive the largest fraction of cardiac output, are first
concentrations increase during the first 24 h after surgery in exposed. Drugs are then redistributed to other relatively
neonates who are receiving a continuous epidural infusion of well-perfused tissues, such as skeletal muscle. There is a
bupivacaine; unbound bupivacaine concentrations, however, much slower tertiary distribution to relatively underperfused
may not increase; any accumulation depends on clearance. tissues of the body that is noted with long-term drug infu-
Fig. 3.7 Alpha-1 acid 25

glycoproyein changes with
age. Adapted from Booker
P. Br J Anaesth
20
1996;76:365–8
AAG (mcmol/l)
15
10
0
0 50 100 150 200 250 300 350 400
Postnatal age (weeks)
sions. In addition to perinatal circulatory changes (e.g., duc- cerebral perfusion in neonates may delay the onset of action
tus venosus, ductus arteriosus), there are maturational of intravenous drugs, an effect that may be offset, in part, by
differences in relative organ mass (Fig. 3.8) and regional the reduced protein binding of those drugs in neonates. As a
blood flow, while a symptomatic patent ductus arteriosus result, the onset time for each drug must be investigated in
may also result in differences in distribution. Blood flow to neonates to establish the net effect of these competing fac-
the kidney and brain, when expressed as a fraction of the tors. Offset time is also delayed, because redistribution to
cardiac output, increases with age, whereas flow to the liver well-perfused and deep underperfused tissues is more
decreases through the neonatal period [49]. Cerebral and limited.
hepatic mass as fractions of the total body weight in the
infant is much greater than in the adult [50]. Although the lood–Brain Barrier (BBB)
B
onset times of drugs in neonates are generally more rapid The blood–brain barrier (BBB) is a network of tight junc-
than in adults (a size effect), the reduced cardiac output and tions that restricts paracellular diffusion of compounds
Fig. 3.8 The increase in %

weight of different organs
expressed as a percent of their 4500
weight in the newborn. From
Friis-Hansen B. Pediatrics
1971; 47, Suppl 2: 264–274
4000 Muscles
3500 Prostala
3000
2500
Weight
2000
Heart
1500
Liver
1000
500
Brain
Length
Adrenal
100
50
1/2 1 5 10 20 30 40 50 60 70
Age in years
between blood and brain tissue. Confusion over the impor- Elimination
tance of this barrier in the neonate may be attributed to early
studies that reported respiratory depression after morphine The main routes by which drugs and their metabolites are
and meperidine administration [51]. Early investigations eliminated from the body are the hepatobiliary system, the
reported that the respiratory depression after morphine was kidneys, and the lungs. The liver is the primary organ for
greater than that after meperidine. This difference was attrib- clearance of most drugs, although the lungs have a major
uted to greater brain concentrations of morphine, because the role for inhalational anesthetics. Drug-metabolizing enzymes
BBB in the neonate was poorly developed [51]. It was postu- are generally divided into phase I and phase II reactions.
lated that BBB permeability to water-soluble drugs, such as Phase I reactions are nonsynthetic reactions like oxidation,
morphine, decreases with maturation [51]. However, the reduction, and hydrolysis. The most important group of
respiratory depression observed after morphine in neonates enzymes involved in phase I processes are the cytochrome
could have been explained by age-related pharmacokinetic P450 (CYP) iso-enzymes. Phase II reactions convert lipid-
differences. For example, the Vd of morphine in term neo- soluble drugs to water-soluble compounds, for example,
nates 1–4 days (1.3 L/kg) is less than that in infants 8–60 days uridinediphosphate-glucuronosyltransferase (UGT).
of age (1.8 L/kg) and adults (2.8 L/kg) [52]. Consequently, Metabolism may transform a prodrug into an active drug
the initial concentrations of morphine in neonates may be (e.g., codeine to morphine by CYP2D6, propacetamol to
greater than those in adults, resulting in more pronounced paracetamol by esterase, morphine to morphine-6-
respiratory depression in the former. However, respiratory glucuronide by UGT2B7) or a toxic compound (halothane to
depression, measured by carbon dioxide response curves or trifluoroacetyl chloride by CYP2E1 causing halothane
by arterial oxygen tension, is similar in neonates, infants, and hepatitis).
children from 2 to 570 days of age at the same morphine
blood concentration [53]. The BBB theory in this particular epatic Metabolic Clearance
H
circumstance lacks strong evidence. It is more likely that the Constitutional, environmental, and genetic factors all con-
increased respiratory depression after morphine in neonates tribute to the variability in clearance, but in the young neo-
is explained by age-related pharmacokinetic differences than nate, age is the dominant covariate. Most CYP iso-enzymes,
BBB permeability or other factors. except for CYP3A7, have small phenotypic activity until
The BBB however may impact drug responses in other birth [59, 60]. CYP2E1 activity surges after birth [61],
ways. Small molecules are thought to access fetal and neo- CYP2D6 becomes detectable soon thereafter, CYP3A4 and
natal brain tissue more readily than adult brain tissue [54]. CYP2C (Fig. 3.9) are detectable during the first week post-
BBB function improves gradually, possibly reaching matu- natally, whereas CYP1A2 is the last to appear [62]. Neonates
rity by full-term age [54]. Kernicterus, for example, is more depend on the immature CYP3A4 for levobupivacaine or
common in preterm neonates than in full-term neonates. In midazolam clearance and on CYP1A2 for ropivacaine clear-
contrast to drugs bound to plasma proteins, unbound lipo- ance, dictating reduced epidural infusion rates in this age
philic drugs passively diffuse across the BBB, equilibrating group [1, 63, 64]. Formation of the M1 metabolite of trama-
very quickly. This may contribute to the propensity of bupi-
vacaine for inducing seizures in neonates. Decreased protein
binding, as in the neonate, results in a greater proportion of * ** **
unbound drug that is available for passive diffusion into the 40
brain.
In addition to passive diffusion, there are specific trans-
CYP2C9 (pmol/mg)
30
port systems that mediate active transport. Pathological CNS
conditions can cause BBB breakdown and alter these trans-
port systems. Fentanyl is actively transported across the BBB 20
by a saturable ATP-dependent process, while ATP-binding
cassette proteins such as P-glycoprotein actively efflux opi- 10
oids such as fentanyl and morphine from the brain [55, 56].
P-glycoprotein modulation significantly influences opioid
0
brain distribution and onset time, magnitude, and duration of
Age = 8 – 24 wks 25 – 40 wks 0 – 5 mos >5 mos – 18 yrs
analgesic response [57]. Modulation may occur during dis-
N= 55 16 92 74
ease processes, fever, or in the presence of other drugs (e.g.,
Mean ± SD = 0.3 ± 0.2 5.0 ± 4.0 11.8 ± 7.0 18.0 ± 6.1
verapamil, magnesium) [55]. Genetic polymorphisms that
affect P-glycoprotein-related genes may explain differences Fig. 3.9 Developmental expression of human hepatic CYP2C9
in CNS-active drug sensitivity [56, 58]. enzyme. [60]
dol, a reflection of CYP2D6 activity [65], appears rapidly at Glucuronidation is the major metabolic pathway for
term and reaches 84% of mature values by 44 weeks PMA. propofol. This pathway is immature in neonates, although
Pharmacogenomics (PG) investigates variations of DNA multiple CYP iso-enzymes (CYP2B6, CYP2C9, CYP2A6)
and RNA characteristics related to drug response that incor- also contribute to its metabolism and cause a more rapid
porates both PK and PD. Large interindividual PK variability maturation profile than expected from glucuronidation
depends to a large extent on polymorphisms of the genes that alone [26] (Fig. 3.12). Urine collections after intrave-
encode for metabolic enzymes [66]. The effect of genetic nous boluses of propofol in neonates (PNA 11 days, PMA
variability on plasma cholinesterase activity and its effect on 38 weeks) support this contention. Urinary metabolites
the termination of action of succinylcholine is a well-known included both propofol glucuronide and 1- and 4-quinol
example and the first polymorphism described in anesthe- glucuronide in a ratio of 1:2. Hydroxylation to quinol
sia. Another example is the CYP2D6 single nuclear poly- metabolites was active in these neonates [77], contributing
morphism (SNP), inherited as an autosomal-recessive trait to the rapid increase in clearance at this age that is faster
that may result in poor analgesia from codeine, because the than that reported for glucuronide conjugation alone (e.g.,
active metabolite morphine is not formed. Both PMA and paracetamol, morphine).
CYP2D6 activity explain the interindividual variability in Disease characteristics also contribute to the variability
tramadol metabolism (Fig. 3.10). The interplay between in UGT-related clearance. Maturation of morphine clear-
maturation of tramadol clearance, M1 metabolite formation, ance occurs more quickly in infants undergoing noncardiac
and maturing GFR on M1 concentration (and subsequent surgery compared with those after cardiac surgery [78].
analgesia) is shown in Fig. 3.11. Neonates requiring extracorporeal membrane oxygenation
Some phase II iso-enyzmes are mature in full-term [79] or positive pressure ventilation [71, 80] also have
neonates at birth (sulfate conjugation), whereas others reduced clearance (Fig. 3.13). Similarly, the clearance of
are not (acetylation, glycination, glucuronidation) [68]. propofol is reduced after cardiac surgery in children [81].
Glucuronidation is important in the metabolic clearance of
drugs (paracetamol, morphine, propofol) frequently admin- xtrahepatic Routes of Metabolic Clearance
E
istered by anesthesiologists. Allometric body-size scaling Many drugs undergo metabolic clearance at extrahepatic
complemented by maturation models [12, 69] has unraveled sites. Remifentanil and atracurium are degraded by nonspe-
the effects of maturation of the pharmacology of morphine cific esterases in tissues and erythrocytes and these processes
[70, 71] and paracetamol [72, 73]. Both drugs are cleared appear mature at birth, even in preterm neonates [24].
by specific isoforms (UGT1A6 and UGT2B7). In both Clearance, expressed per kilogram, is increased in younger
instances, clearance is immature in the preterm 24 week children [82–86], and is likely attributable to size, because
PMA neonate and matures to reach adult rates by the end clearance is similar when scaled to a 70 kg person using
of the first year of life (Fig. 3.12). Dexmedetomidine is also allometry [82]. Succinylcholine clearance is also increased
cleared predominantly by the UGT system and has a similar in neonates [87, 88] suggesting butyryl-cholinesterase activ-
maturation profile [74]. ity is mature at birth.
30 Pulmonary Elimination
The factors that determine anesthetic absorption through
M1 formation clearance (L/h/70kg)
population trend CYP 0.5 the lung (alveolar ventilation, FRC, cardiac output, solu-
bility) also contribute to elimination kinetics. We might
population trend CYP 2
20 anticipate more rapid washout in neonates for any given
population trend CYP 3 duration of anesthesia because of the greater alveolar ven-
tilation to FRC ratio, greater fraction of cardiac output per-
fusing vessel-rich tissues, reduced solubility in blood and
10 tissues, and reduced distribution to fat and muscle content.
Furthermore, younger age (as in the neonate) speeds the
elimination of more soluble inhalational anesthetic such
as halothane to a greater extent than the less soluble anes-
0 thetic, desflurane and sevoflurane primarily. Halothane,
25 30 35 40 45 50 and to a far lesser extent isoflurane (1.5%) and sevoflurane
Postmenstrual age (weeks) (5%), undergoes hepatic metabolism. Halothane is reported
to undergo as much as 20–25% metabolism, but at typical
Fig. 3.10 Tramadol M1 metabolite formation clearance (CYP2D6)
increases with postmenstrual age. Rate of increase varies with genotype anesthetizing concentrations, hepatic halothane removal is
expression. Adapted from Allegaert K. et al. [65] extremely small [89].
Fig. 3.11 Time- 0.4 0.05

concentration profiles for 34 weeks CYP0.5
tramadol and the M1 34 weeks CYP3
metabolite in neonates.
46 weeks CYP0.5
CYP2D6 activity has been
assigned a score of 0–3. 46 weeks CYP3 0.04
Clearance of the parent drug
M1 metabolite concentration (mg/L)

0.3
is reduced in the 34 week
Tramadol concentration (mg/L)

PMA neonate compared to
the 46 week PMA neonate
and CYP activity has little 0.03
impact on profiles. At
46 weeks, both total clearance
0.2
and CYP2D6 activity has
increased, resulting in distinct
profiles. The M1 metabolite is 0.02
cleared by renal function and
the rapid maturation of
glomerular filtration rate
around 40 weeks PMA has 0.1
impact on the M1 metabolite 0.01
profile, resulting in a peak
concentration and subsequent
decrease. Adapted from
Allegaert K. et al. [9]
0 0
0 4 8 12 16
Time (h)
Fig. 3.12 Clearance 100

maturation, expressed as a
percentage of mature
clearance, of drugs where Tramadol GFR
glucuronide conjugation 80 TM50 41.8 weeks TM50 47.6 weeks
(paracetamol, morphine, Hill 5.7 Hill 3.4
dexmedetomidine) plays a
% Adult Clearance
major role. These profiles are

Propofol Morphine
closely aligned with 60
TM50 38.5 weeks TM50 54.2 weeks
glomerular filtration rate Hill 4.6 Hill 3.92
(GFR). In contrast,
cytochrome P450 isoenzymes
also contribute to propofol 40 Levobupivaca- Paracetamol
metabolism and cause a faster -ine TM50 35.7 TM50 52.2 weeks
maturation profile than weeks Hill 3.82 Hill 3.4
expected from glucuronide
conjugation alone. Tramadol 20 Dexmedetomidine
clearance maturation (Phase I, TM50 46.5 weeks
CYP2D6, CYP3A) is also Hill 2.78
rapid. Maturation parameter
estimates were taken from 0
0 30 60 90 120 150
Refs. [64, 65, 69, 71, 74–76]
Postmenstrual age (weeks)
Renal Elimination dose is predicted by PMA because it predicts the time course
Renal elimination of drugs and their metabolites occurs pri- of renal maturation [90]. The kidney is also capable of
marily by two processes: glomerular filtration and tubular metabolizing drugs; CYP2E1, which metabolizes ether inha-
secretion. Glomerular filtration rate (GFR) at 25 weeks is lational anesthetics, is active in the kidney. The very pres-
only 10% that of the adult value, 35% at term, and 90% at ence of CYP2E1 in the kidney is responsible for the
1 year of age (Fig. 3.12) [75]. Aminoglycosides are almost degradation of ether inhalational anesthetics and the release
exclusively cleared by renal elimination and maintenance of nephrotoxic inorganic fluoride [91].
Fig. 3.13 Morphine 18
clearance in neonates during
ECMO. The maturation of 16
clearance to morphine-6-
glucuronide (CL2M6G) and 14
morphine-3-glucuronide
CL2M6G (L/h/70kg)
(CL2M3G) is faster (open 12
squares) in children requiring
ECMO than those not 10
requiring ECMO (open
8
triangles) From Peters JWB,
Anderson BJ, Simons SHP, 6
Uges DRA, Tibboel
D. Morphine metabolite 4
pharmacokinetics during
venoarterial ECMO in 2
neonates. Clinical
Pharmacokinet 2006; 45: 0
705–714 0.1 1 10 100 1000 10000
PNA (days)
140
120
100
CL2M3G
80
60
40
20
0
0.1 1 10 100 1000 10000
PNA (days)
Immaturity of the clearance pathways can be used to our firmed in 26-week PMA preterm infants whose milrinone
advantage when managing apnea after anesthesia in the pre- clearance was 0.96 L/h/70 kg [93]. Similarly, the clearance
term neonate. N7-methylation of theophylline to produce of the neuromuscular-blocking drug NMBD, d-tubocurare,
caffeine is well developed in the neonate, whereas oxidative can be directly correlated with GFR [94]. Some drugs such
demethylation (CYP1A2) responsible for caffeine metabo- as the nonsteroidal anti-inflammatory agents (NSAIDs) may
lism is deficient. Theophylline is effective for the manage- compromise renal clearance in early life: ibuprofen reduces
ment of postoperative apnea in the preterm neonate, in part GFR by 20% in preterm neonates, independent of gestational
because it is a prodrug of caffeine, which is effective in age [95, 96].
controlling apnea in this age group and can only be cleared
slowly by the immature kidney [92].
Milrinone, an inodilator, is used increasingly in chil- Neonatal Pharmacodynamic Differences
dren after congenital cardiac surgery. Renal clearance is the
primary route of elimination. A clearance of 9 L/h/70 kg Children’s responses to drugs have much in common with
is reported in adults with congestive heart failure, and we the responses in adults once developmental PK aspects are
might anticipate that clearance in preterm neonates is considered [97]. The perception that drug effects differ in
reduced to 10% of this rate, because renal function is cor- children arises, because these drugs have not been adequately
respondingly immature in this cohort. This has been con- studied in pediatric populations who have size and age-
related effects as well as different diseases. Neonates, how- Changes in regional blood flow may influence the amount
ever, often have altered pharmacodynamics as well. of drug that reaches the brain. Inhalational anesthetics are
The minimum alveolar concentration (MAC) is commonly believed to affect the CNS via gamma-aminobutyric acid
used to express the potency of inhalational anesthetics. The (GABAA) receptors. Receptor numbers or developmental
MAC values for most anesthetics in neonates are less than shifts in the regulation of chloride transporters in the brain
those in older infants (Fig. 3.14) [39]. The MAC of isoflu- may change with age, altering the response to these anesthet-
rane in preterm neonates <32 weeks gestation is 1.28% (SD ics. Midazolam acts on the same receptors. Data from rodents
0.17), and in preterm neonates 32–37 weeks gestation, 1.41% from birth to PNA 40 days have shown developmental PD
(SD 0.18), which in turn is less than in full-term neonates changes for sedation that mimic those observed in human
[98]. Similarly, the MAC of halothane in full-term neonates childhood [106]. Such models offer potential to improve our
(0.87% SEM 0.03) is less than that in infants 1–6 months of understanding of developmental pharmacology [107].
age (1.20% SEM), but the decrease in blood pressure and the Neonates demonstrate an increased sensitivity to the effects
incidence of hypotension in neonates and infants at approxi- of neuromuscular blocking drugs [94]. The reason for this
mately 1 MAC of halothane are similar [99]. sensitivity is unknown, but the finding is consistent with the
Assessment of sedation using modified electroencephalo- observation that there is a three-fold reduction in the release of
graphic signals in neonates remains difficult. Three methods acetylcholine from the infant compared with the phrenic nerve
(Neonatal Pain, Agitation and Sedation Scale, amplitude- in the adult rat [108, 109]. Reduced clearance and increased
integrated Electroencephalogram, and Bispectral Index), and sensitivity prolong the duration of neuromuscular effect.
their combination, have been used to detect different levels Similarly, the smaller concentrations of epsilon-aminocaproic
of sedation in neonates. Although none of the three meth- acid required to inhibit fibrinolysis may be attributed to the
ods alone were satisfactory to discriminate between degrees immature coagulation system in neonates [110].
of sedation, the combination was effective in distinguishing The duration of regional block with amide local anes-
between light and deep sedation [100]. The processed EEG thetic agents in infants is reduced compared with older chil-
(spectral edge frequency, BIS, entropy) may not be reliable dren. Moreover, infants require a larger weight scaled dose
in neonates and infants, but the EEG waveforms and changes to achieve a similar dermatomal level when local anesthetics
in the dimensionless number that is its output have permit- are given by subarachnoid block. This may in part be due to
ted some interpretation [101]. Age-dependent EEG changes reduced myelination in infants, increased spacing of nodes
with sevoflurane anesthesia reflect cerebral maturation and, of Ranvier, and the length of nerve exposed.
in particular, neuronal myelination [102–105]. Clinical signs Expression of intestinal motilin receptors and the mod-
rather than processed EEG are currently required to assess ulation of antral contractions in neonates depend on age.
the depth of anesthesia in neonates and infants. Prokinetic agents may not be useful in extremely preterm
neonates, useful only in part in older preterm infants, but
very useful in full-term infants. Similarly, bronchodilators
2.0
are ineffective in neonates because of the paucity of bron-
1–6 months chial smooth muscle that can cause bronchospasm.
1.8 Cardiac calcium stores in the endoplasmic reticulum
are reduced in the neonatal heart because of immaturity.
Exogenous calcium has a greater impact on contractility in
MAC (% isoflurance)
1.6 this age group than in older children or adults. Conversely,

Neonates calcium channel–blocking drugs (e.g., verapamil) can
32–37 weeks gestation
cause life-threatening bradycardia and hypotension [111].
1.4 Catecholamine release and the response to vasoactive
drugs vary with age. These pharmacodynamic differences
< 32 weeks gestation
are based in part upon developmental changes in myocar-
1.2 dial structure, cardiac innervation, and adrenergic recep-
tor function. For example, the immature myocardium has
fewer contractile elements and therefore a decreased ability
1.0
0.5 1.0 5 10 50 100 to increase contractility; it also responds poorly to standard
Post conceptual age (years) techniques of manipulating preload [112]. Dopaminergic
receptors are present in the pulmonary vasculature and may
Fig. 3.14 Effect of age on the minimum alveolar concentration (MAC)
be responsible for mediating pulmonary vasoconstriction
of isoflurane. MAC increases as age decreases, reaching a zenith in
infants 1–6 months of age and decreases thereafter as age decreases to in preterm neonates. However, systemic vasoconstriction is
24 weeks gestation [98]. greater than that observed in the pulmonary circulation and
this differential response contributes to the use of dopamine is fundamentally different from that in older children; there
in neonates with known pulmonary hypertension after car- remains a need for specific neonate-derived algorithms if
diac surgery. Neonates have underdeveloped sympathetic EEG-derived anesthesia depth monitors are to be used rou-
innervation and reduced stores of norepinephrine. Signs of tinely in neonates [120, 121].
cardiovascular α-receptor stimulation may occur at lower The existence of a large number of sedation or pain scales
doses than β-receptor stimulation, because β-receptor matu- should not suggest that all of the difficulties in assessing pain
ration lags behind α-receptor maturation during the devel- in the neonate have been solved. Most scores are validated
opment of the adrenergic system [113]. The preterm neonate for the acute, procedural setting and perform less reliably for
has immature metabolic and elimination pathways, leading subacute or chronic pain or stress. Scoring systems seldom
to increased dopamine concentrations after prolonged infu- take into account the limited capacity of the more immature
sions [113–116]. These maturational changes in PK and PD infants to mount a consistent behavioral and physiological
may contribute to dopamine’s continued popularity in the response to pain. Validation is based on the assessment of
neonatal nursery, while its popularity wanes in the adult intra- and interindividual variability and correlations with
population. neuroendocrine markers of stress or pain. Future research
may provide us with objective tools to quantify pain and
sedation but will have to take maturational aspects of the
Pharmacodynamic Measures neonate into account.
In general, outcome measures are more difficult to assess in

neonates than in children or adults. The common effects Induction Agents
measured in anesthesia are circulatory and respiratory
depression, neuromuscular blockade, depth of anesthesia, Intravenous induction agents exert their anesthetic effects by
and sedation or pain. Circulatory responses may be assessed achieving adequate cerebral concentrations. Termination of a
using heart rate and blood pressure, although more detailed drug’s effect may be attributed to redistribution rather than
analyses require echocardiography and electrophysiology of rapid clearance. With less body fat and muscle, less drug is
the conduction systems. Similar respiratory responses may apportioned to these “deep” compartments in neonates.
be recorded in terms of respiratory rate and gas exchange Accordingly, a delay in emergence from anesthesia in neo-
(oximetry and capnometry), but more sophisticated effects nates can be attributed directly to greater concentrations of
require CO2 response curves and compliance changes. anesthetic in the brain that result from reduced redistribution
Electromyography response of the adductor pollicis is a con- compared with older children.
sistent metric to investigate neuromuscular blockade in both
neonates and adults. Differences are minor, for example,
neonates tolerate repetitive stimulations for briefer periods Propofol
than older children, because the former have limited acetyl-
choline reserves. Assessment of outcome variables, however, Mechanism
becomes more difficult when the depth of anesthesia, seda- The hypnotic actions of propofol result from its interaction
tion, and pain in neonates are considered. with the GABAA receptor [122, 123].
A common metric to assess the depth of anesthesia is the
electroencephalogram (EEG) or a modification of detected Pharmacodynamics
EEG signals (spectral edge frequency, Bispectral index, Integrated PK-PD studies in neonates are lacking, partly due
entropy). Physiological studies in adults and children indi- to a lack of consistent effect measures. Consequently, the tar-
cate that EEG-derived anesthesia depth monitors provide an get concentration for anesthesia in neonates is unknown. The
imprecise and drug-dependent measure of arousal. They can equilibration half-time (T1/2keo) for the effect compartment
be used as guides for anesthesia and have improved out- is unknown, but is assumed to be less than the 3 min described
comes in adults. In older children, the physiology, anatomy, in adults [124, 125]; T1/2keo becomes smaller as age decreases
and clinical observations indicate the performance of the [126] and relates to weight with an allometric exponent of
monitors may be similar to that in adults. However, the 1/4 [127]. Reduced GABAA receptor numbers in the neona-
depth of anesthesia (based on the BIS) after ketamine is tal brain may contribute to a reduced target concentration,
inconsistent. In the case of sevoflurane, the BIS in children but this hypothesis remains untested. A circadian night
paradoxically increases when the end-tidal concentrations rhythm effect has been noted in an investigation of propofol
increase beyond 3% [117]. In infants, the use of these moni- sedation in infants after major craniofacial surgery [128], but
tors cannot yet be supported in theory or in practice [118, such an effect is unlikely in neonates who do not have estab-
119]. Both outside and during anesthesia, the EEG in infants lished day/night sleep cycles.
A target propofol concentration of 2–3 mg/L is commonly resistance (associated with hypoxemia and acidosis) [142,
sought for sedation in children, whereas 4–6 mg/L is used for 143]. Profound low cardiac output state, together with pro-
anesthesia. Both the loss and return of consciousness occur found oxygen desaturation, has been reported in several neo-
at similar target effect-site propofol concentrations (2.0 SD nates that were refractory to usual resuscitation measures
0.9 mg/L vs. 1.8 SD 0.7 mg/L) in adults [129] and a “wake- including most inotropes [144]. Additionally, hypotension of
up” concentration of 1.8 mg/L in children [130]. However, 30 min duration has been reported in preterm neonates given
PKPD relationships in neonates are rarely described because propofol 3 mg/kg for procedural sedation in a neonatal inten-
of difficulties in interpreting effect measures (e.g., EEG sig- sive care unit [145], although the severity of the hypotension
nals). Propofol infusion rates for infants have been suggested was similar to that reported after inhalational anesthetics at 1
[131]. Those regimens were determined by adapting an adult MAC [144]. Other adverse effects (bradycardia, propofol
dosage scheme to the requirements of the younger popula- infusion syndrome, respiratory depression, immune func-
tion. The total number and time of administration of boluses tion) are poorly documented in neonates and require further
and time to awakening were registered and used as criteria to investigation. Neonates can experience pain with an injec-
adjust the dosage scheme. Predicted infusion rates are large tion of propofol; some recommend IV lidocaine to amelio-
(e.g., 24 mg/kg/h for the first 10 min in neonates) and should rate this effect.
be used cautiously. Delayed awakening, hypotension, and
an increased incidence of bradycardia were reported in neo-
nates and infants at this rate [131]. Thiopentone
Pharmacokinetics Mechanism
Propofol is metabolized in the liver with an extraction ratio Thiopentone is an analog of pentobarbitone. The greater
of approximately 0.9. Clearance is limited by the hepatic lipid solubility of thiopentone is achieved by substituting a
blood flow and reduced in children in low cardiac output sulfur atom in place of an oxygen atom on the barbiturate
states [81]. Clearance is affected primarily by UGT1A9 with acid ring [146]. Greater penetration of the BBB has been
contributions from CYP2B6, CYP2C9, and CYP2A6 isoen- described in neonatal compared with older animals, possibly
zymes resulting in a more rapid maturation profile than attributable to the greater blood–brain flow in the former
expected from glucuronide conjugation alone (Fig. 3.12). [147]. The most likely mechanism of action of thiopentone is
Although propofol is widely used for target controlled via binding to GABAA receptors, which increases the dura-
infusion (TCI) anesthesia in children, commonly used TCI tion of GABA-activated chloride opening.
data sets [125, 131–134] have only investigated propofol PK
in children beyond infancy. In an effort to link neonatal data Pharmacodynamics
with those from children [76], Allegaert used allometry and The ED50 of thiopentone varies with age: 3.4 mg/kg in neo-
the Hill equation [69] to suggest a maturation half-time of nates, 6.3 mg/kg in infants, 3.9 mg/kg in children aged
44 weeks and a Hill coefficient of 4.9 [135]. Clearance at 1–4 years, 4.5 mg/kg in children 4–7 years, 4.3 mg/kg in
28 weeks gestation is only 10% of the mature value (1.83 children 7–12 years, and 4.1 mg/kg in adolescents aged
L/min/70 kg) and at term, it remains reduced, at only 38% 12–16 years [148, 149]. The reduced dose requirements in
of the mature value. A full-term neonate achieves 90% of neonates may be explained by altered PK, PD, or a combina-
the adult clearance by 30 weeks PMA. Although PMA is tion of the two. The effect-site concentration of thiopentone
the major descriptor of maturation, it is possible that PNA for induction of anesthesia in neonates may be less than that
may also contribute to the maturation of propofol clearance, in infants, because the neonate has relatively immature cere-
increasing the clearance beyond that predicted by PMA [26]. bral cortical function, rudimentary dendritic arborizations,
Further longitudinal studies that examine individual neonates and relatively few synapses [150]. However, integrated
as they grow are required to clarify this aspect of maturation. PKPD studies with thiopentone in neonates have not been
performed to confirm this notion [151]. The plasma concen-
Adverse Effects tration (EC50) of thiopentone required for induction of anes-
Propofol is used for tracheal intubation by neonatologists thesia in adults based on the EEG is 17.9 mcg/mL;
[136, 137] and anaesthesiologists [138, 139]. Propofol doses comparable data in neonates are lacking [152]. The T1/2keo
of 2–3 mg/kg have been reported for intubation [139–141], in adults is 0.6 min [152], but there are no estimates in neo-
although caution should be advocated in the early postnatal nates. Children aged 13–68 months given rectal thiopentone
period during which a transient return to fetal circulation is (44 mg/kg) 45 min before surgery were either asleep or ade-
possible (“flip-flop” phenomenon) due to reduced systemic quately sedated with plasma concentrations in excess of
vascular resistance concomitant with increased pulmonary 2.8 mg/kg [153].
Pharmacokinetics Ketamine
Peak concentrations of thiopentone in the brain and other
well-perfused organs are achieved within one circulation Mechanism of Action
time. Recovery results from redistribution. Reported phar- The analgesic properties of ketamine are mediated by mul-
macokinetic parameter estimates have been derived from tiple mechanisms at central and peripheral sites. The contri-
infusions administered for seizure control in neonates suf- bution from N-methyl-D-aspartate (NMDA) receptor
fering hypoxic-ischemic insults. Clearance estimates in antagonism and interaction with cholinergic, adrenergic,
neonates range from 66 to 320 mL/h/kg with a volume of serotonergic, opioid pathways, and local anesthetic effects
distribution at steady state (Vss) of 3.6–5.4 L/kg [154–157]. remain to be fully elucidated.
Interindividual variability was considerable [151]. While
most clearance estimates are less than those in adults Pharmacodynamics
(200 mL/h/kg) [152], interpretation is difficult, because the Ketamine is available as a mixture of two enantiomers; the
hypoxic-ischemic insult also affects the clearance. S(+)-enantiomer has four times the potency of the R(-)-
Clearance is achieved through oxidation (CYP2C19) to an entantiomer. S(+)-ketamine has approximately twice the
inactive metabolite, thiopentone carboxylic acid, and neo- potency of the racemate. The metabolite norketamine has a
natal immature hepatic function decreases oxidizing capac- potency that is one-third that of its parent. Plasma concentra-
ity. CYP2C19 microsomal activity is approximately 30% tions associated with hypnosis and amnesia during surgery
of mature values in the third trimester of pregnancy, but are 0.8–4 μg/mL; awakening usually occurs at concentra-
increases dramatically at term [60]. Thiopentone clearance tions less than 0.5 μg/mL. Pain thresholds are increased at
maturation is consistent with this CYP2C19 maturation. 0.1 μg/mL [161–163]. Data from neonates are not available.
Clearance rapidly increases during the neonatal period
from 33 mL/h/kg at 24 weeks PMA to 160 mL/h/kg at term; Pharmacokinetics
within 20% of the adult clearance [158]. Neonates (25.7– Ketamine is very lipid soluble with rapid distribution.
41.4 weeks PMA) undergoing surgery on the first day of Ketamine undergoes N-demethylation to norketamine.
life resulted in an elimination half-life of 8 h (interquartile Elimination of racemic ketamine is complicated by the R(-)-
range (IQR) 2.5–10.8) and a clearance 92 mL/min/kg (IQR ketamine enantiomer, which inhibits the elimination of the
20–100) [159]. Thiopental has a low hepatic extraction S(+)-ketamine enantiomer [164]. Clearance in infants within
ratio (0.3), exhibiting capacity limited elimination. In the first six months of life is similar to adult rates
adults, 10–12% of thiopentone is metabolized per hour; (80 L/h/70 kg, i.e., liver blood flow), when corrected for size
comparable data are not available in neonates. Michaelis- using allometric models [46]. In contrast, clearance in the
Menten kinetics are reported in adults as well as in neo- neonate is reduced (26 L/h/70 kg) [165–167], while the Vss
nates. The Michaelis constant in neonates (Km 28.3 mg/L) is increased (3.46 L/kg at birth, 1.18 L/kg at 4 years, 0.75
is similar to that reported for adults (26.7 mg/L). The maxi- L/kg at adulthood [165]). This larger Vss in neonates
mum rate of metabolism (Vmax) increases from 0.44 explains, in part, why neonates require a four-fold greater
mg/min/kg at 24 weeks PMA to 5.26 mg/min/kg at term; an dose to prevent gross motor movement than 6-year-old chil-
adult Vmax of 7 mg/min/kg has been reported [158]. dren do [168]. The hepatic extraction ratio is high and the
relative bioavailability of oral, nasal, and rectal formulations
Adverse Effects is 30–50%.
These are similar to those described for propofol.
Thiopentone has little direct effect on vascular smooth mus- Adverse Effects
cle tone. Cardiovascular depression is centrally mediated by Ketamine can cause psychotic reactions and hallucinations
inhibition of sympathetic nervous activity and direct myo- that can cause distress in older children. These can be ame-
cardial depression through effects on trans-sarcolemmal and liorated by benzodiazepines. An antisialagogue may be
sarcoplasmic reticulum calcium flux [160]. There is no pain required to diminish copious secretions after parenteral
with IV injection. Because the action of thiopentone is ter- administration. Tolerance in children may occur with
minated by redistribution and metabolism is slow, recovery repeated use. Increases in intracranial pressure can be ame-
may be very slow after an infusion of thiopentone. liorated by maintaining normocarbia.
The use of ketamine in neonates is limited because of Pharmacokinetics

concerns that the NMDA antagonists cause neuronal apop-
tosis during periods of synaptogenesis in newborn mam- In the 1960s, investigators determined that the wash-in
mals. Neonatal rats that did not undergo surgical stimulation curves for halothane (Fig. 3.15), and N2O in neonates were
or inflammatory response but were exposed to high-dose
ketamine sustained widespread neuronal apoptosis and
long-term memory deficits [169, 170]. The applicability of 1.0
extrapolating rodent data to the care of human neonates con-
tinues to be debated [163, 171, 172]. 0.9
children, 1–5 years
0.8
Inhalation Agents
Physicochemical Properties 0.7

FA
The chemical structures of the inhalational anesthetics are FI 0.6
adults
based on a polyhalogenated ether skeleton (with one excep-
tion): isoflurane and desflurane are methyl ethyl ether anes-
0.5
thetics and sevoflurane is a methyl isopropyl (original
Table 3.1). The single exception to the ether skeleton is halo-
thane, a polyhalogenated alkane that is infrequently used 0.4
HALOTHANE
today. Desflurane differs from isoflurane only in the substitu-
tion of a fluoride atom for a chloride on the alpha carbon of 0.3
isoflurane, whereas sevoflurane differs by the substitution of
a trifluoromethyl group for a chloride atom on the alpha car- 0 10 20 30 40 50 60
bon of isoflurane. These minor atomic substitutions and minutes
structural differences confer substantial differences in the
Fig. 3.15 Rate of rise of alveolar to inspired partial pressures of halo-
physicochemical and pharmacological properties of the ether thane in children and adults (reproduced with permission, Salanitre &
anesthetics that are elucidated below (Table 3.1). Rackow [38]
Table 3.1 Pharmacology of inhaled anesthetics

Halothane Enflurane Isoflurane Sevoflurane Desfluranee
Pharmacology
Chemical structure
INSERT CHEM STRUCTURES HERE
PLEASE
Molecular weight 197.4 184.5 184.5 200.1 168
Boiling point (°C) 50.2 56.5 48.5 58.6 23.5
Vapor pressure (mmHg) 244 172 240 157 664
Saturation concentration (%) 34 24 34 26 93
Odor Mild, pleasant Etheric Etheric Pleasant Etheric
Solubility
λb/g adults 2.4 1.9 1.4 0.66 0.42
λb/g neonates 2.14 1.78 1.19 0.66 –
λbrain/b adults 1.9 1.3 1.6 1.7 1.2
λbrain/b neonates 1.5 0.9 1.3 – –
λfat/b adults 51.1 – 45 48 27
MAC
MACadults 0.75 1.7 1.2 2.05 7.0
MACneonates 0.87 – 1.60 3.2 9.2
b/g Blood/gas, brain/b Brain/blood, fat/b Fat/blood, MAC Minimum alveolar concentration (percent), λ Partition coefficient
Reproduced in part, from Ref. [39]
more rapid than in adults [38, 173]. Although the rate of sures that are similar to those in the blood that left the heart.
increase of alveolar to inspired partial pressures of N2O in Hence, a diminishing quantity of inhalational anesthetic
adults is rapid, achieving an FA/FI ratio of 0.8 within 10 min, is taken up from the FRC, allowing the partial pressure in
it is even more rapid in neonates and infants, achieving a the FRC to increase. At the same time, the blood and tissue
ratio of 0.9 within 5 min. The fundamental principle underly- solubilities of inhalational anesthetics in neonates are less
ing the pharmacokinetics of these anesthetics in neonates is than those in older children and adults. (Fig. 3.16, Table 3.1)
the movement of inhalational anesthetics among body [40, 175, 176]. This is true for the more soluble inhalational
organs. Outside of the body, inhalational anesthetics exist in anesthetics with solubilities that are 18% less than those in
the gas phase where the concentrations and partial pressures neonates compared with older children and adults. However,
are interchangeable (assuming the ideal gas law). However, in the cases of the less soluble anesthetics, sevoflurane and
inside the body, the concentrations of inhalational anesthet- desflurane, the solubilities in neonates do not differ substan-
ics in any fluid or solid tissue exceed the equivalent partial tially from those in adults [40]. Hence, blood solubility dif-
pressure (determined by the dissolved fraction), because ferences of the less soluble inhalational anesthetics do not
they are bound to proteins and lipids. In addition, these anes- contribute substantively to the rapid wash-in of sevoflurane
thetics move across tissue membranes into the blood or from and desflurane in neonates. Similarly, age-related differences
blood into tissues without impediment, following partial in hemoglobin, serum concentration of α1-acid glycoprotein,
pressure, not concentration, gradients. This movement of and prematurity do not significantly affect the solubility of
anesthetics across membranes continues until the partial most inhalational anesthetics in blood [177]. Accordingly,
pressures equilibrate, despite differences in the concentra- the uptake of anesthetics by blood and tissues in neonates
tions of the anesthetics. Conceptually, this is identical to the is relatively small, leaving the partial pressure in the FRC to
movement of oxygen and carbon dioxide within the body. As increase unabated.
a result, we only refer to inhalational anesthetics in terms of To understand the wash-in of inhalational anesthetics, the
their partial pressures within the body. rate of rise of the anesthetic partial pressure (e.g., wash-in
Four factors explain the more rapid wash-in of inhala- of anesthetic) follows an exponential curve, the variables of
tional anesthetics in neonates compared with older children which are determined by the volume of the reservoir and the
and adults (Table 3.2). The first is the delivery of anesthet- flow into the reservoir. The equation that describes such a
ics to the lungs. Alveolar ventilation delivers the anesthetic wash-in is a simple, first-order exponential equation:
and the FRC is the lung compartment into which the anes-
thetic is delivered [174]. The greater the ratio of the alveolar
ventilation to FRC, the more rapidly the anesthetic partial Blood / Gas Partition Coefficient
pressure in the FRC increases. In neonates, this ratio is 5:1,
3
three-fold greater than in adults, 1.5:1. The remaining fac-
tors (Table 3.2) explain the rapid wash-in of anesthetics in
neonates by their effects on the uptake of anesthetics from
the lungs. Although a greater cardiac output should actually Halothane
slow the wash-in of anesthetic into the FRC, in neonates, it
speeds the wash-in, because the greater cardiac output pri- 2 20
marily distributes anesthetic to the vessel-rich group (VRG)
of tissues (brain, heart, kidneys, and gastrointestinal and
Enflurane
endocrine organs), which, in neonates, comprises a larger
Methoxyflurane
fraction (18%) of the bodyweight than it does in children/
adults (6%). With the VRG receiving such a large proportion
of the cardiac output, the anesthetic partial pressures in the
VRG equilibrate very rapidly, leaving a large partial pres-
sure of anesthetic in the blood returning to the heart, pres-
Isoflurane
Table 3.2 Determinants of the rapid wash-in of inhalational agents in 1 10

infants 0 40 80
1. Greater alveolar ventilation to functional residual capacity ratio Age (years)
2. Greater fraction of the cardiac output distributed to the
vessel-rich group Fig. 3.16. Effect of age on the blood/gas partition coefficient of the
four inhalational agents: isoflurane, enflurane, halothane, and methoxy-
3. Reduced tissue/blood solubility
flurane. The solubility of all four agents in neonates is 18 % less than in
4. Reduced blood/gas solubility adults (reproduced with permission, Lerman et al. [175])
C / Co 1 e kt , where k is 1 / t (3.1) FA / FI
N2O
1.0
where τ is the time constant, which is defined by Eq. (3.2):
Desflurane
Volume of the functional residual capacity L (3.2)
min
Alveolaar ventilation L / min
Four time-constants are required to reach 98% equilibra- 0.8 Sevoflurane

tion of anesthetic partial pressures in the FRC. Hence, with
an FRC of 0.5 L and an alveolar ventilation of 1 L/min, is
0.5 and the time to reach 98% equilibration of inspired and
alveolar anesthetic partial pressure is 2 min.
Isoflurane
The increase in anesthetic partial pressure in tissues is
also determined by a simple first-order exponential curve 0.6
that depends on the delivery of anesthetic to the tissues (tis-
sue blood flow) and the capacity of the tissues for anesthetic
Halothane
to reach partial pressure equilibration (the product of the
volume of the tissue and the solubility of anesthetic in the
tissue). This is expressed by an equation that is similar to Eq.
(3.2) as follows for the wash-in to the brain: 0.4
Volume of the brain mL Brain / blood solubility

brain (3.3)
Brain blood flow mL / min

Understanding the wash-in of inhalational anesthetic into
the brain is essential to appreciating the pharmacokinetics 0.2
of induction of anesthesia with an inhalational anesthetic.
Assuming the blood flow to the brain is 50 mL/min/100 g of
brain (and the brain density is 1 g/mL) and the brain/blood Mean±SD
solubility for a particular inhalational anesthetic in an adult
is 2.0, then the time constant is as follows:
0.0
100 mL 2 0 10 20 30
brain 4 min (3.4) MINUTES OF
50 mL / min
ADMINISTRATION
Thus, the time to reach 98% equilibration of anesthetic Fig. 3.17 Wash-in of N2O, desflurane, sevoflurane, isoflurane, and
halothane in adults. The order of wash-in parallels the solubility of
partial pressures is 16 min. If the brain/blood solubility were these agents in blood (reproduced with permission from Yasuda N, et al.
halved, as in the case of a neonate [176] to 1.0, then the [178])
time to 98% equilibration would decrease by 50% to 8 min,
resulting in a more rapid onset of anesthesia in the neonate
and explain the early onset of cardiorespiratory sequelae. the first minute would be ~0.5 for both adults and neonates
The wash-in curves for the commonly used inhalational (as sevoflurane is an insoluble anesthetic). With an inspired
anesthetics have been reported for adults [178]. The alveolar concentration of 8% and an MAC of 3.3%, the alveolar par-
to inspired concentrations for halothane reach 0.35 in the first tial pressure would be 8 × 0.5/3.3 or 1.2 × MAC, which is
minute of the start of anesthesia, independent of level of ven- less than one-half that with halothane. Thus, sevoflurane is
tilation (Fig. 3.17). In the neonate, the wash-in of halothane less likely to cause hemodynamic depression in the neonate
in the first minute is closer to 0.5, based on the more rapid in the early period of anesthesia as would halothane, and a
wash-in of halothane in neonates. With a maximum inspired depth of anesthesia that is less than that achieved with halo-
concentration for halothane of 5% and an MAC (minimum thane in the first minute.
alveolar concentration) in neonates of 0.87%, the alveolar The rate of increase of alveolar to inspired partial pres-
partial pressure would be 5 × 0.5/0.87 or 2.9 × MAC. If sevo- sures of inhalational anesthetics varies inversely with the
flurane were substituted for halothane, then the wash-in in solubility in blood as follows: N2O > desflurane > sevoflu-
rane > isoflurane > enflurane > halothane > methoxyflurane anesthetic partial pressure in the exhaled or alveolar gases.

(Fig. 3.17) [178]. After a step-wise change in the inspired Thus, the reduced tissue solubilities of inhalational anesthet-
partial pressure of less soluble anesthetics, the alveolar par- ics in neonates speed the wash-in of anesthetic partial pres-
tial pressure equilibrates very rapidly with the new inspired sures compared with adults.
partial pressure. Since the washout of these anesthetics is The pharmacokinetics of inhalational anesthetics during
equally rapid (see below), the inspired partial pressure can be the first 15–20 min depends primarily on the characteris-
returned to its initial value rapidly by decreasing the inspired tics of the vessel-rich group, whereas the pharmacokinetics
partial pressure. Thus, anesthetic depth can be controlled during the subsequent 20–200 min depends on the charac-
more rapidly with less soluble than with more soluble inha- teristics of the muscle group [174]. The solubility of inha-
lational anesthetics. lational anesthetics in skeletal muscle varies directly with
The solubilities of the inhalational anesthetics in the age in a logarithmic relationship [176]. This effect of age on
vessel-rich tissues in neonates are approximately one-half the solubility of anesthetics in muscle has been attributed to
those in adults (Fig. 3.18) [176]. These reduced tissue solu- age-dependent increases in protein concentration in the first
bilities for halothane, isoflurane, enflurane, and methoxyflu- five decades of life and in fat content in the subsequent three
rane are attributable to two differences in the composition of decades of life [176]. Since the muscle mass in the neonate
tissues in neonates compared with those in adults: (1) greater is small, this effect is attenuated.
water content and (2) decreased protein and lipid concen- The net effect of these differences between neonates and
trations. The reduced tissue solubilities decrease the time adults is to speed the equilibration of anesthetic partial pres-
for partial pressure equilibration of anesthetics in tissues sures in alveoli and tissues and thereby speed the rate of
(see time constant for tissues, above). Although the partial equilibration of alveolar to inspired anesthetic partial pres-
pressures of inhalational agents in tissues cannot easily be sures in neonates compared with adults [38, 173]. However,
measured in vivo, they may be estimated by measuring the the difference in the rate of wash-in of less soluble anesthet-
ics between neonates and adults may be less pronounced
than that of more soluble anesthetics.
BRAIN / GAS PARTITION COEFFICIENTS
6
5 Ventilation
4 Changes in alveolar ventilation directly affect the wash-in of

inhalational anesthetics: as alveolar ventilation increases, the
HALOTHANE wash-in of the anesthetics increases (Fig. 3.19) [174].
3 30 Ventilation is the primary determinant of the delivery of
anesthetics to the lungs to affect the wash-in of the anesthet-
ics. The effect of ventilation on the wash-in is more pro-
nounced with more soluble anesthetics, for example,
2 20 halothane, and less pronounced or limited with less soluble
METHOXYFLURANE
anesthetics, for example, sevoflurane, and desflurane. The
ENFLURANE reason for the differential effect of ventilation rests with the
ISOFLURANE
dependency of the anesthetic on its speed of delivery to
achieve partial pressure equilibration: those anesthetics that
are more soluble in blood (and tissues) are taken up from the
lungs into blood (and tissues) more rapidly, and thus, their
1 10
wash-in is slowed. The wash-in of these soluble anesthetics
0 20 40 60 80 depends more on their delivery (alveolar ventilation) than do
AGE (YEARS) the less soluble anesthetics. Conversely, inhalational anes-
thetics such as sevoflurane and desflurane, which are less
Fig. 3.18 Effect of age on the solubility of isoflurane, enflurane, halo- soluble in blood, are delivered to the lungs with very little of
thane, and methoxyflurane in the human brain. The solubilities of all
anesthetics in the neonatal brain are less than those in older adults the anesthetics taken up by blood, thus facilitating a more
(reproduced with permission, Lerman J, et al. [176]) rapid wash-in that depends less on alveolar ventilation.
VENTILATION cokinetic and pharmacodynamic factors including (1) the

(I/min) rate of equilibration of anesthetic partial pressures (deter-
1.0 8 mined by the four factors in Table 3.2), (2) the maximum
4
2 N2O inspired concentration, (3) airway irritability, and (4) the
MAC value. It is the interaction of these four factors that
determines the relative speed of induction of anesthesia.
FA The rate of wash-in of inhalational anesthetic into the
FI lungs varies inversely with the solubility of inhalational
8 anesthetics in blood as outlined above [178]. However, only
sevoflurane and halothane are devoid of irritating the upper
airway when delivered by face mask. Although less soluble
anesthetics wash-in to the FRC more rapidly than more
0.5 4 HALOTHANE
soluble anesthetics, the more rapid wash-in may be offset
by the limited maximum concentration deliverable from the
vaporizer (overpressure technique) and their greater MAC as
2 described on p.30 (Table 3.1).
8
4 ETHER Control of Anesthetic Depth
2 Two feedback mechanisms modulate the depth of anesthesia

during inhalational anesthesia: respiratory and cardiovascu-
0 lar. During spontaneous ventilation, respiratory depression
20 40
MINUTES limits the depth of anesthesia by stopping the delivery of
anesthetic to the lungs. As the depth of anesthesia increases,
Fig. 3.19 Effect of alveolar ventilation on the wash-in of soluble alveolar ventilation decreases, the neonate arouses from
(ether), intermediate (halothane), and insoluble (N2O) anesthetics. anesthesia as the anesthetics are redistributed away from the
Changes in ventilation affect the wash-in of more soluble than less solu-
ble anesthetics (reproduced with permission, Eger EI 2nd. Anesthetic VRG and spontaneous ventilation resumes. This is known as
uptake and action. Baltimore: Williams & Wilkins; 1974) [174] a negative feedback effect [179]. This protective mechanism
permits the use of inspired concentrations of inhalational
anesthetics several-fold greater than MAC (overpressure
Cardiac Output technique) while protecting against excessive circulatory
depression. However, if ventilation is controlled, this protec-
Changes in cardiac output inversely affect the wash-in of tive mechanism is bypassed. The alveolar to inspired anes-
inhalational anesthetics as presented above: the greater the thetic partial pressure ratio increases relentlessly as cardiac
cardiac output through the lungs, the more rapidly anesthetic output decreases. This decrease in cardiac output limits the
is removed from the lungs and the slower the wash-in of removal of anesthetic from the lung, leading to a further
anesthetic into the alveoli [174]. In the neonate, the effect of increase in the alveolar partial pressure of anesthetic. This is
cardiac output is paradoxical as the greater cardiac output known as a positive feedback effect [179]. In such a circum-
actually speeds the wash-in, since most of the cardiac output stance, this leads to a downward spiral that might profoundly
is directed to the VRG, which comprises 18% of the cardiac depress the cardiovascular system resulting in death if the
output, that speeds the equilibration of alveolar to inspired cycle is not interrupted [179].
anesthetic partial pressures. These feedback loops hold particular relevance for neo-
nates. When halothane was administered to neonates, hypo-
tension (and bradycardia) occurred frequently; however, when
Induction sevoflurane was introduced, despite the more rapid wash-in
of this new insoluble anesthetic, circulatory instability did
Although many associate the more rapid wash-in of insolu- not occur. As described on P.30 [THIS MANUSCRIPT], the
ble versus soluble anesthetics to a more rapid induction of slower wash-in but greater achievable MAC-multiple of halo-
anesthesia, this notion is probably untrue. Whereas the wash- thane offsets the more rapid wash-in of sevoflurane with the
in is determined by the pharmacokinetics of the agents, the smaller achievable MAC-multiple of sevoflurane, introducing
speed of induction of anesthesia depends upon both pharma- an element of safety with the later agent.
Shunts (Fig. 3.20) [39]. When the tracheal tube is positioned with its
tip at the midtrachea level (Fig. 3.20a), ventilation is divided
Shunts exist in two forms: left-to-right or right-to-left. Left- equally between both lungs, thereby yielding equal anes-
to-right shunts refer to conditions in which blood recircu- thetic partial pressures in both pulmonary veins (PV = 1).
lates through the lungs (usually an intracardiac defect such However, when the tip of the tube is advanced into the right
as a ventricular septal defect). In contrast, right-to-left shunts bronchus (Fig. 3.20b), all of the ventilation is delivered to
refer to conditions in which venous blood returning to the one lung, that is, the ventilation to that lung is doubled and
heart bypasses the lungs (as in an intracardiac (cyanotic heart ventilation to the nonventilated lung is zero. Under these
defect) or intrapulmonary (pneumonia or an endobronchial conditions, the partial pressure of CO2 remains unchanged.
intubation) defect. In general, left-to-right shunts do not sig- When a soluble anesthetic is administered in the presence
nificantly affect the pharmacokinetics of potent inhalational of an endobronchial intubation (right-to-left shunt), the par-
agents, provided cardiac output remains unchanged. In con- tial pressure of anesthetic in the combined pulmonary veins
trast, right-to-left shunts can significantly delay the wash-in is approximately the same as in the presence of a tracheal
of inhalational anesthetics [180]. The magnitude of the delay intubation. The similar anesthetic partial pressure occurs
with a right-to-left shunt depends on the solubility of the because the increased ventilation to the ventilated lung
anesthetic: the less soluble the anesthetic (N2O, desflurane, compensates to a large extent for the shunt and speeds the
and sevoflurane), the more delayed the wash-in compared increase in alveolar to inspired anesthetic partial pressures.
with that of the more soluble anesthetics. These effects are However, when a less soluble anesthetic is administered in
independent of the anatomical level of right-to-left shunts: the presence of a right-to-left shunt, the effects on the wash-
intracardiac or intrapulmonary (as in the case of an endo- in of the inhalational agent are quite dramatic. In this case,
bronchial intubation). the increase in ventilation to the ventilated lung minimally
To understand why right-to-left shunts affect the phar- increases the wash-in of the anesthetic (Fig. 3.20c). As a con-
macokinetics of inhalational anesthetics and less soluble sequence, the minimal increase in wash-in to the ventilated
anesthetics, in particular, it is useful to consider a simplified lung cannot offset the effects of the shunt. The anesthetic
model of the lung in which each lung is represented by one partial pressure in the combined pulmonary vein thus lags
alveolus and each lung is perfused by one pulmonary artery behind the partial pressure in the veins when both lungs
a No Shunt b Right-to-Left Shunt c Right-to-Left Shunt

Soluble Anaesthetic Insoluble Anaesthetic
Tracheal Tube
Trachea
Right Left
Lung
VA=1 VA=1 VA=2 VA=0 VA=2 VA=0
Pv=1 Pv=1 Pv=2 Pv=0 Pv=1 Pv=0
Pulmonary Vein
Pv=1 Pv=1 Pv=0.5
Fig. 3.20 Effect of shunt on the wash-in of anesthetic partial pressure However, (c) illustrates the dramatic effect of a right-to-left shunt on the
in blood. (a) illustrates the normal wash-in with no shunt, equal ventila- wash-in with a less soluble anesthetic. Since the increased alveolar ven-
tion to both lungs and normocapnia. (b) illustrates the effect of a right- tilation to the intubated lung does not substantively affect the wash-in to
to-left shunt (via an endobronchial intubation) on the wash-in of a the lung, when the blood from the ventilated lung combines with that
soluble anesthetic. Normocapnia is maintained, and hypoxic pulmonary from the shunted lung, the net effect is a slower wash-in of anesthetic
vasoconstriction is negligible. The doubled ventilation to the intubated (with permission, Lerman J [ 39].)
lung offsets the effect of the shunt. The wash-in is similar to (a).
were ventilated. Induction of anesthesia with a less soluble In neonates, recovery after inhalational anesthesia is
anesthetic is thereby slower in the presence of a right-to-left somewhat slower than that predicted solely by the washout
shunt than in the absence of a shunt. The less soluble anes- curves. In part, this area of investigation has been hampered
thetics, desflurane and sevoflurane, are two such anesthetics by a lack of consensus on the essential factors associated
whose wash-in characteristics may be significantly slowed in with emergence in the neonate [186]. Many anesthesiolo-
the presence of a right-to-left shunt. These anesthetics would gists have struggled to explain why neonates recover at a
require supplemental IV medication to maintain a steady and slower rate than expected after a brief anesthetic with only
deep level of anesthesia. inhalational anesthesia. Nonetheless, infants recover more
The wash-in of halothane has been evaluated in children rapidly after desflurane than with sevoflurane and halothane
with fenestrated Fontans before and after closure of the [187]. No clear answers to explain this curiosity have been
fenestration [180]. The authors noted that before the fen- forthcoming.
estration was closed (the right-to-left shunt was open), the
wash-in of halothane as determined by the increase in arte- Pharmacodynamics
rial to inspired partial pressures was delayed compared with In 1969, the MAC of halothane was noted to increase as age
that after the fenestration was closed. Closure of the fenes- decreased [188]. The MAC of halothane reached its maxi-
tration increased the pulmonary to systemic blood flow ratio mum value (1.1%) in the youngest age group, which included
from 0.58 to 0.88. Importantly, they noted that the increase in 2 neonates and 4 infants 1–6 months of age. Based on this
the end-tidal partial pressure of halothane did not parallel the MAC measurement, one study cautioned against the use of
arterial partial pressure. This observation is consistent with halothane in neonates because it caused more hypotension
published evidence that the correlation between the end-tidal than it did in older infants [189]. Clinicians deduced at the
and arterial partial pressures of a gas (carbon dioxide) in time that neonates were more sensitive to the myocardial
children with cyanotic heart disease is poor [181]. depressant effects of halothane than children. Subsequently,
when we measured the MAC of halothane in neonates as a
group distinct from older infants 1–6 months of age, the
Metabolism MAC in the former group, 0.87 ± 0.1%, was 15–25% less
than that in the latter, 1.2% [99]. Furthermore, when 1 MAC
The metabolism of inhalational anesthetics is discussed of inhalational anesthetics were administered, the systolic
below under Renal and Hepatic effects. blood pressure and heart rate responses in neonates were
similar to those in older infants [99, 190, 191]. The MAC
(mean ± SD) values in full-term neonates for the inhalational
Emergence anesthetics in use today are: 1.60 ± 0.01% for isoflurane
[192], 9.2 ± 0.02 % for desflurane [190] and 3.3 ± 0.2% for
The washout of inhalational agents follows an exponential sevoflurane [191]. Also, there is evidence that the primary
decay (the inverse of the wash-in curve) [178]. The order of cause of the increased sensitivity of neonates to cardiode-
the washout of the anesthetics parallels their blood/gas solu- pression by inhalational anesthetics may be attributed to the
bilities; that is, the anesthetic that is washed out first, desflu- immaturity of the cardiovascular system [193]. Using echo-
rane, is the least soluble in blood [178]. The order of washout cardiography, the cardiodepressant effects of halothane and
in children is expected to be similar to that in adults. isoflurane in concentrations up to 1.5 MAC in neonates were
Recovery of motor function in rats parallels the washout noted to be greater than in older infants [194]. The increased
of inhalational anesthetics from fastest to slowest: desflu- susceptibility of neonates to the depressant effects of inhala-
rane < sevoflurane < isoflurane < halothane [182]. Notably, tional anesthetics has been attributed, in part, to a decrease in
the rate of recovery increases in parallel with the duration of myocardial contractile elements, the decrease in calcium
anesthesia [178]. In studies in which the recovery from two or sensitivity of myocardial fibers [193], and the incomplete
more inhalational agents were compared, the end-tidal concen- sympathetic innervation of the heart and vascular system.
trations of the anesthetics were maintained at approximately 1 Evidence also indicates that both pressor and depressor baro-
MAC until the conclusion of surgery after which the anesthet- responses are depressed in the presence of isoflurane in the
ics were abruptly discontinued [183–185]. In this paradigm, preterm and full-term neonate [195]. These data suggest that
it is not surprising to find that the rates of recovery paralleled the magnitude of the cardiovascular depression by inhala-
the rates of washout, which in turn paralleled the blood solu- tional anesthetics at 1 MAC in neonates is similar to that
bilities of the inhalational agents. In clinical practice however, reported in older infants and that at concentrations greater
anesthetic concentrations are gradually tapered as the end of than 1 MAC, it may be greater than in older infants.
surgery approaches. This practice attenuates the differences in To attenuate the cardiodepressant effects of inhalational
the rates of recovery amongst inhalational agents. anesthetics in neonates, the heart rate should be maintained
and preload optimized. Neonatal myocardium evolves dur- The additivity of MAC fractions of inhalational agents (as
ing the first month after birth, improving in ventricular com- well as N2O) is well established. However, the concept of
pliance [196]. Because neonates depend on a rapid heart rate additivity in children 1–3 years of age does not hold for all
to maintain cardiac output, cardiovascular depression partic- inhalational agents: the additive contribution holds for the
ularly in the presence of halothane, can be reversed or offset MAC of halothane and isoflurane [203, 204] but not for the
in part by intravenous atropine (0.02 mg/kg) [194, 197]. To MAC of sevoflurane and desflurane [191, 205]. Sixty percent
optimize preload, balanced salt solution or albumen in a vol- N2O decreases the MAC of sevoflurane in young children by
ume of 5–20 mL/kg, should be administered before anesthe- only 24% and that of desflurane 22% [191, 205]. Whether
sia is induced [98]. Neonates who have had cardiorespiratory the same holds in neonates is unknown. Additional evidence
dysfunction in the presurgical period or were managed in the from the MAC response to tracheal intubation supports this
Neonatal Intensive care unit, often present to the operating attenuated effect of N2O on the MAC of sevoflurane in chil-
room relatively dehydrated because of aggressive diuretic dren [206]. This differential effect of nitrous oxide on the
therapy and/or third space fluid losses. After rehydration but MAC values of inhalational agents in children and of its
in the absence of chronotropic agents, systolic arterial pres- effect on the MAC of sevoflurane and desflurane between
sure decreases ≈20–25% at 1 MAC halothane, desflurane children and adults has not been explained.
and sevoflurane compared with awake values in neonates, Although N2O is a common adjunct to general anesthesia,
with either no changes or minimal decreases in heart rate it is infrequently used in neonates because their surgery is
[99, 190, 191]. Similar responses have been reported with 1 often emergent and includes the risk of bowel distention and
MAC of these anesthetics in infants 1–6 months of age. there is a risk of adverse effects from high oxygen concen-
Curiously, the MAC values for sevoflurane in neonates trations. The avoidance of N2O in patients who have bowel
and infants 1–6 months of age are similar, 3.3 and 3.2%, obstruction or gas-filled closed spaces is well accepted
respectively [191]. It remains unclear why the relationship [207]. However, its avoidance in neonates who are at risk for
between the MAC of sevoflurane and age in infancy differs oxygen toxicity is less clear. The maximum PaO2 currently
from that for the other inhalational anesthetics. Whether recommended to preclude oxygen toxicity is 80 mmHg (that
the conformational structure of sevoflurane, a methyl iso- is, a SaO2 of 93%). This value lies at the shoulder of the
propyl ether, or some other physicochemical characteristic steep descending portion of the oxyhemoglobin dissocia-
is responsible for this unique relationship between MAC of tion curve. If N2O were used to maintain the arterial oxy-
sevoflurane and age remains unclear. gen tension below this value, then any minor difficulty with
The MAC of isoflurane decreases steadily in neonates as the airway could lead to a rapid oxygen desaturation. This
gestational age decreases to 24 weeks (Fig. 3.14) [98]. Not potential problem would be mitigated if nitrogen supplanted
only did this study characterize the relationship between the N2O since the former is 34 times less soluble in blood than
MAC for isoflurane in preterm neonates and age, but it also the latter. As a result, most recommend N2O be avoided and
confirmed the notion that neonates as young as 24 weeks replaced with an air/oxygen mixture in neonatal surgery.
gestation respond to noxious stimuli predictably. Although The MAC responses to stimuli other than skin incision;
several explanations have been posited to explain the age- ie., tracheal intubation, LMA insertion, extubation, and
dependent change in MAC in the perinatal period including return of wakefulness (MAC awake) have also been deter-
residual effects of placentally transmitted female hormones, mined in children, although their applicability to neonates
central nervous system substance P, and maturation of the has not been established [208].
central nervous system, the cause remains speculative.
Several factors moderate the MAC of inhalational anes- Central Nervous System
thetics in infants and children. The MAC of halothane in For the past decade, the anesthesia literature has been domi-
children with cerebral palsy and severe mental retardation nated and preoccupied with the effects of anesthesia on neu-
is approximately 25% less than that in children without dis- roapoptosis in the brain of the human neonate. Neuroapoptosis
abilities [198]. Whether these same relationships are true is discussed further in Chapter 18 (Do anesthetic drug harm
in neonates has not been established. Acute administration neonates? A global perspective) and will not be discussed
of barbiturates and benzodiazepines decreases MAC [199, further here.
200], chronic administration of similar medications (such as Although cerebral blood flow (CBF) is autoregulated,
in the case of children who have been treated with anticon- there are limits in mean blood pressures beyond which CBF
vulsants) does not affect MAC [201]. The effects of specific is pressure passive. Evidence suggests that neurological
anticonvulsants such as valproic acid and phenytoin on the sequelae are increasingly likely when the CBF decreases
MAC of inhalational agents remains unclear. Adults who are below 20 mL/kg/min. However, there is a dearth of evidence
homozygote for melanocortin for desflurane require ~20% to support this notion in neonates and during general anes-
more anesthetic (6.2% vs 5.2%) than for brunettes [202]. thesia [209]. CBF to the cortex is 3–4-fold greater than to
white matter, in part, explaining the increasing vulnerability rane [221]. None of the children displayed either clinical or
to periventricular leukomalacia in the perinatal period. EEG evidence of seizure activity. The EEG patterns for both
In general, all potent inhalational agents depress the cen- halothane and sevoflurane were characteristic even though
tral nervous system with dose-dependent decreases in the all of the children had been premedicated with midazolam.
cerebral vascular resistance and the cerebral metabolic rate The association between myoclonic movement and seizures
for oxygen. The decrease in vascular resistance causes a during sevoflurane anesthesia remains tenuous [228]. In
reciprocal increase in CBF that starts at 0.6 MAC [210]. The neonates, only a single case of a seizure has been reported
extent of the increase in CBF however, depends on the inha- after sevoflurane anesthesia [229]. EEG differs substantively
lational agent: halothane > enflurane > isoflurane [210]. The through gestation [220]. A meta-analysis of studies in which
effects of sevoflurane on CBF are similar to those of isoflu- amplitude-integrated EEG and/or NIRS were monitored dur-
rane, however the effects of desflurane differ substantively. ing anesthesia was unable to identify clear monitoring strate-
Desflurane blunts the cerebral autoregulatory response [211, gies for EEG and NIRS in neonates [230]. However, 3–5%
212]. The net effect of inhalational agents is to increase the of children experience at least 1 seizure in childhood, with
ratio of the cerebral blood flow to metabolic rate, with des- the greatest incidence occurring in infants <1 year of age
flurane increasing the ratio the greatest and therefore is the [231, 232]. Since epileptiform activities are weakly associ-
least preferred agent in these children. ated with clinical seizures [233], the clinical relevance of this
The effects of inhalational agents on the cerebral activity in the perianesthetic period is unknown.
blood flow in infants and children are poorly understood.
Preliminary data suggest that cerebral blood flow velocity Cardiovascular System
in children varies directly with the end-tidal carbon dioxide Inhalational agents affect the cardiovascular system either
partial pressure during halothane anesthesia [213]. Cerebral directly (by depressing myocardial contractility or the con-
blood flow velocity increases as the concentration of duction system, or by dilating the peripheral vasculature) or
halothane increases [214] but does not change significantly indirectly (by affecting the balance of parasympathetic and
in the presence of increasing concentrations of isoflurane. In sympathetic nervous systems, neurohumoral, renal or reflex
a retrospective study of infants <6 months of age who were responses). The cardiovascular responses to inhalational
anesthetized with 1 MAC sevoflurane and were normocap- agents in children are further complicated by maturational
neic, a MAP >35 mmHg maintained positive regional cere- changes in the cardiovascular system and its responsiveness
bral oxygen saturations, that is the oxygen delivery exceeded to these anesthetics [193, 196]. This is particularly a concern
the cerebral metabolic rate of oxygen consumption [215]. in neonates, although few studies have specifically addressed
The EEG activities of desflurane and sevoflurane are myocardial contractility in the neonate.
similar to those of isoflurane [216, 217] although the activ- Assessment of cardiovascular variables in infants and
ity of sevoflurane differs substantially from that of halothane children presents a challenge for clinicians. Blood pressure
[218]. The shift of power of the EEG from low (1–4 Hz) to may be measured either invasively (arterial line) or nonin-
medium frequencies (8–30 Hz) is greater for halothane than vasively. Electrocardiography is routinely used in all age
it is for sevoflurane. The unique EEG tracing in the neonate groups to detect arrhythmias. In contrast to blood pressure
evolves rapidly through gestation and with postnatal age in and electrocardiography, measurement of cardiac output and
infancy [219–221]. During the neonatal period, up to 2% myocardial contractility are much more difficult to quantitate
sevoflurane exerts limited effects on the EEG; however, by in this age group. Two-dimensional echocardiography and
3–5 months postnatal age, the EEG is responsive to increas- impedance cardiometry have been used to estimate cardiac
ing sevoflurane concentrations. The clinical relevance of output and myocardial contractility in infants and children
these EEG differences remains unclear at this time, although [194, 234–236], although the echocardiographic measure-
the BIS responses to sevoflurane, which are derived from ments are subject to variability depending on the preload
the EEG, differ substantively from those of halothane [222, and afterload. Load-independent derived echocardiographic
223]. Since brain monitors are infrequently used in neonates, variables (stress-velocity and stress-shortening indices) have
this issue is moot. since improved the accuracy of echocardiographic estimates
In children who were anesthetized with sevoflurane, both of myocardial function and are used with increasing fre-
epileptiform activity in the form of myoclonic movement of quency [237].
the extremities and transient spike and wave complexes on In neonates, several factors affect the blood pressure
EEG have been reported in a very small number of young responses to inhalational agents including the particular inha-
children [224–227]. To determine whether these involuntary lational anesthetic, the dose, the preload status of the infant,
movements could have as their origin a cortical focus, the the presence of co-existing diseases, and the techniques used
EEG was analyzed for evidence of seizure activity in children to measure the systemic pressure (invasive versus noninva-
who had been anesthetized with either halothane or sevoflu- sive) and cardiac function (echocardiography). Most stud-
ies demonstrated modest, dose-dependent decreases in blood directly depress myocardial contractility by decreasing
pressure with all of the inhalational agents. At ~1 MAC, sys- intracellular Ca2+ flux. Inhalational agents decrease the Ca2+
tolic blood pressure decreased ~24% with halothane, 30% flux by their action on the calcium channels themselves,
with sevoflurane, and 34% with desflurane [99, 190, 191]. ion exchange pumps, and the sarcoplasmic reticulum [193].
Systolic pressures may further decrease with concentrations Inhalational agents may also attenuate contractility of ven-
up to 1.5 MAC. Few data exist regarding the hemodynamic tricular myocytes via voltage-dependent L-type calcium
responses beyond 1.5 MAC. On balance, all of the inhala- channels (which are responsible for the release of large
tional agents (in concentrations up to 1.5 MAC) modestly amounts of calcium from the sarcoplasmic reticulum) [193,
depress systemic blood pressure in parallel with the dose. 196, 248, 249].
Many neonates arrive in the operating room from the That neonates and infants are more sensitive to the depres-
NICU relatively hypovolemic. To restore euvolemia and sant actions of inhalational agents than older children is sup-
attenuate the decrease in blood pressure under anesthesia, we ported by experimental evidence of maturational differences
administer at least 10 mL/kg IV balanced salt solution before between neonatal and adult rat, rabbit, and feline myocar-
anesthesia is induced [98]. Defining hypotension in neonates dium [249–251]. Structural differences that may account,
and infants (<6 months of age) is controversial. Two defini- in part, for the changes in myocardial sensitivity to inha-
tions are currently recognized for hypotension under anesthe- lational agents with age include a reduction in contractile
sia in this age group: a decrease in systolic or mean arterial elements, immature sarcoplasmic reticulum, and functional
pressure >20% below the awake or baseline value (relative differences in calcium sensitivity of the contractile elements,
hypotension), or an absolute value such as a mean arterial calcium channels, and the sodium-calcium pump in the neo-
pressure <35 mmHg or a systolic pressure of ≤45–50 mmHg natal myocardium [193, 248–254]. The determinants of Ca2+
[238–241]. The frequency of hypotension, both relative and homeostasis in ventricular myocardial cells in the neonate
absolute, during anesthesia is greatest before surgical inci- depend on trans-sarcolemma Ca2+ flux to a far greater extent
sion, in emergency procedures and with decreasing age (e.g., than on the sarcoplasmic reticulum [193]. This is based upon
in preterm infants) [240, 242]. The feared complication of a growing body of experimental evidence that includes the
persistent hypotension in the preterm and full-term neonate finding that the concentration of the Na+-Ca2+ exchange pro-
is neurocognitive dysfunction. Decreases in blood pressure tein in the neonatal myocardium, a protein that regulates
and prematurity predispose to cerebral oxygen desaturation trans-sarcolemma flux of Ca2+, exceeds that in adult cells by
under anesthesia, with almost 20% of neonates experiencing 2.5 fold and that its concentration decreases with age as the
cerebral desaturation >20% from baseline. However, recent concentration of L-type voltage-dependent calcium channel
evidence suggests that <20% decreases in systolic blood increases [250]. Furthermore, halothane reversibly inhibits
pressure in neonates predicted <10% probability of cerebral the Na+-Ca2+ exchange protein in immature myocardial cells
desaturation occurring, although a decrease in systolic blood [250]. The sarcoplasmic reticulum is poorly developed in
pressure >37.5% predicted >90% probability of cerebral neonatal myocardial cells and this finding weighs heavily
desaturation [243]. Severe hypotension (<25 mmHg), which against the SR being the major source of Ca2+ required for
is associated with cerebral oxygen saturation (<70%), occurs myocardial contractility.
rarely (in ~2% of infants) under anesthesia [244]. Currently, The baroreflex response is also depressed in neonates
we posit that hypotension under anesthesia is an unlikely with both halothane [255] and isoflurane [195], albeit to
precursor for neurocognitive dysfunction. a greater extent with the former than the latter. Given the
The effects of inhalational anesthetics on myocardial con- greater incidence of hypotension in neonates and infants than
tractility and cardiac output in the neonate are incompletely in older children, an intact baroreflex could offset, in part,
understood. Cardiac output in neonates decreases at 1.0 and the cardiovascular consequences. However, inhalational
1.5 MAC halothane and isoflurane similarly [194]. Knowing agents blunt this response, leaving the infant vulnerable to
the limited effects of sevoflurane and desflurane on myo- the cardiovascular depressant actions of inhalational agents.
cardial contractility, one might expect that these anesthetics Prophylactic anticholinergics and preload augmentation may
decrease cardiac output and myocardial contractility at 1 and attenuate the decrease in cardiac output in the presence of
1.5 MAC less than halothane [245]. To offset the circula- inhaled anesthetics.
tory depression by inhaled agents, intravenous atropine and Inhalational anesthetics vary in their effect on cardiac
a bolus of balanced salt solution (10 mL/kg) before induction rhythm. Halothane may slow the heart rate, in some cases,
of anesthesia may be effective in neonates [197, 246, 247]. leading to junctional rhythms, bradycardia, and asystole.
The mechanism by which inhalational agents depress These are dose-dependent responses. Three mechanisms have
myocardial function remains controversial. Studies in both been proposed to explain the genesis of halothane-associated
animal and human myocardial cells suggest that the potent dysrhythmias: a direct effect on the sinoatrial node, a vagal
inhalational agents, halothane, isoflurane, and sevoflurane, effect, or an imbalance in the parasympathetic/sympathetic
tone. It has also been suggested that the etiology of the bra- Sevoflurane depresses respiration to a similar extent as
dycardia during halothane anesthesia may be a withdrawal halothane up to 1.4 MAC but depresses respiration to a
of sympathetic tone. Bradycardia is particularly marked in greater extent than halothane at concentrations >1.4 MAC
the neonate, presumably because parasympathetic influences in adults [271]. Sevoflurane does not decrease the tone of
predominate over the sparse sympathetic innervation of the the intercostal muscles to the same extent as halothane [269,
myocardium in this age group. Junctional rhythms are also 273]. The compensatory changes in respiratory rate differ
common during halothane anesthesia. Atrial or ventricular among the anesthetics; respiratory rate increases at ≥1.4
ectopic beats are rare except in the presence of hyper- or MAC halothane, is unchanged with isoflurane but decreases
hypocapnia. In infants anesthetized with halothane, 10 μg/kg at ≥1.4 MAC enflurane [266, 267]. When 8% sevoflurane
atropine increases the heart rate ≥50% and promotes sinus was compared with 5% halothane, minute ventilation and
rhythm [256]. This dose of atropine also increases blood tidal volume decreased, and respiratory rate increased with
pressure in infants ≥6 months of age and children. both agents to similar extents [278].
Halothane also sensitizes the myocardium to catechol-
amines, particularly during hypercapnia. It decreases the Renal
threshold for ventricular extrasystoles during epinephrine The potent inhalational agents may affect renal function via
administration three-fold [257–259]. In contrast, isoflurane, four possible mechanisms: cardiovascular, autonomic, neu-
desflurane, and sevoflurane maintain or increase heart rate roendocrine, and metabolic. Although the first three mecha-
during the early induction period of anesthesia [190, 191, nisms pose no direct threat to renal function, the fourth
234, 236, 245, 246, 260–263]. When bradycardia occurs mechanism, metabolism, is a serious clinical concern that
in an anesthetized neonate, the primary cause is always has resulted in renal dysfunction and death after some inha-
hypoxia, even during anesthesia before other causes such lational anesthetics.
as a direct drug effect are given serious consideration. The Inhalational agents are metabolized in vivo to varying
ether anesthetics, isoflurane, desflurane, and sevoflurane, extents (Table 3.3). Halothane is the inhalational anesthetic
do not sensitize the myocardium to catecholamines to the that is most metabolized in vivo but releases very little fluo-
same extent as halothane [257, 258, 264]. The mechanism by ride in the inorganic form. Most of the fluoride that is liberated
which the sinus node controls automaticity is incompletely from the metabolism of halothane exists in an organic form,
understood but may include K currents, hyperpolarization- trifluoroacetate. This compound has been linked to halothane
activated current, and T and L forms of Ca2+ currents [193]. hepatitis (see below). Metabolism of inhalational agents by the
Moreover, developmental changes in these channels likely CYP450 2E21 releases inorganic fluoride [279]. Sevoflurane
account, in part, for the differential effects of inhalational releases the most fluoride of the available anesthetics, fol-
agents on heart rate with age [252]. lowed by isoflurane and desflurane, proportional to the extent
of metabolism (Table 3.3). Even after prolonged anesthesia,
Respiratory System 131 MAC•h isoflurane, the cumulative inorganic fluoride
Inhalational agents significantly affect respiration in infants concentration is small [280]. The metabolism of sevoflurane
in a dose-dependent fashion via effects on the respiratory yields both an inorganic and organic fluoride moiety [281].
center, chest wall muscles, and reflex responses. Halothane The organic form, hexafluoroisopropanol (HFIP), is rapidly
depresses respiration by decreasing tidal volume and attenu- conjugated and excreted by the kidneys [281]. It poses mini-
ating the response to carbon dioxide [265–267]. This depres- mal threat to renal function in humans; however, inorganic
sion is offset in part, by an increase in the respiratory rate fluoride that is released from these three ether anesthetics has
[266, 267]. These ventilatory responses to halothane are age- garnered great interest in establishing a relationship between
dependent; minute ventilation in infants decreases to a inhalational anesthetics and renal dysfunction.
greater extent than in children [268]. In infants and young Peak plasma concentrations of inorganic fluoride after
children, intercostal muscle activity is inhibited at greater exposure to inhalational agents follow an order that is similar
concentrations than the diaphragm [265, 269]. This effect is
most pronounced in preterm and full-term neonates and Table 3.3 In vivo metabolism of inhalational agents
infants and when a tracheal tube is used in place of an LMA Inhalational agent % Metabolized
[270]. Isoflurane, enflurane, sevoflurane, and desflurane Methoxyflurane 50%
depress the ventilatory drive and tidal volume and attenuate Halothane 20%
the respiratory responses to carbon dioxide [265, 267, 271– Sevoflurane 5%
277]. The increase in respiratory frequency that follows Enflurane 2.4%
respiratory depression may not restore minute ventilation to Isoflurane 0.2%
preanesthetic levels. Desflurane 0.02%
to that in Table 3.3): methoxyflurane > sevoflurane > enflu- tic acid and inorganic fluoride, causing not only a diuresis
rane > isoflurane > halothane ≈ desflurane [282–286]. In the but also renal tubular cell necrosis. With methoxyflurane’s
case of methoxyflurane, two metabolites are produced: inor- greater affinity for CYP450 2E1 than sevoflurane and its
ganic fluoride and oxalic acid. Both have been implicated in O-demethylation to dichloroacetic acid, nephrotoxicity after
the pathogenesis of renal dysfunction although clinically, the the former anesthetic was far more serious than after the lat-
renal injury was more consistent with the concentration of ter [91, 296].
inorganic fluoride rather than oxalic acid [287]. Subsequent Sevoflurane may also indirectly affect renal function
studies demonstrated that >2.5 MAC•h methoxyflurane through by-products of in vitro metabolism in the presence
resulted in subclinical nephrotoxicity erroneously attributed of carbon dioxide absorbents, for example, soda lime. Five
to a plasma concentration of inorganic fluoride that exceeded by-products have been identified with two that are potentially
50 μM and that >5 MAC•h resulted in frank nephrotoxicity nephrotoxic compounds: Compounds A and B. Compound A
also erroneously attributed to concentrations that exceeded is produced in concentrations that may be toxic in rats (not
90 μM [288]. These clinical concerns led to the voluntary in humans), whereas B does not reach toxic concentrations.
withdrawal of methoxyflurane from clinical practice. Nonetheless, the FDA in the USA set the minimum fresh
In contrast to the adult experience with methoxyflurane, gas flow with sevoflurane to 2 L per minute for >2.5 MAC-h
renal dysfunction was not a feature after this anesthetic in exposure, although this becomes a moot point if absorbents
children. The peak plasma concentrations of inorganic flu- devoid of sodium hydroxide and potassium hydroxide (e.g.,
oride in children anesthetized with methoxyflurane were Amsorb®) are used (see below). Despite this federal recom-
significantly less than that in adults after an equivalent anes- mendation, low fresh gas flows (<2 L per minute) with sevo-
thetic exposure [289]. The reduced plasma concentrations of flurane are widely used clinically in infants and children and
fluoride in children were attributed to several possible fac- have yet to yield any reports of renal insufficiency [297].
tors including a decreased metabolism of methoxyflurane,
greater uptake of fluoride by bone, increased excretion of Hepatic
fluoride ions, or a reduced renal sensitivity to fluoride in chil- In vivo metabolism of inhalational agents matures with age,
dren. Another plausible explanation for the reduced plasma increasing within the first two years of life and reaching
concentrations of inorganic fluoride in children may have adult values after this time. The developmental changes in
been an immature CYP450 2E1 isozyme system in the kid- metabolism may be attributed to several factors including
neys (see below). reduced activity of the hepatic microsomal enzymes, reduced
That the plasma concentrations of inorganic fluoride in fat stores, and more rapid elimination of inhalational agents
children who were anesthetized with sevoflurane were simi- in infants and children compared with adults. Halothane, iso-
lar to or greater than those after enflurane raised concerns flurane, enflurane, sevoflurane, and desflurane have all been
about possible renal dysfunction after prolonged exposure to associated with postoperative liver dysfunction and/or fail-
sevoflurane [290–292]. However, despite large plasma con- ure [298–302]. A recent prospective study in adults con-
centrations of inorganic fluoride after sevoflurane anesthesia, cluded that the incidence of drug-induced liver injury from
there was no evidence of renal dysfunction. To unravel this desflurane and sevoflurane in adults was a surprising 4%
mystery, two hypotheses put to rest the notion that the cir- [303]. Comparable studies in infants and children have not
culating inorganic plasma fluoride concentration was neph- been forthcoming. Halothane and sevoflurane have also been
rotoxic. The first identified the primary isozyme responsible associated with transient hepatic dysfunction in infants and
for the degradation of enflurane, isoflurane, sevoflurane, and children, but not in neonates [ 304–306]. Several case reports
methoxyflurane anesthetics to be CYP450 2E1 [279, 293– of transient postoperative liver failure and one case of fulmi-
295]; with secondary contributions from CYP450 2A6 and nant hepatic failure and death have been attributed to “halo-
3A [293]. Large quantities of CYP450 2E1 were found not thane hepatitis” that were confirmed serologically to
only within the liver (where degradation of ether inhalational antibodies to halothane-altered hepatic cell membrane anti-
agents yielded large plasma concentrations of inorganic gens in children [304]. The exact mechanism of the hepatic
fluoride) but surprisingly within the kidneys [91]. However, dysfunction after halothane remains unclear, although some
the affinity of renal CYP450 2E1 for methoxyflurane was have speculated that it is caused by an immunologic response
five-fold greater than that for sevoflurane, which resulted in to a metabolite of halothane. This putative toxic metabolite,
large intrarenal concentrations of inorganic fluoride with the a trifluoroacetyl halide compound, is produced during oxida-
former, damaging the renal tubules and causing a diuresis, tive metabolism of halothane. It is believed that this com-
whereas with the latter, intrarenal concentrations were small pound induces an immunologic response in the liver by
and renal dysfunction did not occur [91]. The second mecha- binding covalently to hepatic microsomal proteins, thereby
nism addressed the metabolic pathway for methoxyflurane, forming an immunologically active hapten. A subsequent
which uniquely included O-demethylated to dichloroace- exposure to the inhalational agent then incites an immuno-
logic response in the liver [307]. Hepatic enzymes may also Central Neuroexcitation
be induced by previous administration of drugs such as bar-
biturates, phenytoin, and rifampin. Although some have Paroxysmal increases in blood pressure (both systolic and
admonished clinicians of the risks of repeat anesthetics with diastolic pressures) and heart rate have been reported in
halothane and sevoflurane in children, given the millions of adults after a rapid increase in the inspired concentration of
uneventful repeat inhalational anesthetics in infants and chil- isoflurane or desflurane [319–322]. Neuroexcitatory
dren worldwide, there is insufficient evidence at present to responses have not been reported in neonates with either of
admonish this practice in neonates and infants. these agents nor have they been reported during sevoflurane
or halothane anesthesia at any age [321]. This rapid increase
in the inspired concentration of isoflurane or desflurane trig-
Clinical Effects gers a massive sympathetic response, mediated by norepi-
nephrine and/or epinephrine, resulting in tachycardia and
Induction Techniques hypertension [322]. Further increases in the inspired concen-
tration of the inciting agent will not control these hyperdy-
Physico-chemical characteristics of the ether series of anes- namic responses, but rather will perpetuate or possibly
thetics would predict that anesthesia could be induced augment the excitatory responses. To restore normal vital
smoothly and more rapidly with these agents than with halo- signs, the inciting agent must be discontinued and replaced
thane (Table 3.1) [175, 176]. However, this has not proved to with another inhalational or intravenous agent. Repetitive
be the case. All methyl ethyl ether anesthetics irritate the small increases (1%) in the inspired concentration of the
upper airway in children, resulting in a high incidence of putative agent produce transient, although attenuated cate-
breath-holding, coughing, salivation, excitement, laryngo- cholamine bursts and cardiovascular responses compared
spasm, and hemoglobin oxygen desaturation [184, 260, 308– with larger increases in concentrations [323, 324]. Fentanyl
310]. Consequently, most clinicians avoid inhalational (2 μg/kg), esmolol, and clonidine have all been effective in
inductions with these anesthetics. preventing, attenuating, or eliminating these sympathetic
In contrast to the irritant airway effects of the methyl responses [325]. The site or sites responsible for triggering a
ethyl ether anesthetics, the methyl isopropyl ether anes- neuroexcitatory response are unknown, although the rapidity
thetic, sevoflurane, is well tolerated when administered of the response suggests that the lung is a primary site [326].
by mask to infants and children at any concentration [185, Others however dispute this notion contending that two sites
191, 311–315]. The incidence of coughing, breath-holding, must be responsible for triggering the sympathetic discharge;
laryngospasm, and hemoglobin oxygen desaturation during the lung and a vessel-rich organ [327]. Of these two sites, the
inhalational inductions with sevoflurane, whether by slow vessel-rich organ is believed to mediate the greater response
incremental increases in concentration or a single breath, is [327].
similar to those that occur during inductions with halothane.
The observation that the airway reflex responses are infre-
quent after a single breath induction with 8% sevoflurane or Emergence
5% halothane casts doubt on the adage that high concentra-
tions of inhalational agents trigger airway reflex responses Emergence or recovery has been arbitrarily divided into
[313]. In fact, the induction is so smooth with sevoflurane early (extubation, eye-opening following commands) and
even in neonates that dialing 8% sevoflurane in one step is late (drinking, discharge time from recovery or hospital).
routine to achieve rapid induction of anesthesia in the neo- Although most studies have demonstrated a more rapid early
nate without triggering airway reflexes. By increasing the recovery after less soluble anesthetics [261, 310, 328, 329]
inspired concentration in one step, the period of excitement few have demonstrated a more rapid late recovery with these
or agitation during induction is minimized. anesthetics than the more soluble anesthetics [183, 185, 330,
Both intravenous and inhalational agents have been used 331]. Clinicians have been at a loss to explain why neonates/
for induction of anesthesia in neonates with congenital heart infants with pyloric stenosis recover slowly after a pure inha-
disease. Sevoflurane compares favorably with halothane for lational anesthetic. In theory, they should recover rapidly
induction of anesthesia in such patients scheduled for car- based on the rapid washout of the sevoflurane; however, this
diac surgery and may be preferred because it maintains car- has not been our collective clinical experience.
diovascular stability to a greater extent than halothane, but The speed of recovery from anesthesia should follow
similar to isoflurane [316–318]. the order of washout of the inhalational agents: desflu-
rane > sevoflurane > isoflurane > halothane > methoxyflu-
rane [178]. Those agents with lower solubility in blood Neuromuscular Junction
and tissues are eliminated more rapidly than those with
greater solubility; the contribution of metabolism to recov- Inhalational agents potentiate the actions of nondepolarizing
ery is minor, because the relative rate of metabolism is muscle relaxants [342–344] and decrease neuromuscular
small compared with the duration of exposure to anesthet- transmission [345], the latter, however only at large concen-
ics. This is true for desflurane, which is associated with a trations. The mechanism of the reduced neuromuscular
more rapid recovery in infants than after sevoflurane [332, transmission is unknown but may arise from the depression
333]. Although some advocate switching inhalational agents of the central nervous system. The mechanism of the poten-
from a more soluble to less soluble agent toward the end of tiation of nondepolarizing muscle relaxants by inhalational
surgery for economy and to facilitate a rapid emergence, the agents is also unknown but is likely attributable to the actions
only evidence suggests that switching from isoflurane to des- of inhalational agents at the neuromuscular junction rather
flurane 30 min before the end of anesthesia in adults does not than pharmacokinetic or central nervous system effects. The
speed emergence [334]. However, these results were based potentiation of action of nondepolarizing relaxants follows
on one specific set of clinical conditions in adults that may the order: isoflurane ≈ desflurane ≈ sevoflurane > enflu-
not apply to all conditions or to neonates and children. rane > halothane > N2O/opioid technique [346]. However,
The incidence of complications, such as airway reflex this potentiation may depend on the type of nondepolarizing
responses and vomiting during emergence from anesthesia, relaxant with longer-acting relaxants affected to a greater
is similar for all inhalational agents [261, 311, 330, 331, extent than intermediate-acting relaxants [347] and the con-
335]. In the case of neonates, airway reflex responses are centration of inhalational agents (in a direct dose-dependent
very common, whereas vomiting after anesthesia is not. manner). During 0.6 MAC isoflurane, the first twitch recov-
ered to 75% of baseline in 56 min after 0.45 mg/kg
rocuronium and 100 min after 0.6 mg/kg [348].
Emergence Delirium
The introduction of the new inhalational agents, desflurane Malignant Hyperthermia (MH)
and sevoflurane, has rekindled interest in a clinical entity
known as “emergence delirium.” Emergence delirium is All inhalational anesthetics (except Xenon) trigger MH reac-
defined as a dissociated state of consciousness in which a tions in susceptible patients [349]. To date, MH has not been
child is inconsolable, irritable, uncompromising, and/or reported in a neonate. Nonetheless, neonates with a family
uncooperative. The child is often demanding that all moni- history of MH should be managed with MH precautions. For
tors and all bandages be removed and that they are dressed in the most recent management of MH susceptible patients, the
their clothes. Parents who witness this transient state, which reader is referred to the MHAUS website (www.MHAUS.
lasts, on average, 10–20 min and occurs primarily in org) or the local national MH website.
preschool-age toddlers, usually volunteer that this behavior
is unusual and uncustomary for their child [336]. However,
emergence delirium is rare and unreported in neonates. The Stability
incidence of emergence delirium after isoflurane, sevoflu-
rane, and desflurane appears to be similar, but significantly Inhalational agents may be degraded via one of several path-
greater than after halothane [329, 337, 338]. ways in the presence of most CO2 absorbents to form several
The etiology of emergence delirium is unknown. Although potentially toxic by-products. Enflurane, isoflurane, and des-
pain was initially thought to be responsible for triggering flurane (but not halothane and sevoflurane) react with dessi-
this disorder, a report of a high incidence of delirium after cated soda lime to produce carbon monoxide. Both halothane
sevoflurane anesthesia for MRI established that pain was not and sevoflurane may be degraded when incubated with some
the primary causative agent of delirium after these newer CO2 absorbents, yielding compounds that are potentially
anesthetics [339]. The diagnosis of delirium after inhala- organ toxic (see Canizarro reaction below) [350]. Two new
tional anesthesia was bolstered by the introduction of the absorbents may address these clinical risks: molecular sieves
Pediatric Anesthesia Emergence Delirium (PAED) scale [351] and absorbents lacking sodium and potassium acceler-
[340], although this scale has not been validated in neonates. ants (e.g., Ambsorb™) [352–355]. Amsorb™ absorbs CO2
Several preventative measures and interventions have been without releasing carbon monoxide or compound A [352,
proposed for the child with delirium after anesthesia [341]. 353]. Carbon dioxide absorbents differ in their composition
and, therefore, in their affinity to interact with inhaled agents. ing the absorbent before introducing an inhalational agent.
Soda lime contains 95% calcium hydroxide, either sodium or Alternatives to conventional absorbents such as the molec-
potassium hydroxide, and the balance as water. Baralyme ular sieve and Amsorb™ may very well obviate all reac-
contains 80% calcium hydroxide, 20% barium hydroxide, tions that occur with current absorbents [352, 353]. When
and the balance as water, but is no longer available due to the these same ether anesthetics are incubated with desiccated
flammability risks [356]. Amsorb™ contains 70% calcium Amsorb™, carbon monoxide is not produced [352, 353].
hydroxide, 0.7% calcium chloride, 0.7% calcium sulfate, Carbon monoxide poisoning is an extremely rare but poten-
0.7% polyvinylpyrrolidine, and the balance as water. tially devastating event during anesthesia when soda lime is
Amsorb™ and other nonreactive absorbents contain neither used as the CO2 absorbent. In contrast, the frequency of car-
sodium nor potassium hydroxide, compounds added to bon monoxide poisoning with Amsorb™ is zero.
improve CO2 absorption efficiency [353]. Sevoflurane is both absorbed and degraded via the
Carbon monoxide may be released into the anesthetic Canizarro reaction in the presence of soda lime absorbent,
breathing circuit when isoflurane or desflurane is incubated resulting in five degradation products [360]. Although the
with a desiccated CO2 absorbent. The absorbent within a degradation of sevoflurane by the absorbent was initially pos-
CO2 canister may become desiccated if dry fresh gas flows ited to delay the wash-in of sevoflurane, recent evidence sug-
through the canister at a rate sufficient to remove most of gests that the quantity of sevoflurane degraded is of limited
the moisture (i.e., >5 L per minute continuously through the clinical significance to the speed of wash-in of sevoflurane
absorbent canister for 24h or greater while it is not in ser- [361]. Of the five degradation products between sevoflurane
vice). If the circuit reservoir bag is detached from the can- and soda lime, compounds A and B appear in the greatest
ister, then gas flows through the canister and exits through concentrations in the inspired limb of the breathing circuit,
two possible sites: the smaller fraction of the fresh gas exits compounds C, D, and E are present in such low concentra-
through the inspiratory limb of the canister and the larger tions in the breathing circuit that they do not merit further
fraction flows retrograde through the canister and exits at the consideration. Compound A, fluoromethyl-2,2-difluoro-
site where the reservoir bag should be attached. If the reser- 1-(trifluoromethyl) vinyl ether (also known as PIFE), is neph-
voir bag is attached to the canister, then limited gas flows ret- rotoxic in rats at concentrations ≥100 ppm and has an LC50
rograde through the canister and the absorbent is unlikely to of 1100 ppm. Compound B, a methoxyethyl ether compound
desiccate. However, once the absorbent becomes desiccated, that is minimally volatile at room temperature, is present in
carbon monoxide will be released into the inspiratory limb of closed circuits at <5 ppm and poses little risk to animals and
the breathing circuit if one of the methyl ethyl ether inhala- humans. In a low-flow (≤2 lpm) closed-circuit model with an
tional agents (desflurane, isoflurane, or enflurane) is admin- inspired concentration of 2.5% sevoflurane (up to 3.6 MAC-
istered [357, 358]. The magnitude of the carbon monoxide h) or end-tidal concentration of 3% for 8h, the concentration
production follows the order from greatest to least: desflu- of compound A peaks at 20–67 ppm after several hours of
rane ≥ enflurane > isoflurane ≫ halothane = sevoflurane. anesthesia without demonstrable evidence of renal tubular
Other factors that determine the magnitude of the carbon dysfunction [361–364]. Furthermore, low flow sevoflurane
monoxide concentration produced include the concentra- (<2 lpm) has not been shown to exacerbate renal dysfunc-
tion of the inhalational agent, the dryness of the absorbent, tion in patients with pre-existing renal dysfunction (serum
the type of absorbent, and the temperature of the absorbent creatinine > 1.5 mg/dL) [365, 366]. In children, compound
[357]. Currently, carbon monoxide is not detectable by most A concentrations are ≤16 ppm after 5.6 MAC•h sevoflurane
freestanding anesthetic agent analyzers, pulse oximeters, or in a closed circuit with 2 L per minute fresh gas flow [367].
blood/gas analyzers (except for cooximeters), although it is Factors that are known to increase the production of com-
detectable by mass spectrometry. The key to this problem is pound A include an increase in the inspired concentration of
prevention: turn off the anesthetic machine at the end of the sevoflurane, Baralyme > soda lime, ventilation, carbon diox-
day, disconnect the fresh gas hose to the absorbent canis- ide production, and temperature of the absorbent [368, 369].
ter, always leave the reservoir bag connected to the canister, Studies in rats indicate that under low flow conditions,
and avoid contact between potentially desiccated absorbent compound A is nephrotoxic [370]. In contrast, similar stud-
and the three ether anesthetics, desflurane, enflurane, and ies in humans have yielded inconsistent results [361–363,
isoflurane. Others have suggested that high flow anesthesia 371]. The mechanism behind compound A-induced nephro-
should be avoided whenever a circle circuit is used to pre- toxicity is believed to be ß-lyase-dependent metabolism to
vent inadvertent desiccation of absorbent. If the absorbent is nephrotoxic fluorinated compounds, although this has been
desiccated, then some recommend “rehydrating” the absor- the subject of intense debate [372]. More recent evidence
bent, although this too is fraught with potential problems suggests that differences in the evidence of nephrotoxicity
(including clumping of the absorbent) [359]. If one suspects from compound A in rats and humans relate to differences in
that the absorbent is desiccated, then we recommend replac- metabolic pathways between species [373, 374].
Analgesic Drugs Analgesic Pharmacodynamics

The ED50 for rectal acetaminophen to avoid any supplemen-
Acetaminophen (Paracetamol) tal opioids after ambulatory surgery is 35 mg/kg [376]. Time
delays of approximately one hour between peak concentra-
Mechanism of Action tion and peak effect have been reported [377, 378]. Pain
Acetaminophen is widely used in the management of pain fluctuations, pain type, and placebo effects complicate inter-
but lacks anti-inflammatory effects. Acetaminophen has a pretation of the clinical studies. A maximum effect of 5.17
central analgesic effect that is mediated through the activa- (the greatest possible pain relief (VAS 0-10) would equate
tion of descending serotonergic pathways. Prostaglandin H2 to an Emax of 10) and an EC50 of 9.98 mg/L are reported for
synthetase (PGHS) is the enzyme responsible for the metab- pain after tonsillectomy. The equilibration half- time
olism of arachidonic acid to the unstable prostaglandin H2. (T1/2keo) of the analgesic effect compartment was 53 min
The two major forms of this enzyme are the constitutive [377]. A target effect compartment concentration of 10 mg/L
PGHS-1 (COX-1) and the inducible PGHS-2 (COX-2). was associated with a pain reduction of 2.6/10 [377]. Similar
PGHS is comprised of two sites: a cyclooxygenase (COX) parameters have been estimated in neonates [379].
site and a peroxidise (POX) site. The conversion of arachi- Poor analgesic effect after oral and rectal acetaminophen
donic acid to PGG2, the precursor of the prostaglandins formulations for painful procedures [380, 381], after circum-
(Fig. 3.21), depends on a tyrosine-385 radical at the COX cision [382] and during heel prick [383] are reported. These
site. Formation of a ferryl protoporphyrin IX radical cation poor analgesic effects in neonates may be attributable to
from the reducing agent Fe3+ at the POX site is essential for inadequate serum concentrations (attributable to slow enteral
the conversion of tyrosine-385 to its radical form. absorption), type of pain stimulus, or assessment tools for
Acetaminophen acts as a reducing cosubstrate on the POX the discrimination of pain. Intravenous paracetamol has been
site and reduces the availability of the ferryl protoporphyrin successfully used for neonatal analgesia [384].
IX radical cation (Fig. 3.22). This effect can be reduced by
the presence of hydroperoxide-generating lipoxygenase Pharmacokinetics
enzymes within the cell (peroxide tone) or by swamping the The relative bioavailability of rectal to oral acetaminophen
POX site with substrate such as PGG2. Peroxide tone and formulations (Frectal/oral) is approximately 0.5 in children,
swamping explain acetaminophen’s lack of peripheral anal- although the relative bioavailability in neonates is greater,
gesic effect, platelet effect, and anti-inflammatory effects. approaching unity [32]. Acetaminophen has a pKa of 9.5 and
Alternatively, acetaminophen effects may be mediated by an in the alkaline medium of the duodenum, it is nonionized.
active metabolite (p-aminophenol). P-aminophenol is conju- Consequently, the absorption half-time of the nonionized
gated with arachidonic acid by fatty acid amide hydrolase to form from the duodenum is rapid in children (T1/2abs 4.5 min)
form AM404. AM404 exerts its effect through cannabinoid when it was given as an elixir [385]. The absorption half-
receptors [375]. time in infants under the age of 3 months was delayed
(T1/2abs 16.6 min), consistent with delayed gastric emptying
in young infants [32, 385]. Rectal absorption is slow and
Phospholipids
erratic with large variability. For example, absorption param-
Inhibited by steroids Phospholipase A2 eters for the triglyceride base were T1/2abs 1.34 h (CV 90%)
with a lag time of 8 min (31%) before absorption began. The
Arachidonic acid + Iysophospholipids absorption half-life for rectal formulations in infants less
Inhibited by NSAIDs Cyclooxygenase than three months of age was 150% greater than in older
children [72].
PGH2
Sulfate metabolism is the dominant route of elimination
Peroxidase
in neonates, while glucuronide conjugation (UGT1A6) is
PGF2a reductase PGG2 dominant in adults. Glucuronide/sulfate ratios range from
TXA2 synthetase
0.12 in preterm neonates of 28–32 weeks PCA, 0.28 in those
at 32–36 weeks PCA [386], and 0.34 in full-term neonates
PGE2 PGI2
synthetase
<2 days old [387]. A total body clearance of 0.74 L/h/70 kg
synthetase
at 28 weeks PMA and 4.9 (CV 38%) L/h/70 kg in full-term
PGF2a TXA2 neonates after enteral acetaminophen has been reported
PGE2 PGI2
using an allometric 3/4 power model [72, 388]. Clearance
Fig. 3.21 Phospholipid metabolism to the prostaglandins increases during the first year after birth, reaching 80% of
Fig. 3.22 Prostaglandin H2 PGG2

synthetase (PGHS) is the (hydroperoxide substrate)
enzyme responsible for
metabolism of arachidonic PGH2
acid to the unstable Tyr385* radical
prostaglandin H2. Formation Fe3+
Arachidonic Acid
of tyrosine-385 radical
(Tye385*) at the COX site is
dependent on the reduction of
Reducing O2
a ferryl protoporphyrin IX
radical cation (Fe4+ = OPP*+) cosubstrate paracetamol
at the POX site. Paracetamol e.g.
is a reducing cosubstrate that paracetamol Fe4+=OPP*+
partially reduces
Fe4+ = OPP*+, decreasing the Fe4+=O electron transfer
Tyr385
amount available for
regeneration of Tyr385*.
Figure adapted from Aronoff
et al. [215].
PGG2*radical
PGG2
Peroxidase Cyclooxygenase
that in older children by six months of age (Fig. 3.12) [32, despite both reporting satisfactory analgesia. Hence, it seems
69]. Similar clearance estimates are reported in neonates safer to recommend the smaller dosing regimen in neonates.
after intravenous formulations of acetaminophen (Fig. 3.12) Variability in the clearance and the lack of a suitable marker
[389, 390]. The relative bioavailability of the oral formula- of reduced clearance in the neonate during the first few days
tion is 0.9. after birth also support recommending the smaller dosing
The volume of distribution for acetaminophen is (49– regiment [397]. A larger dose has been advocated, for exam-
70 L/70 kg). The volume of distribution decreases expo- ple, when the PMA is between 32 and 44 weeks, such as a
nentially with a maturation half-life of 11.5 weeks from loading dose of 20 mg/kg IV followed by a maintenance dose
109.7 L/70 kg at 28 weeks postconception to 72.9 L/70 kg of 10 mg/kg every 6 h to achieve steady-state plasma concen-
by 60 weeks [32], reflective of fetal body composition and trations associated with reasonable analgesia. The interval
water distribution changes over the first few months of life between two maintenance doses should be increased to up to
(Fig. 3.6). 12 h for infants with a PMA between 28 and 31 weeks [398].
In older infants and children, the recommended IV mainte-
Adverse Effects nance dose is 15 mg/kg every 6 h.
The toxic metabolite of acetaminophen, N-acetyl-p- Preliminary data from neonates suggest that current dos-
benzoquinone imine (NAPQI), is formed by the cytochrome ing regimens are safe [390, 399]. It must be stressed, how-
P450s CYP2E1, 1A2, and 3A4. This metabolite binds to ever, that these are preliminary data only. The combined
intracellular hepatic macromolecules to produce cell necro- subject numbers were only 239 neonates. These numbers
sis and damage. Expression of CYP2E1 activity in vitro is were too few to exclude the possibility of future hepatotox-
decreased in infants less than 90 days PNA compared with icity; caution and continued monitoring of neonates given
that in older infants, children, and adults [61]; CYP3A4 acetaminophen is vital.
appears during the first week after birth, whereas CYP1A2
appears later [62]. Neonates can produce hepatotoxic metab-
olites (e.g., NAPQI), but the reduced activity of cytochrome Nonsteroidal Anti-Inflammatory Drugs
P-450 in neonates may explain the rare occurrence of
acetaminophen- induced hepatotoxicity in neonates [390]. Mechanism of Action
Nonetheless, careful attention must be paid to dosing guide- Nonsteroidal anti-inflammatory drugs (NSAIDs) are a het-
lines as several reports of massive acetaminophen overdose erogeneous group of compounds that share common anti-
have been reported in neonates [391–393]. pyretic, analgesic, and anti-inflammatory properties.
Two European centers have published intravenous dos- NSAIDs act by reducing prostaglandin biosynthesis through
ing guidelines for acetaminophen in neonates [394, 395], inhibition of cyclo-oxygenase (COX) site of the PGHS
with the drug used widely by anesthetists in the UK [396]. enzyme. The prostanoids produced by the COX-1 isoenzyme
However, the daily doses differed two-fold in the two studies protect the gastric mucosa, regulate renal blood flow, and
induce platelet aggregation. NSAID-induced gastrointestinal tion pathway for the commonly used NSAIDs. Variability
toxicity, for example, is likely mediated through blockade of in the pharmacokinetic parameter estimates is large, in part,
COX-1 activity, whereas the anti-inflammatory effects of attributable to covariate effects of age, size, and pharma-
NSAIDs are likely mediated primarily through inhibition of cogenomics. Ibuprofen, for example, is metabolized by the
the inducible isoform, COX-2. CYP2C9 and CYP2C8 subfamily. Considerable variation
exists in the expression of CYP2C activities among individ-
Pharmacodynamics uals, and functional polymorphism of the gene coding for
The NSAIDs are commonly used in children for antipyresis CYP2C9 has been described [409]. CYP2C9 activity is low
and analgesia. The anti-inflammatory properties of the immediately after birth (21% of adult), subsequently increas-
NSAIDs have also been used in diverse disorders such as ing progressively to reach a peak activity within 3 months
juvenile idiopathic arthritis, renal and biliary colic, dysmen- when expressed as mg/kg/h [410].
orrhoea, Kawasaki disease, and cystic fibrosis. The NSAIDs Clearance (L/h/kg) is generally greater in children than
indomethacin and ibuprofen are also used to treat delayed it is in adults, as we might expect when a linear per kilo-
closure of patent ductus arteriosus (PDA) in preterm infants. gram model is used. Ibuprofen clearance increases from
There are no linked PK-PD studies of NSAID anal- 2.06 mL/h/kg at 22–31 weeks PCA [406], 9.49 mL/h/kg at
gesia or fever in neonates or infants. Investigation of a 28 weeks PCA [407] to 140 mL/kg/min at 5 years [411].
concentration-response relationship for PDA closure shows Similar data exist for indomethacin [412–414]..
that a target serum concentration of 3.5 mg/L is associ- Many NSAIDs exhibit stereoselectivity [415]. Ibuprofen
ated with 90% PDA closure. Dosing increases with PMA stereoselectivity is reported in preterm neonates (<28 weeks
to achieve this target, because clearance increases with age gestation). R- and S-ibuprofen half-lives were about 10 h
[400]. Concentration-response relationships for pain have and 25.5 h, respectively. The mean clearance of R-ibuprofen
been described in children and adults. The maximum effect (12.7 mL/h) was about 2.5-fold greater than for S-ibuprofen
(Emax) for both diclofenac and ibuprofen was similar (5/10 (5.0 mL/h) [416].
VAS) to that described for acetaminophen, although the During pregnancy, there is relatively little transfer of
T1/2keo was smaller (20–30 min), suggesting quicker onset NSAIDs from maternal to fetal blood. Very small quanti-
of effect [401]. The onset of analgesia may correlate with ties of NSAIDs are secreted into breast milk, for example,
CSF concentrations. CSF penetration by ketorolac, diclof- ketorolac in breast milk is estimated to be 0.4% of maternal
enac, ibuprofen, and indomethacin is rapid in children; peak exposure [417].
concentrations reached ~30 min after intravenous adminis- Ketorolac (Toradol) is an NSAID with very potent analge-
tration of routine doses [402–405]. sic properties that can be administered intravenously [418].
Ketorolac has been safely used to provide analgesia for pre-
Pharmacokinetics term and term infants, although the PK in this age group has
NSAIDs are rapidly absorbed in the gastrointestinal tract not been described [419]. A major concern with ketorolac is
after oral administration in children. The relative bioavail- that it inhibits platelet function through inhibition of cyclo-
ability of oral preparations approaches unity. The rate and oxygenase, which increases the risk of postsurgical bleeding.
extent of absorption after rectal administration of NSAIDs There is a dose-response relationship for this bleeding risk; a
such as ibuprofen, diclofenac, flurbiprofen, indomethacin, greater and clinically important risk is associated with larger
and nimesulide are less than after the oral routes. doses, older subjects, and durations greater than 5 days
The apparent volume of distribution of NSAIDs in adults [420]. Ketorolac can be used to treat pain after congenital
is small (<0.2 L/kg), but larger in children. Intravenous ibu- heart surgery (median age 10 months, range 2.5–174), with-
profen has a volume of distribution of 0.62 (S.D. 0.04) L/ out an increased risk of bleeding complications [421].
kg in preterm neonates (22–31 weeks gestational age) [406].
Its central volume is dramatically reduced after closure of Drug Interactions
the PDA in preterm neonates (0.244 vs. 0.171 L/kg) [407]. NSAIDs undergo drug interactions through altered clearance
The NSAIDs, as a group, are weakly acidic, lipophilic, and and competition for active renal tubular secretion with other
highly protein bound. The bound fraction is greater in chil- organic acids. A high fractional protein binding has been
dren and preterm neonates but less than in adults. The impact proposed to explain drug interactions between NSAIDs and
of altered protein binding is probably minimal with routine oral anticoagulant agents, oral hypoglycemics, sulfonamides,
dosing, because NSAIDs cleared by the liver have a low bilirubin, and other protein-bound drugs.
hepatic extraction ratio [408]. An additive effect from combination therapy between
NSAIDs undergo extensive phase I and phase II enzyme acetaminophen and an NSAID has been reported in children
biotransformation in the liver, with subsequent excretion into [422, 423]. Although the maximum effect was unchanged
urine or bile. Renal elimination is not an important elimina- with combination therapy (Emax 5/10, VAS 0-10), the dura-
tion of effect was prolonged beyond that observed for either The large pharmacokinetic and pharmacodynamic variability
drug alone. suggests that morphine is often titrated to effect using small
incremental doses (0.02 mg/kg) in neonates and infants suf-
Adverse Effects fering postoperative pain [433, 434]. The effect compartment
NSAIDs have the potential to cause gastrointestinal irrita- equilibration half-time (T1/2keo) for morphine is ~17 min
tion, blood clotting disorders, renal impairment, neutrophil in adults [435] and is estimated to be 8 min in the full-term
dysfunction, and bronchoconstriction, effects that are attrib- neonate [436]. The role of morphine for nursing procedures
uted to the COX-1/COX-2 ratios, although this concept may in the neonatal unit remains controversial. Morphine did not
be an oversimplification. reduce pain responses during endotracheal suctioning, despite
Ibuprofen reduces the GFR by 20% in preterm neonates, plasma concentrations up to 400 ng/mL [71].
affecting aminoglycoside clearance, an effect that appears to The principal metabolites of morphine, morphine-3-
be independent of gestational age [95]. No significant differ- glucuronide (M3G), and morphine-6-glucuronide (M6G)
ence in cerebral blood volume, cerebral blood flow, or tissue have pharmacologic activity. Contributions to both the desired
oxygenation index was found between the administration of effect (analgesia) and the undesired effects (nausea, respira-
ibuprofen or placebo in neonates [424]. tory depression) of M6G are the subject of clinical controversy
The risk of acute GI bleeding in children given short-term [437]. It has been suggested that M3G antagonizes morphine
ibuprofen was estimated to be 7.2/100,000 (CI 2-18/100,000) and contributes to the development of tolerance [438].
[425, 426], a prevalence similar to that in children given
acetaminophen. The incidence of clinically significant gas- Pharmacokinetics
tropathy in children given NSAIDs for JIA is comparable Oral bioavailability is ~35% due to this first-pass effect.
with that in adults given long-term NSAIDs in children given Morphine is primarily metabolized by the hepatic enzyme
NSAIDs for JIA [427, 428], but the prevalence of gastro- UGT2B7 into M3G and M6G. Sulfation and renal clearance
duodenal injury may be very much greater depending on the are minor pathways in adults but are more dominant in neo-
assessment criteria (e.g., abdominal pain, anemia, endos- nates. Clearance is perfusion limited with a high hepatic
copy) applied. Data from neonates are not available. extraction ratio. The metabolites are cleared by the kidney
The commonly used NSAIDs have reversible antiplatelet and, in part, by biliary excretion. M3G and M6G accumulate
effects, which are attributable to the inhibition of thrombox- in the presence of impaired renal function.
ane synthesis. Bleeding time is usually slightly increased Morphine clearance matures with PMA reaching adult
but remains within normal limits in children with normal values at 6–12 months [71]. Clearance increases from
coagulation systems. The frequency of intraventricular hem- 3.2 L h−1.70 kg−1 at 24 weeks PMA to 9.3 L.h−1.70 kg−1 at
orrhage in neonates who were given prophylactic ibuprofen 32 weeks PMA in and 19 L.h−1.70 kg−1 at term (Fig. 3.12). The
to close the PDA was unchanged [429]. volume of distribution is increased in preterm ventilated neo-
nates (190 L.70 kg−1) compared with full-term neonates who
were breathing spontaneously (122 L.70 kg−1) [71]. The vol-
Opioid Analgesic Drugs ume of distribution in term neonates increased from 83 L/70 kg
at birth to a mature value of 136 L/70 kg within 3 months.
Morphine Metabolite (M3G, M6G) clearance increases with age similar
Morphine is among the most commonly used opioid in neo- to that described for GFR maturation in infants [70].
nates and infants. Morphine’s main analgesic effect is by Morphine dosing in neonates can be estimated using
supraspinal μ1-receptor activation. The μ2-receptor in the spi- clearance estimates (Fig. 3.23). Although an infusion of
nal cord plays an important analgesic role when the drug is 5 mcg/kg/h will achieve a target concentration of 10 ng/mL
administered by the intrathecal or epidural route [430]. in a typical neonate at term, clearance is affected by PMA
Morphine is soluble in water, but lipid solubility is poor and pathology. Morphine pharmacokinetic parameters show
compared with other opioids. Morphine’s limited oil/water large interindividual variability contributing to the range of
partition coefficient, 1.4, and its pKa of 8 (10–20% union- morphine serum concentrations observed during constant
ized drug at physiologic pH) contribute to delayed onset of infusions. Protein binding of morphine is small in preterm
peak action with slow CNS penetration. neonates and has minimal impact on the disposition changes
with age. The M6G/morphine ratio also changes with age
Pharmacodynamics (Fig. 3.24) because of the desynchrony between the matura-
Target analgesic plasma concentrations are believed to be tion of metabolite formation and elimination pathways, but
10–20 ng/mL after major surgery in neonates and infants the clinical effect of these ratio changes is unclear.
[78, 431]. The concentration required for sedation during Although morphine is usually administered intravenously
mechanical ventilation may be greater (125 ng/mL) [432]. to neonates, other routes have been used. Rectal administra-
a 0.5 morphine 447]. It is difficult to quantify this adverse effect in awake

M3G healthy neonates who commonly regurgitate after feeding.
M6G
0.4 Withdrawal symptoms may be observed in neonates after

cessation of a continuous morphine infusion for >2 weeks
0.3 and after infusion periods <2 weeks if the morphine infu-
sion rate is >40 μg/kg/h. Strategies to prevent withdrawal
0.2
from morphine include the use of neuraxial analgesia,
nurse-controlled sedation management protocols, ketamine
0.1
or naloxone mixed with morphine infusion, and the use of
0
alternate agents (e.g., methadone) with reduced potential for
0 5 10 15 20 25 30 tolerance [448, 449].
Time (h)
b 0.5 Fentanyl
morphine Fentanyl offers greater hemodynamic stability than mor-
0.4 M3G phine, a rapid onset (T1/2keo = 6.6 min in adults) and a short

M6G duration of effect. Its relative increased lipid solubility and
0.3
small molecular conformation enables efficient penetration
0.2 of the BBB and redistribution.
0.1
Pharmacodynamics
0 Fentanyl is a potent μ-receptor agonist with a potency 70–125
0 5 10 15 20 25 30 times greater than that of morphine. A plasma concentration
Time (h) of 15–30 ng/mL is required to provide total intravenous
Fig. 3.23 Morphine administered as a bolus 0.07 mg/kg with subse-
anesthesia (TIVA) in adults, whereas the EC50, based on EEG
quent infusion 0.03 mg/kg/h in a neonate (a) and a 1-year-old child (b). evidence, is 10 ng/mL [450, 451]. Fentanyl has been shown
The concentrations of parent drug and metabolites are different in the to effectively prevent preterm neonates from surgical stress
two individuals because of the complex interplays between formation responses and to improve postoperative outcome [452].
and elimination clearances. (Data from Bouwmeester NJ, Anderson BJ,
Tibboel D, Holford NH. Developmental pharmacokinetics of morphine
Single doses of fentanyl (3 mcg/kg) can reduce the physio-
and its metabolites in neonates, infants and young children. Br J logic and behavioral measures of pain and stress associated
Anaesth. 2004;92:208–17) [70] with mechanical ventilation in preterm infants [453].
Fentanyl has similar respiratory depression in infants and
tion of morphine results in a large variability in the analge- adults in the presence of comparable plasma concentrations
sia conferred, which is a major disadvantage of this route. [454].
Although the rectal route is commonly used [439], delayed
absorption after multiple doses leading to respiratory arrest Pharmacokinetics
has been reported [440]. Morphine (25–50 mcg/kg) can also Fentanyl is metabolized by oxidative N-dealkylation
be given via the caudal route to neonates [441, 442]. While (CYP3A4) into nor-fentanyl and hydroxylated. All metabo-
systemic absorption is slow, morphine spreads within the lites are inactive, and a small amount of fentanyl is elimi-
CSF to the brainstem where it may cause respiratory depres- nated via the kidneys unchanged. Fentanyl clearance is
sion lasting from 6 h to >18 h [443]. 70–80% of adult values in term neonates and, when stan-
dardized to a 70-kg person, reaches adult values (approx.
Adverse Effects 50 L/h/70 kg) within the first 2 weeks of life [46]. Clearance
Respiratory depression may occur at concentrations of 20 ng/ matures with gestational age: 7 mL/min/kg at 25 weeks
mL [53] in infants and children, but concentration-response PMA, 10 mL/min/kg at 30 weeks PMA, and 12 mL/min/kg
relationships in neonates, particularly preterm neonates at 35 weeks PMA [455]. Fentanyl’s volume of distribution at
prone to physiological apnea, are unknown. Hypotension, steady state (Vss) is ~5.9 L/kg in term neonates and decreases
bradycardia, and flushing reflect morphine’s histamine- with age to 4.5 L/kg during infancy, 3.1 L/kg during child-
releasing characteristics. These are more pronounced with hood, and 1.6 L/kg in adults [42]. This increased Vss results
rapid intravenous bolus administration [444, 445]. The inci- in a smaller blood concentration after bolus administration in
dence of vomiting in postoperative children is related to the neonates and infants. Administration of fentanyl 3 mcg/kg in
dose of morphine: doses >0.1 mg/kg are associated with a infants intraoperatively neither depresses respiration nor
>50% incidence of vomiting in infants and children [446, causes hypoxemia in a placebo-controlled trial [456, 457].
Fig. 3.24 Age-based infusion 25

dosing for morphine with a
target average steady-state
concentration of 10 mcg/L in
children not receiving positive 20
Morphine infusion (mcg/kg/h)

pressure ventilation. The
dotted line is the predictions
based on age and typical
weight for age. The solid line 15
is the suggested practical
infusion rate dose in mcg/kg/h
at different postnatal ages.
PNA years = (PMA 10
weeks − 40)/52. The upper
panel shows dose related to Dose mg/kg/h
postnatal age. The lower
panel shows dose related to 5 Practical Dose
PMA. From Anderson
BJ. Arch Dis Child 2013; 98:
732–6, with permission
0
–1 1 3 5 7 9 11 13 15
Postnatal Age year (0 y = 40 week GA)
25
20
Morphine infusion (mcg/kg/h)
15
10
Dose mg/kg/h
Practical Dose
5
0
0 20 40 60 80 100 120 140
PMA Age (weeks)
Fentanyl clearance may be impaired with decreased hepatic slow and rapid metabolizers, their contribution to the metabo-
blood flow, for example, from increased intra-abdominal lism of fentanyl is small. Redistribution rather than clearance
pressure in neonatal omphalocele repair. Infants with cya- is responsible for offset of the drug effect after single-dose
notic heart disease exhibit a reduced Vss and greater plasma therapy. The context-sensitive half-time (CSHT) after a 1 h
concentrations of fentanyl with infusion therapy [458]. These infusion of fentanyl is ~20 min, which increases to 270 min
greater plasma concentrations result from a reduced clear- after an 8 h infusion in adults [460]. While the CSHT is
ance (34 L/h/70 kg), that was attributed to hemodynamic dis- reduced in children [461], there are no data in neonates.
turbance and consequent reduced hepatic blood flow [459]. Alternative administration routes (e.g., transdermal and
Fentanyl is widely distributed with a short duration of transmucosal) have not been studied in neonates, although
effect as a result of redistribution to deep, lipid-rich com- intranasal fentanyl has been used for palliative care in neo-
partments. Fentanyl redistributes slowly from lipid-rich tis- nates [462, 463]. Epidural fentanyl is widely combined
sues after discontinuation of therapy, resulting in prolonged with an amide local anesthetic for postoperative analge-
periods of sedation and respiratory depression. Although sia, although there is no evidence that fentanyl is required
CYP3A4 is subject to single nuclear polymorphisms with as usual concentrations of local anesthetics in children are
100% effective [464]. Though spread beyond the spinal level 477]. The smaller the child, the greater the clearance when
of administration is dose dependent, respiratory depression expressed as mL/min/kg. These estimates have been con-
is uncommon [465, 466]. firmed over an even greater age range (5 days to 85 years,
weight range 2.5 to 106 kg) [2]. Clearance decreases with
Adverse Effects age, with rates of 90 mL/kg/min in infants <2 years of
Neonatal tolerance to synthetic opioids develops more rap- age, 60 mL/kg/min in children 2 to 12 years of age, and 40
idly (3–5 days) than it does with morphine (2 weeks) and mL/kg/min in adults [81, 479, 480]. The steady-state vol-
diamorphine (>2 weeks) [3, 467]. Fentanyl also has a pro- ume of distribution was greatest in infants <2 months
pensity to cause muscular rigidity and laryngospasm in neo- age (452 mL/kg) and decreased to 308 mL/kg in children
nates with doses as small as 2 mcg/kg IV [468, 469]. Other 2 mo-2 y and to 240 mL/kg in children >2 y [83]. Elimination
drugs metabolized by CYP3A4 (e.g., cyclosporin, half-life appears to be constant: ~3 to 6 min independent of
erythromycin) may compete for clearance and increase fen- the age of the patient and duration of the infusion [83, 470].
tanyl plasma concentrations. Intravenous remifentanil doses of 0.25 μg/kg/min appear to
Respiratory depression (hours) may outlast fentanyl’s be safe and effective in neonates [473, 474], although PK-PD
analgesic effect (35–45 min) due to the prolonged CSHT data in this age group remain limited [2].
and/or recirculation of fentanyl bound to the gastric acid Although covariate effects such as cardiac surgery appear
medium (up to 20% of an iv dose) or delayed release from to have a muted effect on PK, as is seen with propofol, cardio-
peripheral compartments. pulmonary bypass (CPB) does have an impact. Remifentanil
dose adjustments are required during and after CPB due to
marked changes in its volume of distribution [481]. Other PK
Remifentanil changes during CPB are consistent with adult data in which
a decreased metabolism occurred with a reduced tempera-
Remifentanil resembles fentanyl, sufentanil, and alfentanil in ture [482] and with reports of greater clearance after CPB
chemical structure. It is a selective μ-receptor agonist with a (increased metabolism) compared with during CPB [480].
greater potency than alfentanil. Its brief elimination half-life
of 3–6 min [83, 470] means it is usually given as an infusion Adverse Effects
[471, 472]. Intravenous remifentanil doses of 0.25 μg/kg/min Respiratory depression is concentration dependent [483,
appear to be safe and effective in neonates [473, 474]. 484]. Muscle rigidity is a concern with bolus doses >3
mcg/kg, but not 2 μg/kg during intubation in neonates [485,
Pharmacodynamics 486]. The initial loading dose of remifentanil may cause
A target plasma concentration of remifentanil of 0.2– hypotension and bradycardia [487], prompting some to target
0.4 mcg/L is adequate for analgesia, 2–3 mcg/L for laryngos- the plasma rather than effect-site concentration when initiat-
copy, 6–8 mcg/L for laparotomy, and 10–12 mcg/L might be ing infusion. This hypotensive response has been quantified
sought to ablate the stress response associated with cardiac in children undergoing cranioplasty surgery. A steady-state
surgery [475]. The T1/2keo of 0.64–1.16 min in adults [2, 83] remifentanil concentration of 14 mcg/L would typically
decreases with age. Analgesic alternatives should be avail- achieve a 30% decrease in MAP. This concentration is twice
able when the short-duration analgesic effect from remifent- that required for laparotomy, but is easily achieved with a
anil has dissipated. Reports of a rapid development of bolus injection. The T1/2keo of 0.86 min for this hemody-
μ-receptor tolerance with remifentanil use are conflicting. namic effect [488] is less than remifentanil-induced spectral
Activity at δ-opioid receptors may contribute [476]. edge changes described in adults (T1/2keo = 1.34 min) [82,
489]. Neonatal data are very limited.
Pharmacokinetics Because the inhibitory neurotransmitter, glycine, is
Remifentanil is metabolized by nonspecific esterases in tis- included in the formulation of remifentanil, it should not be
sues and erythrocytes to carbonic acid [477, 478] and these used for spinal or epidural applications [490].
esterases appear to have mature function even in preterm
neonates [24]. Carbonic acid is excreted via the kidneys.
Metabolism is independent of liver and renal functions. Alfentanil
Clearance in patients with butyryl-cholinesterase deficiency
is unaffected. Alfentanil is a synthetic opioid that is chemically related to
Remifentanil clearance can be described in all age groups fentanyl. It has a rapid onset (T1/2keo = 0.9 min in adults), a
by the simple application of an allometric model [479]. This brief duration of action, and one-fourth the potency of fen-
standardized clearance of 2790 mL/min/70 kg is similar to tanyl. Alfentanil has reduced lipid solubility and causes less
that reported by others in children [84, 480] and adults [83, histamine release than fentanyl [491]. The analgesic dose of
alfentanil for tracheal intubation and suctioning in preterm The free fraction of sufentanil decreases with increasing
neonates is 10–20 μg/kg [492–494]. A target plasma concen- age (neonates 19%; infants 11%; children and adults 8%)
tration of 400 ng/mL is used in anesthesia. Metabolism is and is strongly correlated with the alpha 1-acid glycoprotein
through oxidative N-dealkalation by CYP3A4 and plasma concentration [496]. The reduced concentration of
O-dealkalation and then conjugation to end-products that are alpha 1-acid glycoprotein in neonates and infants increases
excreted via the kidney [495]. The plasma protein binding of the free fraction of sufentanil in these age groups. Although
alfentanil increases from 65% in preterm neonates to 79% in sufentanil, fentanyl, alfentanil, and remifentanil have >70%
term infants and then to ~90% in adults [496, 497]. The vol- protein binding and have high hepatic (or nonhepatic for
ume of distribution (Vss) in children (0.163 L/kg) is one-third remifentanil) extraction ratios, protein-binding changes are
that in adults (0.457 L/kg) [498]. Clearance in neonates (20– probably clinically unimportant [510], because the dose is
60 mL/min/70 kg) is one-tenth that in adults (250–500 titrated to effect, and variability in the clearance has a much
mL/min/70 kg) [499]. In preterm neonates, the elimination greater impact.
half-life ranges is 6–9 h, 4–5 fold greater than in infants and Epidural sufentanil (0.7–0.75 mcg/kg) has been effective
children [500, 501]. Alfentanil cannot be used without neu- in children lasting >3 h [511–513], although pruritus can
romuscular-blocking drugs in neonates because of the fre- be bothersome [511]. Nasal sufentanil may have a role for
quency of rigidity [492, 502]. sedation in children although data in neonates are lacking
[514–516].
Sufentanil
Codeine
Sufentanil is 5–10 times more potent than fentanyl, with a
t1/2keo of 6.2 min in adults [503]. A concentration of 5–10 ng/ Codeine, or methylmorphine, is a morphine-like opioid with
mL is required for TIVA and 0.2–0.4 ng/mL for analgesia. 1/10 the potency of morphine. It is primarily metabolized by
Pharmacodynamic differences are suggested in neonates. glucuronidation, with secondary (minor) pathways including
The plasma concentration of sufentanil at the time of addi- N-demethylation to norcodeine and O-demethylation to
tional anesthetic supplementation to suppress hemodynamic morphine. Approximately 10% of codeine is metabolized to
responses to surgical stimulation was 2.51 ng/mL in neo- morphine. As the affinity of codeine for opioid receptors is
nates, notably greater than the concentrations of 1.58, 1.53, very low, the analgesic effect of codeine is mainly due to its
and 1.56 ng/mL observed in infants, children, and adoles- metabolite, morphine [517]. Codeine is effectively a prodrug
cents, respectively [504]. analgesic. The continued use of this minor opium alkaloid to
Elimination of sufentanil has been suggested by treat perioperative analgesia in infants and children has
O-demethylation and N-dealkylation in animal studies. remained baffling in light of it being a prodrug, although
Like fentanyl and alfentanil, the P-450 CYP3A4 enzyme reports of fatal consequences after use in children have
is responsible for the N-dealkylation [505]. Clearance in resulted in its use being severely restricted or proscribed in
neonates undergoing cardiovascular surgery (6.7 (SD 6.1) pediatrics in many jurisdictions [518].
mL/kg/min) is reduced compared with values of 18.1 (SD The CYP2D6 enzyme catalyzes the metabolism of codeine
2.7), 16.9 (SD 3.2), and 13.1 (SD 3.6) mL/kg/min in infants, to morphine. A genetic polymorphism of this enzyme causes
children, and adolescents, respectively [504]. Clearance distinct phenotypes responsible for the presence of ultrar-
rates in infants (27.5 (SD 9.3) mL/kg/min) were greater than apid (UM), extensive (EM), and slow or poor (PM) codeine
those in children (18.1 (SD 10.7) mL/kg/min) in another metabolizers [519, 520]. Between 7% and 10% of Europeans
study of children undergoing cardiovascular surgery [506]. are PM of codeine [520–522], depending on race [520, 521].
Maturation of clearance is rapid [507] and clearance mat- PM do not benefit from pain relief from codeine, although
uration, standardized to a 70-kg person using allometry, is its side effects persist [522], whereas UM amass very large
similar to that of other drugs that depend on CYP3A4 for concentrations of morphine that may lead to an alarming fre-
metabolism (e.g., levobupivacaine, fentanyl, alfentanil) quency of adverse side effects including apnea.
(Fig. 3.12) [508]. The volume of distribution at steady state Codeine can be administered by intramuscular, oral,
(Vss) was 4.15 (SD 1.0) L/kg in neonates, greater than the and rectal routes. Intravenous codeine is not recommended
values of 2.73 (SD 0.5) and 2.75 (SD 0.5) L/kg observed in because of hypotensive effects [523]. Blood concentrations
children and adolescents, respectively [504, 509]. Clearance after rectal codeine are less than those after intramuscu-
in healthy children (2–8 years) was greater (30.5 (SD 8.8) lar codeine, because the rectal route results in incomplete,
mL/kg/min) than those undergoing cardiac surgery [509]. slower, and more variable absorption [524]. Codeine is often
Decreased hepatic blood flow reduces clearance [509]. combined with acetaminophen or NSAIDs to improve post-
operative pain relief in infants [525] and children [526, 527]. Meperidine was initially synthesized as an anticholinergic
Maturation of CYP2D6 follows that of M1 production from agent but was soon discovered to have analgesic properties.
tramadol (Fig. 3.10), a metabolite also produced by CYP2D6. Although meperidine’s anticholinergic effects were demon-
This enzyme matures rapidly after 40 weeks PMA, sug- strated in vitro, the anticholinergic effects on the biliary and
gesting that postterm neonates could benefit, although this renal tracts have not been demonstrated in vivo. Studies have
drug has not been investigated in neonates. Several deaths demonstrated that meperidine is no more effective for treating
or near-deaths have been reported after codeine use in chil- biliary or renal tract spasm than comparable μ opioids [540].
dren subsequently identified as UM [528, 529]. Codeine use Because morphine results in better analgesia with fewer side
in neonates and children has been strongly discouraged ever effects, there are no particular advantages of meperidine as
since [530]. an analgesic [541]. Accumulation of the metabolite norme-
The pharmacokinetics of codeine is poorly described in peridine may cause seizures and dysphoria [542], although
children despite several decades of use. A volume of distri- the metabolism of meperidine to normeperidine is reduced
bution (V) of 3.6 L/kg and a clearance (CL) of 0.85 L/h have 7-fold in neonates compared with adults [539].
been described in adults, but there are few data of the devel- Intramuscular administration of meperidine was fre-
opmental changes in pediatric pharmacokinetics. The half- quently used in pediatric patients in the past, but this route is
life in neonates (4.5 h) is greater than that in infants (2.6 h) as generally avoided today because it is painful and may lead
a result of immature clearance [531]. Administration (espe- to sterile abscesses. Meperidine was used for several years
cially of codeine preparations with an antihistamine and a as a component of various “lytic cocktails” that provided
decongestant) in the neonate may cause intoxication [532]. sedation in infants and children. It was administered either
One fatal event occurred in a neonate that was attributed to rectally or orally. The safety of these admixtures, especially
morphine poisoning after his mother used codeine while in neonates, is not evidence based and, consequently, is used
breastfeeding. The mother, an UM, produced much more infrequently [543]. Meperidine’s local anesthetic properties
morphine than most adults, and it was purportedly trans- have been found useful for epidural techniques [544].
ferred to the neonate [533, 534].
The adverse effects of codeine are broadly similar to
those of other opioids. Adverse effects at small doses are Methadone
directly related to the plasma concentrations of morphine,
but are caused by codeine at greater doses [535]. There is a Methadone is a synthetic opioid with an analgesic potency
broad belief that codeine causes fewer adverse effects, such similar to that of morphine but with a more rapid distribution
as sedation and respiratory depression, compared with other and a slower elimination. Methadone is used as a maintenance
opioids, but this belief is not evidence based. The analge- drug in opioid-addicted adults to prevent withdrawal.
sic effect of codeine depends on its conversion to morphine. Methadone might have beneficial effects, because it is a long-
Consequently, when other, nonopioid medications compete acting synthetic opioid with a very high bioavailability (80%)
for the CYP2D6 enzyme (e.g., quinidine), the analgesic by the enteral route. It also has NMDA receptor antagonistic
effect of codeine may be attenuated. activity. Agonism of this receptor is associated with opioid tol-
erance and hyperalgesia. Methadone is a racemate with clini-
cal effects attributed to the R-methadone isomer. Methadone is
Meperidine (Pethidine) 2.5–20 times more analgesic than morphine [545].
Although only limited data on the efficacy and safety of
Meperidine is a weak opioid, primarily μ-receptor, agonist methadone are available, methadone is widely used for the
that has a potency of 1/10 that of morphine. In adults, the treatment of opioid withdrawal (neonatal abstinence syn-
analgesic effects are detected within 5 min of intravenous drome) in neonates and children [448, 546, 547]. Methadone
administration, with the peak effect reached within 10 min treatment reduces the length of stay for abstinence syndrome
[536, 537]. Meperidine is metabolized by N-demethylation by 22% compared with morphine in full-term neonates,
to meperidinic acid and normeperidine. Meperidine clear- although a recent systematic review failed to establish the
ance in infants and children is approximately 8–10 mL/min/ superiority of either medication [548, 549]. Intravenous
kg [502, 538] The elimination half-life in neonates is greatly methadone is also an effective analgesic for postoperative
reduced compared with older children and elimination half- pain relief [550], and oral administration has been recom-
time in neonates who have received meperidine by placental mended as the first-line opioid for severe and persistent pain
transfer is 2–7 times greater than that in adults [539]. The in children [551]. It is also safe as an enteral alternative
Vss in infants, 7.2 (3.3–11) L/kg [502], is greater than that in for intravenous opioids in palliative pediatric oncological
children 2–8 years of 2.8 (SD 0.6) L/kg [538]. patients [552]. Although some have proposed that metha-
Fig. 3.25 Simulation for a 0.15

3.5-kg neonate given a methadone bolus 0.6 mg/kg maintenance 0.15 mg/kg 8 h
methadone loading dose of 0.6
mg/kg followed by a EDDP
maintenance dose of 0.15 mg/kg
8 h. EDDP concentrations track methadone 0.2 mg/kg 8 h
parent drug concentrations. The
methadone target concentration 0.1
of 0.06 mg/L is achieved rapidly
when compared to the neonate
given 0.2 mg/kg 8 hourly without
a loading dose. From Ward RM,
Drover DR, Hammer GB,
Stemland CJ, Kern S, Tristani-
Firouzi M, Lugo RA, Satterfield
K, Anderson BJ. The 0.05
pharmacokinetics of methadone
and its metabolites in neonates,
Infants and children. Pediatr
Anesth 2014: 591–601, with
permission [23]
0
0 8 16 24 32 40 48
Time (hours)
done should assume a predominant role in the management trations decrease to less than EC50. It should be noted that
of prolonged pain in neonates, its role in this regard needs to methadone, like other opioids, has large between-subject PK
be evaluated in a clinical research setting [449]. variability that could result in drug accumulation and pos-
Methadone has a high lipid solubility [553] with a large sible fatal outcomes with long-term administration [560].
volume of distribution in children and adults [554–556].
Pharmacokinetic parameters, standardized to a 70 kg
adult using allometry, have been estimated using a three- Sedatives
compartment linear disposition model. Population parameter
estimates (between subject variability) were central volume Benzodiazepines
(V1) 21.5 (29%) L/70 kg, peripheral volumes of distribution
V2 75.1 (23%) L/70 kg, V3 484 (8%) L/70 kg, clearance These drugs produce anxiolysis, amnesia, and hypnosis.
(CL) 9.45 (11%) L/h/70 kg and intercompartment clearances They are commonly used as adjuncts to both local and gen-
Q2 325 (21%) L/h/70 kg, Q3 136 (14%) L/h/70 kg [23]. eral anesthesia. Currently, midazolam is the most commonly
These parameter estimates in children and neonates are con- used benzodiazepine in the perioperative period. It is water
sistent with those reported by others in neonates, children, soluble in an acid pH carrier, but becomes lipid soluble at
adolescents, and adults [557–559]. The clearance of metha- physiological pH, which facilitates rapid BBB entry.
done does not mature with age, because CYP3A7 is active Midazolam is highly bound to serum albumin (>96%).
in neonates before maturation of CYP3A4, which plays a Midazolam is a medium extraction drug and changes in the
primary role in clearance later in life. Neonatal enantiomer plasma protein concentrations will not affect clearance.
clearances were also similar to those described in adults However, a reduced albumin concentration will increase the
[23]. The major metabolite 2-ethylidene-1,5-dimethyl-3,3- unbound fraction after bolus intravenous administration.
diphenylpyrrolidine (EDDP) is often measured in urine as
part of a drug abuse testing program. Mechanism of Action
The target concentration for both opioid withdrawal in Benzodiazepines bind to GABAA receptors, increasing chlo-
neonates and analgesia in adults is 0.06 mg/L. An intrave- ride entry into cells. This hyperpolarizes the GABAA recep-
nous regimen of 0.2 mg/kg 8 h in neonates achieves a target tors, rendering them resistant to excitation.
concentration of 0.06 mg/L within 36 h (Fig. 3.25). Analgesic
response in adults on chronic methadone programs suggests Pharmacodynamics
a steep concentration-response relationship for pain relief PKPD relationships have been described for intravenous
(Hill = 4.4) with very rapid equilibration between plasma midazolam in adults. When an EEG signal is used as an
methadone concentrations and the sites mediating pain effect measure, the EC50 is 35–77 ng/mL, with a T1/2keo of
relief. Consequently, the drug rapidly loses effect as concen- 0.9–1.6 min [561–563]. The T1/2keo is increased in the
elderly and in low cardiac output states, but estimates in neo- of the liver, its blood flow, and environmental factors.
nates are lacking. Decreased clearance in neonates means Midazolam has a hepatic extraction ratio in the intermediate
that the duration of effect persists despite decreasing the range 0.3–0.7. Metabolic clearance depends on both liver
plasma concentrations (Fig. 3.26) [564]. PKPD relationships perfusion and enzyme activity.
are more difficult to describe after oral midazolam, because Clearance in neonates is reduced (0.8–2.2 mL/min/kg)
the active metabolite, 1-hydroxy metabolite (1-OHMDZ), [570–575], but increases exponentially after 39 weeks PMA
has approximately half the activity of the parent drug [565]. [573, 576]. Central volume of distribution is related to
Sedation in children is more difficult to quantify. PKPD weight (V1 0.591 SD 0.065 L/kg), whereas peripheral vol-
relationships were not established in children (aged 2 days– ume of distribution remains constant (V2 0.42 SD 0.11 L)
17 years) who were given a midazolam infusion in inten- in 187 neonates 0.7–5.2 kg [573]. It has been suggested that
sive care. Midazolam dosing could, however, be effectively midazolam self-induces its clearance [567]. The latter obser-
titrated to the desired level of sedation, using the COMFORT vation from infants after cardiac surgery likely results from
scale [566]. Consistent with this finding, desirable sedation the improved hepatic function after the insult of cardiopul-
in children after cardiac surgery was achieved at mean serum monary bypass. Neonates who require extracorporeal mem-
concentrations between 100 and 500 ng/mL [567–569]. brane oxygenation (ECMO) have an increase in Vss during
ECMO therapy (0.8 L/kg to 4.1 L/kg) caused by sequestra-
Pharmacokinetics tion of midazolam by the circuitry, although clearance (1.4
Midazolam is metabolized mainly by hepatic hydroxylation SD 0.15 mL/min/kg) was unchanged [577].
(CYP3A4) [58]. These hydroxymetabolites are glucuroni- Clearance may be reduced in the presence of pathology.
dated and excreted in the urine. CYP3A7 is the dominant The clearance of midazolam is reduced after circulatory
CYP3A enzyme in utero; it is expressed in the fetal liver and arrest for cardiac surgery [578]. Covariates such as renal fail-
appears to have activity from as early as 50–60 days postcon- ure, hepatic failure [569], and concomitant administration of
ception. There appears to be a temporal switch in the imme- CYP3A inhibitors [579] are important predictors of altered
diate perinatal period with the expression of CYP3A4 midazolam and metabolite pharmacokinetics in pediatric
increasing dramatically after the first postnatal week. Hepatic intensive care patients [580]. The clearance of midazolam
CYP3A4 activity begins to increase dramatically at about was reduced by 30% in neonates receiving sympathomimetic
1 week PNA, reaching 30–40% of adult expression by amines, probably as a consequence of the underlying com-
1 month [508]. Midazolam clearance does not parallel promised hemodynamics [573].
CYP3A4 activity, because clearance also depends on the size
0.35 0.5
0.3
0.4 Amplitudes 11.5-30 Hz (µV)
0.25
0.3
0.2
0.15
0.2
0.1 Plasma
Effect 0.1
0.05
0 0
0 60 120 180 240 300 360 420
Time (min)
Fig. 3.26 Plasma concentrations and effect in a neonate given protocol Pharmacokinetic-pharmacodynamic modeling of the central nervous
midazolam bolus (0.1 mg/kg) on two early occasions (5 min interval) to system effects of midazolam and its main metabolite alpha-
achieve sedation. Plasma concentration declines slowly because of slow hydroxymidazolam in healthy volunteer. Clin Pharm Ther 1992;51:715–
clearance. Sedation recovery lags way behind the decline in plasma 28 [561]. From Wolf A, Blackwood B, Anderson BJ. Tolerance to
concentration even though a maintenance infusion was not even given. sedative drugs in PICU: Can it be moderated or is it immutable?
Pharmacodynamic parameter estimates were from Mandema J et al. Intensive Care Medicine 2016; 42(2):278–81 [564]
Adverse Effects major metabolite of clonidine is p-hydroxyclonidine,

Metabolites can accumulate in the presence of renal failure, formed by hydroxylation of the phenol ring, which is pres-
causing increased sedation. Respiratory depression and ent at <10% of the concentration in the urine [596]. CYP2D6
hypotension after midazolam are well recognized. Cessation is involved in this process.
of long-term sedation with midazolam can cause withdrawal There are limited pharmacokinetic data in neonates
symptoms often manifest as irritability, agitation, tremors, and none in preterm neonates. A pooled pediatric analysis
and sleeplessness. reported the clearance of clonidine at birth to be 3.8 L/h/70 kg
(0.12 L/h/kg), a rate that matured with a half-time of
25.7 weeks to reach 82% adult rate by 1 year PNA. The cen-
Alpha-2 agonists tral volume of distribution (V1) was 62.5 (71.1%) L/70 kg,
intercompartment clearance (Q) 157 (77.3%) L/h/70 kg, and
Clonidine peripheral volume of distribution (V2) 119 (22.9%) L/70 kg.
Clonidine is an alpha-2 adrenoreceptor agonist that produces The volumes of distribution, but not clearance, increased after
sedation, anxiolysis, analgesia, and hypotension. It is com- cardiac surgery. There was a lag time of 2.3 (CV 73.2%) min
monly administered in the caudal and epidural space where before absorption began after rectal administration [599].
it prolongs the duration of analgesia approximately 3 h The absorption half-life from the epidural space was slower
[581–583]. than that from the rectum (0.98 CV 24.5% h vs. 0.26 CV
32.3% h). The relative bioavailability of epidural and rec-
Pharmacodynamics tal clonidine was unity (F = 1) compared with intravenous
The plasma concentration of clonidine that provides analge- administration [600]. A study of 36 neonates (0.5–26 days
sia in adults is 1.5–2 mcg/L [584–586]. Clonidine-mediated PNA) given oral clonidine for neonatal abstinence syndrome
analgesia, sedation, and anxiolysis are dose dependent in estimated an apparent clearance of 0.16 L/h/kg [601]., which
adults [587–589]. The target concentration for analgesia in is consistent with intravenous clearance estimates given
adults is greater than that for sedation. To achieve satisfac- probable reduced oral bioavailability; oral bioavailability is
tory preoperative sedation with clonidine in children 0.55 in children [602].
1–11 years, a plasma concentration of 0.3–0.8 mcg/L is
required [590]. The concentration required for 50% of chil-
dren to achieve a sedation scale of 4 (appears asleep, pur- Dexmedetomidine
poseful responses to verbal commands but at louder than
usual conversation level or requiring light glabellar trap) or Dexmedetomidine has a seven times greater specificity for the
greater is slightly more, 0.85 μg/L and 90% of children alpha-2 adrenoreceptor than clonidine. Dexmedetomidine is
achieve this by 1.15 μg/L. [591] At a concentration of 4 μg/L, a unique alpha-2 adrenoceptor agonist that, unlike traditional
levels of general anesthesia are achieved (BIS <60) [584]. sedative agents, is reported to produce its sedative effect, at
When clonidine is added to analgesic regimens [584, 592] at least in part, through an endogenous sleep-promoting path-
a plasma clonidine concentration of 1.5–2 mcg/L, the mor- way that does not produce clinically significant respiratory
phine use is reduced up to 30% [585, 586]. depression [603–606]. The use of dexmedetomidine in neo-
When administered intravenously at clinically relevant natal intensive care and sedation practice is increasing [607,
doses, alpha-2 agonists have a biphasic effect on blood pres- 608]. Dexmedetomidine use in neonates and children has
sure but produce a dose-dependent decrease in heart rate. This even expanded to include early extubation after cardiac sur-
biphasic effect on blood pressure results from two different gery, prevention of emergence delirium, postoperative pain
sites of alpha-2 adrenoceptor stimulation – an initial direct management, invasive and noninvasive procedural seda-
action on peripheral vascular resistance and a delayed central tion, and the management of opioid withdrawal [603–605,
sympatholysis [593, 594]. The net effect of these responses 608–615]
was a 26.3% reduction in mean arterial blood pressure after
intravenous doses of 2.5 mcg/kg in children 1–10 years [595]. Pharmacodynamics
A plasma concentration greater than 0.6 μg/L produces satis-
Pharmacokinetics factory sedation in adult ICU patients [616] and similar tar-
Approximately 50% of clonidine is eliminated unchanged get concentrations are estimated in children, but there is a
by the kidney and there is considerable interindividual vari- lack of neonatal experience [617]. When administered as a
ability [589, 596, 597]. It remains unclear which drug- single IV bolus dose in infants after cardiac surgery, dexme-
metabolizing enzymes are responsible for nonrenal detomidine produces a biphasic effect of mean arterial blood
clearance. Between 40% and 60% of clonidine after intrave- pressure (Fig. 3.27). The peripheral vasopressor effect is
nous administration undergoes hepatic biotransformation, directly related to a plasma concentration with an Emaxpos of
although the exact percent is unclear [589, 596–598] The 50.3 (CV 44.50%) mmHg, EC50pos 1.1 (48.27%) μg/L, and a
Hillpos coefficient of 1.65. The delayed central sympatholytic anesthetic drugs. Consequently, the drug is being explored in
response is described with an Emaxneg of -12.30 (CV 37.01%) animal models for possible use in neonates who have suffered
mmHg, EC50neg 0.10 (104.40%) μg/L, and a Hillneg coefficient perinatal asphyxia. Its neuroprotective, analgesic, anti-inflam-
of 2.35. The equilibration half-time (T1/2keo) is 9.66 matory, and sympatholytic properties may be beneficial when
(165.23%) min [619]. These results have not been repro- combined with therapeutic hypothermia [626–628].
duced in children presenting for sedation during radiological
procedures. There was a 5% incidence of hypertension in Pharmacokinetics
these patients; the incidence was greatest in those less than Population parameter estimates for a two-compartment
1-year of age and those who required an additional bolus model were clearance (CL) 42.1 (CV 30.9%) L.h−1.70 kg−1,
dose to maintain sedation [618]. central volume of distribution (V1) 56.3 (61.3%) L.70 kg−1,
Upper airway changes associated with increasing doses intercompartment clearance (Q) 78.3 (37.0%) L.h-1.70 kg−1,
of dexmedetomidine (1–3 μg/kg) in children without OSA and peripheral volume of distribution (V2) 69.0 (47.0%)
are small in magnitude and do not appear to be associated L.70 kg−1. Clearance increases from 18.2 L.h−1.70 kg−1 at
with clinical signs of airway obstruction. Even though these birth in a full-term neonate to reach 84.5% of the mature
changes are small, all precautions to manage airway obstruc- value by 1 year PNA (Fig. 3.12). Children given a dexme-
tion should be taken when dexmedetomidine is used for detomidine infusion after cardiac surgery had reduced clear-
sedation [620]. Upper airway changes during dexmedetomi- ance (83.0%) compared with a population given a bolus dose
dine (2 μg/kg/h) compared with propofol sedation yielded [617]. Others have described similar parameter estimates
similar requirements for airway support [621]. with reduced clearance in children receiving dexmedetomi-
Dexmedetomidine is not associated with neuroapoptosis dine infusion after cardiac surgery [629].
or other neurodegenerative effects as evident from two ani-
mal studies involving infant rodents and fetal primates [622, Adverse Effects
623]. Dexmedetomidine also attenuates isoflurane-induced Intravenous use for CT scanning has been associated with
neurocognitive impairment in neonatal rats [624]. A contrary modest fluctuations in heart rate and blood pressure that
report suggested that dexmedetomidine may have detrimen- required no pharmacologic interventions or reporting as
tal effects on the brain, but those areas affected differ from adverse events [630]. Similar results were noted for MRI
other drugs. Ketamine resulted in cellular degeneration and scanning. Although high-dose dexmedetomidine (≥2
apoptosis in limbic brain regions, but nonsignificant changes mcg/kg/h) was associated with decreases in heart rate and
in primary sensory brain regions. In contrast, dexmedetomi- blood pressure outside the established “awake” normal val-
dine produced cellular degeneration and apoptosis in primary ues for children, the deviations were generally within 20% of
sensory brain regions of rat pups, but nonsignificant changes normal. Nonetheless, some infants developed profound bra-
in limbic regions [625]. The bulk of current evidence suggests dycardias and hypotension. No adverse sequelae were
fewer consequences attributable to α2-agonists than most other reported [631]. Less favorable results have been noted in the
Fig. 3.27 Composite Emax Concentration (µg/L)

model, showing hyper- and 0 0.5 1 1.5 2 2.5 3
hypotensive effect of 120 120
dexmedetomidine on mean
arterial blood pressure. From EC50pos=1.1
Mean Arterial Blood Pressure (mmHg)
Mean Arterial Blood Pressure (mmHg)

Potts A et al. [619] 100 100
80 EC50pos=50.3 80
Hypertensive effect
60 60
Emaxneg=12.3
40 40
Hypotensive effect
EC50neg=0.09
20 20
0 0
0 0.5 1 1.5 2
Concentration (µg/L)
electrophysiology laboratory. Heart rate decreased while Pharmacodynamics

arterial blood pressure increased significantly after 1 mcg/kg
IV over 10 min followed by a 10-min continuous infusion of Local anesthetics are antiepileptics at reduced concentra-
0.7 mcg/kg/h. Sinus node function was significantly affected tions, acting either on GABA-glutamate regulation or by
and atrioventricular nodal function was also depressed. The blocking sodium channels like phenytoin. At serum concen-
use of dexmedetomidine may not be desirable during elec- trations less than 5–7 μg/mL, lidocaine possesses anticonvul-
trophysiology studies as it may cause bradycardia or atrio- sant properties in infants [638–640]. At concentrations
ventricular nodal block [632]. greater than 7–10 μg/mL, lidocaine causes convulsions,
while at serum concentrations greater than 15–20 μg/mL,
lidocaine induces global depression with coma and cardio-
Local Anesthetic Agents vascular collapse.
The effect of local anesthetics on sodium channel prepa-
Mechanism of Action rations is difficult to quantify, because they depend on the
type of channel investigated, biochemical and electrophysi-
Local anesthetics are grouped as either amino amides (ligno- ological conditions, or stereospecificity [641]. Sodium chan-
caine, bupivacaine) or amino esters (prilocaine, tetracaine), nels expressed in nerve fibers have an EC50 ranging from
although their mechanisms of action are the same. They act ~100 μM to 800 μM for lidocaine and to 150 μM for bupi-
principally by inactivating the fast sodium channels that ini- vacaine [642–644]. Successful neuronal blockade in vivo
tiate neural action potentials. Inactivation occurs on the cyto- requires concentrations 200 times greater, because penetra-
solic aspect of the membrane. Drug must first traverse this tion of the perineural area is poor. Vascular removal and
phospholipid bilayer membrane before exerting an effect. degree of ionization result in only a small amount of drug
Effect from individual agents depends on the molecular size, reaching the sodium channel. Hydrophobic drugs (e.g., bupi-
lipid solubility, unbound drug availability, and degree of ion- vacaine) cross into neural tissue more readily than those that
ization at physiological pH. Neonates have reduced concen- are more hydrophilic (e.g., prilocaine)
trations of AAG, and this increases the unbound concentration Levobupivacaine and ropivacaine are less cardiotoxic
[633, 634] compared with adults. A decrease in pH will also than bupivacaine. A mean plasma concentration of levobupi-
increase the unbound concentration in plasma. Neonates vacaine in healthy adults of 2.38 mg/L is less cardiodepres-
with their greater metabolic rate and reduced bicarbonate sive than a bupivacaine concentration of 1.87 mg/L [645],
stores may be more prone to acidosis during convulsions but there are no recommendations regarding the “safe”
caused by local anesthetic toxicity increasing susceptibility serum concentration of levobupivacaine in children.
to subsequent cardiac toxicity. A decrease in intracellular pH Prilocaine is combined with lignocaine in the EMLA, a
also causes ion trapping of the active moiety of the local eutectic mixture of topical local anesthetic. Neonates tend
anesthetic molecule, leading to further exacerbation of toxic- to form methemoglobin, because they have reduced met-
ity [635]. hemoglobin reductase activity and fetal hemoglobin is
Cardiac sodium channels are more sensitive and stereospe- more readily oxidized compared with adult hemoglobin.
cific than nerve channels. Consequently, the R(+) enantiomer This proclivity, combined with the increased percutane-
of bupivacaine has greater toxicity than the S(−) enantiomer ous absorption, resulted in a reluctance to repeat doses of
(levobupivacaine) in cardiac myocytes [636]. Local anesthet- lidocaine-prilocaine cream in neonates [36], although single
ics also affect potassium and calcium ion channels. Nodal dose application is safe [646].
conduction in the heart depends on calcium channel activity
and influence at this site can cause dysrhythmias. Neonates
have a relative immaturity of the sarcoplasmic reticular Pharmacokinetics
regulation of cytosolic calcium, and force development and
relaxation in the immature heart depend more on the trans- The major hepatic clearance pathway for lidocaine to its
sarcolemma calcium flux than in the adult [637]. active metabolites monoethylglycinexylidide and glycinex-
Unmyelinated fibers are more sensitive to local anesthetic ylidide is CYP1A2. Lidocaine is a high extraction drug that
effects than myelinated fibers and myelination is incomplete displays perfusion limited clearance. Clearance is equiva-
at birth. Local anesthetics need to block 2–3 adjacent nodes lent to hepatic blood flow and a reduction in hepatic blood
of Ranvier to block conduction in myelinated fibers. Thinly flow reduces clearance. The total body clearance of lido-
myelinated fibers have shorter distances between nodes caine in neonates, expressed per kilogram, is similar to that
than thickly myelinated fibers. Consequently, neonates and reported in adults (0.55 vs. 0.61 L/h/kg). Although hepatic
infants need only small concentrations of local anesthetic to blood flow is increased in neonates [49], CYP1A2 activity
achieve a similar blockade as that observed in adults. is not detectable until well after birth [59]. CYP3A4, which
has a minor role in lignocaine clearance in adults, is also caine [64, 648, 652], the volume of distribution of unbound
immature in neonates. CYP3A7 is expressed in the fetal ropivacaine increased over the first six postnatal months
liver and may contribute to clearance. Neonates excrete a [653], attributed to a corresponding increase in alpha-acid
greater fraction of the dose unchanged in urine and the uri- glycoprotein [651].
nary metabolites, which account for more than 70% of the In contrast to the amide local anesthetics, esters are rap-
dose in adults, account for less than 30% of the dose in idly metabolized by plasma cholinesterases. Chloroprocaine
neonates [647]. Renal function is also immature in neo- is neither protein bound nor does it depend on hepato-renal
nates [75] and thus, we might anticipate a reduced clear- elimination [654]. Two studies reported their experience
ance of lidocaine in neonates. Allometric scaling reveals a with epidural 3% and 1.5% 2-chloroprocaine in neonates
standardized clearance that is one-third that of adults. and infants [655, 656]. After a loading dose of 1–1.5
CYP3A4 assumes a greater role in the clearance of bupi- mL/kg epidural, effective analgesia was achieved with
vacaine and levobupivacaine. Bupivacaine is predominantly 1–1.5 mL/kg/h continuous infusion resulting in plasma lev-
metabolized into pipecoloxylidide by CYP3A4. Maturation els of chloroprocaine of 0–0.5 mg/L.
patterns are similar for bupivacaine and levobupivacaine. The clearance of esters in adults, 2.37 L/min, far exceeds
Levobupivacaine clearance is 5.8 L/h/70 kg at 1-month PNA the hepatic blood flow, supporting its extensive extrahepatic
and increases with a maturation half-time of 2.3 months to metabolism [652]. Some patients have reduced plasma con-
reach 80% of the mature value of 22.1 L/h/70 kg by 6-month centrations of cholinesterase with consequent reduced clear-
PNA (Fig. 3.7). Ropivacaine is mainly metabolized into ance of ester local anesthetics. There are a great number of
3′- and 4′-OH-ropivacaine by the CYP1A2 and to a minor plasma cholinesterases genotypes that lead to wide varia-
extent to pipecoloxylidide by CYP3A4. Maturation of tions in plasma cholinesterase activity [657].
ropivacaine may be slower [59]. An unbound clearance of Disposition may be altered by anatomical differences
120 L/h/70 kg at 30 days PNA is 33% that of the mature between infant and child. In neonates and young infants,
estimate for ropivacaine [63, 648]. Clearance is considered an epidural catheter can be threaded easily from the cau-
capacity limited as the extraction ratio for both bupivacaine dal space to the thoracic region. Anatomical studies have
and ropivacaine is 35% in adults. Failure to appreciate the shown that in neonates and young infants, the epidural fat
reduced clearance of bupivacaine in neonates has resulted in is spongy and gelatinous in appearance with distinct spaces
convulsions during continuous epidural infusion [649, 650]. between individual fat globules [658]. With increasing age,
Safe continuous epidural infusion rates of bupivacaine in fat becomes more tightly packed and fibrous. Local anesthet-
neonates, 0.2–0.25 mg/kg/h (maximum 72 h) and children, ics bind to epidural fat. Absorption half-life (Tabs) and the
0.4–0.5 mg/kg/h, were empirically derived [1]. These rates time to peak concentration (Tmax) are increased in this neona-
maintain steady-state concentrations of ~1 mg/L and mirror tal age group [64]. Reduced clearance and slow absorption
age-related clearance changes for up to 48 h. The volume of both contribute to the observed increase Tmax (Fig. 3.28). The
distribution of lidocaine in neonates is twice that of adults absorption half-time would be consistent with increased epi-
(2.75 vs. 1.1 L/kg) [647]. Although changes in the volume of dural fat rather than reduced epidural fat and the increased
distribution of bupivacaine have not been reported with age Tabs may have more to do with the surface area available for
[651] or with its enantiomers, ropivacaine and levobupiva- absorption in the epidural space.
a 0.7 b
0.6
Absorption half-life (h)
4
0.5
3.5
0.4 3
2.5
Tmax (h)
0.3
2
0.2 1.5
1
0.1
0.5
0 0
0.1 1 10 100 0.1 1 10 100
Log post natal age (months) Log postnatal age (months)
Fig. 3.28 (a) Individual predicted levobupivacaine absorption half- to peak concentration (Tmax) after 2 mg/kg, standardized to a 70-kg
time (Tabs), standardized to a 70-kg person, are plotted against post- person, is plotted against postnatal age. The solid line represents the
natal age. The solid line represents the nonlinear relation between nonlinear relation between Tmax and postnatal age. From Chalkiadis
Tabs and postnatal age. (b) Individual predicted levobupivacaine time GS et al. [64]
Observations in neonatal lambs with surgically created Neuromuscular transmission is immature in neonates and
left-to-right shunts revealed both reduced clearance and vol- infants until the age of 2 months [665, 666]. In response to
ume of distribution of lignocaine [659]. These data are yet to tetanic nerve stimulation, neonates deplete acetylcholine
be confirmed in humans. vesicle reserves more rapidly than infants >2 months old and
children [665],. Data from phrenic nerve-hemidiaphragm
preparations from rats aged 11–28 days suggests this is due
Adverse Effects to a low quantal content of acetylcholine in neonatal endplate
potentials [109]. Neonates display an increased sensitivity to
The major adverse effects are related to cardiovascular and NMBDs. An alternative proposal to explain this increased
central nervous systems. Cardiac toxicity is more commonly sensitivity is based on NMBD synergism observations [667,
reported in children than neurotoxicity, although this may be 668]. Neonates display poor synergism and this has been
attributable to masking of neurotoxic symptoms and signs explained on the basis that NMBDs occupy only one of the
during anesthesia. The use of benzodiazepines may suppress two α-subunit receptor sites in neonates as opposed to two
seizure activity, while inhalational drugs may exacerbate car- in children and adults [668]. If true, then neonates may use
diovascular signs. NMBDs more efficiently than children.
Plasma concentrations of lignocaine from 10 mcg/mL Skeletal muscle fibers can be grouped into two broad
and bupivacaine 3–5 mcg/mL in adults may be expected to types: type I, slow-contracting fibers are rich in oxidative
produce adverse effects. However, adverse events range in enzymes, whereas type II, fast-contracting fibers that are rich
severity and correlate with total concentrations. The rate of in glycolytic enzymes. In the neonate, the diaphragm con-
plasma concentration, protein binding, ionization, arterial tains only 10% of the type I fibers. This proportion increases
oxygen tension, and maturity of the blood–brain barrier also to 25% at term and 55% by 2 years of age. This explains, in
influence the risk of toxicity. With reduced protein-binding part, why infants tolerate respiratory loads poorly. A similar
capacity, immature BBB, metabolic acidosis during seizure maturation pattern is observed for intercostal muscles. Type I
activity, propensity to desaturate rapidly, and immature car- fibers tend to be more sensitive to NMBDs than type II fibers
diac physiology, neonates are at greater risk for adverse and consequently, the diaphragmatic function in neonates
effects [660]. may be better preserved and recover earlier than peripheral
muscles.
Changes in the ECF in infants (Fig. 3.6) affect the volume
Neuromuscular Blocking Drugs of distribution of drugs. Polar drugs such as depolarizing and
nondepolarizing neuromuscular-blocking drugs (NMBDs)
Neonatal Physiology distribute rapidly into the ECF but enter cells more slowly.
The initial dose of such drugs is greater in infants compared
The neuromuscular junction is immature and structurally dif- with children and adults. Increasing muscle bulk adds new
ferent in neonates, skeletal muscle properties change in acetylcholine receptors. This greater number of receptors
infancy, the relative proportion of muscle to body weight is requires a greater amount of drug to block activation of
reduced, the extracellular fluid that neuromuscular-blocking receptor ion channels.
drugs (NMBDs) distribute to is increased, metabolic clear-
ance pathways are often immature and the relationship
between parasympathetic and sympathetic tone unbalanced Pharmacodynamics
in early life. Surprisingly, NMBDs behave differently in neo-
nates both in the desired effects and adverse effects. Age-related variability in the dose required to achieve a pre-
Fetal neonatal postjunctional acetylcholine receptors dif- determined level of neuromuscular blockade has been
fer from receptors in adults [661, 662]. Adult receptors pos- reported for nondepolarizing NMBDs during balanced
sess five subunits, namely, two α, one β, δ, and ε subunits, thiopental-N2O-fentanyl anesthesia (Fig. 3.29). The ED95 of
whereas neonates (<31 weeks PMA) have a γ-subunit instead vecuronium was 47 (SD 11) μg/kg in neonates and infants,
of an ε-subunit in their neuromuscular receptor [663]. The 81 (SD 12) μg/kg in children between 3 and 10 years of age,
opening time of fetal receptors is greater than that in adults, and 55 (SD 12) μg/kg in children aged ≥13 years [670].
allowing more sodium to enter the cell with a resultant larger Similar profiles have been reported for other NMBDs [669,
depolarizing potential. The resulting increased sensitivity to 671–674]. Furthermore, the duration of neuromuscular
acetylcholine is at odds with the observed increased sensitiv- blockade is greater in neonates than it is in children [675].
ity to NMBDs but may compensate for reduced acetylcho- The reduced dose requirement in neonates has been attrib-
line stores in the terminal nerve endings [664]. uted to the immaturity of the neuromuscular junction. The
100 kg) of succinylcholine is 35–55 s in children and adoles-

cents. The onset time after 3 mg/kg in neonates is even faster,
80 ED95 30–40 s [687]. The onset time depends on both age and dose;
Dose (mcg/kg)
the younger the child and the greater the dose, the quicker
60 the onset time. The onset times of equipotent doses of suc-
cinylcholine (0.9 min) and mivacurium (1.4 min) in infants
40 (2–12 months) and children (1–12 years) are similar [688].
ED50 Consequently, an argument can be made for the use of larger
20
doses of an intermediate-duration NMBD rather than succi-
nylcholine for rapid sequence intubation. However, increased
doses of such drugs in the neonate will also prolong neuromus-
o
rs
rs
rs
rs
rs
rs
rs
a
cular blockade and increase the risk of adverse effects (e.g.,

m
a
ye
ye
ye
ye
ye
ye
ye
ye
1
3
1-
1
<
pain on injection, tachycardia). Phase II blockade may also

2
10
6
o-
1-
2-
3-
5-
-1
-1
m
7-
10
13
3
develop with large or repeat doses of succinylcholine [689].

Fig. 3.29 Dose changes with age for vecuronium during balanced Succinylcholine may be injected intramuscularly for tra-
anesthesia. ED50 is the dose that achieves 50% of the maximum cheal intubation in children [690]. Few data are available
response, while ED95is the dose that achieves 95% of the maximum in neonates, but studies in infants suggest that a dose of up
response. Data from Meretoja et al. [669]
to 5 mg/kg may be required to achieve satisfactory intubat-
ing conditions [691]. The time interval from the onset to
increased volume of distribution from an expanded ECF in maximum blockade is slow, 4 (SD 6) min and the time to
neonates implies a similar initial dose in neonates and teen- full recovery of T1, 15.6 (SD 0.9) min after injection [691].
agers. The reason for the greater dosing in children com- The slow onset time limits the usefulness of this technique.
pared with adults is unclear, although it could be attributed to Intralingual or submental routes have also been used in chil-
increased muscle bulk. dren, but data in neonates are lacking.
Investigation into the concentration-response relation-
ships is more revealing. The plasma concentration required
to achieve the same level of neuromuscular block in neonates Pharmacokinetics
as in children or adults is 20–50 % less [676–679], consistent
with immaturity of the neuromuscular junction. Plasma con- The dose of NMBDs at different ages depends on a complex
centration requirements are reduced by volatile anesthetic interweaving of pharmacodynamic and pharmacokinetic fac-
agents [680–682]. tors. Age-related pharmacokinetics of d-tubocurarine in chil-
The onset time for NMBDs in neonates is faster than it is dren is displayed in Table 3.4 [94]. The volume of distribution
in older children than adults. Onset time (time to maximal mirrors changes in ECF and can be predicted using either an
effect) after vecuronium 70 μg/kg was most rapid for infants allometric 3/4 power model or the surface area model, both
(1.5 SD 0.6 min compared with that for children (2.4 SD of which approximate changes in the ECF with weight [499].
1.4 min) and adults (2.9 SD 0.2 min) [675]. These observa- This occurs, because ECF is a major contributor to the vol-
tions are similar to those reported for other intermediate- and ume of distribution at steady state (Vss). These volume
long-acting NMBDs [683]. The more rapid onset of these changes are true for both depolarizing (succinylcholine)
drugs in neonates has been attributed to a greater cardiac out- [692, 693] and nondepolarizing NMBDs [694].
put based on the per kilogram model [683]. The clearance of d-tubocurarine, standardized to an allo-
Cardiac output is commonly used as a surrogate measure metric or surface area model, is reduced in neonates and
for muscle perfusion. Onset time is a function of size. An infants compared with older children and adults [94]. These
onset time standardized to a 70 kg person using an allometric age-related changes in clearance follow age-related matura-
1/4 power model is about 3 min. In children with low cardiac tion of glomerular filtration in the kidney [75], which is the
output or decreased muscle perfusion, onset times are pro- elimination route of d-tubocurarine. Total plasma clearance
longed. The onset of neuromuscular paralysis is proportional of other nondepolarizing muscle relaxants (alcuronium,) that
to T1/2keo. Increasing the inspired concentration of halothane are cleared by renal and/or hepatic pathways (pancuronium,
increases the t1/2keo of d-tubocurare [684]. The explanation pipecuronium, rocuronium, and vecuronium) are all reduced
for the delayed onset of action of tubocurarine may be halo- in neonates [676, 678, 695–697]. In contrast, the clear-
thane’s negative inotropy [685] and decreased muscle blood ances of atracurium and cisatracurium are independent of
flow [686]. renal and hepatic pathways; rather, clearance depends on
Succinylcholine remains the NMBD with the most rapid Hofmann elimination, ester hydrolysis, and other unspeci-
onset of action. The onset time of a paralyzing dose (1.0 mg/ fied pathways [698]. Clearance of these drugs is greater in
Table 3.4 Age-related pharmacokinetics (SD) of d-tubocurarine (data taken from Fisher DM et al. Anesthesiology 1982; 57: 203–8) [94]
CL Surface Area CL Allometric 3/4 (mL/
Weight (kg) CL (mL/min/kg) (mL/min/m [2]) min/70 kg)
(A) Total body clearance
Neonate 3.5 3.7 (2.1) 56 (32) 122 (70)
(1 d–2 mo)
Infant 7 3.3 (0.4) 59 (7) 130 (15)
(2 mo–1 y)
Child (1–12 y) 22 4 (1.1) 110 (30) 210 (58)
Adult (12–30 y) 60 3 (0.8) 115 (31) 202 (54)
(B) Volume of distribution at steady state
Weight Vdss (L/kg) Vdss Surface Area Vdss Allometric (power 1) Vdss Allometric
(kg) (L/m [2]) (L/70 kg) (power 3/4) (L/70 kg)
Neonate 3.5 0.74 (0.33) 11 (5) 52 (23) 25 (11)
Infant 7 0.52 (0.22) 9 (4) 36 (15) 21 (9)
Child 22 0.41 (0.12) 11 (3) 29 (8) 22 (6)
Adult 60 0.3 (0.1) 12 (4) 21 (7) 20 (7)
(C) Half-times
Chronological time (min) Physiological time (min)
T1/2α T1/2β T1/2keo T1/2α T1/2β T1/2keo
Neonate 4.1 (2.2) 174 (60) 6.3 (3.5) 8.7 (4.7) 368 (127) 13.3
(7.4)
Infant 7.0 (4) 130 (54) 7.5 (3.5) 12.9 (7.4) 240 (100) 13.9
(6.5)
Child 6.7 (2.4) 90 (23) 7.9 (2.7) 8.9 (3.2) 120 (31) 10.6
(3.6)
Adult 7.9 (4.1) 89 (18) 6.8 (1.9) 8.2 (4.3) 93 (19) 7.1 (2.0)
neonates when expressed on a per kilogram basis [699–701]. tice [702, 703]. The distribution volumes of neostigmine are
When clearance is standardized using allometric 3/4 power similar in infants (2–10 months), children (1–6 years), and
scaling, the clearances for atracurium and cisatracurium are adults (Vss 0.5 L/kg), whereas the elimination half-life is
similar across all age groups. The clearance of succinylcho- less in the pediatric patients [704]. Clearance decreases as
line, expressed on a per kilogram basis, also decreases with age increases (13.6, 11.1, 9.6 mL/min/kg in infants, children,
increasing age [87, 88]. Succinylcholine is hydrolyzed by and adults 29–48 years) [704] as we might expect from allo-
butyryl-cholinesterase. These observations are consistent metric scaling. The dose of neostigmine required to reverse
with that observed for the clearance of remifentanil [476], d-tubocurare blockade was 30–40% less for infants and chil-
which is also cleared by plasma esterases. These clearance dren than for adults (expressed as per kilogram) with a dura-
pathways are mature at birth. tion of effect of neostigmine similar in both pediatric and
Conversion of d-tubocurarine half-times from chrono- adult patients. Other studies have confirmed that a train-of-
logical time to physiologic time is revealing. T1/2α increases four (TOF) ratio recovers to 0.7 in less than ten minutes
with age in chronological time, but in physiologic time, it is when a 90% neuromuscular blockade from pancuronium is
the same at all ages, as expected from a distribution phase antagonized with neostigmine 30–40 μg/kg in infants, chil-
standardized by allometry. T1/2β decreases with age in physi- dren, or adults [703, 705–707].
ologic time, consistent with reduced clearance related to vol- Neonates have the more rapid times to full recovery after
ume in the very young. The T1/2keo is large in neonates and neostigmine antagonism [703, 708]. For example, rever-
infants, reduced in children, and further reduced in adults. sal of an atracurium-induced 90% neuromuscular block in
The cause for this change with age is unclear, but it may infants and children by neostigmine 50 μg/kg was fastest in
be related to an increased muscle bulk and concomitantly the youngest age group [702]. The time to a TOF-ratio of 0.7
increased muscle perfusion in older children and adults. was 4 min in neonates and infants, 6 min in 2–10 years old
children, and 8 min in adolescents. These observations are
consistent with allometric models for size [46].
Antagonism of Neuromuscular Blockade Sugammadex is a new drug that reverses the NMB effects
of rocuronium and, to a lesser extent, vecuronium. It has a cyl-
Although edrophonium may establish a faster onset of effect, inder-like cyclodextrin structure that irreversibly encapsulates
final recovery is invariably greater with neostigmine, which rocuronium into its cavity. An early sugammadex study in chil-
is why the latter is recommended for routine pediatric prac- dren suggests that sugammadex 2 mg/kg reverses a rocuronium-
induced moderate neuromuscular blockade in infants, children, also proven popular for cardiac surgery to capitalize on its
and adolescents [709]. The average time to recover a TOF-ratio vagolytic activity that increases heart rate. Unfortunately,
of 0.9 at the time of appearance of the second twitch response rocuronium also causes local pain when injected rapidly and
was 1.2, 1.1, and 1.2 min in children, adolescents, and adults, may trigger anaphylaxis [721]. Atracurium can liberate his-
respectively. Sugammadex is cleared through the renal system tamine, precipitating bronchospasm and hypotension. These
and the elimination kinetics of rocuronium is prolonged in case effects are attenuated with the isomer cis-atracurium.
of renal failure [710]. Although GFR is immature in neonates,
this is unlikely to be of consequence here. Sugammadex has
been used in patients with end-stage renal failure [711, 712] Anticholinergic Drugs
with similar reversal characteristics as those with normal renal
function. Sugammadex has been associated with hypersensitiv- These drugs block acetylcholine at the postganglionic cho-
ity and anaphylactic reactions in adults, although similar evi- linergic (parasympathetic) endings. They also block the
dence has not been forthcoming in children except anecdotally direct vasodilator effect of acetylcholine on blood vessels
[713, 714]. (antimuscarinic) and in the CNS. They cause mydriasis and
increase intraocular pressure, tachycardias, inhibit sweating,
reduce salivation, decrease lower oesophageal sphincter
Adverse Effects tone, and have similar effects on tone in the digestive and
urinary tracts. Atropine, scopolamine, and glycopyrrolate are
Succinylcholine is the most pilloried NMBD despite its the three commonly used anticholinergic drugs in anesthesia.
importance for rapid sequence intubation [715–717]. Its Differences in clinical effects are not very prominent in
molecular structure resembles that of two acetylcholine mol- healthy patients [722].
ecules joined by an ester linkage. Consequently, stimulation While these drugs are commonly administered with
of cholinergic autonomic receptors can be associated with the anti-cholinesterases to reverse residual neuromuscular
cardiac arrhythmias, increased salivation, and bronchial blockade, their routine use in neonatal anesthesia is declin-
secretions. Muscle fasciculation is also associated with mild ing [723]. The benefits of reduced secretions or prevention
hyperkalemia (0.2 nmol/L), increased intragastric and intra- of bradycardia during otolaryngological surgery, eye sur-
ocular pressure, masseter spasm, and skeletal muscle pains. gery, and endoscopic procedures in children less than one
Severe hyperkalemia may occur in patients with burns, upper year of age justify their use by some [724], although this
and lower motor neuron lesions, trauma, and disuse atrophy. continues to be debated [725]. They were used in the past to
This may be associated with rhabdomyolysis and myoglo- reduce salivation associated with ketamine, but ketamine use
binemia in those patients suffering neuromuscular disorders. is also declining in neonates, while neuroapoptotic effects
These disorders are not always diagnosable in neonates. are investigated.
Congenital myotonic dystrophy, for example, may present
with mild respiratory dysfunction or feeding difficulty in the
neonate. The response to succinylcholine in these neonates, Atropine
however, remains dramatic with sustained muscle contrac-
tion [718]. Succinylcholine is a trigger for malignant hyper- Atropine is metabolized in the liver by N-demethylation fol-
thermia, particularly in combination with inhalational lowed by conjugation with glucuronic acid [726]; both pro-
anesthesia. Succinylcholine has a prolonged effect in chil- cesses are immature in the neonate. Half the drug is also
dren with butyryl-cholinesterase deficiency (plasma cholin- eliminated by the kidneys. An old technique to diagnose
esterase). This is an inherited disease due to the presence of atropine poisoning was to put a drop of the victim’s urine
one or more abnormal genes (atypical, fluoride-resistant, and into the eye of a cat and observe for mydriasis.
silent genes) [657]. On the other hand, one genetic variant, It is anticipated that clearance is reduced in the neona-
the Cynthiana or Nietlich variant [719], represents an ultra- tal age range because of an immaturity of renal and hepatic
rapid rate of degradation of succinylcholine [720]. function, but data remain elusive. Children, less than 2 years
The nondepolarizing NMBDs all have different adverse of age, have an increased volume of distribution at steady
effects that are often used to therapeutic advantage. state (3.2 SD 1.5 vs. 1.3 SD 0.5 L/kg) compared with those
d-tubocurarine may produce hypotension and bronchospasm older than 2 years [727] Clearance was similar in those aged
after large doses and a rapid administration. Pancuronium less than 2 years (6.8 SD 5.3 mL/min/kg) and those older
confers sympathomimetic effects as a result of blocking the than 2 years (6.5 SD 1.6 mL/min/kg). The elimination half-
reuptake of noradrenaline; the resultant tachycardia may life in healthy adults is 3 SD 0.9 h, whereas in term neonates,
augment cardiac output during induction for cardiac surgery it is 4 fold greater [726]. There are no data from preterm
in neonates. Doses greater than the ED95 of rocuronium have neonates [727, 728].
Atropine 0.1 mg is widely reported to be the minimum Scopolamine is poorly absorbed from the GI tract (10–
intravenous dose in neonates and young infants. The prove- 25%) [739]. Clearance in infants less than 1 year of age
nance of this recommendation is a single study in which two (n = 8) was 1.01 (range 0.32–1.85) L/kg/h and Vss 1.83
infants and three children suffered neither bradycardia nor (range 0.70–3.87) L/kg), although there are no neonatal data.
sequelae after small serial doses of atropine [729]. The risk The renal system accounts for 85% of elimination [740], and
from adhering to this minimum dose is a relative overdose clearance is anticipated to be reduced in neonates, because
of atropine in very low birth weight and extremely preterm renal function is immature [75].
infants. A dose of 5 μg/kg in infants (total <0.1 mg) dem-
onstrated no adverse bradycardia or other adverse effects
[730]. Systolic blood pressure did not change for any dose Adverse Effects
of atropine (5–40 μg/kg). Maximum heart rate change and
minimum saliva flow occurred within 7–8 min after intra- Poisoning signs and symptoms in adults can be described as
venous drug administration in adults, but neonatal data are “hot as a hare, blind as a bat, dry as a bone, red as a beet and
lacking [731]. mad as a hen.” [741] These relate to the peripheral effects of
dry mouth, blurred vision, and hot, dry skin; central effects
contribute hyperpyrexia, restlessness, anxiety, excitement,
Scopolomine hallucinations, delirium, and mania. Cerebral depression and
death can occur in severe poisoning. The mydriatic effect on
Scopolamine is a tertiary amine with greater CNS effects the eye when solanaceous plant (e.g., Atropa belladonna)
than atropine, causing sedation and amnesia. Its moder- extract is used topically has been employed to lure male suit-
ate antiemetic activity [732] is of little use in neonates. The ors even though it causes the female to be somewhat uncer-
drug, combined with morphine, was a popular intramuscu- tain of her beau’s features.
lar premedication but is unsuitable in neonates. Routine The vagal response is greater in neonates than adults. The
intramuscular premedication has lost favor; intramuscu- resulting tachycardia may be beneficial during anesthesia in
lar morphine-scopolamine causes hypercarbia and oxygen neonates with their rate-dependent cardiac output. Propofol
desaturation [733]. Scopolamine is considered a less effective in combination with remifentanil can cause profound brady-
agent to block cardiac vagal responses but confers a greater cardia during induction, as may repeat dosing of succinylcho-
drying effect compared with atropine, although these differ- line, laryngeal instrumentation, and surgical manipulation of
ences in clinical effects are not very prominent in healthy the eye, testes, and hollow viscera. Prophylactic use of atro-
patients [722]. A direct correlation between serum concentra- pine may prove useful [742]. Hypoxaemia, however, is the
tions of scopolamine and changes in EEG signals in adults commonest cause of bradycardia and this is managed with
has been reported, but data in neonates are lacking [734]. oxygen, not atropine.
Scopolamine has a distribution volume of 1.4 L/kg [735]
in adults. Glucuronide conjugation, sulfate conjugation, and
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The Selection of Anesthesia Techniques
for the Neonate 4
Nada Sabourdin, Nicolas Louvet, and Isabelle Constant
art 1. General Principles and Aims

P Prevention of nociceptive stress requires adequate analgesia,
of Anesthesia in the Neonate which may be a tricky balance, particularly if extubation is
planned at the conclusion of the surgery.
To identify the optimal anesthetic technique for neonates, it The anatomical and physiological pathways of nocicep-
is incumbent to articulate the goals of a safe and effective tion are present and functional in utero, although central
neonatal anesthesia. modulation may be primitive at that time. Optimal analgesia
can be obtained by various techniques including inhalational
• To allow the surgical procedure to be performed under the agents, intravenous opioids, and/or regional anesthesia. The
best possible conditions, while optimizing the physiologi- most common option is to provide a “balanced analgesia,”
cal state and to provide analgesia sufficient to obtund combining inhalation agents, opioid and nonopioid analge-
physiological and neuroendocrine responses to the surgi- sics, together with regional analgesia when appropriate. In
cal stimulation. Special attention is needed to optimize the neonatal period, medullary reflexes are very robust: an
oxygenation and ventilation, ensure thermal homeostasis, adequate level of hypnosis and an adequate analgesia are
and glucose metabolism (see related chapters). required to ensure immobility at surgical incision. MAC
• To minimize unpleasant implicit memories. values for inhaled anesthetic agents increase with decreas-
• To minimize the risk of cerebral insults and damage ing age, but are less in neonates than in older infants, with
whether hypoxic/ischemic, metabolic, or neurotoxic. the exception of sevoflurane (see Chap. 3). This may pres-
ent challenges to maintaining circulatory homeostasis while
delivering adequate anesthesia. The balance between corti-
irst Objective: To Provide Optimal Conditions
F cal and subcortical processes in the neonate may differ from
for Surgery and Maintain Homeostasis. that in older children or adults with subcortical structures,
at least at the level of the spinal cord, being less sensitive to
Neonatal surgery is very precise and requires a totally immo- sevoflurane-induced inhibition.
bile operative field. Any movement during surgery exposes Hypnotics and analgesics (above their minimum dose nec-
the neonate to the risk of surgical and/or anesthetic compli- essary) decreases motor responses but may not be tolerated
cations. Neuromuscular blockade can ensure immobility, in some and may compromise the circulatory indices, return
but it should be used with adequate analgesia. Disturbances of spontaneous respiration and delay emergence. For these
in homeostasis can occur when the neonate is stressed reasons, anesthesia in the neonate may be complemented
from metabolic, hypothermic, hypovolemic, or nociceptive by neuromuscular-blocking agents. In the past, they might
sources. Regulation of the metabolic balance, temperature have been used instead of adequate analgesia, but today, they
monitoring, and intravenous fluid management are crucial are combined with adequate analgesic and hypnotic drugs to
endpoints for the safe conduct of anesthesia in the neonate. ensure immobility during surgery. Given the immaturity in
clearance and renal function in the neonate together with the
N. Sabourdin · N. Louvet · I. Constant (*) interindividual variability in pharmacodynamic responses,
Department of Anesthesiology and Intensive Care, every drug should be titrated in the neonate to achieve the
Armand Trousseau Hospital, APHP, desired endpoint.
Sorbonne University, Paris, France
e-mail: [email protected]; [email protected];
[email protected]

168 N. Sabourdin et al.
econd Objective: To Avoid the Storage

S ences before the age of 10 years is sparse and incomplete [3].
of Unpleasant Implicit Memories Numerous theories have been proposed to explain the long-
term inability to recall episodic memory in infancy includ-
Special attention should be directed in the perioperative ing the lack of linguistic abilities, but after similar memory
period, before and after anesthesia to avoid the perception, loss was discovered in young animals, the theories pointed
integration, and memorization of stressful experiences com- to developmental aspects of specific regions of the brain. In
monly encountered at this time: fear, cold, hunger, loud fact, our inability to recall episodic events from infancy may
noise, bright lights, inadequate handling, uncomfortable in part be attributed to immaturity of the dentate gyrus of the
position, unfamiliar voices, faces or smells, and, most impor- hippocampus, amygdala, and prefrontal cortex. The former
tantly, pain. This will not only limit the temporary unpleas- matures by 3–5 years age, which corresponds to the age at
antness of the procedure but might also preclude long-term which “infantile amnesia” ceases to be a consideration and
behavioral and/or emotional disturbances. the latter by adolescence and early adulthood. Further evi-
The development of memory processes in very early life dence suggests that our inability to recall those early events
is poorly understood [1]. Freud described the inability of may stem more from a process retrieval problem rather than
adults to recall birth and those events early in life in the con- a decay in or loss of the actual memory [3]. At the same time,
sciousness as “infantile amnesia.” Although episodic events when the neonate experiences smells, voices, vision, and
in the early postnatal years cannot be recalled later in life music, each experience contributes to the functional matu-
as conscious recollection (explicit memory), that does not ration and learning system of the hippocampus. Although
mean that the events did not impact our developing subcon- explicit memory only achieves maturity after several postna-
science through implicit memory [1, 2]. Memories of epi- tal years, implicit memory is probably fully functional from
sodic events involving the “who, what, when and where” or birth and possibly in utero as well (Fig. 4.1) [4–8].
“wwww” memories are referred to as hippocampal memory, Paradoxically, one may question how psychopathogical
which depend on a collaborative integration of memory external factors (such as neglect or pain) that are experienced
traces or engrams with other regions of the brain including in early life can impact behavior later in life (e.g., personal-
the medial temporal lobe, amygdala, and cortical regions to ity disorder or exaggerated response to a noxious stimulus)
consolidate long-term memory. After studying the fading of if the early memories cannot be retrieved? [9–11] Implicit
episodic memory in rodents, studies undertaken in humans memory is memory that has been retained not in the con-
indicated that the 3 year old can retain episodic experiences sciousness but in the subconscious. Even though the events
in the short term but that those memories fade rapidly and are are not retrievable, these events help develop and adapt our
forgotten in the long term. In most, recall of episodic experi- behaviors and responses to subsequent situations. Implicit
Fig. 4.1 Critical windows of Amygdala-dependent learning

sensitivity for brain functions. (cued conditioning,
Solid curves indicate the Implicit learning) Hippocampus-dependent learning Higher cognitive
normal expression of the function
critical period within each Somatosensory
brain region in infancy and (vision,
childhood. Hippocampal- hearing,
touch)
dependent learning includes
sequential waves of
sensitivity, which enable
Plasticity
w
e
acquisition of increasingly
e
spac
www
ct
Plac
complex functions including

Obje
object, place, space and

wwww (who, what, when and
where). Reproduced with
permission, Ref. [2]
Infancy Childhood
Birth
Development
4 The Selection of Anesthesia Techniques for the Neonate 169
memory is primarily associated with different areas of the Cerebral blood flow is most commonly insufficient due to
brain unlike explicit memory, specifically the striatum, cer- systemic hypotension. In nonanesthetized term neonates, the
ebellum, and amygdala, areas that are present in nonhuman normal MAP increases from approximately 52–61 mmHg
primates and the first to mature [12]. Implicit memory has during the first month of life [15], SBP from approximately
been detected in fetuses in studies in which they were pro- 62 to more than 80 mmHg [16]. The slope of the blood
voked with a noxious stimulus. Implicit memory develops pressure increase is maximum during the first week of life.
throughout postnatal life after stabilizing after 8 months of Blood pressure in preterm neonates tends to exceed that in
age, integrating experiences and responses in life into the term neonates of similar postmenstrual age [17]. Despite our
subconscious. Testing implicit memory in early infancy, knowledge of these data in awake neonates, there has been
however, has proved to be challenging although research has a lack of knowledge regarding the normal range of blood
demonstrated that the responsiveness to a stimulus (often pressure in anesthetized neonates. This was due in part to a
noxious) is more rapid and severe after a prior exposure [13]. lack of attention to the correct way to measure blood pres-
Although the infant may not have had explicit recall of the sure in the neonate (cuff size, position, and device) to obtain
prior event, the vigor and extent of their responses to the precise results. Attention was drawn to this issue when a case
subsequent stimuli were greater than their responses without series described postoperative encephalopathy in six young
a prior exposure or a painless exposure [14]. These experi- infants (<48 weeks postmenstrual age) who developed early
ences, which may have occurred in the preverbal period or postoperative seizures [18]. One patient died, another had
under anesthesia, nonetheless led to exaggerated or more severe neurodevelopmental sequelae. Although these post-
extreme responses when subsequently challenged. Hence, it operative complications had no definitive explanation, the
behooves us to minimize nociceptive stimuli in the neonate six cases shared a common feature: the intraoperative mean
and infant at all ages by providing adequate analgesia and arterial pressure was relatively low. In 2016, a retrospective
anesthesia to preclude the development of implicit memory. observational study including more than 100,000 ASA 1-2
children, 2122 of whom were less than 2 months postnatal
age, provided the first pediatric descriptive data for normal
hird Objective: To Ensure That the Techniques
T intraoperative blood pressure [19]. This report, however, did
Employed Minimize the Risk of Cerebral not analyze the relationship among blood pressure levels,
Damage (Hypoxic/Ischemic, metabolic, or organ perfusion, and postoperative outcomes.
neurotoxic) The lower limit of intraoperative blood pressure below
which brain damage may occur in neonates remains uncer-
The brain in the neonate is fragile and can be harmed in tain. Cerebral perfusion pressure is defined by the differ-
many ways during anesthesia. Any severe homeostatic dis- ence between mean arterial pressure (MAP) and intracranial
turbance might lead to brain injury. Most commonly, inade- pressure (or central venous pressure). If intracranial pres-
quate cerebral oxygen delivery is the underlying cause. This sure remains constant, cerebral perfusion pressure depends
may result from ventilatory or circulatory causes, or a com- directly on the MAP. Cerebral autoregulation delivers a con-
bination of the two. Less commonly, metabolic (e.g., hypo- stant cerebral blood flow within the normal range of MAP
glycemia, hypothermia) or neurotoxic causes may be by increasing or decreasing the caliber of the cerebral ves-
implicated. sels inversely to the change in MAP. When MAP decreases
below the lower limit of autoregulation, cerebral vasodila-
Cerebral Hypoxia/Ischaemia tion is maximized and cerebral blood flow becomes pressure
Hypoxia occurs when cerebral cells do not receive sufficient dependent, for example, it depends directly on the MAP.
oxygen to meet their basic metabolic needs. This can occur Below a critical level of MAP, cerebral blood flow becomes
under three conditions: low oxygen content (as measured by insufficient to supply sufficient oxygen to the brain cells and
the saturation), low delivery (cerebral blood flow), or both is cellular hypoxia ensures. In anesthetized neonates, the auto-
present. Low arterial oxygen saturation is most frequently regulation plateau is narrower than in adults, but its limits
secondary to loss of the airway (e.g., failed intubation or have not been definitely established. Moreover, in recently
inadvertent extubation) or impaired ventilation/perfusion asphyxiated neonates, the plateau may be narrower or pos-
mismatch that arises from primary pulmonary disorders sibly nonexistent. Using cerebral blood flow velocity and
(e.g., chronic bronchopulmonary dysplasia) or intracardiac near infrared spectroscopy (NIRS), studies performed at 1
shunts. It is vitally important to monitor oxygenation and MAC sevoflurane showed that the lower limit of autoregula-
ventilation meticulously during anesthesia (See Chap. 7). tion in infants less than six months of age was an MAP of
45 mmHg. Cerebral oxygenation was impaired at an MAP practice has remained unchanged over the past three decades
of under 35 mmHg of MAP in these infants [20], although despite the introduction of newer, less soluble inhalational
there was an element of interindividual variability in the anesthetics [31].
measurements. No specific recommendations were made for In 2015, a Cochrane review on “regional (spinal, epidural,
the minimum MAP in neonates, although these findings pro- caudal) versus general anesthesia in preterm infants undergo-
vided a solid foundation on which to base the hemodynamic ing inguinal herniorrhaphy in early infancy” [32] concluded
management of neonates under anesthesia. Thus, to limit that there is “moderate-quality evidence to suggest that the
the risk of brain damage, the minimum MAP should exceed administration of spinal in preference to general anesthesia
35 mmHg at all times during neonatal anesthesia. without pre- or intraoperative sedative administration may
Insufficient cerebral blood flow can also be the conse- reduce the risk of postoperative apnea by up to 47% in pre-
quence of excessive vasoconstriction [21, 22], the result of term infants undergoing inguinal herniorrhaphy…”. For
hyperventilation and hypocapnia. As carbon dioxide vaso- every 4 infants treated with spinal anesthesia, one may be
reactivity in children is particularly marked, avoiding hypo- prevented from having an episode of postoperative apnea.
capnia is of paramount importance during anesthesia. Finally, the beneficial effects of spinal versus general anes-
thesia in this context were confirmed in a recent meta-analy
sis based on 6 studies, including a total of 512 patients born
etabolic, Neurotoxic, and Other Potential
M prematurely and undergoing inguinal hernia repair [33].
Causes of Cerebral Damage. The conclusion published was that compared with general
anesthesia, spinal anesthesia reduced the risk for any post-
The neonate, in particular, the asphyxiated and the preterm operative apnea, bradycardia, and the need for mechanical
neonate, is prone to hypoglycemia. Consequently, an infu- ventilation in this population.
sion of glucose should be delivered perioperatively while the One of the studies included in this last meta-analysis was
blood glucose concentrations are monitored. Caution should the General Anesthesia compared to Spinal anesthesia trial
be exercised to avoid the possibility of both hypoglycemia (GAS) [34]. This study was the largest international random-
and hyperglycemia. The latter state may increase the danger ized controlled trial ever published on the issue of postop-
of cerebral damage and also cause fluid and electrolyte erative apnea in infants undergoing inguinal herniorrhaphy,
disturbance. although its primary aim was to assess neurodevelopmental
The neurotoxic potential of anesthesia drugs is discussed outcome after anesthesia in early infancy. The GAS study
in detail in Chap. 18. included infants aged 60 weeks or younger postmenstrual
age, randomly allocated to sevoflurane-based general or
awake regional anesthesia. The main result of the second-
Part 2. Techniques of Anesthesia ary outcome of that study was that the risk of apnea beyond
12 h after surgery allocation was unaffected by which anes-
Spinal Anesthesia thetic technique was used, regional or general anesthesia.
However, regional anesthesia did reduce the incidence of
In the 1980s, spinal anesthesia became popularized as an early apnea (within 30 min of the end of surgery), as well
alternative to general anesthesia in preterm and ex-preterm as its severity: all children (0.8%) who had an apneic epi
infants as it did not increase the risk of postoperative apnea sode requiring positive pressure ventilation or cardio-pul-
[23, 24]. In 1998, a landmark study reported that the fre- monary resuscitation had received general anesthesia. Also,
quency of postoperative apneas in infants who were born postoperative desaturation was less frequent with regional
prematurely and who underwent inguinal hernia repair under anesthesia. The strongest risk factor for postoperative apnea
spinal anesthesia was less than in those who underwent gen- was preterm birth: 24 of the 25 patients who had postopera-
eral anesthesia using thiopental and halothane [25]. For the tive apnea were born prematurely, the last one was born at
infant born prematurely, an analysis of four trials determined 37 weeks and one day. Thus, in 2015, using modern agents
that the risk of apnea decreased steadily between birth and and techniques of anesthesia, the incidence of postoperative
60 weeks post-conceptional age (PCA), at which point it was apnea in preterm infants was 6.1% compared with 0.3% in
less than 1% [26]. At 45 weeks PCA, this risk was approxi- term infants. Because of the significant risk of postoperative
mately of 5% [26]. Anemia (hematocrit <30%) [26–28] apnea, infants aged less than 60 weeks PCA who were born
hypothermia [29] premature neonates with a pre-existing prematurely require 12 h of apnea-free respiratory monitor-
impaired respiratory function than spinal anesthesia [30]. ing after surgery, irrespective of the anesthetic provided.
Spinal anesthesia has increasingly become the preferred Some have suggested that those infants who were born pre-
technique for brief surgical procedures in the inguinal and mature but are now greater than 46 weeks PCA without ane-
lower abdominal areas in neonates born prematurely. This mia or comorbidities may be discharged earlier, that is, after
six hours of monitoring [35]. This recommendation requires ade requiring ventilatory assistance (0.67% in one series) or
prospective evaluation. intubation (0.33%) [52] is also unlikely, provided the correct
In addition to its benefit on the incidence of postopera- dose is administered, and the infant remains strictly horizon-
tive apnea and desaturation, spinal anesthesia has several tal. Neuraxial hematoma has not been reported in a child,
advantages in terms of safety and comfort. First, the patient although it has been described in an infant undergoing diag-
breathes spontaneously, avoiding all possible complications nostic lumbar puncture, who had undiagnosed hemophilia
related to airway devices. Second, as opposed to older chil- A [53]. The utility of tests of coagulation indices in chil-
dren, spinal anesthesia does not induce clinically significant dren undergoing lumbar punctures under spinal anesthesia
hemodynamic disturbances in the neonate. In particular, arte- remains contentious [54] and is not standard practice.
rial blood pressure remains stable [36, 37]. When no general The main concern regarding spinal anesthesia in the neo-
anesthetics are administered, blood pressure levels do not nate is its failure rate. The reported failure rate of spinal
significantly decrease intraoperatively [38, 39]. In the GAS anesthesia is between 3% and 20%, depending on the experi-
study, the mean minimum systolic blood pressure in infants ence of the anesthesiologist with spinal blocks [32, 34, 47,
who received spinal anesthesia was greater than that in infants 49, 52, 55–57].
who received general anesthesia (70.7 versus 54.8 mmHg) Regarding the duration of spinal anesthesia, there is
and the infants were less likely to need an intervention for interindividual variability, and the duration of analgesia and
hypotension during the procedure. Finally, infants who have motor block varies according to the type and dose of the
received spinal anesthesia were very calm and peaceful dur- local anesthetic chosen. In most cases, the duration of the
ing the surgery and some actually fell asleep. Interestingly, block is a maximum of 90 min [47], which limits the dura-
the BIS has been recorded in unpremedicated infants who tion of the surgical procedure under spinal anesthesia. Spinal
were born premature undergoing surgery with spinal anes- anesthesia has been used for various infra-umbilical proce-
thesia. The BIS decreased during the first 25 min after the dures, but also occasionally for pyloromyotomy [38, 58, 59]
spinal, to reach a nadir of 60, that remained unchanged for and at least once for duodenal atresia repair [60].
the next 20 min, and finally returned to 100 during the final In conclusion, spinal anesthesia offers numerous advan-
20 min [40]. This decrease in the BIS measurements during tages over general anesthesia and is associated with few
spinal anesthesia has been attributed to an attenuation of the complications. Although useful in the infant who was born
ascending sensory input to the brain, permitting sleep. premature and remains less than 60 weeks’ PCA, it may be
Does the use of spinal analgesia remove the possibility considered in the neonate undergoing any mid and lower
of anesthesia-related cerebral toxicity? Based on clinical abdominal surgery of less than 60 min in duration. Recent
observations of transient or persistent neurological symp- concerns about potential local anesthetic neurotoxicity have
toms after spinal anesthesia in adults [41], a direct cytotoxic- been articulated in the literature. However, the evidence
ity of local anesthetics has been suspected and investigated. arises primarily from animal and experimental studies, and
Neurotoxicity was first characterized in animal studies [42] the clinical relevance to humans is yet to be established.
and then in in vitro human neuronal cells models [43]. The When the location and duration of surgery make it appro-
mechanisms are still unclear and may be multifactorial. priate, spinal anesthesia may be the optimal option for the
However, all local anesthetics, and particularly bupivacaine neonate.
and lidocaine, have triggered dose-dependent neuronal cell With the substantial failure rate from spinal anesthesia as
dysfunction, death, or apoptosis, at in vitro concentrations mentioned above, as well as its limited duration of action
similar to or less than clinical concentrations observed in the (<90 min) and the infrequency of performing spinal blocks
CSF after standard spinal anesthesia. Evidence suggested in young infants, clinicians have turned to continuous caudal
that spinal anesthesia does not trigger apoptosis in newborn anesthesia as an alternate regional anesthetic technique. Here,
rodents that received spinal anesthesia on postnatal day 3, the infant is curled in the lateral decubitus position, the cau-
7, 14, and 21 [44], including on day 3 at the peak of rapid dal space is prepared aseptically and a short epidural catheter
synaptogenesis in the dorsal horn of the spinal cord [45, 46]. (18 or 20 gauge) is introduced through an intravenous cath-
Although a certain degree of local anesthetics toxicity might eter or epidural needle. The catheter is fixed in place with
exist in the neonatal period, data from in vitro and animal sterile dressing to use throughout the surgery. Initially, lido-
studies are so far rather reassuring. caine 1.5% with epinephrine (diluted to 0.75–1% with ster-
Complications from spinal anesthesia as documented from ile saline) was administered in a dose of 7 mg/kg lidocaine
several large studies are rare [47–50]. In neonates, the rate of for the procedure without supplemental sedation. However,
complications may be as low as 0.29% [45]. The theoretical as repeated doses of lidocaine could not be administered,
risk of septic or aseptic meningitis is very small and has only some have turned to 3% 2-Chloroprocaine in 10–30 mg/kg
been reported in two children. In both instances, the role of boluses through the epidural catheter: this may be admin-
dural puncture remained uncertain [50, 51]. A high block- istered until the desired height of the block is achieved fol-
lowed by 15–30 mg/kg/h.(see Chap. 16) [61] Some have potential to trigger epileptiform EEG activity [63], which
diluted the 3% 2-Chloroprocaine to 1.5% to increase the vol- might be observed during deep anesthesia, preceding the
ume spread of the epidural solution [62]. Since the action of appearance of burst suppression. Epileptiform EEG activity
chloroprocaine is terminated by pseudocholinesterase, there occurs more frequently in the presence of both large concen-
is no fear of accumulating doses of chloroprocaine that could trations of sevoflurane and hyperventilation [64, 65]. Major
lead to an overdose or toxic sequelae. Oral sucrose via the epileptoid signs were reported in 50% of children anesthe-
pacifier and music may be added to soothe the child during tized with 1.5 MAC of sevoflurane in one study [66].
the surgery. This technique has a high success rate, provides Evidence has shown that opioids and nitrous oxide decrease
excellent quality of anesthesia, and avoids any limit on the the incidence of epileptiform EEG activity [66]. However,
duration of surgery. epileptiform EEG patterns only weakly portend seizures. To
date, there has been a dearth of EEG studies in neonates with
only a single case of tonic clonic activity reported [67]. Since
Induction of General Anesthesia for Elective that single report, no further cases or reports of seizures in
Surgery neonates and infants have been reported, nor have any restric-
tions been placed on the concentration of sevoflurane that
In the past, anesthesiologists faced hemodynamic and respi- may be administered to neonates and infants.
ratory consequences of anesthetic agents in children. Tracheal intubation can be performed with sevoflurane
Halothane, in particular, caused myocardial depression, bra- alone in most infants and children undergoing elective sur-
dycardia, and arrhythmias. gery [68]. The main factor associated with success is to pro-
Hypnotics, opioids, and muscle relaxants in excessive vide sufficient time from the beginning of the inhalational
dose could produce severe hypotension, tachycardia, brady- induction until an adequate depth of anesthesia has been
cardia, dysrhythmia, chest rigidity, or respiratory depression. achieved, one that often occurs after loss of spontaneous
These could lead to fatal hemodynamic consequences or ventilation [69]. Both positive end-expiratory pressure (10
respiratory failure. To lessen the risk of such adverse events cmH2O) and assisted ventilation speed the onset of a deep
in neonates, practitioners administered the smallest possible level of anesthesia [70]. Alternately, the time to tracheal intu-
doses of these drugs and limit the number of different drugs bation may be abbreviated by supplementing the inhalational
administered. In addition, many older drugs had prolonged induction with IV drugs such as propofol, opioids, and/or
durations of action or diverse dose-dependent side effects muscle relaxants [71]. These strategies have been studied
that prompted a polypharmacy approach to minimize these in children and may be extended to neonates, although evi-
effects. dence in neonates remains lacking. In neonates, the time
With the introduction of receptor-specific and better- to induce anesthesia is rapid; however, with an MAC of
tolerated anesthetics, induction of general anesthesia for 3.2% sevoflurane, the maximum MAC multiple that can be
elective surgery even in neonate is infrequently a problem. achieved within the first minute or two of anesthesia is only
As cardiopulmonary morbidity has substantively decreased, 1.2 (unlike halothane, which can achieve an MAC multiple
latent fears have emerged about potential deleterious effects of 2.5 within the same time) (see Chap. 3). Hence, to speed
of anesthetics on neurologic development. Currently, these the induction of deep anesthesia, an IV dose of 1–2 mg/kg
latter fears should not deter the clinician from administering propofol may be administered [70, 71].
appropriate anesthesia care.
Use of Opioid Drugs to Facilitate Anesthesia
Inhalational Induction Induction
An inhalational induction is a suitable technique to induce The analgesic properties and adverse events of all opioids are
anesthesia in the neonate undergoing elective surgery. In this dose dependent. But each opioid differs in its potency, onset
age group, induction is rapid, smooth, technically easy to of action, and duration of action.
perform, and pain free. One of its main advantages is that it Fentanyl (1–5 μg/kg) is one of the most frequently used
does not require that IV access be established while the analgesics for tracheal intubation in the NICU [72, 73]. This
infant is awake, a procedure that can be particularly difficult, synthetic opioid has an analgesic potency 50–100 times that
prolonged, painful, and stressful for the struggling infant as of morphine. It is quite lipid soluble and highly bound to
well as for the anesthesiologist. Sevoflurane is the inhala- plasma proteins. Its onset of clinical activity is approximately
tional agent of choice for induction of anesthesia in infants. 1 min, with a duration of effect after a single IV dose of
Unlike halothane, sevoflurane has an excellent cardiovascu- 30–45 min. Fentanyl’s large hepatic extraction ratio implies
lar profile, high concentrations of sevoflurane can be admin- that its termination of the action depends on both liver blood
istered without leading to excessive circulatory depression. flow and CYP450 3A4/7 activity [74]. When hepatic blood
However, theoretical concerns have been raised regarding its flow is attenuated, as in several neonatal abdominal patholo-
gies with increased intra-abdominal pressure, the elimina- tanil is metabolized by nonspecific plasma and tissue ester-
tion rate may be dramatically reduced (approaching zero), ases, with activities at birth similar to those in adults. Thus,
with a correspondingly longer half-life [75, 76]. the elimination of remifentanil is rapid and independent of
Fentanyl should be injected slowly IV, since it is asso- hepatic and renal functions. The elimination half-life is very
ciated with thoracic rigidity when injected rapidly. It pro- brief irrespective of the dose; its context-sensitive half-life is
vides excellent conditions for rapid intubation and with also independent of the age of the child, dose, and duration
few hemodynamic adverse events when it is combined with of infusion, approximately 3–5 min. Side effects associated
atropine and a neuromuscular blockade [77–79]. Whether with bolus doses of IV remifentanil, like other opioids, may
administered in bolus doses or as a continuous infusion, fen- be problematic: bradycardia, chest wall rigidity, respiratory
tanyl maintains excellent hemodynamic stability [80]. depression, nausea and vomiting, and hyperalgesia may
Sufentanil is a synthetic opioid that is ten times more occur [77, 90, 91]. Remifentanil is 26–65-fold more potent
potent than fentanyl. It is highly lipid soluble and strongly than fentanyl, primarily binding to μ opioid receptors and
bound to alpha-1-acid glycoprotein. In the neonate, the elim- secondarily to κ and σ receptors. There is no defined dosing
ination half-life of sufentanil is increased. This is attribut- in neonates. IV doses range from 1 to 5 mcg/kg for boluses
able to an increased volume of distribution and diminished and from 0.025 to 5 mcg/kg/min for infusions, depending on
clearance [81, 82]. It has an excellent hemodynamic toler- concurrent medications [91]. In neonates, a single bolus of
ance, even at large doses [83]. Sufentanil can attenuate the 3 mcg/kg IV remifentanil for nonurgent intubation yielded
cardiovascular response to intubation. Studies performed less favorable intubating conditions than a combination of
on a neonatal population are lacking, but some data on chil- fentanyl and succinylcholine [92]. Remifentanil boluses
dren 2–9 years of age, 0.3 μg/kg sufentanil combined with have also been evaluated as adjuvants to propofol during
2.5 mg/kg of propofol, and vecuronium, effectively blunted intravenous induction of anesthesia in infants and children
the cardiovascular responses to tracheal intubation [84]. [93]. Although neonates have not been studied as a group
The ED50 for sufentanil for excellent intubating conditions distinct from infants, the ED50 and ED95 for remifentanil
decreased as the expired fraction of sevoflurane increased in after propofol 5 mg/kg in neonates and infants <3 months
children [85]. For example, at 3% of sevoflurane, the ED50 of age to provide excellent intubating conditions were 3.1
was 0.32 mcg/kg sufentanil. However, considering the sig- and 5.0 mcg/kg [94]. A continuous infusion of remifentanil
nificant pharmacokinetic changes that occur during the first has also been recommended to complement sevoflurane dur-
month of life, the extrapolation of these results to neonates ing induction of anesthesia although studies in neonates are
should be viewed cautiously. lacking. The principle of providing opioid analgesia before
Although fentanyl and sufentanil remain the most fre- intubation seems reasonable, but the risk-benefit ratio in neo-
quent opioids administered to neonates before laryngoscopy nates is unknown. Nonetheless, it is important to administer
and tracheal intubation, even shorter-acting opioids such as sufficient doses of hypnotics, like sevoflurane or propofol, to
alfentanil and remifentanil have been evaluated. attenuate the nociceptive and reflex responses to laryngos-
Alfentanil is a synthetic opioid, derived from fentanyl. copy at a cortical and even subcortical level.
It is 5–10 times less potent than fentanyl and has a shorter
onset and duration of action, mainly because of its reduced Intravenous Induction
volume of distribution. Alfentanil is strongly bound to albu- An intravenous induction of anesthesia is a common induc-
min but also to the plasma alpha-1 acid glycoprotein, a mol- tion technique in neonates globally, since most neonatal sur-
ecule present at reduced concentrations in the plasma of gery occurs in the peripartum period, is associated with a full
neonates compared with older children or adults [86]. Thus, stomach, and requires an RSI. These neonates arrive in the
like sufentanil, its free fraction is increased. The metabolism operating room from the NICU with an IV (or PICC line) in
of alfentanil is mainly via hepatic enzymes, using metabolic place. Thiopental (where it is available) or propofol is com-
pathways that are still immature at birth. In neonates, the monly used for induction of anesthesia.
elimination half-life is tenfold greater than in infants and Tracheal intubation can be performed effectively after
children [87], attributable primarily to its decreased clear- IV propofol alone, but cannot be after thiopental or other
ance [88]. In neonates, a bolus of 9–15 mcg/kg of alfent- IV hypnotic agents [95]. This property of propofol may be
anil facilitates tracheal intubation and decreases the stress attributed to its ability to profoundly depress the laryngeal
response to that procedure. However, alfentanil may induce reflexes and relax the oropharyngeal muscles [96]. When
a greater incidence of muscle rigidity compared to other compared with a combination of morphine, atropine, and
opioids [89]; this adverse effect together with its prolonged succinylcholine, propofol 2.5 mg/kg led to a more rapid,
elimination half-life limits the use of alfentanil in neonates. successful intubation, less desaturation episodes, and a more
Remifentanil is the most recent synthetic opioid to become rapid recovery time in 63 premature neonates undergoing
commercially available. In contrast to other opioids, remifen- nonurgent procedures [97]. However, it should be noted that
most anesthesiologists would use a larger dose of propofol if unnecessary to achieve a quick and stress-free tracheal intu-
it were the only induction agent. The times to intubation were bation, as most opt for hypnotics and opioids instead [102].
120 versus 260 s for propofol versus the three drug regimen, The latter drugs suppress consciousness, blunt the hemody-
times that far exceed those acceptable to anesthesiologists, namic response to intubation, and, in sufficient doses, pre-
and all neonates were intubated nasally. Finally, the intuba- vent movement. However, to limit hypotension after an
tions were performed by trainees, not attending faculty, again intravenous induction, particularly in neonates from the
raising doubts about the external validity of the data. Similar NICU, a bolus of balanced salt solution (10 mL/kg) should
criticisms hold true for much of the evidence emerging from be given before induction of anesthesia. It should also be
the neonatology literature [98]. When inducing anesthe- noted that despite preoxygenation (see strategies below),
sia with propofol, the clinician should gently hold the limb neonates and in particular small neonates (<2 kg) may pres-
where the IV is located, in order to prevent brisk withdrawal ent challenges to ventilate and oxygenate by facemask
movements that might result in loss of the line before all the should tracheal intubation prove to be challenging. In such
drugs are injected. The IV site should also be visible at least cases, paralysis with succinylcholine or a nondepolarizing
until all the drugs have been infused. Accidental disconnec- muscle relaxant may facilitate ventilation while alternate
tions can lead to underdosage and airway or hemodynamic intubation strategies are prepared. Succinylcholine is seldom
reactivity during laryngoscopy. The injection may be done used in pediatric anesthesia any longer, not because it causes
slowly, titrating the optimal dose of hypnotic drugs to the anaphylaxis (a rare complication), but primarily because it
clinical state of the neonate. Pain during injection of propo- caused hyperkalemia in children with undiagnosed myopa-
fol is an issue in neonates, even if local anesthetics are added thies or neurological disorders (eg., undiagnosed Wernig
to the propofol. However, it may be attenuated by the prior Hoffman) that was misdiagnosed as malignant hyperthermia
injection of an opioid (see Anesthetics for RSI, below). and treated with dantrolene in several cases [103, 104].
Dexmedetomidine is an IV sedative agent that has inter- Correct treatment with intravenous calcium chloride or glu-
esting potential in neonatal anesthesia. This α2-adrenoceptor conate was delayed or omitted, which led to adverse out-
agonist has sedative, anxiolytic, sympatholytic, and comes and a proscription of succinylcholine use in children.
analgesic-sparing effects, associated with minimal depres- With succinylcholine proscribed, the NDMAs became the
sion of respiratory function. Dexmedetomidine is increas- standard in pediatric anesthesia with the benylisoquinolones
ingly used off-label in infants and children with cardiac and steroidal compounds (e.g., rocuronium) the most com-
diseases, in anesthesia and intensive care [99]. Its phar- monly used. Reports of anaphylaxis to relaxants highlighted
macokinetic and pharmacodynamic profile is still under succinylcholine, benzylisoquinolones (atracurium, mivacu-
investigation (see Chap. 3). Dexmedetomidine and general rium) and rocuronium as the primary putative agents [105].
anesthesia have been compared in preterm and full-term Interestingly, the frequency of anaphylaxis to rocuronium in
infants <3 months of age for the perioperative outcomes children in Europe far exceeded that reported in North
after open inguinal hernia [100]. Both groups received a cau- America. Some suggested that anaphylaxis after the first
dal block during surgery. Dexmedetomidine was given as a exposure to rocuronium was due to cross-reactivity with epi-
loading dose, 2 μg/kg over 10 min, followed by a variable topes (e.g., pholcodine) in specific products used in Europe
infusion between 0.2 and 1 μg/kg/h as needed. Perioperative [106]. As the use of these epitopes waned, so too has anaphy-
outcomes were similar the infants who received dexmedeto- laxis to rocuronium. In instances where the neonate has been
midine had lower heart rates and higher mean arterial blood paralyzed with ≥1 mg/kg rocuronium and in whom tracheal
pressures. Fewer infants who received dexmedetomidine intubation failed and ventilation proved difficult, reversal
required tracheal intubation and NICU admission than gen- with 16 mg/kg immediately after rocuronium can restore
eral anesthesia. Dexmedetomidine has also been used as a spontaneous ventilation in this life-saving situation [107,
postoperative adjunct to opioids after surgery in neonates in 108]. Anaphylaxis to sugammadex has also been reported,
the NICU [101]. An infusion of 0.36 μg/kg/h significantly although such events are rare in neonates and infants [109].
reduced the use of opioids postoperatively in neonates after In general, anaphylactoid and allergic reactions as well as
surgery, a benefit that was associated with a two-fold greater anaphylaxis are extraordinarily rare in neonates [110, 111].
frequency of self-bradycardia compared to the opioid-alone Many jurisdictions have recommended that succinyl-
group. choline only be used for rapid sequence inductions and in
emergencies (e.g., laryngospasm) because of its potential
Other Issues During Anesthetic Induction side effects. For the remainder of circumstances, a nonde-
polarizing agent can be used. In part, the proscription of
Muscle Relaxants for Tracheal Intubation succinylcholine can be traced back to some individuals mis-
All NMBDs improve the conditions for tracheal intubation diagnosing hyperkalemia after succinylcholine for malig-
in neonates. However, for elective surgery, NMBDs are often nant hyperthermia and failing to resuscitate the child with
calcium in a timely manner. In its stead, dantrolene was docholinesterase level in the first month of life and then a
given. This delayed the appropriate treatment and resulted slower increase toward adult values [120]. In a neonatal case
in unfavorable outcomes. Nonetheless, many younger anes- report of prolonged neuromuscular blockade after an injec-
thesiologists are unaware of the history behind the pro- tion of 0.2 mg/kg of mivacurium, plasma levels of cholin-
scription of succinylcholine and have been trained to avoid esterases were conclusive, and the diagnosis could only be
succinylcholine except in emergent situations. This is most confirmed by molecular investigation [121].
unfortunate as succinylcholine will be used in emergencies Cisatracurium is one of the ten stereoisomers that com-
without appreciating the need for pretreatment with atropine prise the muscle relaxant, atracurium [119]. Cisatracurium
to avoid bradycardia/asystole or the fact that the dose in neo- is associated with less histamine release than atracurium.
nates and infants is 2 mg/kg IV, twice that in adults. A dose of 0.15 mg/kg provides excellent intubation condi-
In an effort to understand the role of sugammadex to tions after 120 s in infants anesthetized with nitrous oxide-
reverse rocuronium, investigators analyzed the economics thiopental-fentanyl anesthesia [119]. In the same study, the
and quality of care of high-dose sugammadex to reverse onset time was more rapid and the recovery time greater in
high-dose rocuronium for RSI. They noted that compared younger patients.
with placebo, infants are more sensitive to NMBDs than
older children: fewer than 50% of the receptors have to be Nitrous Oxide
occupied to achieve intubating conditions in young infants In children, odorless N2O speeds induction of anesthesia
compared with 90% of the receptors in adults [112]. Hence, with sevoflurane, without substantive respiratory or hemody-
neonates require smaller doses of nondepolarizing relaxants namic adverse effects [122]. However, nitrous oxide may not
to achieve a targeted effect, but the duration of paralysis be ideal for anesthesia in the neonate for the several reasons.
will be markedly prolonged compared with that in children First, many surgeries in neonates are emergencies that
and adults [113]. Increasing the amount of injected NMBD involve bowel obstruction or a risk of bowel distention,
speeds the time to peak effect, dramatically prolongs the hence N2O is often relatively contraindicated. Second, loss
duration of action of the NMBD [114]. of the neonatal airway during induction of anesthesia with
The advantage of rocuronium is its rapid onset of action: N2O speeds the rate of desaturation as the ratio of oxygen
0.6 mg/kg induced good intubation conditions in 60 s in consumption to pulmonary oxygen reserve would be very
older children anesthetized with propofol [115]. However, large. Third, N2O has been shown to stimulate opioid and
the duration of action of rocuronium in neonates is prolonged adrenergic centers that activate descending inhibitory neu-
and unpredictable [116]. In contrast, the onset times to pro- rons (DINS) in adults. These DINS transmit from supraspi-
found neuromuscular block with mivacurium and atracurium nal centers in the brain to the posterior horn of the spinal
(2–3 min) are greater than those for other muscle relaxants cord. When activated, DINS provide potent antinociception.
but their duration of action is brief. Mivacurium 200 μg/kg In the neonate, DINS are poorly developed and immature
IV provides good intubating conditions after 90 s in children [123], thus limiting the analgesic effects of N2O [124].
[117]. The addition of fentanyl decreased the number of Fourth, N2O potentiates the neurotoxicity of other anesthetic
attempts and also the frequency of desaturation during tra- agents on the developing brain in neonatal animals [125],
cheal intubation in premature and full-term neonates [79, although there is no evidence that N2O is neurotoxic in
118]. Intubating conditions were scored as excellent with humans. Fifth, when administered concomitantly with pro-
muscle relaxation occurring within 94 s although the time pofol or sevoflurane, N2O decreases the regional oxygen
to return of spontaneous movements was 15 min. However, extraction fraction and creates a possible imbalance in the
a hypnotic drug was not included in this regimen. To date, cerebral metabolic rate [126].
the intubating conditions after mivacurium-fentanyl have In conclusion, the combination of propofol, opiates, or
not been compared to a hypnotic-fentanyl combination in muscle relaxants to an inhalational induction provides bet-
neonates. ter conditions for tracheal intubation and permits the use of
Mivacurium is degraded spontaneously by pseudocholin- smaller concentrations of sevoflurane, although the optimal
esterase, leaving no active metabolites. Similarly, atracurium doses of these compounds have not yet been determined in
is degraded spontaneously but by Hoffman degradation, neonates.
a process that depends on pH and temperature [119]. In
patients with plasma pseudocholinesterase deficiency (esti- Tracheal Intubation: Oral or Nasal Route?
mated frequency 1:2000), mivacurium may cause prolonged The decision to intubate the trachea in the neonate orally or
neuromuscular blockade. In neonates, the activity of these nasally is often an institutional or clinician’s preference,
esterases is less than in older patients, approximately 50% of based on local practice and experience.
the adult normal rate. The maturation profile of this enzyme Oral tracheal intubation is quicker [127] and easier to
remains unclear: there may be a rapid increase in the pseu- perform than nasal intubation, thereby reducing the period
of apnea and the time interval during which the airway is [133–136]. Breast milk may be up to 4 h before anesthesia,
unprotected. A Cochrane review of nasal versus oral tracheal and artificial milk (e.g., cow’s milk) up to 6 h before anesthe-
intubation in neonates in the neonatal intensive care unit sia [135–137]. A recent consensus statement on clear fluid
yielded only two studies, precluding any definitive recom- fasting for elective pediatric general anesthesia (not includ-
mendations [128]. Nonetheless, the hemodynamic responses ing neonates) reduced the fasting interval after clears from
were similar when hypnosis and analgesia were provided, 2 to 1 h before surgery, although this has been challenged
failed intubation occurred more frequently after nasal com- [138–140]. If it is necessary to start surgery before the stom-
pared with oral intubations, and atelectasis occurred more ach is predicted to be empty, an RSI should be performed.
frequently after nasal intubations [130]. The only metric that may yield insight into the time interval
Mobility of orotracheal tubes during head movement may for gastric emptying after an injury or trauma in a child is
be greater than that of nasotracheal tubes, although Cochrane the time interval between last food ingested and the trauma
review of two trials reported that the incidence of complica- or insult [141]. These data have little impact on the clinical
tions, including accidental extubation, was similar with nasal scenarios that present in neonatal surgery.
and oral intubations [130]. Published studies in neonates and Some conditions associated with functional or mechanical
preterm infants (560–2000 g) with orotracheal tubes demon- ileus in the neonatal period require an RSI, independent of
strated that 55° flexion of the neck yielded less movement the fasting interval. These include disorders of the digestive
of the tip of the tube than 55° extension of the neck (3.1 tract: atresia, obstruction, volvulus or perforation, necrotiz-
versus 7.4 mm) [119–131]. In 15 neonates and infants, aged ing enterocolitis, omphalocele, gastroschisis, and congenital
14 days to 15 months, extension of the neck displaced the diaphragmatic hernia. In the first month of life, infants with
tip of the orotracheal tube 6.5 mm in the cephalad direction, gastroesophageal reflux, untreated or persistent, may also be
almost twice the 3.5 mm displacement of the nasotracheal candidates for RSI. Pyloric stenosis, which usually occurs
tube [132]. Thus, movement of the tip of the tube in the tra- at the end of the first month of postnatal life, is certainly a
chea is greater with orotracheal intubation. Given the short condition with “full stomach.” It would be extraordinary that
length of the trachea in neonates (4–4.5 cm), extension of the a neonate with a full stomach does not present with intra-
neck in a neonate with an orotracheal tube could lead to an venous access already established. Nonetheless, inhalational
unexpected extubation. inductions have been performed in some centers for infants
In conclusion, the use of oro- and nasotracheal tubes in with full stomachs without substantial consequences! [142]
neonates appears to have advantages and disadvantages.
Nasotracheal intubation tends to be more difficult and takes Preoxygenation
more time, thereby increasing the risk of desaturation, Preoxygenation is an essential component of an RSI. The
although it is more secure, and the trachea is less likely to aim of preoxygenation is to maximize oxygen reserves to
be extubated than orotracheal intubation. In contrast, orotra- preclude significant desaturation during the apneic period
cheal intubation is easier, faster, but may facilitate more acci- when anesthesia is induced, and the trachea is intubated. The
dental extubations. Carefully taped tracheal tubes minimize frequency of desaturation during uncomplicated tracheal
excessive tube displacement, although nasotracheal tubes intubation in neonates is 42% and increases to 75% in diffi-
are associated with less displacement. The final decision to cult intubations [143]. This subject has been poorly investi-
employ oral or nasotracheal intubation depends on the clini- gated in neonates. Nonetheless, some pediatric studies have
cian’s experience, the size of the infant, the context of sur- included infants less than 1 year of age and it is their data that
gery, and the postoperative destination of the infant. we can extrapolate to predict the effects preoxygenation on
desaturation during intubation in neonates.
The younger the age of the infant, the more rapidly they
apid Sequence Induction for General
R desaturate occurs once the facemask has been removed. In
Anesthesia healthy infants whose lungs were ventilated manually, the
saturation decreased from 100 to 95% in approximately 90 s
RSI is indicated for every child who has a full stomach to after the onset of apnea and then from 95 to 90% in <10 s
minimize the risk of regurgitation of gastric contents and [144, 145]. In infants, 15 months of age, the time to desat-
possibly pulmonary aspiration. To minimize these risks, uration to <95% after 2 min of preoxygenation was 110 s.
induction of anesthesia may be delayed in the case of nonur- Desaturation to <90% occurred as briefly as 8 s later [146].
gent procedures, although in cases that are more urgent, the An end-tidal oxygen fraction of 0.9 should be used as the
anesthetic should proceed with an RSI. target end-point for preoxygenation in infants 0–6 months of
Current fasting rules were developed based on the best age to ensure denitrogenation 36 ± 11.4 s or ~60 s to become
estimate times for gastric emptying. Clear fluids may be fully preoxygenated [147]. Despite preoxygenation with
ingested up to 2 h before anesthesia/surgery in neonates a tightly applied facemask, we should anticipate desatura-
tion to occur after a short interval of apnea if a supplemental nates at risk for pulmonary aspiration, although cricoid pres-
source of oxygen is not provided.(see below) sure is now infrequently applied [150, 164].
Gastric Emptying Mask Ventilation

Passing an oro- or nasogastric tube before an RSI is neither Although mask ventilation with oxygen is not usually rec-
required nor is it effective in completely emptying the stom- ommended during an RSI in order to avoid gastric insuffla-
ach. However, a gastric tube may be useful in the presence of tion and regurgitation, it must be performed if severe
preoperative ileus or intestinal obstruction. Since neonates hemoglobin desaturation occurs before the trachea is intu-
are exclusively fed liquids, a gastric tube may significantly bated. Neonates should never be allowed to become hypoxic
reduce the volume of the gastric fluid contents, although pul- out of concern that mask ventilation might theoretically
monary aspiration may still occur. inflate the stomach and trigger regurgitation and pulmonary
If a gastric tube is in place, it is not necessary to remove aspiration. The frequency of pulmonary aspiration during
it before induction [148]. Its presence does not reduce the and after an RSI in infants and children is exceedingly rare,
effectiveness of cricoid pressure [149]. The anesthesiologist whereas the incidence of hypoxemia and their harmful
may, however, prefer to remove the gastric tube to ensure sequelae are much more frequent. Without adequate preoxy-
clear visualization of the larynx. genation, severe desaturation can occur in the healthy neo-
nate within 10 s of apnea. This is often too brief an interval
Cricoid Pressure to complete induction of anesthesia, neuromuscular block-
Cricoid pressure has been an integral component of RSI in ade, and tracheal intubation. Hence, many advocate ventilat-
all patients at risk for pulmonary aspiration who require gen- ing the lungs manually after induction of anesthesia during
eral anesthesia although its role and efficacy have been chal- RSI in neonates, limiting the peak airway pressures to
lenged lately, particularly in children [150]. However, cricoid <10 cmH2O to avoid desaturation without inflating the stom-
pressure has caused several clinical problems when exces- ach [165–168].
sive pressure was applied and incorrect location and inap- High-flow nasal oxygen therapy, which extends the safe
propriate timing [151, 152]. Cricoid pressure must be applied apnea time of adults undergoing upper airway surgery and
precisely if it is to be effective and atraumatic. However, sev- during tracheal intubation, is currently being studied in neo-
eral studies have demonstrated that cricoid pressure is not nates and infants. This technique, which might be very rel-
applied directly to the cricoid ring, is applied with inade- evant in neonate to decrease incidence of hypoxemia during
quate force to occlude the esophagus, and that the esophagus tracheal intubation, is currently under investigation [169].
and vertebral bodies are not flat and perfectly aligned [153– Blended oxygen/air flow rates of 70–80 L/min have been
156]. Although the recommended force to occlude the lumen used in adults, which, when scaled down for size in neonates,
of the esophagus in adults is 30–44 N [157], bronchoscopic correspond to 9 L/min flow. These flows not only extended
examination of the cricoid ring in neonates demonstrated the duration of apnea without desaturation in adults, but
that a force as little as 5 N force can reduce the lumen of the also attenuated or prevented the increase in carbon diox-
cricoid ring by 50% [158]. ide during the apnea period. With the ability to maintain
Even if cricoid pressure were correctly applied and com- saturation as well as ventilation, the technique was termed
pletely occluded the lumen of the esophagus, there is no evi- THRIVE or transnasal humidified rapid insufflation ventila-
dence that RSI prevents gastric fluid aspiration [159, 160]. In tory exchange. However, when applied to young children,
one study of 63,180 pediatric general anesthetics, the authors THRIVE has only maintained their oxygen saturations, it did
reported 24 instances of aspiration despite the application of not clear carbon dioxide from the lungs. The ongoing SHINE
cricoid pressure during induction of anesthesia [161]. Most trial should shed further evidence on the utility of this tech-
recognize that cricoid pressure also impairs the view of the nique in neonates when the results are published [169].
glottis during laryngoscopy [149, 160, 162, 163]. This is of
particular relevance in neonates and infants in whom the nesthetic Agents for RSI
A
adult hand that applies the pressure can limit the extent of the The RSI classically associates adequate preoxygenation and
mouth opening, rendering laryngoscopy and intubation dif- the administration of a hypnotic and a neuromuscular-
ficult. In addition, a relatively small force applied to the neck blocking agent in predetermined doses in rapid sequence
might cause subglottic obstruction with difficulty passing intravenously. The objective is to minimize the interval
the tracheal tube [158]. If tracheal intubation is impeded for between the loss of upper airway protective reflexes and tra-
any of the above reasons, cricoid pressure must be released cheal intubation, when the risk of pulmonary aspiration is
immediately to facilitate a rapid tracheal intubation, which greatest.
remains the top priority for an RSI. On balance, clinicians Intravenous hypnotics such as thiopental (3–5 mg/kg)
continue to implement all aspects of a modified RSI in neo- (where available) or propofol (2–3 mg/kg) can be used for an
RSI, although the induction dose of propofol in neonates has For RSI, ketamine has not been embraced for induction,
not been determined. The ED50 for thiopental in neonates (to because it may increase systemic blood pressure and cerebral
tolerate a facemask for 30 s) is 3.4 ± 0.2 mg/kg [170]. blood flow in premature infants. However, in the case of neo-
In neonates, thiopental allows a quick and smooth induc- nates who are full-term and hemodynamically unstable, IV
tion of anesthesia and preserves hemodynamic stability ketamine is a suitable choice.
[171] In the first postnatal month, the dose requirement for Succinylcholine (2 mg/kg) is the muscle relaxant of choice
thiopental is 45% less than in older infants 1–6 months of for RSI because of its rapid onset and brief duration of action
age, probably attributable to the reduced protein binding, [184]. The younger the child, the briefer the duration of the
more permeable blood-brain barrier, and increased brain paralysis after succinylcholine [185]. All muscle relax-
sensitivity to thiopental [170]. However, the elimination ants, especially succinylcholine [173, 186], greatly improve
half-life of thiopental in neonates exceeds 14 h, 2.5-fold the conditions for tracheal intubation [78]. However, life-
greater than midazolam [172]. Hence, continuous infusions threatening side effects have caused many to fear the use of
of thiopental are eschewed. When administered with succi- succinylcholine in young children [77]. Bradycardia may
nylcholine, thiopental increases the success rate and shortens occur after a single dose of IV succinylcholine in infants,
the time interval to tracheal intubation [173]. Propofol has a but is obviated by pretreatment with 0.02 mg/kg IV atropine.
similar onset time to that of thiopental, but a much briefer More ominously, acute hyperkalemia and rhabdomyolysis
duration of action, which is an advantage in RSI. Propofol may occur after succinylcholine when it is administered to
is also more effective than thiopental in limiting the hyper- a neonate with an undiagnosed myopathy, such as Werdnig–
tensive response to laryngoscopy in children 1–6 months and Hoffman disease or muscular dystrophy. Although these
to reduce the delay before extubation although comparable diseases are rare, if electrocardiographic evidence of hyper-
data in neonates has not been forthcoming [174]. Propofol kalemia occurs after succinylcholine, IV calcium chloride
confers two additional advantages over thiopental: it attenu- (10 mg/kg), not dantrolene, should be administered intra-
ates airway reactivity and decreases the muscular tension of venously. Malignant hyperthermia (MH) is an exceedingly
the jaw muscles. When associated with succinylcholine in uncommon disease in neonates and does not present at induc-
healthy children 0–3 months undergoing pyloromyotomy, tion of anesthesia with ventricular arrhythmias, although
propofol caused only a moderate decease in blood pressure succinylcholine should be avoided where a family history of
[175]. Propofol may exaggerate right-to-left shunting in the MH is catalogued.
immediate neonatal period (via a patent foramen ovale, duc- Rocuronium has emerged as the intermediate muscle
tus arteriosus), because it reduces systemic vascular resis- relaxant of choice in infants and children when succinyl-
tance more than pulmonary resistance [176]. When used in choline is contraindicated or eschewed. Although doses as
preterm neonates (30 weeks gestational age, <8 h postna- large as 0.9 mg/kg IV provide excellent conditions for tra-
tal age) in a dose of 1 mg/kg IV bolus, propofol decreased cheal intubation in less than 1 min, the age of the children
the mean arterial blood pressure by 33%, from 38 (29–42) in that study exceeded 1 year [187]. In contrast to succinyl-
mmHg to 24 (22–40) mmHg [177]. This decrease in sys- choline, the duration of action of rocuronium increases with
temic blood pressure is similar to that associated with one greater doses and younger age patients. The optimal dose of
MAC inhalational anesthetics in neonates [178, 179]. rocuronium for RSI in neonates has not been determined.
Administration of 10–20 mL/kg boluses of balanced salt Published studies indicate fairly rapid onset times with 0.45
solution before administration of propofol (and inhalational and 0.6 mg/kg IV rocuronium, although these doses were
anesthetics) may attenuate these hemodynamic effects. In studied in the presence of inhalational anesthetics [116]. The
neonates and infants, propofol allows fast intubation and downside to using large doses of rocuronium in neonates
reduces anesthesia induction time compared with sevoflu- is the prolonged time to recover: 62 and 95 min, respec-
rane [180]. Pain during IV injection of propofol into a small tively [77, 116]. If the surgery is expected to be brief, as in
vein, for example, in the hand, is common in neonates, lead- a pyloric stenosis, then the use of large doses of rocuronium
ing to a brisk withdrawal of the extremity. This may lead to will markedly delay emergence and extubation. The pro-
accidental disconnection or loss of the line, at a critical stage longed duration of action of rocuronium must be considered
of induction. Several strategies have been shown to be effec- when choosing both the neuromuscular-blocking agent and
tive to attenuate the pain during injection including adminis- its dose, although the availability of sugammadex to rapidly
tration of nitrous oxide by mask and a mini-Bier block with antagonize the action of high-dose rocuronium has made this
lidocaine [181–183]. In the absence of effective preventative issue moot (see below).
treatment, the anesthesiologist should secure the limb gen- With the increasing use of propofol in neonates and dur-
tly while propofol is injected and until the neonate is deeply ing RSI, anticholinergics may continue to play a substan-
anesthetized. tive role. Propofol enhances parasympathetic activity, which
can explain the bradycardia often observed after induction [192]. First, the IV lines are particularly fragile in neo-
of anesthesia. Since cardiac output depends to a large extent nates and, as such, introduce the risk of technical problems.
on heart rate in neonates, bradycardia will compromise the Subcutaneous infiltration or accidental disconnects may
cardiac output and decrease tissue oxygenation. Atropine in occur most dangerously during maintenance of anesthesia
a dose of 20 mcg/kg IV may be used to maintain a rapid heart and under the drapes. This is particularly problematic with
rate, without a minimum dose [188]. In addition, neonates IVs sited in the antecubital fossa, which preferably should
are prone to developing hypoxemia during prolonged apneas be switched to hand or foot IVs to preclude undetected intra-
such as during RSI,; hence, a modified RSI is preferrable muscular or subcutaneous infiltration. Moreover, once the
[167, 168]. For both of these reasons, intravenous atropine is drapes cover the neonate, and surgery begins, the IV site is
an appropriate adjunct and should be integrated in the modi- often concealed from the anesthesiologist’s sight and control.
fied RSI in neonates. Most infusion pumps will alarm to an occluded line although
drip IV sets will continue to infuse interstitial fluid. All lines
should have luer lock connections to ensure continuity of
Maintenance of Anesthesia flow and protection from external pressure. There are no
simple monitoring devices that can alert the anesthesiolo-
Hypnosis gist to a disconnected intravenous catheter. As a result, the
Short-acting inhalational anesthetics are appropriate hypnot- patient might awaken, move, or display pain-related hemo-
ics for maintenance of anesthesia in neonates (See Chap. 3). dynamic disturbances while presumed to be anesthetized if
Sevoflurane offers several advantages over intravenous anes- a disconnect occurred during surgery and under the drapes.
thetics in that it is suited for an inhalational induction, is Second, the effect-site concentration of propofol during
minimally metabolized, has rapid pharmacokinetics, and is anesthesia cannot be measured, unlike the breath-by-breath
safe in infants with cardiorespiratory disease. Sevoflurane data provided by the gas analyzer for inhalational anesthet-
does potentiate neuromuscular-blocking drugs (NMBDs) ics. The pharmacokinetic profile of propofol in the first
[113], which means that smaller doses of NMBDs may be weeks of life has received little attention, but recent evidence
required to achieve comparable twitch depression. Desflurane indicates that marked interindividual variability (due to age)
is unsuited for inhalational induction, because it is irritating and a marked reduction in clearance in part attributable
to the supraglottic and glottic structures as well as causes to immature activity of phase 1 and II enzymes may hold
bronchoconstriction [189] although it has more favorable the keys to predictable infusions [193–195]. An important
pharmacokinetics primarily on the basis of its minimal solu- covariate in determining the dose of propofol is the post-
bility in blood and tissues. This latter characteristic leads to menstrual and postnatal ages. Specifically, the clearance
a more rapid return to spontaneous respiration and recovery appears to be diminished with decreasing postmenstrual and
compared with the older, more soluble anesthetics. postnatal ages (> or <10 days). Surprisingly, the induction
Desflurane is also metabolized 10-fold less than sevoflurane dose of propofol in neonates has not been reported, although
in vivo, resulting in virtually no end-organ toxicity. However, modeling suggests that reduced induction doses (1.5–2
carbon monoxide may be liberated into the breathing circuit mg/kg) may portend anesthetic concentrations when fol-
if desflurane (and isoflurane) is incubated with desiccated lowed by infusion rates that are less than those recommended
CO2 absorbent [190, 191]. The minimum fresh gas flow in older children [196, 197].
should be used with all inhalational anesthetics to limit their Third, isolate case reports of profound hypotension and
impact on the environment. near-cardiac arrest has been reported with induction doses
Many have questioned the need for inhalational anesthet- of propofol or postoperatively after a single bolus of pro-
ics for neonatal surgery given the primary goal is to deliver pofol, anesthesia [176, 198]. The pathogenesis of these
stress-free analgesia. Under these conditions, there is no isolated reports of near-cardiac arrest remains unclear,
need to introduce an inhalational anesthetic for maintenance although exacerbation of a right-to-left shunting through a
as its impact is more than likely to lead to hypotension and/or patent foramen ovale or ductus arteriosus after the propofol
bradycardia. Moreover, neonates do not have cortical recall, bolus was not ruled out. Hypotension has also complicated
so ensuring amnesia is not a primary objective of anesthesia. a dose-finding study for propofol for tracheal intubation in
In neonates, many have experienced difficulty maintaining the neonate [176]. Given this history and that most neonates
circulatory homeostasis when an opioid and inhalational are relatively dehydrated in the NICU, it may be prudent to
anesthetic are combined, whereas an opioid-based anesthetic pretreat neonates with 10 mL/kg IV balanced salt solution
confers a stress-free anesthetic and adequate postoperative before administering an IV bolus of propofol. Another rela-
analgesia in the NICU or PACU. tive propofol overdose in neonates occurred after the induc-
Maintenance of anesthesia via the intravenous route in tion dose was followed by an infusion [199]. This may be
neonates has been fraught with pitfalls for several reasons attributed to a failure to appreciate the profoundly reduced
clearance of propofol, possibly as little as 10% of the adult operative analgesics in neonates. In the past two or more
clearance in some subgroups of neonates [197]. To date, pro- decades, the attitudes of anesthesiologists and other physi-
pofol infusion syndrome reported has been reported in only cians have changed radically shifting from “no analgesia”
a single neonate, and that occurred in the original description to “as much analgesia as possible” for neonates. The dose of
of the syndrome in 1992 [200, 201]. This may be the result analgesics administered is limited only by eliminating pain
of the proscription of propofol infusions in infants based and/or the presence of side effects, most notably respiratory
on the early reports of the syndrome. A systematic review depression.
of propofol use in neonates and infants cautioned practitio- In terms of the pharmacokinetic profiles of opioids in neo-
ners to monitor for apneas as the most common sequela in nates, large interindividual variability precludes a relation-
this age group [201]. In the absence of a reliable device to ship between the opioid concentrations and the effect site.
monitor the depth of anesthesia, neonates may be under- or Compared with adults, protein binding of opioids is dimin-
overdosed with propofol, which cannot be extracted from the ished, free fractions are increased, the blood-brain barrier is
bloodstream once administered unlike inhalational anesthet- more permeable, distribution volumes are increased, clear-
ics. Given this experience, neonates who present for general ances are decreased, and elimination half-lives are greater
anesthesia should receive a fluid bolus before induction of in neonates than in older children [211]. Protein binding and
anesthesia. IV atropine and epinephrine should be immedi- hepatic metabolism undergo dramatic changes and matura-
ately available for resuscitation as needed. tion throughout the neonatal and infant periods. Alpha-1-acid
glycoprotein (AAG) is the main binding protein for fentanyl,
Analgesia sufentanil, and alfentanil [212]. Neonates and young infants
Forty years ago, neonates underwent surgery with little to no have reduced concentrations of AAG, which explains, in
analgesia. In the 1980s, several investigators defined the part, the greater free fraction and larger volumes of distribu-
capability of the human neonate to perceive pain and demon- tion of these opioids [213].
strated the importance of preventing pain (see Chap. 15). At birth, most metabolic pathways are immature, espe-
Indeed, further research uncovered that the neonate is actu- cially those involving hepatic enzymes [214]. The CYP450
ally more sensitive to painful stimuli than older subjects 3A4, which is a major hepatic enzyme of the metabolism of
[202, 203]. First, several seminal studies documented the fentanyl and sufentanil, is nonfunctional at birth (replacing
short-term consequences of pain (and the stress response) in the fetal CYP3A7 isozyme) [215], but matures rapidly dur-
the neonate in terms of changes in hemodynamics, metabo- ing the first weeks of life [214, 216]. Moreover, many of the
lism, agitation, and recovery [204, 205]. Second, subsequent P450 cytochromes are subject to genetic polymorphisms that
studies determined that painful experiences such as neonatal can modulate their activity [217]. The maturation processes,
circumcision caused long-term behavioral changes [206]. combined with the genetic variability, result in important
Some of these early painful experiences resulted in persistent interindividual differences in the responses to opioid during
alterations in pain sensitivity [207, 208]. the neonatal period.
How could a child or adult “remember” a painful neo- In neonates, fentanyl and sufentanil are the most fre-
natal experience? Pain sensitivity and behavioral changes quently used opioids during general anesthesia. Both opi-
depend on “implicit memory.” Pain-induced neurotoxicity oids provide relative hemodynamic stability [218]. When
and neuroplasticity can account for some of the symptoms. used in a single-dose before tracheal intubation, both IV
Unrelieved neonatal pain causes apoptosis in cortical and fentanyl (1–5 μg/kg) and sufentanil (0.2–0.3 μg/kg) have a
subcortical areas, associated with abnormal neurocognitive rapid onset of action and a short duration of action. In con-
development in rats [209]. Interestingly, the development of trast, the pharmacokinetics of sufentanil makes it a more
memory was also impaired in this model. Changes caused appropriate opioid for maintenance of anesthesia: if used in
by early painful experiences can also be observed in the repeated injections or by continuous infusion, fentanyl may
peripheral nervous system: neonatal skin wounds caused a accumulate in peripheral tissues (fat, muscle) as its context-
prolonged increase in the innervation of the wound site in sensitive half-life increases as the duration of the administra-
rats [208]. In a study using functional MRI, pain-specific tion increases [219]. To offset accumulation, the drug dose
cortical and subcortical hyperactivation was demonstrated in should be tapered over time. Accumulation of the fentanyl is
children 11–16 years of age, who were born preterm, and even more pronounced in neonates because of the immatu-
who had undergone painful procedures as neonates [210]. rity of metabolic pathways.
Finally, a painful stimulus may activate the amygdala even Alfentanil’s rapid onset and short duration of action are of
during general anesthesia, thereby increasing the probability interest when it is used as a single dose for brief surgical pro-
of recall, even if subconscious. cedures. In the neonate, pyloric stenosis is a good indication
Once the negative consequences of untreated pain were for this opioid. Theoretically, alfentanil can be delivered as a
strongly established, clinicians increased their use of peri- continuous infusion, but its short duration of action is no lon-
ger an advantage over fentanyl or sufentanil. Like fentanyl, But muscle relaxants fell into disfavor in the NICU when it
alfentanil accumulates in a large peripheral compartment, became apparent that paralyzing infants resulted in contrac-
with an increasing context-sensitive half-life as the infusion tures that were difficult to reverse. Furthermore, the introduc-
continues [219]. tion of newer and safer opioids and hypnotics for sedation
Also, it is metabolized by the same cytochromes as fen- replaced the need for paralysis to facilitate ventilation [224–
tanyl and sufentanil and, thus, is susceptible to the same 226]. In some instances, anesthesiologists’ fears of resid-
interindividual variability through genetic and developmen- ual neuromuscular block and/or incomplete antagonism with
tal variability. anticholinesterases led many to restrict the use of NMBDs for
Remifentanil is an ultrashort-acting opioid that is rapidly tracheal intubation. However, nondepolarizing NMBDs may
metabolized by tissues esterases (that are mature at birth) to also improve surgical conditions during surgery, although the
inactive metabolites. Remifentanil achieves its maximum indications are quite few. If NMBDs are required during criti-
end-organ effect rapidly after the infusion begins. Not sur- cal periods of surgery, bolus doses are preferred over infu-
prisingly, these characteristics lead to a context-sensitive sions. If NMBDs are administered, neuromuscular monitoring
half-life that is constant, independent of its duration of infu- should be used. Alternately, bolus doses of propofol have
sion, even in neonates and infants [220]. However, evidence proven to be very effective to “relax” the abdomen when it
suggests that the rate of recovery after remifentanil in neo- appears to be tight, or the bowels will not return easily to the
nates less than 1 week of age may be slower than in infants abdomen as the surgery concludes. Although untested, this
1 week to 3 months of age [221]. Pharmacodynamically, approach to relax the abdomen with propofol is exceedingly
remifentanil may induce bradycardia, an effect classically effective, does not delay emergence, and is ubiquitously used.
attributed to the parasympathomimetic properties of remi- If NMBDs are used, it is imperative to appreciate that the
fentanil, a direct negative chronotropic effect [222]. The doses are smaller and even these smaller doses may confer
decrease in heart rate attributable to remifentanil after 5 μg/ exaggerated effects with a less predictable duration of action.
kg was infused over 1 min, peaks at 3 and 5 min after the The release of sugammadex has changed anesthesiolo-
infusion, but was less impressive in infants ≤2 months than gists’ reticence toward using rocuronium and vecuronium
in older children, although only 8 infants ≤2 months were in neonates [112]. Sugammadex irreversibly binds both
included [223]. NMBDs and excretes them via the kidneys. Current evidence
In terms of using remifentanil during maintenance of in neonates and infants indicates that sugammadex is well
anesthesia, several issues persist. Pharmacokinetic models tolerated in neonates using similar dosing as in adults [107].
integrated in electronic devices for neonates have not been Sugammadex has not been associated with any side effects
developed. Furthermore, chest wall rigidity and postopera- except for hypersensitivity, which has not been reported in
tive hyperalgesia remain concerns after IV boluses of the neonates up to now.
opioid.
In conclusion, the choice of the optimal analgesic for
general anesthesia in the neonate depends on the type and Conclusion
duration of surgical procedure as well as the postoperative
pain that is anticipated and whether airway management is There are many controversies in neonatal anesthesia, and in
expected, that is, rapid extubation or continued ventilation. this chapter, we sought to explore several of these. In doing
Although the neurotoxicity of NMDA antagonists and so, we have outlined both the advantages and disadvantages
GABAA agonists in animal models are a cause for concern, of each approach, what is known and unknown about the evi-
until further data are available in humans (see Chap. 18), we dence, and where future studies are most needed.
do not recommend a change in practice. We strongly recom-
mend the use of potent opioids such as fentanyl or sufent-
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Airway Management
5
Annery G. Garcia-Marcinkiewicz, Paul A. Stricker,
and John E. Fiadjoe
Expertise in neonatal airway management requires an under- textbooks have emphasized the existence of obligate nasal
standing of early human anatomical development as well as breathing in neonates, as a means to facilitate and coordinate
a set of clinical skills to provide safe mask ventilation and the suck-swallow-breathing mechanism. Although neonates
tracheal intubation in this extremely small-sized population. born with congenital choanal atresia occasionally develop
Since neonatal airway experiences are not a daily occurrence life-threatening upper airway obstruction [5], healthy neo-
in most anesthesiology training programs, this skill set is nates readily convert to mouth breathing [6].
acquired only after repeated patient encounters over a span A notable anatomical feature of the neonatal airway is
of many years or decades. In this chapter, we review the the relatively cephalad position of the larynx (i.e., with the
foundations upon which management of the neonatal airway uvula in close proximity with the epiglottis) that facilitates
is based. The chapter is divided into three sections: (1) anat- the swallowing-breathing mechanism. As the infant grows,
omy and physiology of the neonatal upper airway, (2) tech- the position of the larynx moves caudally from the C2–C3
niques for standard neonatal airway management, and (3) level in the infant to the C4–C5 level by 3 years of age. This
techniques for managing the anatomically abnormal neona- increases the distance between the larynx and the mouth [7].
tal airway. The location of the tip of the epiglottis also changes from the
C2 level to the C3 level [8]. This more cephalad position of
the larynx in the neonate dictates that an optimal direct view
Upper Airway of the glottic aperture will be obtained with a straight rather
than curved laryngoscope blade [9].
Anatomy The high compliance of the neonatal chest wall (due to
incomplete ossification of the ribs and weak intercostal mus-
The unique anatomical features of the upper airway in the cles) limits the passive outward recoil that contributes to
neonate define the special considerations required to main- maintaining the functional residual capacity (FRC) in older
tain a patent airway. The occipital portion of the neonatal children. Thus, neonates can only preserve their FRC vol-
skull is relatively larger than that of older infants and chil- ume by using their laryngeal adductor muscles as expiratory
dren (neurocranium-to-face size ratio is 8:1 in neonates, “valves” to restrict exhalation and maintain positive end-
6:1 in 2-year-olds, and 4:1 in 5-year-olds [1, 2]). This ana- expiratory pressure, a process referred to as “laryngeal brak-
tomical feature results in a natural state of cervical flexion ing” [10–12].
that facilitates direct laryngoscopy in the supine child [3] but
may predispose to upper airway obstruction during sponta-
neous and mask ventilation [4]. Many neonatal and pediatric Reflexes
Supplementary Information The online version contains supplemen- Upper airway reflexes protect against the inhalation of for-
tary material available at https://doi.org/10.1007/978-3-031-25358-4_5. eign substances into the lower respiratory tract. Although
these neonatal reflexes have been studied in both the awake
and sedated states, much less is known about their state at
A. G. Garcia-Marcinkiewicz (*) · P. A. Stricker · J. E. Fiadjoe
Department of Anesthesiology and Critical Care, The Children’s deeper levels of anesthetic-induced unconsciousness.
Hospital of Pennsylvania and the Perelman School of Medicine at In children beyond early infancy, mechanisms that protect
the University of Pennsylvania, Philadelphia, PA, USA against the ingestion of foreign materials into the lower respi-
e-mail: [email protected]; [email protected];
ratory tract include swallowing and coughing [13]. Neonates
[email protected]

190 A. G. Garcia-Marcinkiewicz et al.
and young infants, however, primarily gain this protection by ful examination of the facial profile with the neonate in the
central apnea (with bradycardia), upper airway obstruction neutral position may reveal a mandible that is recessed with
[14], laryngospasm, and arousal [15]. Laryngeal chemore- respect to the maxilla.
flexes mature rapidly during early development [16]. These
adaptive responses are more prominent the more premature
the neonate [14, 17–22] and may play a role in the etiology Preoperative Preparation
of sudden infant death syndrome (SIDS) [23]. The apneic
reflex (with bradycardia) may be prolonged in the presence All equipment that may be required to manage the airway
of sedative or anesthetic agents [24–26], hypoxemia [27, 28], should be prepared before the neonate arrives in the operat-
anemia [29], and RSV infection [30, 31] ing room or before anesthesia is induced for procedures in
the neonatal intensive care unit. Induction agents and emer-
gency medications (as appropriate) should be prepared in
Airway Management unit doses to reduce drug errors should an urgent intraop-
erative situation ensue. The laryngoscope should be checked
Airway management in neonates presents challenges that are together with backup equipment before induction of anes-
unique to this age group. Neonates usually require emer- thesia. A tracheal tube (TT) of suitable size, as well as ones
gency procedures; thus, the issues that pertain to the urgent that are one-half size smaller and one half size larger, should
nature of the intervention add to the difficulties and risks. In be available. Appropriately sized oral airways for managing
this section, we address the special considerations when upper airway obstruction should be obtained. Because of
managing the neonatal airway during the perioperative its important role as a ventilation rescue device, a laryngeal
period. mask should also be immediately available. If difficulty with
facemask ventilation or tracheal intubation is anticipated,
additional equipment and personnel should be available as
Anesthesia detailed later.
Preanesthetic Assessment
Airway Management and Equipment
Assessment of the neonate in the preanesthetic period
includes a thorough review of the previous encounters in Face Mask Ventilation
managing the airway. If tracheal intubation has been per-
formed previously, the involved providers should be que- The neonate should be positioned supine to facilitate mask
ried and the medical records reviewed to clarify how the ventilation and direct laryngoscopy. The head should not be
airway was managed and the difficulties encountered. For raised off the bed, but may be supported by a circumferential
all neonates, the underlying diagnoses and conditions head ring [3]. The selected mask size and fit should be
should be reviewed with specific attention to the upper and checked before induction of anesthesia. A properly sized
lower airways, since the management may have to be tai- mask covers the nose and mouth without overlying the eyes
lored accordingly. Some conditions that lack direct airway or extending beyond the chin. After loss of consciousness,
involvement may have implications for airway manage- upper airway obstruction is relieved primarily by a chin-lift
ment. For example, the neonate with a giant omphalocele maneuver, which is easily accomplished by applying the
may rapidly desaturate during induction of anesthesia due straightened middle (or long) finger of the left-hand across
to pulmonary hypoplasia and a reduced FRC. Similarly, the bodies of the left and right sides of the mandible and
neonates with congenital diaphragmatic hernia require spe- extending the neck (Fig. 5.1). However, in anesthetized neo-
cial attention to limit the peak inspiratory pressures during nates, this maneuver closes the mouth, which may obstruct
induction of anesthesia to prevent intestinal insufflation the upper airway, a problem often incompletely relieved by
during mask ventilation and/or a pneumothorax after tra- simply extending the neck. To complicate matters, digital
cheal intubation. pressure is often inadvertently applied to the submental tri-
Physical examination of the airway should focus on the angle, which further obstructs the upper airway. An essential
presence of anatomical abnormalities that may hinder face- maneuver to establish a patent upper airway in neonates and
mask ventilation or laryngoscopy. Physical findings such young infants (in addition to what was mentioned above) is
as micrognathia should alert the anesthesiologist to pre- to sublux the temporomandibular joint, which is accom-
pare appropriate instruments to secure a difficult airway. plished by placing the operator’s fifth digit(s) in the retro-
Diagnosing micrognathia in neonates may be tricky; care- mandibular notch, at the apex of the ascending ramus of the
5 Airway Management 191
may be even more precarious as it may worsen rather than

improve the patency of the airway. Hence, it is crucial to
understand how to optimize the upper airway by manipulat-
ing the temporomandibular joint rather than by only relying
on oral airways.
In most neonates, effective facemask ventilation can be
accomplished at peak inspiratory pressures of <15 cm H2O
and rates of 20–40 breaths per minute. Maintaining positive
end-expiratory pressure during ventilation (5–10 cm H2O)
promotes alveolar patency and improves gas exchange. A
rapid ventilation rate helps to maintain the FRC by limiting
expiration. Occasionally, an alveolar recruitment maneuver
is required (see below).
Fig. 5.1 When mask ventilating a small infant, the middle finger rests aryngeal Mask Airways and Supraglottic
L
on the mandible to provide chin lift without compression of soft tissues Devices
in the submental triangle
Although tracheal intubation remains essential for safe intra-
mandible, immediately below the external auditory canal operative airway management during emergency surgery,
and behind the pinna. The condyle is lifted in an upward some practitioners prefer a supraglottic airway device for
direction, toward the frontal hairline (i.e., a full “jaw thrust”) elective surgery in neonates. However, initial studies and
[32]. This maneuver anteriorly translocates the jaw as well as clinical experience with the Classic Laryngeal Mask Airways
rotates the temporomandibular joint in anesthetized neonates (LMAs) in neonates demonstrated a greater failure rate dur-
and infants, thereby opening the mouth and pulling the ing insertion compared with larger size LMA s in older chil-
tongue off the posterior pharyngeal wall (Video 5.1). The dren [33]. This was attributed to an inappropriately designed
facemask is then held on the face using the operator’s thumbs. cuff that failed to fit the different anatomy of the neonatal
A far less effective “jaw-thrust maneuver” that is widely airway. Further clinical experience suggests that while plac-
taught involves applying digital pressure to the angle of the ing an LMA is no more difficult in this age group than older
mandible. In the latter maneuver, the mandible is translo- children, these small LMAs may be dislodged more easily.
cated anteriorly, but the temporomandibular joint does not Therefore, whenever an LMA is used, the capnogram must
rotate and the tongue continues to lie against the hypopha- be observed continuously and the anesthesiologist prepared
ryngeal wall. In contrast to Larson’s retromandibular maneu- to intervene should the capnogram decay.
ver, this only partially relieves the airway obstruction. To LMAs may offer advantages over tracheal intubation dur-
maintain a patent airway while subluxing the temporoman- ing resuscitation away from the operating room, because the
dibular joint, the long finger is placed at a crease at the base LMA is simple to insert, requires technical skills that are
of the neck and swept upward to the mentum, creating “two easily acquired, and is associated with a high success rate,
chins”. This holds the mandible subluxed and the airway pat- even in the hands of inexperienced operators [34]. Recent
ent while the fingers behind the pinna are removed. To con- studies have demonstrated that the failure rate for tracheal
firm that subluxing the mandible opens up the laryngeal intubation by resident pediatricians in the delivery room
vestibule, Video 5.2 demonstrates movement of the supra- and NICU is substantial [35–38]. Evidence to date suggests
glottic tissues when digital pressure is applied to the retro- that the LMA is effective in neonatal resuscitation in infants
mandibular notch of the ascending ramus of the mandible >34 weeks (>1500 g) and comparable to bag-mask ventila-
(Video 5.2). tion [39, 40]. Also, the LMA was comparable with tracheal
When it is not possible to obtain a patent airway by repo- intubation, although the evidence was of low quality. There
sitioning and an effective jaw thrust, the next step is often to is a lack of evidence for the LMA infants <34 weeks gesta-
insert an oropharyngeal airway. However, if an oral airway tional age. It remains to be established whether the LMA or
is used, it is most important to select the correct size of the other supraglottic airway should be used for primary airway
oral airway. An oral airway that is too large may push the management in neonatal resuscitation [41]. However, its use
epiglottis into the glottic opening, whereas an airway that is has been recommended as a secondary tool in near-term and
too small may push the tongue into the glottic opening. In term neonates who have failed resuscitation with bag-mask
the neonate with a difficult airway, the use of an oral airway ventilation or tracheal intubation [42].
The ProSeal LMA is a reusable laryngeal mask airway supine are required. Tracheal intubation and mechanical ven-
with a wider laryngeal bowl and a channel for gastric drain tilation are also useful in neonates to avoid atelectasis that
tube insertion that runs lateral to the airway tube. The device could develop during prolonged anesthesia with spontaneous
is available in a size 1 and has been studied in neonates and ventilation.
infants weighing 2–5 kg [43, 44]. The initial results sug- The “sniffing position” is classically described as the
gest that in addition to the 100% success rate inserting the optimal head position to facilitate direct laryngoscopy and
ProSeal LMA [43, 44], the quality of the initial airway, the tracheal intubation in adults. In neonates, better alignment
effectiveness of the seal, and the maximum tidal volume of pharyngeal structures is achieved with simple neck exten-
were significantly better than with the classic LMA [43, 44]. sion [48]. Because the occiput is relatively large in the neo-
The LMA Supreme is a second-generation, single-use nate, their head is naturally in the “sniffing position” without
device [45]. It has an airway tube that is curved and is more active head flexion! If the large occiput of the neonate is
rigid to facilitate insertion. The gastric channel runs central placed on a pillow, the neck becomes flexed, which may con-
to the airway tube [45]. tribute to airway obstruction. Although the use of a shoulder
The Ambu Aura Gain is another second-generation LMA roll has been recommended when positioning the neonate
with a gastric drain channel and large cuff. When compared before intubation, a recent randomized controlled trial con-
with the LMA Supreme, the Ambu AuraGain was found firmed that the glottic view in infants with a 2-inch shoul-
to have similar leak pressures in infants and children, with der roll was not improved compared with the view without a
fewer airway maneuvers to maintain a patent airway [46]. shoulder roll [49]. Positioning the neonate on a flat surface
Laryngeal tube suction II (LTS II; VBM Medizintechnik, with a head ring that does not elevate the head is preferred.
Sulz, Germany) is another supraglottic airway device avail- Direct laryngoscopy is a widely used method for achiev-
able in a size suitable for use in neonates. It is inserted ing tracheal intubation in neonates. Traditionally, the Miller
blindly like the LMA. The LTS II has an esophageal and a blade was favored in this age group to facilitate the alignment
pharyngeal cuff that are interconnected as well as a channel of the oral and laryngeal axes [3]. This blade offers greater
for placement of a gastric drain tube. Ventilation is deliv- control and displacement of the base of the tongue, particu-
ered through multiple holes in the tube that are positioned larly for difficult intubation. The smaller size and reduced
between these two cuffs. While a case series describing the profile of the Miller blade (or the Wisconsin or Wis-Hipple
utility of this device in 10 neonates and infants has been pub- size 0 blade) may also give the operator more room to pass
lished [47], larger prospective trials evaluating its safety or the TT through the mouth and pharynx and into the trachea
efficacy in neonates have not yet been conducted. while maintaining the visual pathway. When laryngoscopy
The LMA can be used as a valuable bridge to tracheal is performed with a straight blade, the blade is preferably
intubation in neonates with difficult airways. This will be introduced at the right side of the mouth, not in the mid-
reviewed in a later section of the chapter. line, an approach known as the paraglossal approach, while
pushing the tongue to the left [50, 51]. The blade follows the
right alveolar groove until the tip reaches the epiglottis, at
Laryngoscopy and Airway Instrumentation which point the epiglottis is lifted to expose the glottis. This
approach yields a superior view of the glottis compared with
Indications for tracheal intubation are traditionally deter- that from a midline approach.
mined by the surgical procedure, duration of the surgery, risk Until recently, there was no objective evidence to prove
of aspiration of gastric contents, and pulmonary function. In that the straight blade provides either an improved view or
anesthetized neonates, airway maintenance with a facemask easier tracheal intubation when compared with the curved
is less desirable because of the high dead space-to-tidal vol- blade in neonates [52, 53]. Two recent randomized clini-
ume ratio and concerns for the development of atelectasis. cal trials in infants and children <2 years old reported that
Tracheal intubation is indicated for all emergency surgery, the Miller and Macintosh blades provide similar laryngo-
open cavity procedures of the abdomen or chest, intracranial scopic views and intubation conditions [54, 55], although
procedures, and in cases where control of arterial PCO2 is when the study was repeated in neonates, the glottic views
required. It is also indicated when the anesthesiologist has with the Miller blade size 0 were superior to those with
limited access to the airway during surgeries such as those the Macintosh size 0 [56]. Traditionally, the Miller blade is
involving the head and neck and when positions other than advanced to lift the epiglottis to expose the larynx. Some,
however, use this blade in a manner analogous to the curved Orotracheal Intubation
blade by advancing it into the vallecula to lift the tongue In select circumstances and other than in the obstetric deliv-
[54, 55]. In both neonates and older infants, lifting the ery room, tracheal intubation has been performed in unmedi-
tongue with the Miller blade provides similar views of the cated, awake neonates. Often this involved neonates who
glottic opening [54, 56]. Care should be taken when plac- could not tolerate the cardiovascular depressant effects of
ing the Miller blade in the vallecula as the tip of the blade, anesthetic or sedative drugs or whose airways were com-
unlike the Macintosh blade, is not rounded [50, 57]. If the promised or potentially difficult to secure. This approach is
glottic exposure is suboptimal after advancing the laryngo- now discouraged. Neonates, who perceive pain in response
scope and positioning it, the laryngoscopist can apply exter- to a nociceptive maneuver, experience neural sensitization
nal, posterior pressure to bring the glottis into view. A few or hyperexcitability such that a subsequent laryngoscopy
studies have described the clinical effectiveness of external without sedative premedication or general anesthesia may
laryngeal manipulation in facilitating tracheal intubation result in untoward cardiovascular responses (and behav-
[58]. Adult studies have demonstrated that a small amount ioral) effects and, thus, should be avoided whenever pos-
of external, posterior pressure with or without lateral dis- sible [62–64]. The administration of anesthetic, sedative,
placement often significantly improves laryngeal exposure and neuromuscular-blocking drugs improves conditions for
and facilitates intubation [59–61]. In neonates, laryngeal intubation, decreases the likelihood of trauma to the airway,
manipulation can be performed using the operator’s fifth and improves the first-pass success rate [65–68]. A con-
digit of the left hand (Fig. 5.2). Of note, a recent study in sensus statement published by The International Evidence-
critically ill children found that external laryngeal manip- Based Group for Neonatal Pain states “tracheal intubation
ulation during direct laryngoscopy was associated with a without the use of analgesia or sedation should be performed
smaller initial tracheal intubation success [58]. only for urgent resuscitations in the delivery room or for life-
threatening situations associated with the unavailability of
intravenous access” [63]. In select circumstances such as
difficult facemask ventilation, tracheal intubation may be
performed after sedative premedication rather than general
anesthesia. Various medication regimens have been evalu-
ated for nonemergency tracheal intubation in neonates in the
neonatal ICU [69–73]. However, most of these studies were
quite limited, precluding the determination of an optimal
regimen [74].
Nonetheless, tracheal intubation in an unsedated critically
ill neonate may be a life-saving maneuver. Although it has
been largely abandoned, if the need arises, it is important
to know how to perform an “awake” intubation. This is not
a technique that should be first attempted in a life-saving
situation. When planning an awake intubation, the opera-
tor should ensure that the stomach is empty (e.g., suction
is readily available), and atropine 0.02 mg/kg IV and oxy-
gen have been administered. In advance of the intubation,
a styleted TT of the appropriate size (in a hockey stick con-
figuration), laryngoscope handle, and appropriate size blade,
and suction should be prepared. Although it may seem intui-
tive that a styleted TT should facilitate tracheal intubation,
a Cochrane review failed to prove that the success rate of
Fig. 5.2 Orotracheal intubation in the neonate is facilitated by using
tracheal intubation among pediatric trainees using styleted
the fifth finger of the left hand, which provides posterior or lateral exter- TTs exceeded that with nonstyleted TTs [75]. Evidence to
nal displacement of the larynx support the benefit for stylets during tracheal intubation in
neonates remains lacking. An experienced assistant holds the Alternately, a red rubber catheter may be used in place of
infant’s shoulders against the mattress while simultaneously vasoconstrictors [89]. The catheter is passed through the nos-
fixing the head firmly in a central position. Alternately, the tril with the tip of the nasotracheal tube telescoped into the
arms are hyperextended such that there are held against the flange of the catheter, thereby obviating nosebleeds.
side of the head to prevent the head and torso from wiggling Furthermore, if the neonate has limited oxygen reserves, it
and the shoulders from lifting off the table during laryngos- may be safer to perform an initial orotracheal intubation,
copy. Once laryngoscopy begins, tracheal intubation should then pass a second tube via the nose, and exchange the nasal
be completed within 10–12 s. The laryngoscope blade for the oral tube during laryngoscopy. Although complica-
should be inserted into the mouth at the right commissure tions after nasotracheal intubation in neonates have been
aiming the tip of the blade toward the midline in one fluid limited to anecdotal reports and in aggregate with older chil-
motion. The laryngoscope should be held in one hand and dren, the specific complications that have been reported
the TT in the other. As soon as the neonate gags as the blade include traumatic damage to the cribriform plate, trachea and
is inserted, the epiglottis should be lifted and the tube passed esophagus, false passages, nasal septal ulcers, blocked TTs
between the vocal cords. When carbon dioxide is detected, [90–92].
2–3 mg/kg IV propofol or other anesthetics is administered The success rate of first attempt intubations by trainees
to attenuate any cardiovascular responses to laryngoscopy. and inexperienced staff is generally poor in neonates [93].
The TT should then be taped and secured at an appropriate Initial studies of videolaryngoscopy compared with direct
depth. It is most important to instruct the assistant who is laryngoscopy in children failed to demonstrate a clear
restraining the infant not to release the infant until notified superiority of the videolaryngoscopy, although these were
to do so otherwise the infant may struggle resulting in the not randomized controlled trials. Recent randomized con-
airway being extubated. trolled trials, however, demonstrated that videolaryngos-
Complications from orotracheal intubation in neonates in copy improved the first attempt intubation rate and the time
the short term are infrequent and in the long term are small. to intubation of neonatal airways with poor glottic views
Factors that are associated with increased complications in part, due to the magnified view of the larynx as well as
include prematurity and low body weight, multiple intuba- the guidance offered by the attending compared with direct
tion attempts, cuffed or uncuffed TTs that traumatize the laryngoscopy [94–96]. A recent randomized controlled trial
loose columnar epithelium that lines the subglottic cricoid of standard blade video laryngoscopy compared to stan-
region, glottic and subglottic scaring, stenosis and injury, dard blade direct laryngoscopy in infants with normal air-
pharyngoesophageal injury and previous esophageal sur- ways, demonstrated that video laryngoscopy improved first
gery, subglottic cyst, tracheal perforation, and dental injury attempt success and reduced severe complications, particu-
[76–80] larly in smaller infants [97].
Nasotracheal Intubation
Nasotracheal intubation is more challenging to perform than Selection of Tracheal Tubes
orotracheal intubation, especially in neonates. In the short
term, nasotracheal offers some benefits over orotracheal A variety of methods exist for determining the expected
intubation for certain procedures (e.g., with craniofacial uncuffed TT diameter in children, including formulas based
anomalies [81]. cardiac surgery, posterior fossa neurosur- on age and height. However, in neonates, the diameter of the
gery, and for prolonged intubation in the intensive care in TT is determined empirically, based on the neonate’s weight.
many institutions) although, in the long term, evidence sug- For neonates <1.5 kg, a size 2.5 mm ID uncuffed tube is rec-
gests equipoise between the two TT approaches [82]. Nasally ommended, for those 1.6 to 3.5 kg, a size 3.0 mm ID
instilled 0.025% oxymetazoline (1 gtt/nostril) may be applied uncuffed tube, and for those >3.5 kg, a 3.5 mm ID uncuffed
before intubation to reduce the risk of bleeding. The dose of tube. In the second half of the first year after birth, we use a
the vasoconstrictor should be carefully calculated to avoid 4.0 mm ID tube for infants ≥5 kg. The appropriate TT size
hypertension and reflex bradycardia progressing to cardiac for each neonate may need to be adjusted based on pre-
arrest that have been reported after inadvertent overdoses of existing medical conditions (e.g., subglottic stenosis, Down
phenylephrine [83–86] and oxymetazoline [87, 88]. Hence, syndrome) (Fig. 5.3a–c) and whether the tube is cuffed or
these agents should be used judiciously in neonates. uncuffed.
a b
Fig. 5.3 (a) Bronchoscopic view of a subglottic web. (b) Bronchoscopic Bronchoscopic view of subglottic stenosis after prolonged intubation in
view of subglottic cysts. Courtesy of Dr. M. Benoit, Department of an ex-premature infant. Courtesy of Dr. M. Benoit, Department of
Otolaryngology, Strong Hospital, University of Rochester, NY. (c) Otolaryngology, Strong Hospital, University of Rochester, NY
ncuffed Versus Cuffed Tracheal Tubes

U or an increased incidence of post-extubation stridor during
Uncuffed TTs have traditionally been used in neonates due general anesthesia in children and may reduce operating
to the concern that a cuffed TT may cause subglottic injury. room pollution and anesthetic gas waste compared with
In the past, this was attributed to the walls of cuffed tubes uncuffed TTs [98–100]. In fact, in the pediatric intensive
being significantly thicker than those of uncuffed TTs and care unit, post-extubation stridor and significant long-term
the fact that the cuffs were low compliance, exerting more sequelae did not occur when cuffed TTs were used in infants
pressure on the mucosa of the subglottic region for a given and children for up to 6 days, although only 21 infants were
inflation volume. However, modern thin-walled cuffed TTs allocated cuffed tubes [101]. In a recent study with the
with high-volume, low-pressure cuffs have not been associ- Microcuff® tube in infants and young children, 326 infants
ated with an increased incidence of subglottic airway injury were studied with a 2.8% incidence of stridor [99]. The num-
ber of neonates in the latter study was not reported as a sepa-

rate group. Recently, post-extubation stridor was reported in
three neonates after the use of Microcuff® tubes, although it
should be noted that these particular tubes used were NOT
those recommended for their ages [102]. As of this writing,
only one small retrospective study has compared the
Microcuff and uncuffed TTs in neonates <3 kg [103]. There
was no difference in complications and outcomes although
only 23 infants were included in each group. Readers should
be cognizant of two additional issues regarding the
Microcuff® tubes: 1. the 3.0 (not 3.5) mm ID Microcuff® tube
is recommended for full-term neonates >3 kg up to 8 months
of age, and 2. If the cuff of the Microcuff® tube is inflated, the Fig. 5.4 An uncuffed and an inflated Microcuff® cuffed tracheal tube
cuff pressure should be monitored (maximum cuff pressure for comparison. Note the absence of the Murphy eye and the proximity
with these ETTs is 10 cm H2O due to the elliptical shape of of the cuff to the tip of the tube in the Microcuff® tube. The heavy black
line on the Microcuff® tube corresponds with the vocal cord position in
the cuff) throughout the anesthetic to preclude developing the neonate
excessively high cuff pressures. The critical pressure that
limits tracheal mucosal blood flow in the neonate is unknown.
Currently, neonatologists are reassessing their reticence to reduced lung compliance such as in chronic lung disease.
use cuffed TTs in neonates [104]. Long-term studies regard- The second is for surgical procedures close to the airway
ing the use of and complications from cuffed and uncuffed to limit the escape of oxygen-enriched gases and thereby
TTs in neonates have been forthcoming. decrease the risk of fires by minimizing the oxygen concen-
When a cuffed TT is used, the cuff inflation volume tration delivered and the use of suction Bovie devices.
should be adjusted to achieve the desired leak pressure. The
Microcuff® TT seals the airway at pressures that are less than ssessing Tracheal Tube Size
A
traditional cuffed TTs. Accordingly, the time interval until Before commencing tracheal intubation, it is important to
the cuff pressure requires adjustment with the Microcuff® prepare a selection of appropriately sized TTs. A tube with
tube exceeds that with traditional polyvinylchloride TT an outer diameter that will exert excessive pressure on the
[105]. Irrespective of the brand of TT used and whether subglottic mucosa may cause mucosal ischemia and inflam-
nitrous oxide is used or not, it is prudent to either monitor mation. In the short term, these events can lead to edema of
the cuff pressure intermittently or deflate and reinflate the the loose pseudostratified columnar epithelium that lines the
cuff periodically to preclude excessive cuff pressures and subglottic cricoid region, the narrowest part of the subglottic
possible mucosal ischemia. trachea and the only circumferential cartilage in the trachea.
Cuffed TTs offer several potential advantages when com- This in turn may lead to stridor from the edematous nar-
pared with uncuffed TTs [104]. It seems intuitive that cuffed rowed airway that follows extubation. Since the flow of gas
TTs should provide a better seal of the trachea to prevent is turbulent (defined by a Reynold’s number >2100) as far
macroaspiration than uncuffed tubes although this remains down the tracheobronchial tree as the fifth bronchial divi-
unproven (Fig. 5.4). The incidence of aspiration pneumonia sion, a narrowing of the cricoid ring, for example, by 50%,
with an uncuffed tube is exceedingly small and aspiration is could increase the resistance to breathing by the radius to the
known to occur even with cuffed tubes. They enable the use fifth power or 32-fold (based on the Fanning equation for
of small fresh gas flows (and associated economic advan- turubulent gas flow). With limited type I twitch fibers in the
tages) and decrease operating room pollution. However, intercostal muscles and diaphragm, the extra work of breath-
minimal fresh gas flows are also used with uncuffed tubes ing in such cases could lead to respiratory failure in the pre-
[100, 106]. In addition, cuffed TTs reduce the number of term (and term) neonate. In the long term, such inflammation
laryngoscopies to achieve a proper size tube and reduce the may lead to scarring and, finally, subglottic stenosis.
associated morbidity from multiple tube changes. The mor- The diameter of the uncuffed TT that is most appropri-
bidity from reintubation is exceedingly small in experienced ate for a neonate may be assessed using both the “air leak
hands. Subglottic damage after intubation has been attrib- test” and by manually assessing the resistance to its passage
uted, for the most part, to intubation with oversized TTs, pro- through the subglottic region, which should be very small
longed intubation, and head movement [107]. Finally, two [108]. For the “air leak test,” the tip of the tube is positioned
important and practical advantages of cuffed TTs should be mid-trachea and the adjustable pressure-limiting (APL)
appreciated. The first is to facilitate ventilation of lungs with valve is closed. While the pressure within the breathing cir-
cuit increases, a stethoscope is positioned over the supraster- of the right upper lobe bronchus if a mild hemoglobin oxy-
nal notch. The pressure at which a leak is first heard is noted. gen desaturation persists or air entry is diminished in the
Indirect evidence indicates that the leak pressure should be right upper chest and pull the TT back until the symptoms
limited to 15–20 cm H2O to minimize the risk of mucosal abate. In addition, a mid-tracheal tube position can be
edema and tissue damage in adults [109]. Comparable evi- assessed by palpating the TT tip or the cuff in the supraster-
dence in neonates has not been forthcoming. When perform- nal notch and by chest radiograph [115, 116].
ing the “air leak test,” it is important to avoid a slow and Investigators have determined that the markings on the
prolonged leak test as this might compromise the circula- Microcuff® tube just proximal to the cuff more reliably
tion, similar to that observed during a prolonged Valsalva ensure a properly positioned tube tip and cuff in the trachea
maneuver. than the cm markings at the lips (Fig. 5.4) [117]. Since the
If resistance is detected as the tube passes through the Microcuff® tube has no Murphy eye and does have a cuff, it
subglottic region, then a half-size smaller tube should be is prudent to respect this recommendation and use the tube
inserted. If the tube passes easily through the subglottis, it markings near the tip when positioning the TT rather than
is important to auscultate for excessive gas leak to ensure relying on the distance displayed at the lips.
that the tube is not too small for the larynx; otherwise, it is It is important to recognize that flexion or extension of the
replaced with a tube a half-size larger. A leak test should then head will affect the depth of intubation [118]. Flexion of the
be performed to ensure that it is not too large. head advances the TT down the trachea, whereas extension
withdraws the TT. While the distances involved are quite
Positioning the Tip small in the neonate, it is wise to check the position of the
Ideally, the tip of the tracheal tube should be mid-tracheal tip of the TT after any manipulation of the head or body after
level. A variety of formulae have been developed to predict intubation.
the length of the TT to be inserted to achieve this depth. In
neonates, a commonly used rule of thumb is the “123–789
rule,” where a 1 kg baby should have the tube taped at Rapid Sequence Intubation
approximately 7 cm at the maxillary alveolar ridge, a 2 kg
baby should have the tube taped at 8 cm, and a 3 kg baby The traditional rapid sequence induction (RSI) without ven-
should have the tube taped at 9 cm for a mid-tracheal posi- tilation is not usually feasible in neonates because they rap-
tion. Even when such a formula is used, it is important to idly desaturate during apnea. This is a result of their relatively
confirm optimal positioning. This can be initiated during greater oxygen consumption, reduced FRC, and increased
laryngoscopy. When the cuff passes just beyond the vocal closing volumes compared with older children. Furthermore,
cords, or in the case of an uncuffed tube, when the tip passes it is difficult to pre-oxygenate the neonate because they often
1–2 cm beyond the vocal cords, the centimeter marking on cry and move, preventing the application of a tight facemask.
the tube at the level of the gums (or incisors) should be noted. Therefore most pediatric anesthesiologists perform a “modi-
Some prefer to advance the uncuffed tube until the breath fied” RSI induction in neonates [119]. With this technique,
sounds become unilateral. This identifies the level of the the lungs are gently manually ventilated via a facemask
carina. The TT is then withdrawn 2–2.5 cm depending on the using low airway pressures (<10–15 cm H2O) as conscious-
age of the child. The tip of the TT will then rest approxi- ness is lost. Once anesthetized and apneic, neonates and
mately midway between the vocal cords and the carina. younger infants desaturate more rapidly than older children
Knowing the centimeter marking with this depth of insertion [120]. Thus continuous oxygen flow during laryngoscopy in
as well as the depth of the carina gives the anesthesiologist neonates has been advocated via buccal oxygenation, nasal
an idea of how much TT displacement can safely occur oxygenation or an oxyscope® laryngoscope blade [121, 122].
before an endobronchial intubation or tracheal extubation These approaches reduce the risk of a significant decrease in
occurs. The distance between the glottis and the carina in hemoglobin saturation. Furthermore, multiple intubation
full-term neonates is approximately 4–5 cm [110, 111]. attempts during pyloromyotomy in neonates resulted in more
Therefore, once the distance to the carina is found, the TT is hypoxemia than a single intubation attempt [123].
pulled back approximately 2 cm to achieve a position that is Controversy exists regarding the effectiveness of cricoid
mid-tracheal. A shortened tracheal length (i.e., a more ceph- pressure to prevent regurgitation in patients after induction
alad bifurcation) is associated with certain medical condi- of anesthesia [124]. We do not recommend the routine appli-
tions such as trisomy 21 [112] and myelomeningocele [113, cation of cricoid pressure in neonates. Although a full dis-
114]. These neonates are therefore at greater risk of acciden- cussion of this subject is beyond the scope of this chapter,
tal bronchial intubation, even when the TT is believed to be what is known is that it is oftentimes difficult to palpate the
mid-tracheal. One should always be wary of a tracheal origin cricoid ring in young infants [125], the force that is required
to occlude the lumen of the esophagus in neonates has not Table 5.1 Difficult airway in neonates
been established, that as little as 5 N may deform the airway Difficult mask ventilation
in the infant [126], and that the esophagus is often displaced Maxillary hypoplasia
laterally, an effect that is far more prevalent in younger chil- Crouzon’s syndrome
dren than in adults [127]. In adults, the application of up to Apert’s syndrome (acrocephalosyndactyly type I)
Pfeiffer’s syndrome
50 Newtons force on the cricoid ring reduced the visibility
Choanal atresia
of the glottis by 50% [128]. When 30 Newtons force was
Marshall–Smith syndrome
applied to the cricoid ring, the duration of fiber-optic intuba- Rubinstein–Taybi syndrome
tion was prolonged compared with no cricoid pressure [129]. Possible difficult laryngoscopy/intubation
Although comparable data in neonates and children have not (a) Micrognathia
been forthcoming, it is reasonable to expect the effect of cri- Pierre Robin sequence
coid pressure on the visibility of the glottis opening to be Stickler syndrome
limited even further. Supplementary maneuvers to minimize Smith–Lemli–Opitz syndrome
the risk of aspiration of gastric contents include emptying Treacher Collins syndrome
the stomach before induction of anesthesia, rapidly adminis- Goldenhar’s syndrome; hemifacial microsomia
First arch syndrome; midfacial cleft
tering the induction agents, and rapidly securing the airway
(b) Possible micrognathia and other soft tissue facial anomalies
with a TT. In the event that cricoid pressure is applied, it
Arthrogryposis trisomy 8
should be maintained until pharmacologic paralysis is com- Trisomy 9
plete. In support of this practice, appropriately applied cri- Trisomy 13 (Patau syndrome)
coid pressure has been shown to be effective in preventing Trisomy 18 (Edwards syndrome)
gastric inflation during gentle bag-mask ventilation in anes- CHARGE association
thetized infants [130]. If the initial attempt at tracheal intu- Cornelia de Lange syndrome
bation fails while cricoid pressure continues to be applied, Velocardiofacial syndrome (Shprintzen syndrome)
gentle facemask ventilation should be performed. If ventila- Freeman–Sheldon syndrome (whistling face syndrome)
tion is difficult while cricoid pressure is applied, despite the (c) Macroglossia
Beckwith-Wiedemann syndrome
use of adjunctive devices such as an oral or nasopharyngeal
Congenital hypothyroidism
airway or an LMA, cricoid pressure should be lessened or
Down syndrome
released [131, 132]. The evidence that cricoid pressure pre- Cystic hygroma
vents pulmonary regurgitation in this clinical setting remains Congenital lingual tumor/intraoral tumor
unproven [133]. Mucopolysaccharidoses (Hurler, Hunter, Morquio, and
Maroteaux–Lamy syndromes)1
Lipoid proteinosis trisomy 4p
Managing the Difficult Airway Weaver syndrome
(d) Intraoral/tracheal pathology
Microstomia
Epidemiologically, a difficult airway occurs more frequently
Congenital temporomandibular joint dysfunction
in infants <1 year of age (with neonates comprising the sec- Laryngeal/vallecular cyst, laryngeal web
ond most common age group) than in older children [134]. Laryngotracheal cleft
Airway management in this population may be challenging; Laryngeal/tracheal hemangiomas
congenital and acquired airway difficulties [76, 106] and air- Tracheal and subglottic stenosis
way disorders due to a variety of conditions may cause dif- Other defects that may complicate the airway
ficult ventilation by facemask and/or difficult tracheal Cervical spine immobility
intubation. (Table 5.1). Arthrogryposis
The difficult airway in the neonate presents several unique Emery–Dreifuss muscular dystrophy
Fibrodysplasia ossificans progressiva syndrome
challenges, in addition to those that exist in the older child.
The small dimensions of the face, mandible, and neck pres-
1
Data from Frawley G, Fuenzalida D, Donath S, Yaplito-Lee J, Peters
H. A retrospective audit of anesthetic techniques and complications in
ent problems for maintaining a patent airway with the face- children with mucopolysaccharidoses. Pediatr Anesth 2012: 22;
mask and in the presence of the added difficult airway (e.g., 737–744
small mandible, small mouth, large tongue) these challenges
are magnified. Laryngoscopy and intubation may be very
difficult due to the lack of uniformity of growth of the max- For example, superimposed on the difficulties posed by a
illa and mandible. Interestingly, such difficulties may change normal neonatal airway, the flat face, maxillary hypoplasia,
in magnitude and severity as the child grows and matures and small mouth of the neonate with Crouzon’s disease and
depending upon the underlying condition. Apert’s syndrome often leads to an obstructed airway during
facemask ventilation. In such instances, oropharyngeal air- micrognathia, glossoptosis, and respiratory distress in the
way or laryngeal mask airway may relieve the upper airway first 24–48 h after birth. Direct laryngoscopy may be particu-
obstruction. However, direct laryngoscopy and orotracheal larly challenging in neonates with Pierre Robin sequence in
intubation in these cases is usually easy. As infants with part as a result of a short mandibular body length (Fig. 5.5b)
these syndromes mature, mask anesthesia remains a chal- [136]. However, the airway becomes easier to manage with
lenge, whereas direct laryngoscopy remains easy. age so that by 2 years, the mandible is often aligned with
Neonates with Pierre Robin sequence (Fig. 5.5a) [135], the maxilla [137]. In contrast, laryngoscopy in neonates with
Treacher Collins syndrome (Fig. 5.5c), and Goldenhar’s Treacher Collins syndrome is easier at birth and becomes
syndrome may also present challenging airways. Mask anes- progressively more difficult with increasing age, in some
thesia may be difficult as the mandibular deformities render cases a tracheotomy is required by adolescence [137, 138].
temporomandibular joint subluxation difficult (Fig. 5.5b) This may be directly attributable to a shortened ascending
[136]. Pierre Robin sequence is defined by the triad of ramus of the mandible [136]. In both Pierre Robin sequence
a b
Fig. 5.5 (a) Lateral profile of a 3-week-old male with Pierre Robin J. Girotto, Department of Plastic Surgery, Strong Hospital, University
sequence. Note the retrognathic chin, which will impair laryngoscopy of Rochester, NY. (c) Neonate with Treacher Collins syndrome. Note
and tracheal intubation. (b) A three-dimensional CT reconstruction of a the small mandible, deformed ears, and teardrop eyelids, which are
neonate with Pierre Robin sequence. Note the hypoplastic mandibular characteristic facial features of this syndrome
body length and severely obtuse gonial angle (see text). Courtesy of Dr.
and Treacher Collins syndrome, the gonial angle (or the tomy) (Fig. 5.6) in the event that attempts at tracheal intu-
angle between the ascending ramus and body of the mandi- bation fail. The availability of an otolaryngologist does not
ble) is significantly more obtuse than in unaffected neonates, necessarily guarantee an expeditious airway rescue since the
which may contribute to difficult laryngoscopy exposure. anatomical reasons that may lead to a failed intubation may
The airway in neonates with Goldenhar’s syndrome is split also create difficulties for a tracheostomy [142].
50:50: half have airways are not difficult to manage, and half The approach to the anticipated difficult neonatal airway
are exceedingly difficult to manage. Interestingly, the diffi- is similar to that in older children. Although general anesthe-
culty presented by the airway in this last syndrome does not sia is the preferred approach to securing the airway in these
change with age. infants, topical administration of local analgesia supple-
Neonates with disease of the larynx or trachea present a mented with sedation and awake tracheal intubation should
special challenge to the anesthesiologist. Mask ventilation also be considered as an alternative approach. During induc-
may be difficult and tracheal intubation, if needed, requires tion of general anesthesia, spontaneous ventilation is pre-
careful consideration. The degree of airway obstruction ferred as it makes it likely that ventilation will be maintained
and the dynamic changes that may occur with induction of should the operators fail to secure the airway. However,
anesthesia are often unknown and difficult to predict. Such spontaneous ventilation may be difficult to maintain in some
patients include neonates with subglottic webs (Fig. 5.3a), neonates (particularly in the preterm and those with hypo-
hemangiomas, cysts (Fig. 5.3b), tumors, and laryngomalacia plastic mandibles) because of the small dimensions of their
as well as those with subglottic stenosis from prior tracheal upper airways, sensitivity to inhalational agents, and chest
intubation (Fig. 5.3c) [139, 140]. wall instability in addition to the defect at the root of the dif-
Before embarking on an anesthetic for a child with a diffi- ficult airway. The decision to administer a muscle relaxant
cult airway, it is essential that the operating room and airway depends on the risk/benefit ratio of paralysis. This includes
equipment are set up and immediately available (in the O.R.). difficulty ventilating the lungs and a possible “cannot-
Appropriate expert assistance (e.g., otolaryngologist) should intubate-cannot-ventilate” scenario developing, although the
be present before induction of anesthesia if a tracheotomy or latter is exceedingly rare in neonates [143–145]. Induction
rigid bronchoscopy (Fig. 5.6) is a possibility [141]. In elec- of anesthesia must be carried out carefully, avoiding upper
tive cases, severely dysmorphic neonates and those with only airway obstruction, and the consequent rapid desaturation.
a single means of accessing their airways (e.g., severe tem- Topical anesthesia applied to the airway combined with
poromandibular joint dysfunction that limits mouth opening sedation has been used to blunt cardiorespiratory responses
and eliminates the ability to rescue ventilation with an LMA) during laryngoscopy [1]. Alternately, sedation may be pro-
should be evaluated by an otolaryngologist before induc- vided by midazolam and fentanyl, propofol, dexmedetomi-
tion of general anesthesia. This allows the otolaryngologist dine, or ketamine administered intravenously [65, 66, 69, 71,
to assess the airway for alternate approaches to orotracheal 72, 146–149] These approaches have all been used to secure
intubation (such as rigid bronchoscopy or surgical tracheos- the airway, although the responses were generally optimally
only controlled when a muscle relaxant was coadministered.
Finally, an awake intubation may be necessary in order to
secure the difficult airway, particularly in the absence of oto-
laryngology support or alternatives. The approach described
earlier in this chapter to perform an awake orotracheal intu-
bation should be followed closely in order to reliably and
rapidly secure the airway. Once the airway is secured and
expired carbon dioxide is identified, a bolus of intravenous
propofol should be administered rapidly to induce general
anesthesia.
The prior discussion has provided a detailed description
of how to optimally use the Miller blade in neonates with a
difficult airway. However, in some circumstances, the airway
cannot be secured by direct laryngoscopy and other methods
are required. These methods are described below.
Adjuncts such as an oropharyngeal airway or other supra-
glottic devices may be useful, particularly in the child with
Fig. 5.6 A rigid bronchoscope with telescope and light source.
a dysmorphic face. Proper application of the jaw thrust [32]
Anesthesia breathing circuit with a flexible connector attached to the
ventilation port of the bronchoscope. In the lower right of the photo, an is usually salutary to re-establish an unobstructed upper air-
anterior commissure laryngoscope is shown way. However, in the presence of a dysmorphic face or laryn-
gospasm, emergency intervention is required to establish an 60-degree “D-blade” is also available down to a size MAC
airway before hypoxemia and cardiac arrest occur. If time 2 blade equivalent [45]. The Storz video laryngoscope has
permits, an LMA has served as an effective bridge to trache- been used successfully in the delivery room, to facilitate tra-
ostomy in neonates in several difficult airway reports [137, cheal intubation in neonates as small as 500 g [154]. The
143, 150]. The appropriate size LMA should always be read- detailed view from the camera allows visual inspection of the
ily available in the event it is needed urgently. Alternatively, airway in those suspected of having vocal cord dysfunction,
a video or optical technology may be required to visualize laryngeal clefts (Fig. 5.9), and gastroesophageal reflux.
the glottic opening for tracheal intubation. The GlideScope video laryngoscope has been success-
Several different video and optical technologies are avail- fully used in infants and neonates [155]. The redesigned
able to manage difficult neonatal airways [45, 137]. In the GlideScope Cobalt is a Mac-style plastic blade that fits onto a
past, much of this technology was simply scaled-down ver- video baton. It is available in all pediatric sizes and provides
sions of adult designs [151], which were inappropriate for a clear, crisp view of the glottic opening, except in the most
neonates [45]. This resulted in poor views of the airway anatomically deformed neonatal airways. The GlideScope
and failed intubations [151]. There are several video laryn- has undergone several modifications since it was first intro-
goscopes with pediatric-specific designs and a full range of
pediatric sizes now available [151]. These include the Airtraq
(Prodol, Vizcaya, Spain), Glidescope (Verathon Medical,
Bothell, Washington, USA), McGrath (Aircraft Medical,
Edinburgh, United Kingdom), Pentax AWS (Pentax, Tokyo,
Japan), Storz C-MAC (Karl Storz, Tuttlingen, Germany), and
the Trueview PCD (Truphatek International Ltd, Netanya,
Israel).
Video laryngoscopes can be channeled (Airtraq, Pentax),
or nonchanneled (Storz, GlideScope, Truview, McGrath).
Channeled video laryngoscopes have a groove that houses
the ETT and directs it toward the center of the viewed image
[151]. Nonchanneled video laryngoscopes often require a
stylet to successfully intubate [151].
The Storz Video laryngoscope (Fig. 5.7) and the
GlideScope (Fig. 5.8) are two of the more commonly used
video laryngoscopes that may be used to facilitate tracheal Fig. 5.8 Neonatal-sized GlideScope
intubation in neonates [45, 152, 153]. The Storz video laryn-
goscope blade is available in Miller and Mac blade configura-
tions, as small as a Miller 0 straight blade. A hyperangulated
Fig. 5.7 Neonatal-sized Storz video laryngoscope Fig. 5.9 Laryngeal cleft
duced, in 2000 [45]. The most commonly used variation, the draw the stylet 1–2 cm and rotate the ETT 90° clockwise
AVL-S, is a single-use, digital device consisting of a “baton” so that the bevel faces upward. After either of these maneu-
(adult and pediatric version), and disposable, low profile, vers, the ETT may be advanced, with the bevel glancing off
plastic blades called “stats.” [45] The stat blades range in the anterior commissure or tracheal wall and then continue
sizes for use in preterm neonates to adult size patients: stat beyond the vocal cords.
size 0 (patients weighing <1.5 kg), size 1 (1.5–3.6 kg), size The Airtraq optical laryngoscope (Prodol, Vizcaya,
2 (1.8–10 kg), and size 2.5 (10–28 kg) [45]. As is the case Spain) is a single-use curved laryngoscope that uses mirrors
with any technology, there is a learning curve to navigate and prisms to transmit the image from the tip of the device
the TT into the glottic opening, while focusing on the video to a viewfinder (Fig. 5.10) [153]. It can be used in neonates,
screen. Once this has been mastered, the device has a reli- with sizes ranging up from neonatal size 0 [45]. It has a con-
ably excellent success rate in most neonates with craniofa- duit for the TT along its side that directs the TT toward the
cial anomalies, provided the mouth opening is sufficient to glottic opening as it is advanced. The Airtraq has been used
accept the blade. The TT should always be visualized while successfully in managing the difficult airway in the neonate,
it is advanced through the mouth to avoid tissue injury, espe- although there are no controlled randomized trials in neo-
cially when there is limited oropharyngeal space. The stat nates [153, 162–166]. Despite the built-in channel, one pub-
blade should be placed in the midline or the operators left in lication described two cases (one neonate and one infant) in
the pharynx to facilitate insertion of the tube. It is important which a full glottic view was obtained, and yet, difficulty
to recall the glottic opening is more cephalad in the neonate. was encountered when directing the tube into the trachea.
If the stat blade is inserted too close to the glottis, the ETT The authors attributed the failures to the bulk of the device
may be more difficult to maneuver into the trachea [45]. If that limited its maneuverability [167]. Others have had suc-
the neonate proves to have microstomia, then the blade may cess utilizing a gum elastic bougie to facilitate placement of
have to be inserted slightly to the left of the midline, without the TT when the standard approach failed [168].
sweeping the tongue [45]. Given the 60-degree curvature of The Pentax AWS is a portable vide laryngoscope designed
the GlideScope stat, a styletted ETT must be used [156]. to be uniquely used as an indirect laryngoscope [45]. The
Several authors recommend using a C-shaped stylet follow- device has a small video screen attached to the device as
ing the curvature of the stat [155, 157, 158]. This curvature well as the capability to view the video output on an exter-
is similar to that of the GlideRite stylet [45]. Other authors nal monitor. The Pentax is inserted into the mouth in the
recommend the use of a hockey-stick-shaped stylet [159]; midline, and once the glottis is visualized, an ETT is passed
however, in younger children, this may make maneuver- through a channel embedded in the blade [45]. The device
ing the styletted ETT more challenging and require addi- is available in neonatal to adult sizes. The Truview EVO2
tional maneuvers such as the use of Magill forceps or the (Truphatek, Netanya, Israel) incorporates a prismatic lens in
BURP [160]. an angulated rigid blade (Fig. 5.11) [153]. It has a side port
Given the special features of the neonatal airway dis- for oxygen insufflation during intubation. When the Truview
cussed earlier, difficulty may be encountered passing the was compared with the Miller blade in neonates, the former
ETT beyond the vocal cords despite having an excellent view provided improved Cormack-Lehane views and a clinically
of the glottic opening [151]. If the glottic opening is too close insignificant increase in the time to tracheal intubation [169].
to the tip of the airway device, the leading tip of the ETT Caution should be exercised when insufflating oxygen at
may hang up on the right arytenoid, preventing the tube from excessive flows (i.e., Bonfils recommends <3 L per minute
advancing through the vocal cords [45] or possibly avulsing of oxygen flow) through these intubation devices as subcuta-
the right arytenoid if excess pressure is applied. Obtaining neous emphysema has been reported [170].
a Cormack and Lehane grade 2 view by slightly withdraw- The McGrath video laryngoscope is a portable device
ing or reducing the anterior lift of the device provides a bet- with disposable blade sheaths similar to the standard MAC
ter trajectory for passing the ETT [151]. Another common blade with blade sizes ranging from MAC size 2–4 [45]. A
scenario is difficulty passing the ETT in neonates, because size 1 MAC blade has been developed but is not currently
the tip impacted the anterior commissure of the vocal cords available in the USA [171].
or the subglottic trachea. In this situation, “reverse loading” When using any of the video-assisted intubation devices
the ETT onto the stylet can be helpful [151, 161]. Typically, described above (except for the Airtraq), the selected TT
a styletted ETT has the murphy eye located to the right of should be prepared with a lightly lubricated stylet before
the laryngoscopist due to the natural curvature of the tube. laryngoscopy. An anterior curve matching the blade angle
Reverse loading is accomplished by rotating the ETT so of the selected device facilitates successful placement of the
that the murphy eye is to the left of the operator [151]. This tube. Laryngoscopy is performed by introducing the blade in
reverses the orientation of the ETT curve and directs it more the midline or to the right of the tongue, and airway struc-
in line with the axis of the trachea reducing “hang up” in the tures are progressively visualized until the blade tip is placed
anterior wall of the trachea [151]. Alternately, simply with- either in the vallecula or under the epiglottis. With the tip
Fig. 5.11 Neonatal-sized Truview EVO2 (courtesy of Dan White,

Truphatek, Inc.)
positioned in the vallecula and the glossoepiglottic ligament

engaged, the scope elevates the epiglottis and exposes the
glottic opening in most infants. On occasion, the epiglottis
obstructs the camera view because of its length in neonates
and infants. In this case, the epiglottis should be gently lifted
with the blade to expose the glottic inlet. After a satisfactory
view has been obtained, the TT is passed along the shaft of
the blade (unlike the lateral insertion typical with standard
direct laryngoscopy). This insertion technique guarantees
that the TT will come into the view of the video camera as it
is advanced and reduces the risk of soft tissue injury.
Whether tracheal intubation is easier, faster, or more suc-
cessful on the first attempt with a videolaryngoscope in neo-
nates and infants compared with direct laryngoscope has
been a subject of some debate. In a meta-analysis of video
and direct laryngoscopy in infants and children, a distillation
of 27 trials concluded that time to intubation is similar with
both devices in infants, success was similar on first attempt
to intubation with both, although videolaryngoscopy reduced
the number of traumatic airway events [172]. However, when
videolaryngoscopy was used in neonates with normal airways
during resuscitation, the success rate for tracheal intubation
was improved and intubation time was reduced in the hands of
inexperienced staff compared with no benefit for either in the
hands of more experienced staff [173]. When the success rate
for tracheal intubation using videolaryngoscopy with standard
blades (e.g., Miller or Macintosh Glidescopes, Storz CMAC,
and others) was compared with nonstandard blades (e.g.,
Airtraq, UE Scope, King VL, and others) in the Paediatric
Difficult Intubation Registry, videolaryngoscope with conven-
tional blades resulted in a significantly greater success rate for
intubation in the difficult airway in neonates and infants <5 kg
compared with nonconventional blades [174].
A recent randomized controlled trial of standard blade
video laryngoscopy compared to standard blade direct
laryngoscopy in infants with normal airways demonstrated
that video laryngoscopy improved first attempt success and
reduced severe complications, particularly in smaller infants.
There were also fewer esophageal intubations in the video
Fig. 5.10 Neonatal-sized Airtraq optical laryngoscope
laryngoscopy group.*
The lighted stylet remains a viable option for intubating

the neonate with a difficult airway [175, 176]. A stylet for
neonatal use can easily be fashioned from readily available
equipment in the operating room. A single fiber-optic light
bundle (20 g Fiberoptic Endoilluminator, Cat No. MVS1011, Fig. 5.14 Neonatal-sized Bonfils fiber-optic laryngoscope
Storz, St. Louis, MO, USA) can be inserted into the chosen
TT alongside a rigid stylet, and the fiber-optic bundle is then been successfully used in neonates. Optical stylets can be
connected to a rheostat-controlled fiber-optic light source combined with the anterior commissure laryngoscope or a
(Fig. 5.12) [176]. Transillumination of light in the neck is standard laryngoscope to facilitate intubation; the laryngo-
used to guide the placement of the TT; however, because scope displaces soft tissue and provides an unobstructed
of the relative lack of subcutaneous fat in neonatal patients, path for the stylet to be maneuvered [177]. Some authors
changes in light intensity with esophageal placement may have reported less success with the Bonfils when compared
not be readily appreciated. Thus, lighted stylet intubation with standard laryngoscopy [178], whereas others have
in the neonate requires an element of feel, and observing questioned its utility [179, 180]. The Bonfils has, however,
the transilluminated light continuously. A brief disappear- been used successfully with a 2.5 mm ETT in a small-
ance and reappearance of the transilluminated light suggests for-gestational-age neonate in whom direct laryngoscopy
esophageal placement. The visualization of a cone of light failed [181].
in the caudad direction suggests correct tracheal positioning. The flexible fiber-optic bronchoscope has been widely
Optical stylets combine the rigidity of the lighted sty- used for decades now to pass an ETT into the airway in the
let with fiber optics to allow direct visualization during neonate with a difficult airway when direct laryngoscopy
intubation. The Shikani Optical Stylet (SOS; Fig. 5.13) and failed. A channel has been incorporated in neonatal size
the Bonfils fiber-optic laryngoscope (Fig. 5.14) represent bronchoscopes, which may be used to remove secretions
two designs with neonatal applications. The SOS is mal- [182]. If difficulty is encountered with the oral and nasal
leable, whereas the Bonfils is rigid with a fixed curve of approaches, fiber-optic intubation through an LMA should
40°. Both are limited by the presence of secretions but have be considered. This technique has been used successfully for
tracheal intubation in neonates. A correctly positioned LMA
simplifies intubation with the flexible fiber-optic broncho-
scope and allows continuous ventilation via a swivel adapter
[183–189]. With the increasing use of cuffed tubes in chil-
dren, practitioners should be aware that most neonatal LMAs
will not allow the passage of cuffed TTs without some modi-
fications to the pilot balloon cuff [190]. The exception to this
Fig. 5.12 A single fiber-optic light bundle is attached to a rheostat-
is the air-Q intubating LMA (Mercury Medical, Clearwater,
controlled light source and placed inside a styleted endotracheal tube to FL), which readily accepts the pilot balloon of the cuffed
form a “homegrown” lighted stylet tube [191, 192]. In neonates with severe upper airway
obstruction, the LMA can be placed in the awake infant and
followed by induction of general anesthesia and fiber-optic
intubation [193–196]. Placement of a modified nasal airway
provides an alternative option for oxygenating the neonate
during intubation. In small infants with the potential for
life-threatening upper airway obstruction during induction
of general anesthesia (e.g., large cystic hygroma), moderate
sedation may be administered using small, incremental doses
of ketamine and midazolam after the application of topical
anesthesia [197] to provide suitable conditions while main-
taining spontaneous respiration during the laryngoscopy and
tracheal intubation.
In neonates, multiple attempts at tracheal intubation can
Fig. 5.13 Neonatal-sized Shikani Optical Stylet cause upper airway edema that becomes so severe that it
compromises ventilation. In such a case, an otolaryngologist

should be consulted to evaluate the neonate for a tracheos-
tomy as the airway must be secured.
In a CICV situation, needle cricothyroidotomy has been
traditionally recommended to establish an airway in older
children and adults [198]. However, this is NOT a practi-
cal option in neonates, because the neonatal cricothyroid
membrane is slit-like with overlap of the cricoid and thy-
roid cartilages [199]. The neonatal cricothyroid membrane
is too soft and too small for surgical cricothyroidotomy to
be performed (measuring 2.61 mm in length and 3.03 mm
in width in neonatal cadavers) [200]. Attempts to pass a tra-
cheal or tracheostomy tube could result in laryngeal fracture
or severe airway injury. The lack of a laryngeal prominence
Fig. 5.15 Cervical teratoma in a neonate with an orotracheal tube.
in the neonate combined with a more cephalad glottic posi-
tion makes localizing the membrane in the neonate very dif-
ficult, much more difficult than in the adult. In a recent case If a suspected challenging airway is diagnosed antena-
of CICV in a 3-year-old child, emergency tracheotomy was tally, the time of delivery may be scheduled to ensure that
attempted after multiple failed attempts at cricothyrodec- an ex-utero intrapartum treatment (EXIT) procedure and the
tomy [201]. To date, there are no reports of needle cricothy- EXIT team is present at the delivery to support the neonate
rotomy performed in a neonate of any size. The Quicktrach until the airway has been established [203–205]. The EXIT
baby™ (VBM Medizintechnik GmbH, Sulz am Neckar, procedure is performed with a partially delivered fetus, while
Germany) is a percutaneous cricothyrotomy device that was the uteroplacental circulation remains intact. EXIT proce-
designed and introduced for use in neonates/infants. In a dures permit direct laryngoscopy/bronchoscopy and tracheal
comparative study using dead rabbits (whose size was com- intubation, tracheostomy, or tumor resection depending on
parable to neonates), the Quicktrach baby™ was successful the defect present. Figure 5.16a, b show a neonate and CT
in zero of 13 attempts whereas the cannula tracheotomy was scan of that neonate who presented antenatally with a ham-
successful in 60% [202]. To repeat, we do NOT endorse per- artoma of the hard palate. An EXIT procedure was planned,
cutaneous cricothyrotomies in neonates at this time. although orotracheal intubation was successfully performed
The difficult neonatal airway represents one of the most by an anesthesiologist upon delivery of the fetus. The benign
challenging clinical scenarios for the pediatric anesthesi- tumor was subsequently resected. In some centers, airway
ologist. If the difficult airway is anticipated, then appropriate management is performed entirely by the surgical team.
planning must take place. However, in those rare instances in Once the neonate’s airway is secured using a TT or surgical
which the difficult airway is unanticipated, prior familiarity airway (depending on the size and location of the obstructing
with a difficult pediatric airway algorithm is essential [141] lesion), the placental cord may be ligated and severed.
Consistent success requires adequate preparation, maintenance Fetal anesthetic management consists of transplacental
of skill with indirect visualization devices, and assembling the transfer of volatile anesthetics (via the mother who receives
appropriate personnel when assistance may be required. general endotracheal anesthesia) and an intramuscular injec-
tion of atropine, fentanyl, and vecuronium into the fetus,
once it is exposed via a uterine incision. Total muscle paraly-
anaging the Airway in the Ex Utero
M sis is critical to prevent the fetus from taking a breath, which
Intrapartum Treatment (EXIT) Procedure (See would cause a switch from fetal to transitional circulatory
Chap. 14) pattern.
EXIT procedures may also be performed for resection
Rare conditions may occasionally result in compromised and of congenital pulmonary masses and cannulation for extra-
potentially life-threatening neonatal airway immediately corporeal membrane oxygenator (ECMO) support for select
after birth. These conditions include (but are not limited to) congenital cardiac conditions. The original indication for
congenital cystic hygroma of the neck, congenital high air- the EXIT procedure was to remove a tracheal plug that was
way obstruction syndrome (CHAOS) caused by obstruction placed during mid-gestation in an attempt to promote pulmo-
at the level of the larynx or trachea, and cervical teratoma nary development in fetuses with congenital diaphragmatic
(see Fig. 5.15) or other tumors of the face, mouth, and neck. hernia [206].
a b
Fig. 5.16 (a) Neonate with a hamartoma of the hard palate. (b) CT scan of the neonate demonstrating a clear and patent nasopharyngeal airway
16. Thach BT. Maturation and transformation of reflexes that protect

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Neonatal Ventilation Strategies
and Their Practical Application 6
Adam Balogh and Walid Habre
Recently, large cohort studies demonstrated that ventilation comes. Recently, there has been growing interest in the use of
issues increased perioperative morbidity and mortality in noninvasive ventilation in neonates, although evidence of its
neonates [1, 2]. Inadequate ventilation, manifested as either beneficial effects on both the lungs and the brain has been
hypo- or hyperventilation, had respiratory and systemic con- elusive. Whatever ventilation strategy is used, clinicians
sequences that may have contributed to morbidity and mortal- should be reminded that real-time pulmonary monitoring is
ity [3, 4]. Strategies were developed to improve lung essential to adapt the ventilation strategy to sudden changes
ventilation with a “protective” and “open-lung” strategy to in the mechanical properties of the lung that often occur dur-
optimize functional residual capacity (FRC) and prevent ven- ing surgery. This chapter reviews the pulmonary indices and
tilation-induced lung injury (VILI) and bronchopulmonary function in the neonate, describes the different ventilation
dysplasia (BPD). Clinicians have since become aware of the modes available, and highlights the importance of using a
potential harm of excessive hyperventilation in neonates protective and open-lung ventilation strategy.
because of large tidal volumes (Vt) that overdistend alveoli,
increase wall shear stress, and liberate proinflammatory
cytokines, which are the main features of the so-called VILI Respiratory System
[5, 6]. Moreover, the resultant hypocapnia that results from
extreme hyperventilation induces cerebral vasoconstriction Three specific physiological characteristics distinguish the
and may promote the development of cystic periventricular respiratory system in the neonate. First, the chest wall, which
leukomalacia [7]. Alternately, suboptimal Vt may result in is made up of the intercostal muscles and ribs, is highly com-
poor gas exchange and hypercapnia that potentially increases pliant in the neonate because the ribs are horizontally ori-
the risk of intraventricular hemorrhage (IVH) [8]. Thus, sev- ented and cartilaginous (non-ossified), giving the infant’s
eral different ventilation modes are now available based on thorax a cylindrical shape of the rather than the elliptical
the application of volume guarantee modes to optimize tidal shape seen in older children. Moreover, the effectiveness of
volume and meet the ventilation requirements of the neonate the intercostal muscles to augment and support the chest wall
according to the physiological characteristics of the respira- and minimize chest wall distortion during inspiration is lim-
tory system and the fluctuations in lung compliance. Despite ited, contributing less to the developing tidal volume in neo-
these new developments in ventilation, there is no evidence of nates compared with older children. The main muscle that is
the superiority of any one of these new ventilation strategies responsible to develop the tidal volume in neonates is the
in terms of neonatal pulmonary and neurodevelopmental out- diaphragm. However, in neonates, the diaphragm has less
muscle mass, fewer high-endurance Type 1 twitch fibers, and
inserts more horizontally than in older children [9]. Thus, in
A. Balogh neonates with respiratory distress and increased oxygen
Unit for Anesthesiological Investigations, University of Geneva, requirements, when the diaphragm contracts, the lower rib
Geneva, Switzerland cage moves inwards rather than downwards as seen in older
children. In aggregate, the chest wall characteristics limit the
W. Habre (*) ability of the neonate to increase alveolar ventilation effi-
Unit for Anesthesiological Investigations, University of Geneva,
ciently and effectively in the face of stress. Thus, the neonate
Geneva, Switzerland
will be predisposed to early fatigue [10]. In the preterm neo-
Geneva Children’s Hospital, University Hospitals of Geneva,
nate, these effects are even more extreme with a very low
Geneva, Switzerland
e-mail: [email protected] percentage of slow-twitch, high oxidative fibers that present

214 A. Balogh and W. Habre
as poorly developed ventilatory muscles, even less mature aware that when looking at the total respiratory system
than those in term neonates [9]. resistance, the tracheal tube combined with the resistance
The second important feature in the neonate that limits from the forces generated by the viscoelastic component of
their ability to respond to increased ventilatory demand is the the lung account for more than two-thirds of the total resis-
presence of the so-called “stiff lung.” This latter term relates tance of the airway. In neonates, the use of tracheal tubes
to the increased static elastic recoil of the lung. The elastic with small diameters increase the respiratory resistance, and
recoil is determined by the elastic fibers within the lung and the relatively high elastic recoil of the lung may further
by the surface tension force generated at the air–liquid inter- exacerbate the resistive component of the respiratory system
face within the alveoli [11]. Surfactant reduces surface ten- [15]. Thus, when ventilating the lungs in a neonate, the peak
sion and maintains the patency of the terminal airways, pressure applied should overcome both the frictional forces
independent of the alveolar diameter [12]. The high elastin/ that result from the airway resistances as well as those from
collagen ratio in neonates predisposes the lungs to collapse. both the tissue elastic recoil and the chest compliance. Many
Furthermore, the very compliant chest wall presents little clinical conditions observed in neonates may alter the effec-
resistance to hold the lungs open, resulting in a much smaller tiveness of ventilation, jeopardizing our ability to maintain
resting volume at end-expiration. The forces that favor the normocapnia and adequate oxygenation. Accordingly, posi-
collapse of alveoli are opposed by those that prevent the lung tive pressure ventilation may become challenging in the
from collapsing. The net effect of these opposing forces cor- presence of decreased lung compliance such as that seen
responds to the functional residual capacity (FRC) and rep- with surfactant deficiency or congenital diaphragmatic her-
resents the resting volume of the respiratory system. nia, which result in loss of lung volume. Other congenital or
Consequently, even after externally delivered, effective lung acquired diseases (tracheomalacia, bronchial infection, and
surfactant, the FRC in the neonate is relatively small, and inflammation) may increase resistance to airflow and require
even smaller in the preterm neonate. In the latter age group, specific ventilation modes to avoid very high intratracheal
respiratory distress syndrome arises from a deficiency in sur- pressures that may contribute to VILI.
factant, which causes the terminal airways to collapse. These
changes may lead to atelectasis, loss of lung volume, and
hypoxemia. This phenomenon is further exaggerated in the Key Points
preterm neonate because collateral airflow does not occur at • The specificity of the ventilatory muscles and the
the level of the bronchoalveoli because the terminal airways increased airway resistance contribute to respira-
are immature and alveolarization is disturbed [13, 14]. tory fatigue in neonates.
Finally, the neonatal respiratory system is challenged by • The viscoelastic feature of the neonatal lung is the
the increased airway resistance that arises in the upper air- main determinant for optimal ventilation.
ways and larger conducting airways of the lungs. The resis- • The surfactant plays a key role for alveolar stability
tance of the upper airways can be substantial in neonates, as and prevention of ventilation heterogeneity.
the resistance to airflow in the narrow conducting airways
down to the fifth bronchial division is inversely proportional
to the fifth power of the reduction in the radius of the lumen
as presented by the Fanning equation for turbulent flow Ventilation Modes
(Reynold’s number >2100) (e.g., if the radius of the upper
airway decreases by 50%, the resistance to gas flow increases A better knowledge of the neonatal respiratory pathophysiol-
by 32-fold). The radius of the airway may decrease substan- ogy as well as the advances obtained in ventilator technology
tially due to thickened mucous membranes arising from an have led to various complex ventilation modes, the useful-
inflammatory disorder, infection, or secretions. Thus, the ness of which has not yet been adequately proved primarily
radius of the airway is the most important determinant of the because of the lack of randomized trials in the neonates.
resistance of the upper airway. However, beyond the fifth Although the varied ventilation modes used routinely in the
bronchial division, the rapid increase in the cross-sectional neonatal intensive care unit (NICU) have confusing termi-
area of the airways decreases the velocity of gas flow and nology, many are simply not available on the anesthesia ven-
resistance to flow. With the decrease in gas flow, the tilators to deliver inhalation agents during surgery. However,
Reynold’s number decreases to <1800 and the flow becomes the current ventilation modes can be distinguished based on
laminar. In laminar flow, the resistance is inversely propor- whether they are volumetric (e.g., flow generator), baromet-
tional to the fourth power of the decrease in radius ric (the pressure generator), or a combination of both pres-
(Poiseuille’s equation for laminar flow). Furthermore, air- sure and flow generators (dual modes). New ventilators in
way resistance decreases as the child grows in height [15, anesthetic workstations allow the child to trigger the onset of
16]. In neonates, airway resistance may also increase from the ventilator cycle, which provides partially controlled or
airway closure and the loss in lung volume. One should be support ventilation modes.
6 Neonatal Ventilation Strategies and Their Practical Application 215
Pressure-Controlled Ventilation fore routinely used in clinical practice. Synchronized inter-

mittent mandatory ventilation (SIMV) pressure control mode
This mode is the most popular ventilation strategy in neo- and assist-control (AC) modes have been introduced in the
nates and is often recommended for use in clinical practice. intensive care settings to synchronize the respiratory rate
The basic and most frequently applied mode in NICU is the with the child’s breathing (SIMV) or by assisting each breath
time-cycled, pressure-limited ventilation (also called inter- using positive-pressure ventilation, but with a “control” of a
mittent positive-pressure ventilation (IPPV)), and is also minimum number of ventilator cycles (AC). Nonetheless, if
available with most anesthesia ventilators where it is termed the child breathes very frequently, the ventilator assists all of
pressure-controlled ventilation (PCV). The decelerating flow the triggered breaths by applying the initial Ti, which will
and the limited and constant inspiratory pressure that charac- decrease the Te and may lead to air trapping by reducing the
terize this ventilation mode explain the reduced peak inspira- time required to adequately exhale. This risk is also observed
tory pressure, which is accompanied by the reduced tracheal when using pressure support ventilation (PSV), a mode that
and alveolar pressures. This mode compensates for a poten- has been introduced on almost all new anesthesia ventilators.
tial leak around uncuffed tracheal tubes with leaks, still rou- In the PSV mode, the child’s breathing effort and the changes
tinely used during anesthesia in neonates [17]. The in the airflow together initiate and terminate the ventilator
combination of decelerating flow and constant airway pres- assistance. An important feature of this mode is that the child
sure over time facilitates the equilibration of tracheal and determines the Ti. Depending on the type of ventilator, expi-
alveolar pressures. Evidence suggests this mode improves ration begins when the inspiratory flow level decreases to
ventilation distribution, and thereby gas exchange [18]. between 10 and 25% of the maximum inspiratory flow [22].
However, when applying PCV, three main factors are inte- This mode is of interest to anesthesiologists. This ventilator
gral to determining the tidal volume: (i) the pressure gradient mode has been used in older children to reduce the work of
between the maximum inspiratory set pressure (peak inspira- breathing (WOB) associated with spontaneous breathing and
tory pressure (PIP)) and the positive end-expiratory pressure to counteract the greater resistance due to small tracheal
(PEEP), which defines the driving pressure, (ii) the inspira- tubes. Because of the greater risk of patient–ventilator asyn-
tory time (Ti) that may depend and/or determine the ratio chrony in the ill neonate whose respiration rate is very rapid,
between the inspiratory and expiratory times as well as the PSV may increase oxygen consumption and generate possi-
respiration rate, and (iii) the time constant to equilibrate the ble ineffective ventilatory efforts. Another novel technique
airways and alveoli pressures, which is a function of the total called proportional assist ventilation (PAV) has been devel-
respiratory system compliance and resistance. Therefore, oped to prevent such phenomena, offering to further reduce
when setting the PCV mode, the operator should (i) select the WOB. In this mode, the neonate controls the rate of lung
the Ti and expiratory times (Te) to determine the respiration inflation and thus the peak inspiratory pressure, which is pro-
rate close to the child’s physiological rate, (ii) adjust the peak portional to the neonate’s efforts [23]. Since the pressure
inspiratory pressure (PIP) and the PEEP, (iii) select the inspi- applied depends on the inspiratory flow generated by the
ratory flow rate, and (iv) select the inspired concentration of neonate, this ventilation mode assumes that the neonate is
oxygen. Although ventilating with a short or extended Ti not hypopneic and that there is no leak around the tracheal
does not affect the incidence of chronic pulmonary disease tube [20]. However, this ventilation mode, which is not avail-
(CPD) in neonates, a short Ti may decrease the risk of an air able in anesthesia workstations, is known as the airway pres-
leak and mortality [19]. The normal physiological Ti in neo- sure release ventilation (APRV). This mode is based on the
nates is between 0.35 and 0.5 s, which dictates the initial set- combination of a large continuous positive airway pressure
ting for Ti with a higher Te. This helps to establish the initial and brief releases of the pressure, which are short enough to
respiration rate. However, under anesthesia both Ti and PEEP generate auto-positive end-expiratory pressure [24]. This
can be increased in order to increase the mean airway pres- mode generates large intratracheal pressures, but is advanta-
sure and thus tidal volume and to recruit alveoli [20]. At the geous when the neonate is breathing spontaneously through-
same time, the higher Ti may also jeopardize venous return out the APRV cycle. Although its effectiveness has not been
and cardiac output. Alternately, shortening Ti during weaning elucidated [25], APRV has been associated with better car-
may help to synchronize the neonate’s respiration with the diopulmonary interactions and improved lung perfusion in
ventilator and is more advantageous in neonates. To over- infants after cardiac surgery [26]. Of more widespread inter-
come this limitation, synchronized ventilation with the neo- est is the neurally adjusted ventilator assist (NAVA), which
nate triggering the onset of ventilation is currently the relies on the child’s respiratory control and diaphragmatic
common mode used in NICUs. Among the different trigger- activity [27]. The inspiratory effort is detected via bipolar
ing techniques that have been developed, flow triggering via electrodes mounted on a nasogastric feeding tube and posi-
a flow sensor interposed between the tracheal tube and the tioned at the level of the diaphragm. The level of ventilatory
ventilator’s connection is the most sensitive [21] and is there- support is then proportional to the inspiratory effort. Even
though this mode is unaffected by a leak around the tracheal or guaranteed Vt with an adjustable high-pressure limit to
tube, its utility is still not well-defined in neonates, especially autoregulate the maximum inspiratory pressure (within the
in preterm infants with immature control of the ventilation. A maximum limit set) or the Ti to guarantee the target Vt. These
very recent prospective crossover study demonstrated that modes are known as volume-targeted ventilation modes and
NAVA is associated with improved patient–ventilator syn- include all of the modes that guarantee Vt by adjusting the
chrony and a reduced peak airway pressure in comparison inflating pressure in response to the exhaled Vt, which is
with PSV [28]. More recently, new modes of ventilation that compared with the target Vt [32]. There is evidence that
were based on individualized variable ventilation experi- volume- targeted ventilation reduces adverse outcomes
mentally promoted lung protection while providing adequate including severe intraventricular hemorrhage (Grade 3 or 4),
gas exchange both in normal and injured lungs [29, 30]. periventricular leukomalacia, and CPD when ventilating the
These new ventilation modalities based on the physiological lungs of preterm neonates compared with pressure-limited
variable ventilation in neonates could be beneficial during ventilation [33–35]. New anesthetic workstations now
prolonged ventilation in the absence of a respiratory drive. include ventilators with these modes, although these findings
have not been documented during anesthesia and surgery,
despite the theoretical advantage to deliver the Vt at a reduced
Volume-Controlled Ventilation intratracheal pressure, particularly when compliance and
resistance vary during surgery.
The major disadvantage of pressure-limited ventilation is Among the new ventilation modes developed, the vol-
that the tidal volume (Vt) varies, because of changes in the ume guarantee (VG) ventilation mode is a pressure-lim-
compliance of the lung and resistance of the airways, which ited, volume-targeted time or flow-cycled ventilator that
occur frequently in neonates during both anesthesia and sur- has garnered the interest of clinicians. The driving pres-
gery. As a consequence, some anesthesiologists continue to sure for this mode is based on the difference between the
advocate for volume-controlled ventilation (VCV), a strat- exhaled and predetermined Vts. The software analyzes
egy that is based on the traditional delivery of a fixed prede- each breath individually to maintain constant Vts. This
termined Vt at a preestablished rate. This mode does not, mode can be combined with other standard ventilation
however, take into account the maximum inspiratory pres- modes often used in neonates such as SIMV, AC, or PSV. In
sure needed to deliver the desired Vt. Furthermore, high tra- addition to setting the maximum PIP to limit lung injury,
cheal pressures may be encountered during surgery, both the desired Vt (exhaled Vt) and Ti are set, which
especially when the lung compliance decreases and/or air- determine the duration of insufflation. These ventilator
way resistance increases to deliver the predetermined Vt. characteristics are particularly appealing in preterm neo-
These high driving pressures may be limited either by setting nates who are weaned from spontaneous respiration since
the pressure pop-off valve or by determining the level of Ti in the inspiratory pressure is adjusted in real-time [31]. Other
order to limit excessive peak inspiratory pressures during anesthesia workstations use the pressure-regulated volume
mechanical ventilation of low compliant lungs. Nonetheless, control (PRVC) mode in which the gas flow rate is adjusted
this mode of ventilation is deceptively misleading, particu- to generate an inspiratory pressure sufficient to deliver the
larly in neonates, as the preset Vt is not delivered to the lungs targeted Vt [36]. Thus, this ventilation mode shares many
since this mode does not compensate for the tidal volume similarities with pressure control modes in terms of the
lost to the compression of the gas within the ventilator cir- pressure and flow patterns but delivers the target Vt by
cuit, the compliance of the breathing circuit and the leak adjusting the PIP based on the compliance of the lung. One
around the uncuffed tracheal tubes. It is imperative that ven- study demonstrated that this ventilation mode is very
tilation is monitored using a capnogram and oxygenation effective in very low birth weight (VLBW) preterm infants
using an oximeter. as both the duration of mechanical ventilation and hemo-
dynamic instability are less than those that occur with
other ventilation modes [37, 38]. Furthermore, this mode
Volume-Targeted Ventilation is associated with lower peak intratracheal pressures and
its impact on hemodynamics is less than with other modes
The increasing awareness of the usefulness of direct control [39]. When this mode is combined with other ventilator
of the PIP and the benefit of ventilation with a small, con- options that allow infants to breathe spontaneously with
stant Vt led clinicians to develop dual-mode ventilation strat- pressure support, it is called “auto mode,” which is cur-
egies to guarantee Vt with a limited pressure [31]. Several rently built into some anesthesia workstations. To date,
ventilators and ventilation modes have since been developed there have been no studies that document the advantages of
and are routinely used in the intensive care to deliver a target this ventilation mode in neonates.
High-Frequency Ventilation function [47]. The incidence of chronic lung disease in pre-
term babies may be less if the lungs are ventilated with
High-frequency ventilation (HFV) rapidly became a strate- HFOV but the evidence is weak [47]. Nonetheless, HFOV
gic and favorite ventilation mode in neonates with chronic may still have a great clinical benefit in the operating room,
and severe lung disease as ventilation is ensured by applying particularly to ventilate low compliant lungs in neonates
small tidal volumes at a MAP (mean airway pressure) that is with congenital diaphragmatic hernia or severe respiratory
higher than with conventional ventilation. This strategy is distress.
very effective in infants with severe respiratory failure since
HFV improves the gas exchange by optimizing the lung vol-
ume while ventilating at lower proximal airway pressures, ontinuous Positive Airway Pressure
C
thereby avoiding lung damage [40]. The principle upon and Noninvasive Ventilation
which HFV is based on the natural “resonant” frequency of
the lung and that less pressure is required to move the gas Many neonates may benefit from noninvasive respiratory
into and out of the lungs at its resonant frequency, which is support that applies continuous positive airway pressure
around 10 Hz (1 Hz = 60 bpm) in neonates and even greater (CPAP) and/or the delivery of noninvasive ventilation (NIV).
in preterm infants. HFV improves the gas exchange by Nasal CPAP maintains the FRC by recruiting and maintain-
enhancing both the convection and the diffusion of respira- ing a patent airway and inflated lungs [48]. It also decreases
tory gases. Different ventilators delivering HFV are available the WOB and reduces the frequency of apnea of prematurity
without evidence that one type of HFV ventilator is superior [49]. Therefore, nasal CPAP has become a standard ventila-
to another. The first ventilation modality was high-frequency tion strategy to support the lungs in recently extubated pre-
jet ventilation (HFJV), a technique that has become well- term infants, as an alternative to tracheal intubation and
established in anesthesia. This mode delivers quick bursts of ventilation, to support those experiencing significant apnea
gas (with very short Ti) at very high frequency (up to 600/ of prematurity and for those with respiratory distress soon
min) combined with a constant gas flow that determines the after birth. Some newer systems also provide a phasic posi-
level of PEEP. This technique required a specific tracheal tive increase in pressure (pressure support or pressure-
tube but failed to prove its effectiveness in clinical practice as controlled) in addition to the CPAP and can be synchronized
the neurological and respiratory outcomes in neonates were (SNIMV, synchronized nasal intermittent mandatory ventila-
conflicting [41–43]. Another modality that used HFV is tion) or not (NIMV). During the past decade, the use of NIV
known as high-frequency flow interruption (HFFI), consist- in neonatal intensive care units for acute respiratory failure
ing of a continuous gas flow, which is delivered by a high- has been expanding and the factors that predict the success-
pressure gas source that is interrupted at a high frequency (up ful use of NIV have recently been identified [50]. While
to 20 Hz) [44]. This technique also failed to become widely meta-analyses have failed to demonstrate the benefit of NIV
adopted as it offered no advantages in pulmonary outcomes in the presence of respiratory distress syndrome [51], its
and yielded a greater incidence of air leaks in preterm babies ability to prevent extubation failure in neonates is well estab-
compared with traditional ventilation modes [45, 46]. The lished [52]. Accordingly, the use of NIV to protect against
most frequently used ventilation mode currently is high-fre- the risk of reintubation during the first 72 h is the current
quency oscillatory ventilation (HFOV). This mode is based evidence-based indication for NIV in neonates [48]. For this
on the presence of an electromagnetically driven piston or purpose, NIV is started after the minimal PEEP level is set to
vibrating diaphragms that generate biphasic pressure wave- ~6 cmH2O and the PIP to 10–12 cmH2O.
forms at very high frequencies (up to 15 Hz). Thus, HFOV CPAP can be delivered by one of two techniques: (i) A
has both an active inspiratory phase and an active expiratory continuous flow and a device that varies the exhalation either
phase (by inducing a negative proximal airway pressure dur- by modifying the expiratory orifice size or by immersing the
ing exhalation). When using HFOV it is important to adjust distal end into a water reservoir to a specific level, the depth
the I/E ratio to avoid gas trapping that may occur as a result of which defines the level of CPAP. This latter is known as
of the active exhalation part [22]. HFOV provides very small bubble CPAP—the bubbles creating pressure oscillations
oscillatory tidal volumes that are superimposed on an adjust- that are transmitted to the airway opening. It has been sug-
able MAP. HFOV offers a particular advantage when a large gested that this phenomenon may improve gas exchange by
tidal volume strategy is required to maintain the FRC as facilitating diffusion [53]. (ii) A variable flow that allows
HFOV maintains FRC with a smaller MAP compared with changes in the level of CPAP using nasal prongs, which
other modes of ventilation. Nevertheless, a recent meta-anal- redirect the exhaled gas out of the expiratory limb. The WOB
ysis failed to demonstrate any benefit of HFOV over conven- with the variable-flow CPAP is less than that with the bubble
tional ventilation modes when it is used as a primary or CPAP [54]. Another system that is based on the variable-flow
rescue mode to ventilate infants with acute pulmonary dys- setting is the bi-level CPAP or BiPAP. BiPAP allows the
child to trigger the inspiratory phase and to breathe between patency and end-expiratory lung volume [59]. This pressure
two levels of positive pressure, with some systems including correlates linearly with the flow [58, 60, 61] and depends on
an abdominal wall sensor to synchronize inspiration with the the child’s weight as well as the size of the leak around the
child’s efforts. The BiPAP system may be better at improv- prongs [62]. Unlike CPAP or noninvasive ventilation, NHFO
ing oxygenation and ventilation than the CPAP system in generates pressures that vary during both inspiration and
low birth weight (LBW) infants [55]. expiration. Since airway pressures depend on both the direc-
The application and successful use of CPAP and NIV rely tion and the magnitude of the ventilation flow relative to the
on the airway interfaces and their ability to guarantee com- delivered flow, pressures are minimized at end-inspiration
fort and optimize the delivery of pressure to the airway. Of and maximized at mid-expiration, with end-expiratory pres-
all the interfaces that provide CPAP, the bi-nasal prongs are sures decrease in between the two readings [63]. In preterm
superior [56]. Although bi-nasal prongs are associated with a infants, gas flows of 2–8 L/min delivered by three different
greater incidence of nasal trauma in infants [22], leaks NHFO devices resulted in end-expiratory pharyngeal pres-
remain a major concern in NIV. Such leaks may reduce alve- sures of 2–6 cmH2O, with a mean increase of 0.5 cmH2O for
olar ventilation, impair child–ventilator synchrony, and each 1 L/min increase over 2 L/min [62, 64], albeit with large
increase nasal resistance. variance. Although there is no clear consensus, mouth open-
ing did not affect the pharyngeal pressures in neonates and
infants, unlike in adults [60, 62, 65, 66].
Nasal High-Flow Oxygenation Finally, irrespective of the gas flows being between 2 and
8 L/min, NHFO decreased the WOB as evidenced by trans-
In the last decade, nasal high-flow oxygenation (NHFO) has cutaneous diaphragmatic electromyography and respiratory
gained widespread popularity in several populations, partic- inductance plethysmography [67, 68]. Decreased airway
ularly in neonates, to improve oxygenation and/or as an resistance due to the splinting effect of positive pressure,
alternative to noninvasive ventilation. This method is based decreased minute ventilation due to dead space washout, and
on the delivery of a mixture of air and oxygen via a nasal decreased metabolic demand due to the heating and humidi-
cannula at a high gas flow, matching or exceeding the child’s fication are all plausible mechanisms that individually or in
peak inspiratory flow. Compared with conventional low-flow aggregate decrease the WOB.
(2 L/min) nasal cannulae, NHFO delivers greater gas flow In spontaneously breathing neonates [66] and preterm
rates, at 1–4 L/kg/min in neonates. Such large gas flows infants [62], NHFO improves oxygenation and elimination
necessitate the prior heating and humidification of the gas of CO2, although it failed to prevent hypercapnia in apneic
mixture since the delivery of a cold, dry gas would desiccate children [69, 70]. Nonetheless, during the past decade,
the mucosa of the nasal cavity and the lower airways, leading NHFO has been increasingly used for apneic oxygenation
to trauma and airway edema, as well as impairing mucocili- during intubation and airway procedures to prevent or delay
ary flow. The net result is to retain secretions [57]. Thus, this oxygen desaturation [69–72]. In neonates and infants aged
technique is also referred to as heated, humidified nasal 0–6 months, NHFO increased the mean time to desaturate to
high-flow, and accordingly, current devices integrate a an SpO2 of 92% from 109 s to 196 s [70]. The improved oxy-
heater–humidifier to deliver a gas mixture at a temperature of genation during NHFO is due to pharyngeal dead space
37 °C saturated with water. The choice of the prongs (made washout, greater achievable FiO2, airway splinting effect,
of soft silicone) is of importance in neonates as a sufficient and maintenance of the FRC. However, the failure to aug-
leak (20–50% of the nares’ internal diameter) should be ment CO2 elimination may be explained in part by the struc-
allowed around to cannulae to both facilitate expiration as tural properties of the neonatal airways. A computer
well as to prevent the accumulation of excessive end- simulation suggested that a key mechanism that clears CO2
expiratory pressures generated by the continuous flow [58]. during NHFO is via cardiogenic oscillations augmenting
Several mechanisms have been proposed to explain the alveolar ventilation [73]. However, in the apneic infant and
improved oxygenation with NHFO. First, since the gas flows child, cardiac oscillations are not augmented because airway
delivered by the NHFO match or exceed the peak inspiratory resistance is increased and this might explain why NHFO
flow, and the nasopharyngeal dead space is constantly failed to clear CO2 from the lungs [74]. This peculiarity may
washed out by the gas mixture, room air entrainment and explain the similarity in oxygenation during apnea after
CO2 rebreathing are reduced. Consequently, the partial pres- administering 100% oxygen at 2 L/kg/min via NHFO and
sure of oxygen in the nasopharyngeal space is closer to the that via traditional low-flow cannulae at 0.2 L/kg/min [70].
set FiO2 during NHFO compared with low-flow oxygen- In summary, NHFO may be considered an effective strat-
ation, resulting in a greater diffusion gradient for oxygen egy to oxygenate the infant during airway procedures by pro-
between the upper airway and the alveoli. Secondly, NHFO longing the time available to intubate the trachea, particularly
creates positive airway pressure that increases airway in the neonate, those with a difficult intubation [17] and those
with limited oxygen reserves [70, 75]. It is essential to recog- tion between the airway pressure (Paw) and the alveolar
nize that despite oxygenating the child, NHFO incompletely pressure (Palv), known as the time-constant. Moreover, the
clears CO2 during apnea. Alternately, maintaining oxygen- compressible volume is an important issue in the neonate
ation via a traditional low-flow cannula is a suitable and cost- and it is important to understand whether the ventilator cor-
effective method to routinely implement in clinical practice. rects for this compressible volume in the case of a fixed Vt
setting. Most modern ventilators available in anesthesia cur-
rently correct for the compressible volume when the ventila-
Key Points tor is checked during the machine check. If there is a change
• There is a shift from controlled mechanical ventila- of circuits between infants, it is important to recheck the
tion to combined modes with spontaneous ventila- compressible volume as the neonate’s Vt may be of a similar
tion to improve alveolar ventilation and order of magnitude as the compressible volume. It is also
cardiopulmonary interactions. important to ensure that the tidal volumes displayed on the
• The pressure-regulated volume control mode meets workstation monitor are accurate by performing the pre-use
the specific characteristics of neonatal respiratory anesthesia workstation testing (which compensates for cir-
physiology. cuit compliance) with the circuit tubing in either the com-
• There is still no evidence for the advantage of one pressed or expanded state, depending on how the circuit will
given mode over the other as clinical trials in neo- be used during anesthesia [76]. For a ventilator that predates
nates are sparse with large inhomogeneity. software that corrects for compressible volume or limits
compensation if the pressure exceeds 30 cmH2O [77], it is
essential to account for the compressible volume when set-
ting the Vt. For example, if the compressible volume reaches
pplication of Ventilation Modes
A 1 mL/cmH2O, and the delivered Vt is 7 mL/kg in a 4 kg neo-
in the Operating Theatre nate, the ventilator may generate a PIP of 25 cmH2O during
ventilation, yielding a compressible volume of 25 mL. The
Despite the great advances in the development of new anes- preset Vt should be adjusted to almost 13 mL/kg since 50%
thetic ventilators, which include a variety of modes of venti- or more may be lost due to the compressible volume (not
lation widely used in the operating room and intensive care taking into account the dead space and the potential leak).
setting, the benefits of these modes of ventilation during gen- Thus, the use of the VCV mode requires that the overpres-
eral anesthesia to improve clinical outcomes have not been sure valve be set to protect the lung from any dangerous
forthcoming. In neonates, these ventilation modes contribute increase in peak inspiratory pressure that may result from
to “lung protective ventilation” by optimizing the distribu- changes in lung compliance during the surgery. In neonates,
tion of ventilation in the presence of alveolar instability. particularly those with less compliant lungs, we believe that
Alveolar instability refers to the presence of both collapsed PCV is the preferred Te mode of ventilation in neonates.
and overdistended alveoli in the lungs. The repetitive alveoli The decelerating flow pattern that characterizes the PCV
recruitment and collapse generated by positive pressure ven- mode offers a limited and constant inspiratory pressure with
tilation with each breath may cause excessive dynamic shear a plateau pressure that is reached much faster, but at a lower
stress on the alveolar walls, while overdistensing adjacent PIP and thus driving pressure than VCV. This mode improves
alveoli produces a dynamic strain with each breath. As a con- the distribution of ventilation and decreases the intrapulmo-
sequence, a new concept was recently developed that pro- nary shunt, thereby improving oxygenation. Furthermore,
motes “specific tidal volume,” which is determined by the the PCV mode compensates for the presence of a gas leak
driving pressure determined by the inspiratory pressure over around tracheal tubes. Although PCV better satisfies the cri-
the PEEP level set on the ventilator. The goal is to optimize teria required by the protective-ventilation strategy, Vt will
gas exchange while decreasing lung stress and strain. Thus, fluctuate in this mode, particularly if lung compliance
the most appropriate ventilation mode would be the one that decreases or respiratory resistance increases during surgery.
maintains the smallest driving pressure as possible to meet During PCV, Vt depends on three components: (i) the time
the “lung protective ventilation” concept. constant, (ii) the pressure gradient between the maximal set
Therefore, the traditional mandatory VCV strategy is far peak pressure and the PEEP level, and (iii) Ti, which is deter-
from the ideal strategy to ventilate the lungs in the neonate mined by the respiration rate and the I/E ratio. The time con-
because it connotes a constant flow that generates large driv- stant is characterized by the mechanical properties of the
ing pressures and fails to account for the compressible vol- respiratory system, which include the total respiratory sys-
ume of the breathing circuit and the potential gas leak around tem compliance (Crs) and resistance (Rrs). Application of
uncuffed tracheal tubes. The constant flow characterizing the the time constant concept to the inspiratory phase implies
VCV mode induces large PIPs with less time for equilibra- that Ti is set to allow sufficient time to equilibrate the pres-
Flow Equilibrium between

airway and alveolar
pressures not achieved
Te Time
Ti
Deflation unachieved
Back to 0
Fig. 6.1 Flow vs time curve demonstrating the “time constant con- sufficient duration to preclude intrinsic PEEP. Ti Inspiratory time, Te
cept” with decelerating flows. Ti should be of sufficient duration to per- Expiratory time, PEEP Positive end-expiratory pressure
mit the inspiratory flow to return to 0. Similarly, Te should be of
sures between the airways and alveoli. Accordingly, if Rrs ratory efforts, the level of pressure support, and the
increases and/or Crs decreases, the time to equilibration will mechanical characteristics of the lung as well. Currently, few
increase. Further, it is important to allow sufficient time to modern anesthetic ventilators have cycling adaptation (tran-
complete deflation, as the expiratory flow has an exponential sition from inspiration and expiration). In the case of ventila-
decelerating profile that can take up to 3 to 4 time constants tors with fixed cycling, insufflation will stop when the flow is
of the respiratory system to completely deflate (see Fig. 6.1). less than 25% of the maximum inspiratory flow. This limita-
Finally, it is important to note that anesthetic ventilators tion may have a negative impact on the neonate with obstruc-
that are currently available vary in the maximum insufflation tive disease for which cycling should occur later [80].
flow they can generate. Thus, the Vt generated by a given Although studies using the PSV mode in neonates have not
pressure level may vary from one ventilator to another [78]. been forthcoming, this mode can be applied during anesthe-
Considering Ti is short and the respiratory rate is rapid in sia in clinical practice to compensate for the increase in the
neonates, it is important to note that the physiological Ti does WOB, which is particularly great in neonates. For instance,
not exceed 0.5 s. However, in an anesthetized neonate, who the application of pressure support of 5 cmH2O in addition to
is paralyzed with a muscle relaxant, one may exceed this Ti PEEP at induction will maintain patent airways, thus offset-
to recruit alveoli. At the same time, increasing the Ti may ting the WOB and optimizing the gas exchange during inha-
also impact hemodynamic variables and lead to asynchrony lation inductions. During the maintenance phase of
if the PSV mode is selected. Therefore, the initial ventilator anesthesia, more pressure support may be necessary (up to
settings in PCV mode should include the pressure gradient 10 cmH2O) to overcome the resistance from the tracheal tube
established with a PEEP of 5 cmH2O and a positive inspira- and the anesthesia circuit, as well as to guarantee an optimal
tory pressure over PEEP of 10 cmH2O. The respiration rate Vt for gas exchange [81]. After anesthesia, the PSV mode
will be determined by initially selecting a Ti up to 0.6 s. The allows for a smoother recovery, emergence, and weaning
choice of both the Ti and the pressure gradient will depend on from the ventilator. In all cases, it is important to set a mini-
the compliance and the resistance of the respiratory system mum respiration rate to deliver breaths in a pressure control
and the blood gas analysis. It is also important to consider Te, mode even during an apnea. In such a case, PCV adapts Ti to
particularly in neonates with obstructive lung disease, such avoid asynchrony with the ventilator that may increase the
as bronchopulmonary dysplasia, where the expiratory time WOB. Lastly, some anesthetic ventilators allow changes in
constant should permit sufficient time to exhale to minimize the pressure slope (the time to achieve pressure support). By
auto-PEEP and hyperinflation. increasing this time (and thereby decreasing the pressure
PSV mode has become popular in routine practice in slope), we can limit the auto-trigger activated by the cardiac
pediatric anesthesia as it maintains diaphragmatic activity activity, which is frequently observed in neonates at low
during general anesthesia, which decreases ventilation–per- trigger threshold [82]. To avoid this phenomenon, it is also
fusion mismatch. New ventilators include a flow trigger that possible to increase the trigger threshold with the risk of
is very sensitive to minimal variations in flow rate (similar to increasing the WOB.
those observed with intensive care ventilators) and can there- Recently, the PRVC mode with auto mode (auto-flow)
fore be applied in neonates since a minimal WOB is required was introduced in new anesthetic ventilators in the operating
to initiate an inspiratory effort [79]. The pressure support is theatre. VCV with a decelerating flow in combination with
based on a decelerating flow, which generates a fixed insuf- synchronization with a pressure support of the spontaneous
flation pressure; thus, Vt may vary with the neonate’s inspi- ventilation offers the advantages of pressure modes with a
guaranteed minimum Vt. Theoretically, this mode overcomes use in routine practice popular [85, 86], although they may
the inconvenience of both PCV and VCV and may offer an be less effective in applying a continuous positive airway
enormous advantage in anesthetized neonates, particularly pressure (CPAP) at end-expiration to maintain upper airway
when lung compliance decreases abruptly during surgery patency and FRC. In this context, applying gentle mask ven-
(i.e., laparoscopy, or abdominal or thoracic surgery). To tilation with CPAP to maintain a mean airway pressure
determine the initial guaranteed volume, the child’s lungs around 5–10 cmH2O becomes an increasingly popular venti-
should initially be managed using pressure control and lation strategy at induction of anesthesia, even in the pres-
extract the tidal volume that ensures adequate alveolar venti- ence of a full stomach to avoid airway collapse and to ensure
lation. Thereafter, the determined tidal volume can be con- adequate oxygenation [87, 88]. Alternatively, using PSV at
sidered as the targeted tidal volume in PRVC mode while induction of anesthesia will ensure an adequate CPAP level
adapting the ventilator setting according to PCV mode and to maintain the FRC and a low-pressure support to optimize
by applying a maximum inspiratory pressure of 30 cmH2O to alveolar ventilation. This so-called controlled induction
protect the lungs from overpressure. Nonetheless, no data technique meets the criteria for an “open-lung strategy,”
have been forthcoming regarding the use of this ventilation which should be considered at all stages when ventilating a
mode in the operating theatre, particularly in neonates and neonate’s lungs in the operating theatre.
hence although this mode meets the physiological character- The open-lung strategy primarily addresses concerns
istics of the lung during surgery, its usehas remained anec- about atelectasis and the resultant ventilation inhomogeneity
dotal and based on the experience of different clinicians. observed during general anesthesia, which can significantly
impair pulmonary gas exchange. First, the physiological
characteristics of the chest wall (large compliance) and the
Key Points lung (increased static elastic recoil pressure) in neonates pro-
• Alveolar instability promotes ventilation heteroge- mote airway closure and a decrease in FRC. The decreased
neity with excessive shear stress and enhancement ventilation associated with general anesthetics and inactiva-
of dynamic strain at each breath. tion of the intercostal muscle activity associated with the cra-
• Ventilation modes with decelerating flows provide a nial shift of the diaphragm are also responsible, in part, for
low driving pressure and thus exert less lung stress the lungs collapsing and atelectasis formation. The latter is
and strain. enhanced by the resorption of alveolar gas when an exces-
• Allowing spontaneous ventilation with pressure sive FiO2 is used. Thus, this “open-lung strategy” requires
support as soon as possible improves ventilation that recruitment maneuvers should be regularly performed,
homogeneity and cardiorespiratory hemodynamic particularly after the loss of positive end-expiratory level (at
interactions. zero PEEP level). Such recruitment can be achieved by
applying a vital capacity maneuver (or twice the Vt, but lim-
iting the maximum inspiratory pressure to 30 cmH2O in nor-
entilation Strategy in the Operating
V mal lungs) after induction, after disconnection and suction,
Theatre and thereafter every 30 min during the anesthetic procedure
[89]. However, a minimum PEEP level of 5 cmH2O is
Maintaining adequate ventilation during sedation or anesthe- required to maintain the recruitment of the distal airways
sia is of particular importance in neonates, who are vulnera- [90], while high concentrations of oxygen should be avoided
ble to hypoxemia. Inadequate bag and mask ventilation as tolerated. Nonetheless, an increased PEEP may be
during induction of anesthesia may result in insufficient required in the presence of poorly compliant and atelectatic
alveolar ventilation, hypoxemia, hypercapnia, and gastric lungs to maintain adequate alveolar recruitment.
inflation and regurgitation of gastric contents with subse- Beyond this open-lung strategy, it is crucial to apply “pro-
quent pulmonary aspiration. Furthermore, the accumulation tective ventilation” in an attempt to protect against VILI,
of air within the stomach may further compromise respira- which has been associated with an increase in lung stress and
tory function and gas exchange in neonates whose functional strain [91]. Ventilation with small Vt at optimal FRC is there-
residual capacity is less than its closing volume. While the fore essential in the operating theatre as well. Optimizing the
use of an accessory circuit such as a modified T-piece breath- level of PEEP will increase the lung volume, while adapting
ing system (i.e., Jackson Rees) continues to be advocated as Ti and Te will guarantee adequate lung inflation and deflation,
the best system to ensure both adequate ventilation and respectively, especially if Ti/Te is adjustable based on estima-
maintenance of FRC [83, 84], it is important to monitor air- tions of the time constants. This “protective ventilation”
way pressure during manual ventilation to avoid both exces- strategy should account for the continuous changes in respi-
sive peak inflation pressure and gastric air insufflation. The ratory compliance of the neonate undergoing surgery and the
development of low resistance circle systems rendered their ventilation inhomogeneity.
This ventilation strategy may lead to mild hypercapnia, match should be suspected. A recruitment maneuver at any
6–6.5 kPa (61–67 cmH2O), which is regarded as safe in the FiO2 will re-establish an acceptable SaO2, which may be
absence of high intracerebral pressure and pulmonary hyper- maintained with an adequate level of PEEP. Hence, it is
tension. Furthermore, mild hypercapnia improves both the prudent to maintain the FiO2 at ~30–35% during anesthe-
cerebral oxygen saturation and the subcutaneous tissue oxy- sia in neonates to identify intraoperative alveolar closure
genation [92]. Fetal hemoglobin has a greater affinity for as soon as it occurs and initiate a recruitment maneuver.
oxygen compared with adult hemoglobin, thus explaining
the leftward shift of the oxyhemoglobin dissociation curve in
the neonate and the resultant reduced P50. Further reduction Key Points
in the P50 may occur with hyperventilation (Bohr effect), • Hypoxia and/or hypocapnia are the major burden
thereby further decreasing tissue oxygen delivery [93]. during mechanical ventilation.
Moreover, hyperventilation and/or the application of large • Pressure regulated volume control is the most
tidal volumes may lead to hypocapnia and thus, cerebral appropriate mode in neonate as the inspiratory
vasoconstriction, a major risk factor that predisposes to cere- decelerating flow will adapt continuously to the
bral ischemia and possible neurocognitive impairment in changing respiratory compliance.
young infants [4]. • The inspired oxygen fraction should be titrated to
Therefore, in an attempt to meet the physiological require- avoid hyperoxia and to detect early onset of ventila-
ments stated above, it is advisable to always consider the tion/perfusion mismatch.
pressure-regulated volume control mode. This mode delivers
a constant tidal volume with the smallest inspiratory flow
and driving pressure and prevents perturbations in the carbon
dioxide tension. Studies demonstrated a greater incidence of Monitoring of Ventilation
cerebral insults in infants with extreme carbon dioxide, par-
tial pressures less than 4.6 kPa (47 cmH2O) or greater than Although real-time pulmonary monitoring is essential to
6.6 kPa (67 cmH2O) [94–96]. The required tidal volume can interpret the changes in lung physiology that occur during
be determined first by setting the pressure control mode with mechanical ventilation in neonates, it is crucial to associate
a pressure gradient between a PEEP level of 5 cmH2O and a the information obtained from different waveforms dis-
peak inspiratory pressure of 10 cmH2O as well as a Ti of played by the ventilators and the output on gas exchange and
0.6 s. These variables will dictate the respiration rate and the tissue oxygenation. Applying a protective open-lung ventila-
primary tidal volume. Then, based on the end-tidal carbon tion strategy requires adaptation of the ventilator settings
dioxide tension, the driving pressure should be adjusted according to this real-time pulmonary monitoring. Most ven-
(<13 cmH2O) to obtain the targeted values. In a second step, tilators available in the operating theatre display continuous
the resultant tidal volume will be maintained as ventilation is waveforms of pressure, volume, flow, and loops, as well as
switched to PRVC without changing other settings. automatically derived respiratory mechanical variables. The
Titrating the inspired oxygen fraction (FiO2) in preterm classical pulmonary waveforms are represented by pressure,
and term neonates is not straightforward. It is important to volume, and flow displayed versus time. The pressure and
avoid excessive inspired concentrations as the resulting flow curves are specific for the ventilation mode used and
oxidative stress contributes to potential major organ inju- thus, while displaying the pressure curve is essential during
ries including effects in the lung, brain, and eyes [97]. In VCV (since pressure is the dependent variable), it is equally
addition, given the large affinity of fetal hemoglobin for O2 important to focus on the flow versus time curve in the PCV
and the shape of the oxyhemoglobin dissociation curve, an mode since the effectiveness of alveolar ventilation depends
arterial oxygen saturation (SaO2) >92% may not accu- on the greatest extent on the flow waveform. This allows the
rately correlate with the arterial partial pressure of oxygen anesthesiologist to detect: (i) an interruption in the inspira-
(PaO2). Hence, small fluctuations in the SaO2 may reflect tory waveform, indicating insufficient time to equilibrate the
very large fluctuations in the PaO2 [98]. Knowing the par- alveolar and airway pressures, with the risk being inadequate
ticular harm that an excess of oxygen may cause in pre- lung inflation, and (ii) an incomplete deflation of the lung
term and full-term neonates, the inspired oxygen fraction with the risk of auto-PEEP, overdistension of the lung, and
should be titrated to target a SaO2 between ~90 and ~94% an enhanced risk of barotrauma. Thus, in terms of the flow
[99, 100]. Setting a minimum FiO2 after induction of anes- curve, it is essential to adjust both Ti and Te (either by chang-
thesia would also benefit identifying the loss in lung vol- ing the ratio or by decreasing the respiratory rate) to let the
ume and decrease in FRC, which are at the root of waveform reach the zero-flow state before transitioning to
intraoperative hypoxemia in infants. Thus, when SaO2 the next insufflation or exsufflation [101].
decreases in a neonate or infant, ventilation/perfusion mis-
The pressure–volume and flow–volume loops afford an factor affecting cerebral perfusion and may indirectly indi-
insight into the respiratory mechanics during mechanical cate an inappropriate ventilator setting.
ventilation, namely the respiratory system compliance and
resistance. The flow–volume loop is very useful to detect
changes in the inspiratory or expiratory resistances. For Key Points
instance, increases in airway resistance are obvious in the • Flow versus time curve and pressure–volume loop
flow–volume curve with a decrease in the expiratory flow are essential to adapt the ventilation strategy.
peak, which is expressed by a concave expiration loop. • The near-infrared spectroscopy should be consid-
Moreover, an incomplete flow–volume loop indicates an air ered as an important indirect monitoring of mechan-
leak, which can occur in neonates with uncuffed tracheal ical ventilation.
tubes are present. The dynamic pressure–volume (P–V) • A decrease in oxygen regional saturation may be
loop, which is displayed by the ventilator, describes the due to a decrease in cerebral perfusion as a conse-
mechanical behavior of the respiratory system during infla- quence of decrease in cardiac output or vasocon-
tion and deflation and includes the resistive and convective striction due to hypocapnia.
acceleration components of flow. Thus, the dynamic P–V
curve provides essential information to track the dynamic
trends of the respiratory system compliance (defined by the
slope of the loop), as well as tidal volume. Although some Conclusion
information can be obtained from the curve to help deter-
mine the “best” PEEP, the beginning of the dynamic inspira- There is growing evidence of the benefit of applying an open
tion provides evidence on lung recruitment from tidal and protective lung strategy in neonates. Over the past two
ventilation, independent of PEEP [102], particularly during decades, technological advances have introduced several
PCV when the pressure remains constant. Conversely, when new ventilation modes, which have undoubtedly advanced
ventilating with a constant flow such as under VCV, the P–V neonatal ventilation. Although the superiority of one ventila-
loop may detect overdistension of the lung as evidenced by a tion mode over another in terms of neonatal pulmonary and
change in the slope of the inspiratory P–V curve, namely the neural outcomes has not been established, there is some evi-
upper inflection point. The lower inflection point at the lower dence that pressure-regulated volume control may provide
part of the loop corresponds to the beginning of an alveolar the most appropriate ventilation mode. However, the remain-
recruitment. This may provide insight into the importance of ing challenge is to determine how best to mechanically ven-
airway closure. tilate the lungs based on respiratory physiology of the
The automatically derived values displayed by the venti- preterm and full-term neonate to optimize lung volume and
lator should be interpreted with some caution as the abso- guarantee adequate tissue oxygenation without augmenting
lute values are global parameters including the whole lung stress and strain, which may induce lung injury (par-
respiratory system as well as the equipment (circuit, tra- ticularly in the immature lung) and lead to serious hemody-
cheal tube, filter, and so on) [103]. These values are often namic consequences with subsequent adverse neurological
obtained using the interruption technique, which is based and metabolic outcomes.
on the ratio of the pressure decrease due to the interruption
of the inspiratory flow and that before the interruption. It is
important to note that >40% of the values are related to the References
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Perioperative Monitoring: Methods,
Implementation, and Interpretation 7
Nicola Disma and Christian Breschan
Introduction This chapter describes and discusses methods for periop-

erative monitoring of the cardiorespiratory, neurological, and
Comprehensive, accurate, timely, and absolutely reliable metabolic state of the neonate. The monitors described vary
monitoring is an essential objective for the safe and success- from the simple and noninvasive to the complex and inva-
ful management of the neonate during surgery. The achieve- sive. The selection of the extent of monitoring required for
ment of this objective is complicated by two main factors: any individual neonate will depend upon the severity of the
medical/surgical condition and the proposed surgery. It is
1. The small size of the infant increases the difficulty in assumed that neonatal surgery will only be performed in hos-
applying all types of instrumentation, especially those pital units that have the appropriate equipment to properly
pertaining to vascular access. In addition, the neonate is monitor the neonate.
frequently completely covered during surgery and out of
sight or easy reach by the anesthesiologist. Thus, visual
observation of the neonate is impossible, leaving the Cardiorespiratory Monitoring
anesthesiologist completely dependent upon the applied
monitors. All monitoring lines, probes, or catheters must Precordial Stethoscope
be functioning perfectly before surgery commences and
be protected against any possible compromise intraopera- The precordial stethoscope is the original and simplest
tively, such as pressure from the drapes, surgeons’ arms, method to monitor cardiorespiratory homeostasis in neo-
or other equipment. Sampling respiratory gases or blood nates and infants. It is positioned on the child’s left precor-
is also complicated by the small volumes that may be dium to auscultate both the heart and lungs. However, this
withdrawn from the neonate. monitor has been widely supplanted by newer technologies
2. The extremely dynamic physiology of the neonate may [1]. Nevertheless, the stethoscope deserves mention as it
result in very rapid changes in important parameters. can be applied at zero cost in any case where other tech-
Monitoring systems must be capable of responding niques are either unavailable or unaffordable. If used con-
instantly to these changes and promptly alerting the anes- tinuously, this monitor may immediately warn of a
thesiologist of these changes. significant change, which can be confirmed by other moni-
tors. Recently, pre-tracheal application of a stethoscope has
also been described to detect adverse events in special areas
Supplementary Information The online version contains supplemen- such as the MRI suite. This monitor was the first to diag-
tary material available at https://doi.org/10.1007/978-3-031-25358-4_7. nose adverse events compared with capnography and oxim-
etry (by almost four-fold) [2].
N. Disma (*) The esophageal stethoscope was originally described to
Unit for Research in Anaesthesia, Department of Paediatric monitor small patients during thoracic surgery [3]. It is also
Anaesthesia, IRCCS Istituto Giannina Gaslini, Genova, Italy
e-mail: [email protected] used less frequently today than in the past, but may be valu-
able in some cases [4]. The stethoscope probe may be com-
C. Breschan
Department of Anaesthesia, Klinikum Klagenfurt, bined with an esophageal temperature probe and esophageal
Klagenfurt, Austria ECG leads (E-Probe, Cardell® Esophageal Probe).

228 N. Disma and C. Breschan
rterial Hemoglobin Oxygen Saturation—

A value to the CO-oximeter-measured arterial saturation [5].
Pulse Oximetry This calibration curve was based on arterial saturation val-
ues ranging from 80 to 100%; values less than 80% are
Pulse oximetry was introduced into clinical practice in the extrapolated from the curve and are less accurate because
1980s and rapidly became an indispensable aid to manage- of the curvilinearity of the calibration curve (Fig. 7.1).
ment of the neonate in the perioperative period. The pulse However, it is possible to construct a calibration curve
oximeter probe consists of two light-emitting diodes (LEDs) over a range other than 80–100%. For example, the
that emit red and infrared light, with a semiconductor as a Masimo “Blue Sensor” is calibrated for arterial saturations
detector. Pulse oximetry relies on the Beer-Lambert law, between 60 and 80%, and designed for use in infants 2.5–
which relates the concentration of a chromophore to light 30 kg with conditions associated with low arterial satura-
absorption, optical path length, and extinction coefficient. In tions [6]. The Blue Sensor does measure arterial saturations
pulse oximetry, the chromophores to be detected are oxyhe- of <60% although the accuracy is similar to two other
moglobin and deoxyhemoglobin. Two wavelengths (660 and oximeters [6].
940 nm) in which the extinction coefficient of oxy- and
deoxyhemoglobin differ are required to determine the oxy- ulse Oximetry Use in Clinical Practice
P
gen saturation. Fetal hemoglobin (HbF) and adult hemoglo- Optimally, the LED and the detector should be placed exactly
bin (HbA) have similar absorption spectrum and thus pulse opposite to each other with 5–10 mm of intervening tissue.
oximetry is equally accurate in neonates as in adults. The Low saturation readings or a failure to detect a saturation
pulse oximeter calculates oxygen saturation as the ratio (R) may occur if components of the probe are not exactly aligned
of absorbance of the pulsatile versus the nonpulsatile optical [7]. In neonates, the probe is commonly placed across the
signal at two wavelengths, represented by: thumb (if large enough), the palm of the hand, the lateral
aspect of the foot or the wrist, but it may also be applied to
R = ( AC660 / DC660 ) / AC940 / DC940 ) the ear lobe, cheek, or tongue (Fig. 7.2) [8]. These positions

are highly successful in neonates because their bones are not
where AC is the pulsatile signal and DC is the nonpulsatile calcified, thus facilitating reliable measurements [9]. Pulse
signal at 660 and 940 nm, respectively. The pulse oximeter oximeters vary in their performance, but most claim an accu-
converts R to oxygen saturation through an empirically racy of ±2–4% or less at saturations >80%. As mentioned,
derived curve (Fig. 7.1). The relationship between R and pulse oximeters are less accurate at low saturations. Hence,
arterial saturation is curvilinear, but closely approximates during profound desaturations, their accuracy cannot be
a straight line over a 20% range in arterial saturation. The relied upon. It is also important to realize that the top of the
calibration curve was constructed using healthy adults oxyhemoglobin desaturation curve is flat; hence, at high sat-
who breathed hypoxic gas mixtures and compared the R urations, relatively large changes in arterial pO2 occur with
Fig. 7.1 Calibration curve of

pulse oximetry. The oximeter Red
converts the ratio, R, to an
oxygen saturation through an IR
empirically derived curve
Modulation Ratio (R)
Observed R
SpO2
0 20 40 60 80 100
SaO2 (%)
7 Perioperative Monitoring: Methods, Implementation, and Interpretation 229
Fig. 7.2 Correct positioning of the pulse oximeter probe on the finger, foot and hand of the neonate
only minor changes in saturation. Thus, there has been concentrations. However, pulse oximetry has limitations when
tinuing difficulty in defining a “safe” target saturation for the physiological changes occur. Under conditions of hypother-
preterm infant in order to avoid the consequences of hyper- mia, vasoconstriction, and hypotension, pulse oximeters are
oxia [10–12]. Ideally, intraoperative oxygen saturation less accurate and less reliable. During moderate hypoxemia,
should be maintained at approximately 90–93% to avoid the oximeter measurements may exceed the actual oxygen
hyperoxia and ophthalmic and pulmonary adverse events saturation, although during acute desaturations, oximeters
(see Chaps. 2 and 17). usually underestimate the actual saturation. If methemoglo-
Different models of pulse oximeter vary in their response binemia is present, the SpO2 becomes 85% regardless of the
time to physiological changes in the patient [13]. In general, actual arterial saturation because of the absorbance spectra
the most recent models with “signal extraction technology” of methemoglobin relative to hemoglobin. After carbon
have faster response times and more precise measurement. monoxide exposure, SpO2 overestimates arterial saturation
They are also less affected by motion. because carboxy and oxyhemoglobin absorb red light simi-
The pulse oximeter is extremely useful in neonates larly. In bronze baby syndrome, which may occur after pho-
because intraoperative desaturation occurs most frequently totherapy, SpO2 readings become unreliable [16]. Dark skin
in this age group [14]. However, the oximeter is subject to pigmentation may also cause falsely low readings especially
interference from several factors. Motion artifact is usually at lower levels of saturation (<80%) [8].
not a problem during anesthesia but may be significant dur- In summary, the most common reasons for inaccurate
ing the induction and recovery phases. To prevent this prob- SpO2 measurement are:
lem, use models with signal extraction technology (e.g.,
Masimo), which suppresses the effect of motion on the • Misalignment of the probe sensors due to the site
oximeter signal [13]. A strong external light source may also chosen;
affect the oximeter’s performance. The probe should be cov- • Low oxygen saturation (<80%) when using a standard
ered (aluminum foil is ideal) to exclude extraneous light and oximeter;
protected by a rigid frame to prevent pressure on the sensor. • Inadequate tissue perfusion (hypotension, hypothermia,
In low perfusion states (see below), the signals may not be etc.);
adequate for interpretation and no result will be displayed. • Bronze skin (due to phototherapy) or dark pigmentation;
Under these conditions, later model machines may perform • Equipment malfunction/disturbance including motion
better or apply an ear probe to the pinna to ensure a continu- artifact, incorrect probe size, or strong external light.
ous oximeter display [15].
The performance of the pulse oximeter is unaffected by Complications have been reported from the application of
changes in the hematocrit, hemoglobin, and bilirubin con- oximeter sensors [17, 18]. When applying sensors circumfer-
entially to the finger, caution must be exercised to avoid recommended [12, 24]. This has been confirmed recently in
applying the sensor too tightly, which might cause ischemic a meta-analysis of five randomized clinical trials that
injury [17, 18]. When a reusable clip-type sensor is used on included 4965 infants [25]. Excessive oxygen administration
the ear, care should be taken to ensure that the clip does not may also be deleterious during resuscitation [12, 26]. During
exert excessive pressure and cause ischemia to the underly- neonatal resuscitation, the American Heart Association rec-
ing tissue [14]. Burns and pressure necrosis at the site of the ommends monitoring the pre-ductal SpO2 to titrate the oxy-
probe have also been reported in neonates [18]. gen administration [27].
linical Application of Pulse Oximetry

C
In neonatal anesthesia practice, it is often advantageous to Electrocardiography (ECG)
apply two separate pulse oximeter probes. In some cases, it
may be useful to monitor both pre-ductal (right arm or head) ECG is based on the principle of detecting electric potentials
and postductal saturation (a foot) and in others, the second that originate in the heart across vectors through the chest. It
probe may act simply as a backup should the first probe fail represents an essential part of routine intraoperative monitor-
[19]. Pre- and postductal pulse oximetry may serve as a use- ing at any patient’s age, with the aim of immediately detect-
ful guide in certain conditions. A decrease in the postductal ing cardiac arrhythmias or myocardial ischemia. The three
SpO2 of more than 10% compared with pre-ductal SpO2 indi- lead ECG, routinely used during anesthesia, mainly detects
cates significant pulmonary hypertension, right-to-left shunt alterations in cardiac rate or rhythm, the commonest changes
at the patent ductus arteriosus (PDA) and shift toward fetal in the pediatric age group (Fig. 7.3). However, in special cir-
circulation. If a right-to-left shunt occurs at the level of the cumstances where an ischemic lesion of the myocardium is
foramen ovale, no difference in oxygen saturation will be possible, ventricular leads should be applied.
apparent between the two oximeters. In clinical conditions The most frequent ECG alterations in neonates and
such as single ventricle physiology, pulmonary atresia, or infants undergoing anesthesia are tachyarrhythmias (sinus,
transposition of great arteries, maintenance of the transi- atrial, and supraventricular tachycardia (SVT)) and brady-
tional circulation is essential to maintain pulmonary and/or arrhythmias (sinus bradycardia and junctional bradycar-
systemic blood flow. Monitoring SpO2 estimates the ratio dia). Tachycardia is mainly due to inadequate depth of
between the pulmonary flow and systemic flow (Qp/Qs) and anesthesia during airway manipulation or surgical stimu-
can serve to gauge the balance of pulmonary to systemic lus or hypovolemia. Bradycardia is usually caused by
blood flow. hypoxia or vagal stimuli.
Monitoring SpO2 can also track changes in the arterial The challenge during ECG monitoring in neonates is their
oxygenation from the fetus to the neonate during the first physiological propensity to tachycardia. Heart rates between
minutes after birth. During fetal life, the normal SpO2 is 100 and 150 beats per minute (bpm) are considered normal
approximately 72% whereas during the initial hours after in term neonates. Consequently, discriminating between
birth, there is a rapid and steady increase in SpO2 to the mid- sinus tachycardia and SVT can be difficult as the P-wave is
90s [20]. Pulse oximetry has also been evaluated as a screen- not always apparent on the ECG monitor. For this reason,
ing tool for congenital heart disease in the newborn nursery. ECG changes must be evaluated together with the whole
If SpO2 does not increase to values in the mid-90s by day 2 clinical picture of the neonate, while also considering the
of life, the presence of cyanotic congenital heart disease possibility of artifacts.
should be contemplated. The specificity and sensitivity of
pulse oximetry to diagnose cyanotic congenital heart dis-
ease, 99% and 72% respectively, are superior to a clinical
evaluation [21, 22].
An excessive concentration of oxygen in preterm infants
contributes to the development of retinopathy of prematurity.
In extremely preterm infants (24–27 weeks), the risk of
developing retinopathy of prematurity depends on the dura-
tion and timing of the supplemental oxygen [23]. To limit the
risk of this complication, the SpO2 should be maintained in
the range of 90–93% (see Chaps. 2 and 17). Although an
SpO2 <90% reduces the risk of retinopathy of prematurity
even further, it increases the mortality rate and is thus not Fig. 7.3 Electrocardiographic electrode positioning in neonates
dvanced Pulse CO-Oximetry and Oxygen

A plethysmograph variability index (PVI) and perfusion index
Reserve Index (ORI) (PI), which analyze the optical signals in a specific manner.
PI and PVI are determined by evaluating the interrelation
Advanced pulse oximeter technologies can detect hypovole- between the cardiovascular and respiratory system to detect
mia, hypoperfusion, and anemia noninvasively, all of which hemodynamic changes indicative of circulating blood vol-
occur commonly during neonatal surgery. These conditions ume and peripheral perfusion. This is similar to assessing the
are difficult to monitor in neonates because insertion of arte- effect of ventilation on the pulse pressure during invasive
rial catheters and blood sampling remain challenging in this monitoring of the arterial waveform (Fig. 7.4a). This pulse
population. Thus, a reliable and noninvasive measurement is pressure variation depends on the mode of ventilation. The
a great help for clinicians. effects on venous return, right ventricle afterload, left ven-
Advances in optical technologies, especially light emit- tricle end diastolic pressure, and left ventricle afterload differ
ting diodes (LEDs), permitted the development of pulse during spontaneous or positive pressure ventilation. This
CO-oximetry. Conventional pulse oximetry founded in the dynamic ventilator-linked variation in arterial pulse pressure
1980s used two LEDs at 660 nm and 940 nm, respectively, and systolic blood pressure may be interpreted as a sensitive
which were the only commercially available LEDs at that indicator of circulating blood volume. It is as accurate as
time. Fortunately, the absorption spectrum of oxy- and measuring the central venous pressure and pulmonary artery
deoxyhemoglobin were well differentiated at those wave- occlusion pressure.
lengths, which permitted the measurement of SpO2. However, PI and PVI are the optical signal components that corre-
carboxyhemoglobin and methemoglobin were not differenti- late with the systolic wave amplitude and the systolic wave
ated, and thus conventional pulse oximetry was unable to variation with ventilation, respectively, on the arterial wave-
determine them or the total hemoglobin concentration. In the form (Fig. 7.4b). The PI is the amplitude difference between
near red and infrared region, many LEDs are now commer- the pulsatile and nonpulsatile optical signals and is displayed
cially available, which permit multiwavelength pulse oxim- as a percent of the nonpulsatile optical signal, which remains
etry to measure all hemoglobin species as well as total constant and represented by:
hemoglobin concentration (SpHb). In addition, intravascular
volume and perfusion status can be monitored through the PI = AC / DC × 100%
Fig. 7.4 (a) Respiratory a

variation in the pulse pressure 2 ∆ Up 1 sec
with ventilation during 120 1
3 ∆ Down
invasive monitoring of the
arterial waveform. These 80
hemodynamic changes are
indicative of circulating blood 40
volume and peripheral
perfusion. (b) Plethysmograph 0
variability index (PVI) and
perfusion index (PI) are the b Respiratory Cycle
optical signal components that
correlate with the systolic Ampitude
amplitude and the systolic
amplitude variation with
ventilation, respectively, on
the arterial waveform Optimal
signal
PI max PI min
1
0
Time
where AC is the amplitude of the alternating pulsatile sig- <85% for >30 s and “minor” events as SpO2 <85% for <30 s,
nal and DC is the amplitude of the direct, nonpulsatile signal. although there was no neurocognitive outcome data to vali-
PI directly correlates with the strength of the pulsatile optical date the clinical relevance of these definitions [35].
signal, which correlates with the strength of the manual pulse Alternatively, others consider an SpO2 <90% to be signifi-
(Fig. 7.4b). The PI ranges from 0.02 to 20%, although values cant [36]. Thus, improving oxygenation (through improving
greater than 1% generally represent normal physiologic con- ventilation, alveolar recruitment, and an increased FiO2) is
ditions. PVI is measured from changes in the PI during a recommended for an SpO2 ≤90%.
ventilator cycle. PVI is calculated as the difference between The oxygen–hemoglobin dissociation curve is a graphical
the maximum and minimum PI divided by the maximum PI display of the proportion of saturated hemoglobin on the
during a cycle, as shown by: ordinate against the oxygen partial pressure in blood (PaO2)
on the abscissa (Fig. 7.5a). The dissociation curve is experi-
PVI = ( PI max − PI min ) / PI max mentally determined from in vitro titration of blood with

increasing PaO2. For very low PaO2 values, the SpO2
PVI is reported as a percentage (0–100%), in which larger increases minimally for a given change in PaO2. However,
values correspond to greater pulse oximeter amplitude wave- for PaO2 values between 20 and 60 mmHg, the SpO2
form differences during the respiratory cycle, which corre- increases linearly and steadily. Beyond a PaO2 of 60 mmHg,
late with the severity of hypovolemia. If hypotension is the SpO2 once again levels off and increases minimally
present, PVI greater than 12–14% indicates hypovolemia for between 90 and 100%.
which an intravenous fluid bolus will improve the arterial The difficulty with the pulse oximeter is that there is a
pressure. broad range of PaO2 (i.e., from 100 to >700 mmHg) over
Studies in neonates suggest that PI may have clinical util- which the SpO2 remains almost constant, at 100% (Fig. 7.5b).
ity. Immediately after birth, PI predicts the development of Using the saturation alone, clinicians are unable to determine
chorioamnionitis, a condition associated with significant mor- the PaO2 without blood-gas analysis, the latter being imprac-
bidity and mortality. PI had a 93.7% positive predictive value tical or too slow in many situations. When there is a rapid
and 100% negative predictive value in identifying subclinical decrease of oxygen reserves (as occurs during an apneic
chorioamnionitis; early detection enabled early treatment, spell), clinicians are unable to quantify a decrease in the
which decreased the disease severity and admission to a neo- PaO2 until the SpO2 begins to decrease, which occurs at PaO2
natal critical care unit [28]. Similarly, PI has been evaluated to values <100 mmHg.
predict the severity of illness for other conditions in neonates Clinically, it would be useful to have a real-time, continu-
[29]. PI correlated closely with the Score for Neonatal Acute ous, noninvasive estimation of the PaO2, especially in
Physiology, with a 91.2% positive predictive value and 96.8% patients who are receiving supplemental oxygen and whose
negative predictive value. However, PVI has been proven to be PaO2 is >100 mmHg.
highly variable on the same and different limbs in the same Recently, Masimo developed the oxygen reserve index
stable, preterm infant [30]. On the other hand, PVI may be a (ORI) monitor, which uses their FDA-approved noninvasive
useful noninvasive metric in assessing the volume responsive- hemoglobin sensor to estimate oxygenation in the low hyper-
ness of ventilated neonates during surgery [31, 32]. oxic range, from a PaO2 of ~100 to ~200 mmHg [37]. The
Pulse CO-oximetry detects changes in the hemoglobin ORI, a dimensionless index that ranges from 1 to 0, is calcu-
concentration during surgery earlier than conventional blood lated from a proprietary algorithm based on infrared absorp-
draw-based laboratory measurements. This decreases the tion values obtained from the Masimo pulse CO-oximeter.
number of blood samples needed and guides blood transfu- The sensor uses absorption of seven wavelengths of light to
sion decisions [33]. Like conventional pulse oximetry, erro- estimate blood constituents. The ORI algorithm combines
neous measurements occur during severe hyperbilirubinemia the Fick principle with the infrared absorption properties of
and in the presence of intravascular dyes such as methylene both arterial and venous hemoglobin. By replacing some
blue. In 52 preterm neonates weighing <3 kg, the bias and variables in a chain of equations, the oxygen saturation of
precision of SpHb compared with laboratory blood measure- venous blood (SvO2) is directly proportional to PaO2 at con-
ments were 0.09 ± 1.67 g/dL, with an r-squared value of 0.48 stant oxygen consumption and cardiac output. As PaO2
[34]. Advances in the development of sensor size will soon increases beyond 100 mmHg, SvO2 continues to increase
cement the use of this technology in neonates. until it reaches full saturation at a PaO2 of ~200 mmHg.
Monitoring the ORI may signal impending desaturation and
xygen Reserve Index (ORI)
O a means to avoid hyperoxia in neonates, but this remains to
It is often difficult to evaluate the clinical importance of a be confirmed.
brief, single decrease in SpO2 in pediatric patients. Coté When utilized in conjunction with SpO2 monitoring, ORI
et al. defined “major” events as those in which SpO2 was is intended to provide real-time visibility from hypoxia to the
a b
Fig. 7.5 (a) The oxygen–hemoglobin dissociation curve. Reproduced chure_ori_italian.pdf. (c) Use of ORI for real-time visibility from
from https://www.masimo.it/siteassets/it/documents/pdf/plm-10728a_ hypoxia to the moderate hyperoxic state. Reproduced from https://
brochure_ori_italian.pdf. (b) Oxygenation state. PaO2 between 100 and www.masimo.it/siteassets/it/documents/pdf/plm-10728a_brochure_
200 mmHg is defined as “moderate hyperoxia”. Reproduced from ori_italian.pdf
https://www.masimo.it/siteassets/it/documents/pdf/plm-10728a_bro-
moderate hyperoxic state (Fig. 7.5c). When the ORI is <0.30, sampling using low sampling rates (50 mL/min) from a low
it may provide advance warning of a decreasing PaO2 despite dead space (0.5 mL) tracheal tube adaptor in low birth weight
an SpO2 reading >98% and that the PaO2 remains in excess of infants significantly underestimated PaCO2 levels, but did
the PaO2 at which the SaO2 decreases rapidly. In a recent pilot detect excessively high and low levels [41]. Samples col-
study of 25 healthy children under general anesthesia, the lected from the tip of the tracheal tube correlated much better
ORI detected impending desaturation 31.5 s before changes with PaCO2 levels [42], even in the presence of severe lung
in SpO2 were detected. Even 30 s of advanced warning of disease [41, 44]. Infant-size tracheal tubes with a fine second
impending desaturation might give clinicians enough time to sampling channel external to the lumen of the tube are avail-
implement corrective actions and avoid an insult [38]. ORI is able for this purpose (Mallinckrodt™ Oral/Nasal Tracheal
not intended to replace SpO2 or PaO2 monitoring, but to inte- Tube Cuffless Monitoring Lumen, Sizes 2.5 and larger).
grate these metrics to provide advance warning to allow time Unfortunately, the fine aspirating channel is prone to block-
for corrective action. Of all age groups, neonates are at the age by secretions [41].
greatest risk for acute oxyhemoglobin desaturation. In neonates, high-flow gas sampling should not be used
Preventing this in neonates could dramatically improve peri- because it will entrain fresh gas or inspiratory gas in the sam-
operative morbidity in this age group. Further studies are ple, thereby diluting the EtCO2. This may also dramatically
required to confirm the effectiveness of this monitor. decrease alveolar ventilation if the set tidal volume is small.
Other potential problems include water vapor condensation
obstructing the tubing, leaks or disconnections at the CO2
Inspired and Expired Gas Analysis analyzer, and a delay of several seconds between actual and
monitored changes in the EtCO2. A practical consideration at
The measurement of oxygen, carbon dioxide, and inhaled the present time is that most anesthesia machines are
anesthetic agents in the airway remains an important aspect equipped with a built-in sidestream monitor.
of safe anesthesia practice. Originally, these concentrations
were measured by mass spectrometry. However, as technol- Mainstream Capnography
ogy developed, this was replaced by infrared spectrophotom- Mainstream capnography incorporates the infrared analyzer
etry; the absorption spectra for CO2, N2O, and inhaled within the breathing circuit, thereby eliminating the need for
anesthetics differ, ranging from 7 to 13 μm. As with pulse sampling tubing. This results in a more timely gas analysis.
oximetry and near-infrared spectroscopy (NIRS), the con- Mainstream capnography offers an advantage in neonates
centration of the gases is calculated using the Beer-Lambert because it eliminates the risks of excessive gas sampling and
law. Oxygen concentration cannot be measured by this tech- errors from sampling dead space. However, its disadvantages
nique because it does not absorb infrared light; rather, it is include the weight of the analyzer, which can kink the tra-
measured by electrochemical or paramagnetic methods. cheal tube, the need for frequent calibration, additional dead
Expired CO2 concentration or end-tidal CO2 (EtCO2) can space, and water vapor condensation, all of which lead to
be plotted against time to illustrate changes in the concentra- errors and unreliable measurements.
tion of CO2 during inspiration and expiration. The continu- The capnograph provides important clinical information
ous measurement of EtCO2 is a standard of care in anesthesia during neonatal anesthesia (Fig. 7.6). The waveform is
practice. divided into an inspiratory phase and three expiratory phases.
One of the following two sampling methods is used to The first expiratory phase, A and B in Fig. 7.6, reflects gas in
monitor EtCO2: sidestream or mainstream capnography [39]. the large airways (anatomical dead space) where the EtCO2
is zero (unless there is rebreathing). The second expiratory
Sidestream Capnography phase, B and C, is the rapid upstroke of EtCO2 that results
Sidestream capnography utilizes small caliber tubing con- from the mixed sampling of exhaled gases from the large
nected to the breathing circuit to continuously aspirate gas airways and alveoli (transitional phase). The third expiratory
from the breathing circuit and direct it to a spectrophotome- phase, C and D, also known as the plateau phase, reflects the
try cell in the capnometer. The flow sampling rates are opti- EtCO2 in the alveolar gas. The measured EtCO2 is the value
mal between 50 and 200 mL/min, although some monitors at the apex of the plateau phase before the sudden decrease
use rates as large as 400 mL/min. Gas samples for sidestream in EtCO2 that begins the inspiratory phase. During inspira-
monitoring may be collected either at the level of the tracheal tion, the EtCO2 level rapidly decreases to zero. A gradient is
tube connector or at the tip of the tracheal tube. If collected commonly found between the PaCO2 and EtCO2 (1–5 mmHg
at the connector, the use of a very low dead space system in magnitude), attributed to the physiologic alveolar dead
with a “baffle” between the Y-connector of the circuit and the space. This gradient may significantly increase with an
sampling port is desirable, as well as a small fresh gas flow increase dead space (Vd/Vt ratio) or a decrease in cardiac
to minimize dilution of the aspirated sample and thus the output. In neonates, this may be due to a right-to-left shunt
end-tidal gas concentrations with fresh gas [40]. Sidestream associated with congenital heart disease, meconium aspira-
Fig. 7.6 Normal
capnographic waveform Normal Capnogram Normal EtCO2: 35 – 45 mmHg
CO2 (mmHg) Real Time Trend
60
37 D
C
A B E
0
The “normal” capnogram is a waveform which represents the varying CO2 level throughout
the breath cycle.
Waveform Characteristics:
A-B Baseline D End-Tidal Concentration
B-C Expiratory Upstroke D-E Inspiration
C-D Expiratory Plateau
tion, respiratory distress syndrome, or shock. The correlation nography), or airflow (acoustic) [51]. Of the monitors, trans-
between PaCO2 and EtCO2 improves after treating preterm thoracic impedance is the most popular. Transthoracic
infants with surfactant as the Vd/Vt ratio decreases [43, 45]. impedance measurement is commonly combined with ECG
Phase III of the expiratory tracing changes from a flat plateau monitoring. A small current is transmitted from one ECG
to an upward slope when alveolar dead space increases such pad to another one, and changes in the impedance to this cur-
as with asthma. The PaCO2–EtCO2 gradient should be mea- rent due to the chest expansion or contraction yields the
sured to gauge pulmonary function. During bronchospasm, respiratory rate. Since transthoracic impedance detects chest
the EtCO2 tracing adopts a “Shark Fin” shape due to the movement but not airflow, it cannot detect obstructive apnea,
slower egress of gas from obstructed airways [46]. which simply demonstrates an erroneous respiratory rate.
Capnography as an apnea monitor in patients without instru-
mented airways suffers from an element of unreliability as
ranscutaneous Carbon Dioxide Monitoring
T nasal secretions may obstruct gas sampling to give spurious
(tcpCO2) alarms of apnea or the neonate breathes through the mouth
decreasing or eliminating the signal sensed in the nares. The
Equipment to measure tcpCO2 is routinely used in the neo- proboscis modification of the nasal prongs circumvents this
natal intensive care unit (NICU) and may also be used intra- deficiency to a large extent by sampling exhaled gases from
operatively [38, 47–49]. Transcutaneous measurements both the nares and the mouth. Another technology that senses
more closely equate to venous levels than do end-tidal, the temperature of exhaled breath (Linshom®) accurately
which tend to underestimate true values [49]. Hence, tcpCO2 measures the respiratory rate, detects apneas, and tracks tidal
monitoring may be preferred for situations when tight con- volume noninvasively [52, 53]. Monitoring the airflow with
trol of carbon dioxide levels is essential (e.g., hypoplastic acoustic sensors located on the neck or chest offers theoreti-
left heart syndrome). Placement of the sensor on the fore- cal advantages over transthoracic impedance, capnography,
head is associated with optimal performance and is conve- and pulse oximetry. Acoustic apnea monitors sense vibratory
nient to use intraoperatively in many patients. Chronic sounds produced by turbulent flow in the large airways and
placement has been associated rarely with burns to the skin converts a sound signal into an electrical signal from which
in the past as these sensors heat the skin, although more respiratory rate is calculated. Acoustical monitoring of respi-
recently, skin probes maintained at lower temperatures ratory rate has been reported in two studies in children: in the
(38 °C instead of 42 °C) yielded equally accurate carbon first study, the acoustical monitor was more accurate with
dioxide measurements [50]. less bias than capnography or impedance technologies,
whereas in the second, the two devices yielded similarly
accurate measurements, although the acoustic monitor was
Apnea Monitors better tolerated in surgical patients [54, 55]. The clinical
implications of these conflicting findings are unclear.
Apnea monitors are in common use in the NICU and are use-
ful during postoperative recovery, especially in the preterm espiratory Volume Monitor (RVM)
R
infant. These monitors are classified based on detection of A noninvasive respiratory device (ExSpiron, USA) derives
chest movement (transthoracic impedance), ventilation (cap- Vt, RR, and hence MV from the thoracic impedance utilizing
a pair of electrodes applied to the chest [56]. This monitor is selected (see Chap. 6). The use of cuffed tracheal tubes
reliably records the respiratory rate and can detect hypopneic eliminates the main source of circuit leaks in neonates.
or apneic episodes. The recorded MV correlated well with During a normal breath, the expired tidal volume is less
spirometry measurements in children between 1 and 17 years than the inspired tidal volume because of the greater oxygen
of age [57]. Total airway obstruction may be detected even in uptake at the alveolar–capillary membrane compared with
the presence of chest movements. A limitation of this device the carbon dioxide output from the capillaries into the alve-
is that it only functions well when the patient is positioned oli. Measurement of the expired tidal volume occurs close to
supine. the expiratory valve, which tends to overestimate the actual
volume due again to the compliance of the circuit.
ulmonary Mechanic Monitors
P Monitoring peak inspiratory pressure and tidal volume in
Pulmonary mechanics are defined by inspiratory and expira- neonates provides information about lung compliance and
tory tidal volumes, peak inspiratory pressure, mean airway airway resistance to detect conditions such as an endobron-
pressure, positive end-expiratory pressure (PEEP), and inspi- chial intubation, bronchospasm, and tracheal tube obstruc-
ratory and expiratory cycle time. tion. Monitoring these variables also helps to prevent
Planned inspiratory tidal gas volume is selected by setting volutrauma or barotrauma during the ventilator support in
the ventilator. Traditional anesthesia ventilators then deliver the operating room, especially in neonates with pulmonary
this predetermined volume, which can differ substantially disease or immature lungs, where small tidal volumes and
from the actual tidal volume, especially in neonates, because lower inspiratory pressures decrease the risk of bronchopul-
of the compliance of the breathing circuit in relation to monary dysplasia, a strategy known as permissive hypercap-
pulmonary and chest wall compliance, and the fresh gas nia. During surgical procedures in which substantial changes
flows. As a result of this unpredictability, mechanical venti- in the compliance can occur, the peak inspiratory pressure
lation in neonates historically used a pressure control mode, setting should be adjusted to avoid pressure trauma to the
which is independent of the breathing circuit compliance and lung parenchyma.
fresh gas flows [58, 59]. However, during pressure preset The anesthesia circuit in workstations incorporates
ventilation, the actual tidal volume varies according to the pneumatic or electronic devices to measure airway pres-
total compliance and the airway resistance. Thus, tidal vol- sure. The location of the sensor varies with the anesthesia
ume may suffer if total compliance decreases or airway resis- workstation, ideally it should be closer to the tracheal tube
tance increases. Examples of such situations include (Y-piece) to increase its reliability. However, this location
laparoscopic or thorascopic surgery, insertion of chest or increases the dead space, and also the risks of disconnec-
abdominal sponges or retractors, tracheal tube obstruction, tions, or tracheal tube kinking. More frequently, the loca-
or pulmonary edema. tion is close to the expiratory or inspiratory valves. The
Advances in the anesthesia ventilators have made the sensor incorporates a diaphragm connected to the breath-
delivery of predetermined tidal volumes more predictable ing circuit, which distends according to the airway pres-
during volume control ventilation. These anesthesia sure. The sensor activates a pressure relief valve once the
machines monitor compliance in the breathing circuit and selected peak pressure has been reached. It also detects a
compensate for it by adjusting the delivered tidal volume, for leak in the system if a preset threshold pressure is not
example, when fresh gas flows or compliance changes. A reached. Monitoring ventilatory volumes using equipment
common circumstance that changes compliance in the capable of accurately measuring those appropriate in neo-
breathing circuit is contraction or expansion of the tubing of nates reduces the risk of undetected, under or overventila-
the breathing circuit. The anesthesia workstation compliance tion, and lung trauma.
tests, which are part of the machine check, compensate for Cuffed tracheal tubes are now commonly used in neo-
the compliance of different breathing circuits. Thus, the nates with infrequent complications, although few neonates
compliance test must be repeated if the circuit is changed in were included in these reports (see Chaps. 5 and 6) [61, 62].
any way after testing. When the tidal volume of contempo- The pressure within the cuff should be monitored if it is
rary anesthesia ventilators was set to volume control mode in inflated. However, in neonates, it is often unnecessary to
a model lung with different compliances, volume control inflate the cuff to prevent leaks at normal airway pressures.
ventilation was effective in anesthetized neonates [60]. Some cuffed tracheal tubes (e.g., Microcuff®, Halyard
However, despite these compensatory mechanisms, modern Health, UK) have been approved for use in term neonates
ventilators are unable to compensate for large circuit gas >3 kg; these tubes have not been either studied or approved
leaks regardless of whether volume or pressure control mode for use in premature neonates or in neonates <3 kg.
Systemic Blood Pressure Monitoring Automated noninvasive blood pressure (NIPB) greatly
simplified monitoring the neonate in the operating room. The
oninvasive Blood Pressure (NIBP)
N accuracy of NIBP is controversial, especially in very low
The basic noninvasive equipment to measure blood pressure birth weight infants with a low blood pressure [64–68]. This
is the blood pressure cuff. The width of the cuff used should is the population most susceptible to periventricular leuko-
be 0.44–0.55 times the mid-point circumference of the limb malacia, reduced cerebral blood flow (CBF), and inadequate
utilized, thus the optimal width in the full-term neonate is peripheral perfusion. Studies in such neonates have shown a
approximately 1 inch (Fig. 7.7) [63]. regular overestimation of the mean pressure by 3–8 mmHg
The commonly used automated blood pressure mea- depending on the device used to measure the NIBP [69].
surement systems used in the operating room are based on In the operating room, the most accurate determination of
oscillometry. Several such NIBP devices exist. Each the systolic pressure can be obtained by placing a doppler
employs the same principle but utilizes a proprietary algo- flow probe on an artery distal to the cuff [63]. As stated
rithm to extract systolic, mean, and diastolic blood pres- above, measurements taken with an automated oscillometric
sure from a signal generated by pulse-induced pressure device tend to overestimate systolic and mean blood pres-
fluctuations within in the cuff. The amplitude of these fluc- sures, especially when the neonate is hypotensive [70].
tuations varies with cuff inflation pressure. If the ampli- In healthy infants, blood pressure measurements recorded
tude of the fluctuation in cuff pressure is plotted as a with a cuff applied to the upper and lower extremities are
function of cuff pressure, the result is an oscillogram. Each normally similar. Recent evidence suggests that a discrep-
oscillogram will have a unique shape and set of inflection ancy in noninvasive blood pressures between upper and
points. The algorithms are designed to derive systolic, lower extremities occurs in the smaller infants (<1000 g)
mean, and diastolic pressure from the data stream con- [71]. NIBP devices should not be relied upon in sick infants
tained in the oscillogram. or those who require extensive surgery.
The oscillometric pulse amplitude results from small
pressure changes in the cuff due to the expansion and I nvasive Blood Pressure
contraction of blood vessels within the limb encircled by the Direct measurement of blood pressure using an intra-arterial
cuff as blood is ejected via the arterial tree. The diastolic line is often required in critically ill neonates and those
pressure is related to a fall-off in the rate of decrease in pulse requiring major surgery. Arterial lines may be inserted at
amplitude once the peak has been achieved and the systolic various sites, and each has advantages and potential
pressure is related to the steepest rate of rise of pulse ampli- disadvantages.
tude after a minimum value has been crossed. The point of The umbilical artery is relatively easy to access in the
maximum oscillation during cuff deflation is interpreted as immediate neonatal period and has been widely used in neo-
the mean arterial pressure. natal intensive care units. However serious thromboembolic
Fig. 7.7 Non-invasive blood pressure measurement, the correct cuff size and positioning
complications may follow and involve intra-abdominal tem attached. All connections should be locked. Normal
organs, the lower limbs, and even the spinal cord [72]. saline is preferred to glucose-containing solutions for all
Caution should be exercised in the choice of umbilical cath- monitoring lines [76]. Flushing of radial arterial lines should
eter material and design, and the fluids administered by this be limited to small volumes and slow rates of injection as
route. Silicon rubber catheters with an end hole are the pre- retrograde flow into the cerebral circulation may occur with
ferred type of catheters. Hypertonic and alkaline solutions as little as 0.5 mL flush solution [77]. Blood, which has been
should not be administered via this route. The use of heparin withdrawn while taking a laboratory sample, should be rein-
in the infusion may decrease the incidence of line occlusion jected into a venous access site. Similarly, aspirating blood
but does not reduce the incidence of thromboembolism [72] from radial artery catheters in VLBW infants should be cur-
and poses potential problems of overdosage, especially in tailed as it may compromise cerebral oxygenation irrespec-
very small patients. When managing an infant with an umbil- tive of the speed of aspiration [78].
ical artery catheter, the anesthesiologist should exercise cau- Serious complications with radial artery lines are rela-
tion at the time of withdrawing blood samples or flushing the tively rare in neonates, although instances of ischemic dam-
line, especially in VLBW neonates [73]. Sampling and rein- age to the hand and thrombosis have been described [77,
fusing rates should not exceed 1 mL in 30 s in the preterm 79–81]. Any evidence of impaired circulation or skin changes
infant. Rates in excess of this may significantly and adversely distal to the catheter is an indication for its immediate
affect CBF and oxygenation [74]. removal. There is no evidence that a cut-down approach to
Radial artery lines are more commonly used for intraop- cannulation is accompanied by increased risk of complica-
erative monitoring. Various methods have been recom- tions [82]. Rare instances of long bone growth arrest have
mended to improve the success of percutaneous insertion of been reported in children after both radial and femoral artery
a catheter in neonates. Smooth insertion of the catheter into cannulation [83].
small arteries is more likely to be attained if the level of the Femoral artery cannulation may be used as an alternative
needle is rotated inferiorly after a flashback of blood is if radial puncture is impossible or unsuccessful, and this may
observed. The use of a fine guide-wire may be useful to better reflect true arterial pressure than the radial artery in
thread the catheter into the artery, and has been demon- some instances [84]. The risk of infection at the puncture site
strated to improve success rate. If the artery cannot be pal- is not increased with a femoral artery cannulation. In smaller
pated readily, a Doppler flowmeter probe or infants, the distal circulation should be carefully monitored
trans-illumination of the infant’s wrist may facilitate its as perfusion-related complications may occur [85]. Great
location (Fig. 7.8) [75]. In difficult cases, it may be neces- care should be taken during insertion of femoral lines to
sary to use a cut-down for cannulation of the vessel. The avoid needle injury to the hip joint, which may cause septic
subsequent recovery of normal arterial flow after a cut-down arthritis and damage to the head of the femur [86]. It is
is no worse than after percutaneous cannulation. Allen’s test extremely important that the artery be accessed caudal to the
of the adequacy of collateral flow to the hand is difficult to level of the inguinal ligament; insertion above the ligament
perform in smaller infants and is unreliable even in adults; may cause a retroperitoneal hemorrhage. A Seldinger tech-
hence, it is not routinely performed. Once a radial artery nique with careful aseptic technique is recommended for
access has been successfully established, the limb should be insertion of an arterial catheter, e.g., 3–5 cm polyurethane
immobilized on a splint and a secure continuous flush sys- catheter.1 The puncture site should be covered with a trans-
parent sterile occlusive dressing and should be regularly
inspected. If there is any evidence of impaired circulation in
the limb, the catheter should be removed immediately.
Sepsis is more likely to occur if arterial catheters at any
site are left in place for more than 5 days [86].
The arterial waveform and the actual pressures obtained
from arterial catheters in smaller infants may be affected by
the compliance and length of the pressure tubing and by a
continuous fluid flush. It is necessary to consider the volume
of fluid that is being administered in order to continuously
flush the tubing. The use of a pressurized bag with a con-
COOK MEDICAL INC., P.O. Box 4195, Bloomington, IN 47402-

1
Fig. 7.8 Transillumitation for arterial line cannulation, using Veinlite ™

4195, USA.
trolled infusion device (e.g., intraflo or squeezeflo2 system) Definition of Hypotension

claims to deliver 3 mL/h of flush solution. However, under There is considerable controversy regarding the definition of
some circumstances, it may deliver larger volumes. This may the lower limit of an acceptable blood pressure and thus
also occur if the rapid flush activator is frequently used or hypotension in neonates and infants. Interest in this issue
malfunctions [87, 88]. Such circumstances could lead to may shed light on a possible relationship between general
fluid overload and possible coagulopathy secondary to exces- anesthesia and neurocognitive sequelae in young infants.
sive heparin administration. Cerebral vascular ischemia may Systolic blood pressures at 1 MAC inhalational anesthesia in
occur if the arterial line is flushed with crystalloid solution neonates and infants, measured noninvasively, were reported
continuously. This is especially dangerous when using the to decrease 20–30% from awake (baseline) values without
radial artery, resulting in an ischemic bolus of crystalloid ret- surgical stimulation [93, 94]. In 1999, the lower limit for the
rograde into the carotid artery after 1.5 mL fluid is injected at MAP (measured invasively) for awake, low birth weight neo-
bag pump pressures in excess of 200 mmHg [88]. A prefer- nates on the first postnatal day was determined based on their
able method to continuously flush arterial lines is to use a gestational age (23–35 weeks gestation) and birth weight
syringe pump set [87] to deliver 1 mL/h. (500–1500 g). The results indicated that the 95% CI for the
Alternative sites for invasively monitoring arterial pres- lower acceptable MAP in neonates >800 g correlated numer-
sure have been suggested. The axillary artery is an attractive ically with the gestational age between 26 and 32 weeks but
alternative as it has a very good collateral circulation and it in neonates <800 g at birth, the lower acceptable MAP was
can be easily palpated. It has successfully been used without less (Table 7.1a/b) [95]. This 1999 “rule of thumb” was sub-
serious complication in critically ill neonates [89] though sequently adopted as the lowest acceptable MAP in anesthe-
secure fixation may be difficult. There are also reports of bra- tized neonates beyond the first day of life and using
chial artery cannulation without serious complication [80], noninvasive measurements of blood pressure without evi-
but this must be viewed with caution as this artery has a less dence. A survey of members of the Society of Pediatric
well-developed collateral circulation. Anesthesia and the Association of Paediatric Anaesthetists of
Blood pressure is often used as a surrogate measure of Great Britain and Ireland reported that 87% use the MAP
organ perfusion, particularly for the CNS and kidney. and 72% use systolic blood pressure to define hypotension
However, there are no clear data that blood pressure in neo- [96]; median systolic blood pressure definition of hypoten-
nates and young children correlates with outcomes. The sion in neonates was 50 mmHg (25th to 75th percentile were
quintessential question is, “what is the minimum tolerable 40–60 mmHg) and in infants up to 2 years of age, it was 60
pressure before target organ failure results,” a question that (50–65 mmHg) [92]. A retrospective review of infants
remains elusive in the neonate. In one study of extremely low <6 months of age reported that neonates displayed the great-
birth weight infants, mean arterial pressures (MAPs) est incidence of hypotension (defined as a MAP <35 mmHg)
<23 mmHg were associated with cerebral dysfunction [90]. (25%) after induction of anesthesia and they also experi-
The lower target limit of MAP generally increases with both enced the greatest incidence of sustained hypotension
gestational and postnatal age. However, the lower limit of (>10 min) (44%) compared with the older infants [97].
MAP that maintains adequate CBF in the neonate remains to In 2017, the Pediatric Advanced Life Support and
be established [91]. Although multiple factors are likely American College of Critical Care Medicine defined shock
responsible for cerebral dysfunction after anesthesia, hypo- as a systolic blood pressure <60 mmHg for neonates and
tension or inadequate cerebral perfusion has been posited as <70 mmHg for those ≥2 years of age, although these values
the factor responsible for the new onset of seizures in six bore little relevance to the anesthetized condition (Table 7.2)
preterm infants who received general anesthesia [92]. All [98]. For guiding therapy, the minimum perfusion pressure
infants underwent radiological investigations, which revealed in septic infants was defined as [98]:
hypoperfusion in watershed areas of the brain, suggesting a
role for hypotension in the pathogenesis of the cerebral dys- MAP ( 55 + age ( years ) × 1.5 ) mmHg ( Table 7.2 )
− ( the central venous or mean arterial abdominal pressure)
function. On the other hand, treating hypotension with exces-
sively aggressive fluid or vasoactive drug administration may
itself result in adverse sequelae such as a patent ductus arte- The recommended MAP was based on the formula for the
riosus or intracranial hemorrhage. Treatment of hypotension 50th percentile in the healthy population. According to these
should be prompt but cautious to avoid over-transfusion and guidelines, the minimum MAP in the neonate was 55 mmHg,
hypertension. with a central venous pressure of 0 mmHg [97]. The
Multicenter Perioperative Outcome Group constructed refer-
ence curves for normal blood pressures in infants and chil-
ICU Medical Inc., 951 Calle Amanecer – San Clemente, CA 92673,
2 dren during induction and maintenance of anesthesia [99].
USA. They extracted blood pressure data from the anesthetic
Table 7.1 (a) Lower 95% confidence interval for MAP vs. gestational age
Gestational age (wk) 23 24 25 26 27 28 29 30 31 32 33 34 35
MAP (mmHg)
0-12 h: 20 21 23 23 25 26 27 28 29 30 31 32 33
13-24 h: 20 22 23 25 27 28 29 30 32 33 35 36 37
(b) Lower 95% confidence interval for MAP vs. birthweight
Birthweight (g) 500 600 700 800 900 1000 1100 1200 1300 1400 1500
MAP (mmHg)
0-12 h: 20 21 22 23 24 26 27 28 29 30 31
13-24 h: 21 22 23 25 26 28 29 30 32 33 34
Modified from Lee, et al.91
Table 7.2 Systolic blood pressure (SBP) of Pediatric Advanced Life arrest results in long-term cognitive dysfunction is if they are
Support according to the American College of Critical Care Medicine associated with cerebral ischemia. To that end, when cere-
Age SBP (mmHg) bral oxygen saturation was measured in 453 infants
0 day–1 month <60 <6 months of age, a low cerebral oxygen saturation did not
1–3 months <70
correlate closely with a low MAP [103]. Moreover, severely
3 months–1 year <70
low cerebral oxygen saturation was rare and brief and
1–2 years <70+(2 × age in years)
2–4 years <70+(2 × age in years)
unlikely to explain neurocognitive dysfunction.
4–6 years <70+(2 × age in years) Although it is useful to know the average blood pressure
6–10 years <70+(2 × age in years) of infants, the optimal target value in any particular neonate
10–13 years <90 must take into account the entire clinical picture to ensure
>13 years <90 that adequate organ perfusion is maintained. The exact
MAP or systolic blood pressure and the duration of expo-
sure to that pressure that is needed to adversely impact neu-
records of 100,000 ASA 1 and 2 children and were devel- rocognitive function in neonates in the long-term remains
oped in conjunction with the World Health Organization undetermined.
growth charts (http://www.pediatric-anesthesia.eu/bp_calcu-
lator/) yielded 50th percentile values for the systolic and
mean NIBPs under anesthesia for boys of 48 and 33 mmHg, Central Venous Pressure Monitoring
respectively, with large variability in the data [95].
In 2017, a retrospective review of 735 term and 82 pre- CVP monitoring is frequently indicated in order to assess
term infants undergoing laparoscopic pyloromyotomy deter- volume status and/or cardiac function. The normal CVP in a
mined the frequency of hypotension as well as relative and ventilated neonate is about 4–6 mmHg. Low CVP pressures,
absolute hypotension. They found that, overall, hypotension ≤2 mmHg, suggest hypovolemia or dehydration, whereas
was greatest in neonates compared with older infants and values >8 mmHg suggest cardiac disease.
greater in preterm infants than in full-term infants [100]. Of CVP lines may also be indicated for the administration of
this cohort, 77% developed relative hypotension (a systolic parenteral nutrition fluids and some medications (Fig. 7.9a).
pressure >20% below preinduction values) and 21% devel- In an urgent situation, they may also be used for rapid vol-
oped absolute hypotension (absolute hypotension defined as ume replacement, and only if peripheral IV access is unavail-
a systolic pressure <35 mmHg) primarily during the presur- able. It must be emphasized that this fluid is being directed
gery and even the surgical periods. These subtle findings immediately into the heart and electrolyte and temperature
helped to focus the results of the Apricot study of serious differences may trigger arrhythmias. To avoid serious
adverse events in infants and children undergoing anesthesia sequelae in such cases (e.g., life-threatening arrhythmias),
in Europe [101]. The greatest frequency of both cardiac and the fluid (blood or plasma) should be warm, nonacidic, and
respiratory adverse events occurred in infants <1 year of age. normokalemic.
It was suggested that this resulted from inadequate training Central venous access using ultrasound guidance (USG)
in pediatric anesthesia, a finding confirmed in at least one has been described in preterm and full-term neonates for the
institution where the frequency of cardiac arrest in infants internal jugular vein (IJV), subclavian vein, and brachioce-
decreased three-fold when only specialists trained in phalic (or innominate) vein (BCV) (Fig. 7.9b, c) [104–110].
pediatric anesthesia anesthetized these infants [102]. The Anatomically, cannulation of the BCV at the venous conflu-
final common pathway by which hypotension and cardiac ence of the internal jugular, subclavian, and brachiocephalic
a b
c d
Fig. 7.9 (a) Ultrasonographic long-axis view of the right BCV in a subclavian vein via long axis view: 3.3 mm. B: depth of SCV from the
1.7 kg infant. (b) Short axis view of the collapsing right internal jugular skin surface: 7.7 mm. Small picture: Ultrasound probe placed at the
vein due to puncture needle approach using the out-of-plane technique supraclavicular area across the clavicle so as to obtain an optimum long
in a 3.4 kg infant. Ultrasonographic image: IJV Internal jugular vein, axis view of the left SCV. Cl Clavicle; i.v. cannula indicating the in-
CA Carotid artery, ScmM Sternocleidomastoid muscle, AscM Anterior plane approach to the SCV. (g) Ultrasonographic view of the entire
scalene muscle, VA Vertrebral artery. Small picture: 22-gauge needle long-axis view of the caudally directed right BCV in a 2.1 kg infant.
with attached syringe aiming at the internal jugular vein via the short Ultrasonographic image: AscM Anterior scalene muscle, FR First rib,
axis view. (c) Out-of-plane puncture of the right internal jugular vein in ScmM Sternocleidomastoid muscle, BCV Brachiocephalic vein, white,
a 3.5 kg baby. Ultrasonographic image: IJV Internal jugular vein, CA boldfaced arrow indicating the implied i.v. cannula insertion. Small pic-
Carotid artery, ScmM Sternocleidomastoid muscle, AscM Anterior sca- ture: Ultrasound probe placed in the right supraclavicular region so as
lene muscle. Small picture: 22-gauge needle with attached syringe aim- to obtain the optimum long-axis view of the right BCV. Cl, clavicle; i.v.
ing at the internal jugular vein via the short axis view. (d) cannula indicating the in-plane approach to the BCV. (h) Out-of-plane
Ultrasonographic long-axis view of the left BCV in a 3 kg infant with puncture of the right BCV via an ultrasound probe placed in the supra-
the 22-gauge i.v. cannula clearly inside the vein. Ultrasonographic clavicular region. Ultrasonographic image: SCV Subclavian vein, Cl
image: AscM Anterior scalene muscle, FR First rib; ScmM. (e) Clavicle. Small picture: Puncture needle aiming at the venous conflu-
Brachiocephlic venous catheter fixed on the left shoulder in a 900 g ence via an out-of-plane approach. Cl Clavicle. Cl Clavicle. Ultrasound
baby. (f) Long axis view of the left subclavian vein in a 3.2 kg infant. image: rBCV Right brachiocephalic vein, leBCV Left brachiocephalic
Ultrasonographic image: SCV Subclavian vein, IJV Internal jugular vein, AoA Aortic arch, FR First rib, A..A: A, diameter of the right BCV:
vein, FR First rib, ScmM Sternocleidomastoid muscle. A: diameter of 2.2 mm
e f
g h
Fig. 7.9 (continued)
(or innominate) veins known as the Pirogoff confluence or lumen of the IJV and facilitate a successful cannulation
the BCV itself are less likely to puncture the pleura (Fig. 7.9d) [112]. Effects of a combination of Valsalva maneuver, liver
[110]. The size of the targeted vein should always be deter- compression, and Trendelenburg in infants nominally
mined by ultrasound (US) before cannulation (Fig. 7.9e) increases the cross-sectional area of the IJV, 17% [113]; lim-
[111], inserting a catheter whose outer diameter should be at ited effectiveness of the Trendelenburg position in neonates
least one-third smaller than the vessel lumen. may be attributed to their small length and thus the small
Central venous pressure is commonly monitored via per- vertical distance between the heart and the neck adding very
cutaneously inserted internal jugular catheters. The use of little back pressure on the vein. Rotating the head 40° to the
USG results in a high success rate for first time catheter right when canulating the right IJV provides the greatest
insertion even in low birth weight infants. Alternatively, the cross-sectional diameter with less overlap with the carotid
brachiocephalic vein may also be cannulated using USG. artery as 80° [114]. It is, however, common to place a small
roll under the shoulders. The diameter of the IJV is larger
annulation of the Internal Jugular Vein
C than that of the subclavian vein and as such is often pre-
Transcutaneous insertion of a CVC via the IJV in the neonate ferred; in addition, thrombotic events occur less frequently in
has been greatly facilitated by the use of US [105]. The vein right-sides central lines and in the IJV compared with the
is readily recognized by the ease with which it collapses subclavian vein although the IJV is associated with an
under minimal pressure of the transducer on the neck increased risk of catheter infections (Fig. 7.9g) [115, 116].
(Fig. 7.9f). Application of skin traction with tape applied in The left subclavian vein may also be cannulated, preferably
an upward direction during catheterization will increase the using US to locate the vein accurately [117], which recog-
nizes that its diameter is smaller than the IJV in the neonate The Nervous System
[111]. Complications from cannulating the subclavian vein,
including pneumothorax, are greater than those from cannu- Neurological monitoring in the neonate poses special chal-
lating the IJV. Selecting the correct depth of insertion may be lenges because the immature central nervous system limits
difficult in the smaller infant. The catheter length may be the functional information that can be acquired. However,
estimated using external measurements of the distance the well-being of the nervous system depends on protecting
between puncture site and the upper sternum. However, it during critical illnesses; thus, it is essential to detect and
radiological evidence of the optimal depth of insertion correct situations that may compromise its functioning.
should always be noted. The tip of the catheter should not Monitoring of the nervous system involves a multimodal
rest inferior to the junction of the superior vena cava with the approach integrating electrical activity, CBF, and cerebral
right atrium confirmed by radiology [117]. If the tip is oxygenation.
advanced into the right atrium, serious complications includ-
ing arrhythmias, damage to the tricuspid valve, or cardiac
perforation with cardiac tamponade may ensue. EEG and Amplitude-Integrated EEG (aEEG)
annulating the Brachiocephalic Vein (BCV)

C The EEG has been used to monitor brain electrical activity in
We advocate USG when cannulating the BCV via the supra- the neonatal intensive care unit for many years. Standard
clavicular approach (Video 7.1) [104, 107, 118]. The US montages used in adults were simplified from 21 to 9 elec-
probe should first be positioned to identify the IJV and then trodes to accommodate the smaller head of the neonate. The
shifted caudally to identify the junction with the subclavian EEG recording in the neonate varies considerably with gesta-
vein. The BCV is then identified by tilting the US probe tional and postnatal age. A developmental glossary of EEG in
medially. The right is often chosen over the left BCV because premature and full-term infant was recently published [124],
of a lower risk of catheter-related thrombotic events in the which included a summary of the EEG changes with age
former, although the left BCV is larger and easier to cannu- [125]. Given its complexity, interpretation of the neonatal
late (Fig. 7.9a, h) [104, 106, 118]. Given the risk of compli- EEG requires an experienced technician and a neurologist,
cations during subclavian and BCV punctures due to the effectively limiting the monitoring to only a few hours daily.
proximity of the veins to the pleura, the IJ route is generally Amplitude-integrated EEG (aEEG) was developed in the
preferred by anesthesiologists. late 1960s as an alternative tool for continuous EEG moni-
toring that could be used at the bedside by a trained nurse
entral Venous Access: General Principles
C and a non-neurologist clinician. These changes vastly
Full aseptic precautions should be observed during central improved the use of this monitor. The cerebral function mon-
venous cannulation in neonates for all approaches. The cor- itor, a device using aEEG, was originally developed as a tool
rect choice of skin prep solutions is important: 10% to predict outcomes after cardiac arrest in adults [126]. Since
povidone-iodine solution may affect thyroid function in pre- the publication of a reference atlas for aEEG in infants in
term infants. A solution of 0.5% chlorhexidine gluconate in 2003 [127], aEEG has gained popularity in both Europe and
70% isopropanol has been recommended as its antibacterial North America. aEEG has variable sensitivity and specific-
effectiveness is several-fold greater than betadine [119]. ity, rendering it unsuitable as the sole diagnostic and man-
When CVCs are used to deliver hyperalimentation solutions, agement tool for seizures in neonates [124]. Nonetheless, it
asepsis is obligatory as catheter-related infections and endo- does effectively screen for seizures in this age group. This
carditis are common complications. approach provided continuous cerebral activity information
When access to the superior vena cava is difficult or impos- with minimal interference in patient care [128].
sible, the femoral vein may be cannulated. Pressure in the IVC The aEEG signal is predictably altered during general
(i.e., via femoral vein cannulation) accurately reflects the central anesthesia and may be used as a depth of anesthesia monitor,
venous pressure in the atrium [120]. The success rate for this while also serving as an important index of cerebral
approach is ≥80%, with an arterial cannulation rate that varies well-being.
between 2 and 12% depending on the size of the preterm infant The aEEG relies on signals from either a single pair
and a number of other minor complications [121, 122]. Care (P3 → P4) of electrodes, or two pairs (C3 → P3, C4 → P4). The
should be taken when threading the catheter to ensure the tip central–parietal areas are preferred for monitoring the neo-
does not extend too far, entering the veins of the liver, heart, or nate as this area is at risk for hypoperfusion from the phe-
other organs [122]. The frequency of thrombosis of the femoral nomenon of vascular watershed. Frontal locations are not
vein after cannulation is almost 10 times greater than with a recommended for two channel monitoring as this area is
Peripherically Inserted Central Catheter (PICC) line and 4 times electrophysiologically underdeveloped and seizure activity
greater than with an umbilical vein [123]. may not propagate to the frontal region [129].
The aEEG device is portable and designed for ease of use associated with reduced oxygen consumption in the presence
[130]. The signal from the electrodes is amplified, filtered of high-cerebral oxygen saturations (e.g., low fractional oxy-
(2–15 Hz bandpass), rectified, and presented as a peak-to- gen extraction) after birth asphyxia [134]. Abnormal aEEG
peak voltage. By filtering out signal frequencies in excess of patterns after neonatal H–I have been associated with
15 Hz, interference from muscle activity and electrical decreased glucose utilization as measured by positron emis-
devices is eliminated. Filtering out frequencies less than sion tomography, whereas normal aEEG patterns have been
2 Hz removes low-frequency delta waves. Many algorithms associated with normal glucose utilization [143]. Cooling is
weight the alpha over the theta or delta waves although the frequently instituted as a means of reducing the likelihood of
predominant waves present in the premature neonate are the long-term brain injury in infants, who experience hypoxia–
delta and theta waves. Alpha and beta waves first emerge ischemia. Abnormal aEEG patterns do not portend a poor
after 34 weeks of gestation. The aEEG is displayed at slow neurological outcome in the presence of systemic hypother-
speeds to reveal trends. Raw EEG can be displayed on the mia, unless the patterns persist for more than 36 h [144].
screen so that rapid changes such as seizure activity can be
observed [129]. Several commercial devices measure aEEG,
but the results can vary depending on the peak detection Near-Infrared Spectroscopy
algorithm [131].
The aEEG displays an upper and lower voltage band. A Near-infrared spectroscopy (NIRS) is an optical technology
normal aEEG has a lower voltage >5 μV and an upper volt- based on the relative transparency of biological tissues to
age >10 μV [131]. An aEEG trace with a lower band ≤5 μV near-infrared light (700–900 nm) where oxygen binding
and an upper band >10 μV is moderately abnormal; the com- chromophores, hemoglobin and cytochrome oxidase, have
bination of lower band <5 μV and upper band <10 μV is distinct absorption spectra. Although it is theoretically pos-
defined as severely abnormal or suppressed [132]. An abnor- sible for NIRS to separately determine oxygenation of blood
mal or suppressed aEEG, when present many hours after and the cell through hemoglobin and cytochrome oxidase,
birth asphyxia, is predictive (>70%) of death or neurological measurement of cytochrome oxidase distinct from hemoglo-
disability [132–134]. bin has proven to be difficult. Thus, the application of NIRS
Changes in aEEG voltages occur with decreased cerebral in the clinical setting has focused on monitoring hemoglobin
perfusion and decreased cerebral metabolism. For example, oxygenation.
decrements in the aEEG amplitude that last 10–20 min were Hemoglobin saturation determined using NIRS differs
noted in infants given surfactant who experienced a decrease from that of pulse oximetry in several respects. First, NIRS
in mean blood pressure and increased pulmonary shunting interrogates hemoglobin mainly in small vessels (arterioles,
[135, 136]. Decreased aEEG voltages were also noted in a capillaries, and venules), thereby providing a mixed vascular
subgroup of infants undergoing ductus ligation under anes- oxygen saturation of the gas-exchanging circulation, whereas
thesia who manifested decreases in mean blood pressure and pulse oximetry interrogates hemoglobin in the arterial circu-
decreases in the NIRS-measured ScO2 [137]. lation. Under normal conditions, the NIRS cerebral satura-
aEEG patterns are related to cerebral perfusion from the tion (ScO2) is only 60–80% due to the dominance of venous
first day of life, in both very premature infants and term blood in the tissue circulation. During cardiac arrest, ScO2
infants with congenital heart disease [138, 139]. The rela- decreases as brain tissue consumes oxygen, whereas arterial
tionship between aEEG and blood pressure is less clear as saturation remains constant or unmeasurable with the poor
abnormal aEEG patterns may not manifest in some infants perfusion during the pulseless state.
until the mean arterial pressure is less than 23 mmHg [90]. Second, NIRS views the large, total signal of photons
Additionally, aEEG is not adversely affected by mild hypo- passing through the tissue to derive ScO2, whereas pulse
thermia [140]. However, aEEG output must be scrutinized oximetry selects the tiny portion of photons passing through
for artifact from electrical interference, high-frequency the arteries as a pulse-gated signal to calculate SpO2. In term
ventilator, or ECG interference [141]. Collectively, these and preterm neonates, the superficial layers of skin, bone,
data suggest that aEEG may be a useful monitor to assess and cerebrospinal fluid, which constitute a thickness ≤6 mm,
the adequacy of cerebral perfusion under conditions pres- do not preclude measurement of tissue oxygen saturation
ent in the operating room provided measures are taken to with the NIRS instrument using a model of the brain [145].
minimize interference. During poor perfusion and/or an extremely weak pulse sig-
Neonatal hypoxia–ischemia (H–I) induces significant nal, the NIRS readings remain steady and accurate, whereas
changes in the coupling between cerebral perfusion, metabo- the pulse oximeter fails to provide an accurate measure of
lism, and electrical activity [142]. The aEEG pattern (nor- oxygen saturation. Finally, NIRS ScO2 reflects the balance
mal, moderately abnormal, suppressed) correlates with between oxygen delivery (blood flow, hemoglobin concen-
changes in CBF and metabolism. Abnormal aEEG is also tration, and arterial saturation) and metabolism (oxygen con-
sumption) and function of the tissue, whereas SpO2 only NIRS has been most widely applied for congenital heart
reflects oxygen delivery and function of the lungs. Thus, a surgery in neonates, as well as in addressing the functionality
decrease in ScO2 may be attributable to a decrease in CBF of other organs. In many centers, NIRS has become a stan-
(resulting from hypotension, hypocarbia, or other causes) dard of care for brain monitoring and somatic oxygen satura-
[146], arterial saturation, blood hemoglobin concentration, tion in congenital heart surgery. After balloon septostomy for
or an increase in cerebral oxygen metabolism, although the transposition of the great arteries, NIRS depicted a signifi-
decrease usually results from a decrease in CBF or arterial cant improvement in ScO2 compared with those that did not
saturation. As such, combining pulse oximetry with NIRS undergo septostomy for 24 h [156]. Treatments to increase
facilitates diagnosis of a pulmonary or CBF problem and the ScO2 depend on the type of cardiac malformation. For hypo-
institution of appropriate therapy at the bedside. plastic left-heart syndrome and other similar physiologies,
It is also possible to measure CBF using NIRS and the the following will increase the ScO2: decrease in cerebral
Fick equation with oxyhemoglobin or indocyanine green oxygen metabolism; administration of inotropes, blood
employed as the tracer. Oxyhemoglobin will be an effective transfusion, or fluid bolus to increase arterial pressure and
if the inspired oxygen concentration is increased by an cardiac output; hypoventilation or ventilation with carbon
amount sufficient to increase arterial saturation by at least dioxide to increase arterial PCO2, CBF, and cardiac output;
5% over 6 s [147, 148]. NIRS can measure CBF by rapidly and ventilation with hypoxic gas to decrease pulmonary
injecting intravenously indocyanine green, an FDA-approved blood flow and increase systemic cardiac output [157–159].
compound strongly absorbs at 800 nm, as the tracer instead Administration of oxygen can increase or decrease ScO2,
of oxyhemoglobin. Recent advances in theoretical physics depending on the malformation and physiology. For exam-
and optical technologies have improved the capability of ple, with hypoplastic left-heart syndrome, increasing the
NIRS to measure ScO2. Before 2008, NIRS devices that FiO2 increases the SaO2 but decreases PVR, increases PBF,
measured absolute ScO2 were research oriented and not and decreases the systemic and CBF with a net decrease in
commercially viable, and the commercially available NIRS the ScO2. In critically ill neonates, NIRS has been applied to
devices could only measure trends in ScO2, not absolute the head and flank or abdomen to determine ScO2, SkO2
ScO2 values. Since that time, Somanetics, CasMed, and (kidney), SlO2 (liver), or SgO2 (gut) to guide ICU treatments
Nonin manufacture FDA-approved NIRS devices for neo- or timing of surgery [160, 161]. In neonates undergoing non-
nates, which can determine the absolute ScO2. Evidence sug- cardiac surgery, NIRS reported a frequent regional hypoxia
gests these sensors correlate closely although the absolute (in the cerebral and renal tissues) intraoperatively and post-
ScO2 may differ by as much as 10–15%, which may compli- operatively, two to three times more frequently than pulse
cate the interpretation of clinical studies [149]. oximetry [160]. Moreover, NIRS was effective in detecting
What are the critical ScO2 values that diagnose cerebral postoperative apnea.
hypoxia–ischemia and predict brain damage? In neonatal NIRS has also been employed during surgery to guide
pigs, cerebral function begins to deteriorate when the ScO2 anesthesia and surgical management. Before and after car-
decreases to <45%, noted by slowing of EEG and accumula- diopulmonary bypass, the anesthesiologist uses NIRS to
tion of tissue lactate. As ScO2 decreases to less than 35%, diagnose brain and somatic hypoperfusion and ischemia and
cerebral energy fails, expressed by loss of tissue ATP and guide therapies to restore tissue oxygenation, similar to that
isoelectric EEG [150]. Given normal values of 60–80% for in the ICU [152, 157]. During surgery, NIRS displays char-
the ScO2, a buffer zone of approximately 15% exists during acteristic changes that may be used to monitor the brain dur-
which ScO2 may decrease before brain function begins to ing cardiopulmonary bypass (CPB) [158, 162]. With the
change [151, 152]. The risk of brain damage depends on the institution of CPB, NIRS may be used to verify proper place-
severity and duration of the hypoxic–ischemic insult. For ment of the cannula as ScO2 should not decrease [163].
insults producing isoelectric EEG and loss of ATP, <30 min During CPB cooling, ScO2 should increase to >90% to reflect
of hypoxia–ischemia will inflict brain damage. Consequently, the effect of hypothermia on cerebral O2 consumption.
insults that decrease the ScO2 to <35% require an interven- During hypothermic selective cerebral perfusion or low flow
tion to restore the ScO2 within 30 min to reverse the insult. CPB, ScO2 should not decrease substantially [164]. During
For hypoxia–ischemic insults that cause an ScO2 between 35 reperfusion after deep hypothermic circulatory arrest or
and 45%, the brain will not exhibit evidence of damage for selective cerebral perfusion, ScO2 should increase to >80%
the first 2 h, but thereafter, the risk of brain damage increases to indicate cerebral recirculation. If NIRS does not achieve
15% for each hour of hypoxia–ischemia [153]. Studies in these values during these situations, the anesthetic and surgi-
neonates in the intensive care unit after congenital heart sur- cal team should search for a reason.
gery suggest that the risk of brain injury at ScO2 <45% NIRS has also been used as a metric during neonatal
increases after 3 h [154, 155]. Interventions are warranted resuscitation [165]. In the neonatal ICU it has been used to
within 2–3 h of onset of ScO2 values at 35–45% to preclude guide treatment during circulatory failure, ventilator man-
irreversible impairment. agement during respiratory distress syndrome [166], and
during extracorporeal membrane oxygenation for respiratory who described this phenomenon in 1842. Three types of
insufficiency associated with diaphragmatic hernia [141]. Doppler systems are in clinical use: pulsed wave, continuous
Although the role of NIRS in the NICU is still used as a wave, and color Doppler. Pulsed wave Doppler allows the
research tool, its clinical application is expanding. For exam- user to measure particle velocity up to a limit within a speci-
ple, NIRS identified those asphyxiated neonates who were at fied region of interest. Continuous wave Doppler has no
risk of developing brain injury as soon as 10 h after institu- velocity limit but lacks spatial resolution; the measured
tion of hypothermia treatment and who may sustain dis- velocity is the maximum velocity over the entire beam path.
turbed cerebral autoregulation [167, 168]. Evidence is also Color Doppler translates information about flow direction
emerging that the combination of aEEG and NIRS during the and velocity into a color map. Doppler measurements are
18 and 60 h of cooling after the hypoxic–ischemic insult most accurate when the US beam is directly in line with the
yields the greatest sensitivity and specificity to predict short- moving particles. The measured velocity decreases as the
term outcomes [169]. In terms of long-term brain injury after cosine of the angle between the beam and the vector describ-
hypoxic–ischemic encephalopathy (HIE), there is evidence ing the moving particle path.
that late failure of cerebral autoregulation during hypother- Both continuous wave and color Doppler instruments
mia for brain protection while monitoring mean arterial have been used to measure CBF velocity in the middle cere-
blood pressure and cerebral oximetry, portended pathologic bral artery. The continuous wave devices suffer from lack of
changes on day 3 of hypothermia treatment [170]. In a large spatial specificity that can be achieved with pulsed color
neonatal trial, the long-term benefit from using NIRS in pre- Doppler techniques. The quality of the measurement can be
mature infants in the first 72 h after birth to reduce cerebral further improved by obtaining gray scale images so that the
hypoxia could not be confirmed [171]. optimal probe angle can be determined exactly. US measures
NIRS has been used to monitor neonates and infants of middle cerebral artery blood flow are useful to detect
undergoing major noncardiac surgery [172]. Although mild severe cerebral hypoperfusion in infants at risk for hypoten-
and moderately low levels of ScO2 occurred frequently in sion or large ductal shunts, as retrograde or poor diastolic
this large cohort of neonates, severely low levels of ScO2 flow occurs in the large arteries near the Circle of Willis in
were rare, even in the presence of prolonged hypotension. these cases [174]. Normative data for CBF velocity in
Low mean arterial pressure was common and was not closely “healthy” preterm neonates has been published [175]. In
associated with low ScO2. Unrecognized severely low ScO2 non-hypotensive neonates, both systolic and diastolic CBF
that lasted ≥3 min in neonates and infants is less likely to velocity increases as a function of postnatal and postconcep-
explain the subsequent development of neurocognitive tual age [175].
abnormalities than other causes. Conversion of velocity to flow requires knowledge of the
Transient bradycardia occurs in preterm neonates in the arterial cross-sectional area. This measurement is not easily
NICU and during anesthesia. The effect of these heart rate made and is subject to inaccuracies. However, radiographic
changes on cerebral oxygenation and function is not widely data suggests that vessel diameter is relatively constant over
recognized. In fact, 10% of the bradycardias in one study short periods of time so that changes in velocity are likely to
went undetected by pulse oximetry [173]. Moreover, the represent real changes in flow. Practical limitations of space
nadir of tissue oxygen extraction in very preterm neonates and access to probe application sites make application this
was <55% in 61% of those with moderate/severe bradycar- modality for estimating CBF difficult in the OR environ-
dia (<50% of baseline or an absolute heart rate <60 bpm) and ment. There are numerous reports examining the value of
35% of those with mild bradycardias (60–80% of baseline). Doppler measured CBF before, during and after cardiopul-
The effect of bradycardia on cerebral oxygenation was more monary bypass in neonates [176]. In the context of selective
severe in very preterm (26–31 weeks gestation) than in late cerebral perfusion, low flow cardiopulmonary bypass, and
preterm (32–38 weeks) neonates. deep hypothermic arrest, transcranial Doppler has been used
to detect cerebral hypoperfusion and can guide pump flow
rate, surgical and anesthetic therapies intended to prevent
Transcranial Doppler cerebral ischemia [176].
When sound waves are reflected off a moving object, the fre-
quency of the reflected wave is shifted compared with that of Neurophysiological Monitors
the incident wave; the frequency shift depends on the veloc-
ity of the object. If the object is moving toward the sound The spinal cord and peripheral nerve functions may be moni-
source, the frequency shift is greater; if the object is moving tored during certain operations such as spinal fusion, com-
away from the source, the shift is less. The frequency shift is plex tethered cord releases, and cerebellar–pontine angle
also referred to as the Doppler shift after Christian Doppler, tumor resections. This type of monitoring involves measur-
ing the transmission of sensory information from the periph- series of clicks in one ear and a masking noise in the opposite
eral nerves to the sensory cortex. Alternatively, the conduction ear, and recording potentials using electrodes placed at each
of motor signals from the cortex to the skeletal musculature mastoid and one at the vertex of the head. In order to gener-
may be measured, thus assessing the functional state and ate an ABR, the recording must be time locked to the stimu-
integrity of motor axons from nerve roots to muscle. These lus, filtered, amplified many times, and signal-averaged as
monitoring modalities are known as somatosensory evoked ABRs have very low amplitude (0.1–0.3 μV), which would
potentials (SSEPs), transcranial motor evoked potentials be easily overwhelmed by the much greater amplitude EEG
(TcMEPs), and electromyography (EMG). In our experi- signal without special processing.
ence, one or more of these modalities may prove useful in The ABR from a conscious patient is composed of waves
selected neonatal procedures. that make up the short, middle, and long latency components
It is possible to record SSEPs by stimulating the median of the response. The short latency responses, called Waves
nerve [177] and/or posterior tibial nerves [178] in preterm I–V, are not easily degraded by sedation and anesthesia. The
and term infants in the awake or lightly sedated state. putative anatomic origin of Waves I, III, and V [183] as well
Neonatal and infant median nerve SSEPs have different mor- as the latency of each wave differ with age [184]. The struc-
phology and peak latencies compared with those in the adult tures responsible for the generation of ABR Waves I–V are
(Table 7.3). This age difference may be attributable to the supplied by branches of the basilar–vertebral system; conse-
degree of myelination and other structural differences quently, the ABR is very sensitive to brainstem ischemia or
between the neonatal and adult peripheral and central ner- hypoperfusion [183].
vous systems [179]. In the neonatal ICU setting, both median Recognizable and reproducible ipsilateral ABRs can be
nerve and posterior tibial nerve SSEPs have prognostic detected in preterm infants beginning at about 30–32 weeks
significance for future neurocognitive outcomes in preterm gestation. Reproducing waveforms can be detected on the
neonates after asphyxia [180, 181]. The cortical SSEP signal contralateral side by 34 weeks gestation. The appearance of
is easily obliterated by anesthesia and/or deep sedation in the wave V on the contralateral side is important, as identifica-
neonate. However, subcortical recording from Erb’s point tion of ABR waves (peaks) is typically achieved by identify-
and the posterior neck are more resistant to anesthetic effects ing wave V first and working backwards to identify the other
and are of interest when the brachial plexus is the site of the waves. In children and adults, wave V is frequently and most
injury. Signals from these structures have been recorded, and clearly seen on the contralateral side as auditory pathways
normative data for expected latencies has been published cross the midline at the level of the inferior olivary complex.
[182]. A TIVA technique including propofol and remifent- The neural activation triggered by the clicks used in ABR
anil produces the least suppression of neurophysiologic acquisition travel both ipsilateral and crossed pathways.
signals. Recently, the optimal click rate to assess neurodevelopmen-
The auditory system of the neonate can be monitored tal outcomes with the ABR in premature infants 34 weeks
using auditory brainstem responses (ABRs), otherwise called postmenstrual age was determined to be 29.9/s [185].
brainstem auditory evoked responses. ABRs are similar to The amplitude of the component waves increases with
SSEPs in that a nerve (the cochlear nerve) and far-field gestational age, whereas the latencies to Waves I, III, and V
potentials are recorded. ABRs are obtained by presenting a decrease with gestational age [186]. Analyzing the ABR in
premature infants is particularly challenging, although the
characteristics of the developing ABR in infants as young as
Table 7.3 SSEP latencies as a function of gestation and age 26 weeks gestation have been reported [187]. The greatest
Gestation/ Myelination status of “N12” latency “N 20” latency changes in amplitudes and latencies occur after birth. ABR
age pathways (ms) (ms) wave amplitudes reach their zenith at 4 years of age and
32 weeks ML–PM 68–72 decline slightly to adult values thereafter, whereas latencies
TCP–UM
reach adult values by about 2–3 years of age (Table 7.4)
40 weeks ML–PM 33–38
TCP–UM/PM [184]. ABR wave amplitude is also sensitive to the rate at
6 months ML–PM 6 18 which the click stimuli are presented [183]. Infants maintain
TCP–PM the amplitude of their ABR waves at greater stimulus rates
12 months ML–FM 6 15.5 than do adults [186].
TCP–PM ABRs are frequently used to monitor the eighth cranial
3 years ML–FM 6 15
nerve (CN VIII) and brainstem during neurosurgical proce-
TCP–FM
Adult ML–FM 13 20–21 dures involving the cerebellar-pontine angle and posterior
TCP–FM fossa tumor resections. Traction on CN VIII, changes in
ML Medial lemniscus, TCP Thalamocortical projections, UM blood flow to CN VIII, or the cochlear nucleus will affect
Unmyelinated, PM Partially myelinated, FM Fully myelinated Waves I and II significantly but may also result in loss of
Table 7.4 ABR: change in wave I, II, and V latency with age and wave term [195, 196]. For reasons cited above, the MEPs of very
generators young infants are exquisitely sensitive to anesthesia, thus a
Gestation/ Wave I latency Wave III latency propofol–remifentanil-based technique is recommended
age (ms) (ms) Wave V latency (ms)
whenever MEPs are measured for surgical procedures on the
32 weeks 1.6 ± 0.23 4.37 ± 0.27 6.75 ± 0.44
spinal cord [191].
40 weeks 1.6 ± 0.23 4.30 ± 0.25 6.63 ± 0.39
6 months 1.6 ± 0.23 4.06 ± 0.19 6.17 ± 0.27
Another useful modality for monitoring the integrity of
12 months 1.6 ± 0.23 3.91 ± 0.17 5.91 ± 0.21 the nervous system is electromyography (EMG). EMG mon-
3 years 1.6 ± 0.23 3.78 ± 0.16 5.66 ± 0.19 itors spontaneous muscle activity or stimulated activity. In
Adult 1.6 ± 0.23 3.78 ± 0.15 5.66 ± 0.17 spontaneous EMG, mechanical or thermal irritation of motor
Generators Distal Olivary Contralateral nerves can trigger the release of neurotransmitters at the
cochlear nerve complex inferior colliculus myoneural junction that generate a muscle action potential.
The number of muscle action potentials recorded is a func-
amplitude reduction of all other waves as well. Ischemia in tion of the rate of change of the mechanical or thermal stimu-
the area of the lateral lemniscus or inferior colliculus will lus [197]. Rapid warming from electrocautery use, sudden
affect wave V. A decrease in amplitude of 50% or more or traction, or mechanical trauma can cause a volley of neural
change in latency of wave V by more than 1 ms may be a sign discharges that manifests as a burst or train of EMG activity.
of brainstem hypoperfusion or insipient ischemia. The ABR Conversely, slowly applied mechanical traction does not
is also sensitive to temperature; latency increases about 7% always result in spontaneous EMG activity, thus stimulated
for each 1 °C temperature decrease; and at 26 °C the laten- EMG can be used to test nerves at risk of injury.
cies are double those at 37 °C [188]. ABR amplitude may In stimulated EMG, the surgeon applies an electrical cur-
initially increase as temperature decreases, although hypo- rent and looks for a response from one or more muscle groups
thermia can obliterate the ABR at 20 °C [188–190]. innervated by a given nerve root. The recording of a CMAP at
Special equipment and trained personnel are required for a low threshold current indicates the structure is a nerve. Motor
intraoperative interpretation of ABRs. The acquisition time nerve roots can be stimulated to produce a muscle action
for a single ABR can be on the order of 3–4 min to achieve a potential at very low current levels (<1 mA); the threshold for
reasonable signal-to-noise ratio. However, when available, mixed nerves may be greater (up to 4 mA). Stimulation thresh-
this modality can provide useful information about the ade- olds obtained while dissecting around nerves fibers or roots
quacy of brainstem perfusion and auditory pathway function can guide surgeons to the distance between the site of dissec-
(to level of inferior colliculus). All latency changes must be tion and functional neural tissue. EMG is unaffected by choice
interpreted in the context of the estimated brain temperature. of anesthetic agents as long as neuromuscular blocking agents
Inhaled agents, without nitrous oxide, may be used when are not used. The surgeon may opt to use spontaneous and
acquiring ABRs as they are very resistant to anesthesia [191]. stimulated EMG recording in an attempt to preserve nerve
TcMEPs are generated by electrically stimulating the roots in the neonate, such as during the resection of tumors
motor cortex, either transcranial or directly, and recording and other malformations that involve the spine including teth-
the resultant compound muscle action potentials (CMAPs) ered cord and lipomeningomyelocele, when preservation of
from various muscle groups. The generation of CMAPs neurologic function is expected.
depends on multiple motor neurons innervating a muscle fir-
ing in or nearly in synchrony. In order to reach the firing
threshold, individual spinal motor neurons must receive a Neuromuscular Junction Monitoring
synchronized descending volley of impulses via the cortico-
spinal tract (CST). The conduction velocity of the axons When non-depolarizing neuromuscular blocking drugs
making up the CST of the neonate are much slower and have (NMBDs) are used in neonates, the degree of neuromuscular
a large variance compared with those of the adult CST, blockade should always be monitored. Such monitoring is
resulting in temporal dispersion of descending signals [192, especially important during antagonism of blockade and
193]. In addition, direct corticospinal to motor neuron syn- before extubation. This is important for several reasons as
aptic connections are rare in the neonate but increase with given below.
age [194]. Under the influence of anesthesia, the motor neu- First, acetylcholine receptors are immature in neonates,
rons in a neonate never simultaneously achieve firing thresh- resulting in an altered response to NMBDs.
old in sufficient numbers to record a CMAP after transcranial Second, the proportion of Type IIb muscular fibers in neo-
stimulation. Special stimulation protocols have been devised nates is significantly greater than in adults. As a consequence,
to partially overcome some of these limitations enabling subclinical residual paralysis may persist after antagonism
MEPs to be recorded in infants as young as 2 months post- and lead to post-extubation fatigue. It is prudent to document
the extent of muscle recovery after antagonism of the NMBDs Temperature Monitoring
in neonates before considering to extubate the trachea. If in
doubt, ventilation and sedation should be continued until neu- Body Temperature Monitoring (see Chap. 8)
romuscular blockade has been completely antagonized.
However, few anesthesiologists realize that most neonates Smaller infants are very prone to lose body heat during sur-
in NICUs are neither paralyzed during their admission nor gery, the reasons for this are discussed elsewhere. The main-
are those who return to the NICU partially or completely tenance of normothermia and avoidance of cold stress will
paralyzed with an NMBD given drugs to antagonize the require careful monitoring. However, there are several
residual blockade before extubation. For the most part, neo- important considerations to observe: First, there is no uni-
natologists depend on clinical indices to judge the neonate’s form “normal” body temperature, different tissues are in dif-
suitability for extubation, which may result in postoperative ferent metabolic states, and thus will have different
respiratory failure, reintubation, and other complications that temperatures. Second, the core body temperature may be
might have been avoided had the paralysis been antagonized. normal but the infant maintains this while in a state of cold
Two major factors that resulted in a seven-fold increase in stress [200]. If the objective is to maintain the infant in a
the risk of a major respiratory event after extubation follow- thermoneutral state, it is suggested that this may be indicated
ing surgery are weight <1.58 kg and postmenstrual age by a core temperature of 36.7–37.3 °C and a change in core
<41 weeks [198]. In our institution, a review of 23 preterm and skin temperature of less than 0.2–0.3 °C/h [201]. These
infants determined that of the infants whose paralysis was considerations may influence the choice of temperature-
antagonized, all 12 were extubated successfully within 1 day monitoring options.
whereas of the 11 whose paralysis was not antagonized, their Common sites to monitor the body temperature in the
tracheas remained intubated for 17 days [199]. It has become infant are the axilla, rectum, skin, esophagus, and ear.
our practice to reverse the neuromuscular blockade in all Measuring the body temperature in the axilla depends
neonates who were paralyzed during surgery before they are upon positioning the probe close to the artery and adducting
discharged from the anesthesiologist’s care. the arm to close the axillary space, procedures that may not
The most commonly used monitor to assess the integrity be easily accomplished in the neonate. A warm-air heating
of the neuromuscular conjunction consists of two electrodes device may directly heat an axillary probe tip exposed out-
placed to stimulate a motor nerve and elicit a twitch. The side the axillary skinfold. It has also been suggested that
possible placements are over the ulnar, facial, or posterior active non-shivering thermogenesis may influence readings
tibial nerves. A train-of-four (TOF) is the commonly used at this site [200].
pattern of stimuli over a period of 2 s (2 Hz): the ratio of Rectal temperature is often considered the best index
strength of the first and the last twitch elicited represents the (Gold Standard) of core temperature, although these read-
percentage of fibers blocked by NMBDs. A zero response ings may be influenced by the depth of insertion of the probe,
represents full paralysis. It must be recognized, however, that rectal contents and metabolic activity therein, the tempera-
neonates normally exhibit a decreased response to the fourth ture of an underlying blanket, and the temperature of blood
stimulus. This so-called “Myasthenic response” is due to returning from the lower limbs [202]. It is generally recom-
ACH (acetylcholine) depletion at the pre-junctional site. mended that the probe be gently inserted to a depth of 5 cm
Hence, in the neonate a ratio of 0.95 may represent a com- [203]. The very rare complication of rectal perforation must
plete return of neuromuscular conduction. be considered [204].
It is also possible to use the neuromuscular monitor to Skin temperature is easily measured and, if this is done
deliver a tetanic stimulation at 50, 100, or 200 Hz. This is with a “zero heat flow” method, it may be preferable to con-
accompanied by fade if neuromuscular block is present. tinuous rectal temperature monitoring [205]. The “Zero heat
Post-tetanic twitches performed after 5 s of tetanic stimula- flow” method requires an insulated probe placed on the skin
tion with a frequency of 1 Hz may demonstrate post-tetanic where it rests on the mattress; this achieves zero heat flow
potentiation but this is less pronounced in neonates than in and measures the temperature of deep tissues [206].
older patients. These post-tetanic twitches might be per- When measuring the esophageal temperature, it is impor-
formed to detect the depth of paralysis in patients with a tant to position the probe in the lower esophagus, posterior to
lack of any response to TOF stimuli. The tetanic stimulus the left atrium. This can be achieved by using a combined
triggers the synthesis of acetylcholine in the pre-junctional esophageal stethoscope and temperature sensor and position-
site, delivering the earliest sign of return to muscular func- ing the sensor retrocardiac by auscultating maximum heart
tion. Post-tetanic stimulation is usually reduced in the neo- sounds through the stethoscope. Temperatures in the upper
nate due to the immaturity of the pre-junctional ACH esophagus may underestimate the true body temperature due
production sites. to cooling by room air fresh gas flow.
The ear is an unsatisfactory site to monitor temperature in increases from 6 mL/h in a 20-week fetus to 60 mL/h at
most smaller infants because of the small size of the ear 40-week gestation. Important information regarding the fluid
canal. Infrared technology may permit intermittent measure- status of the patient and/or the onset of impending renal fail-
ments from the tympanic membrane; this is most often used ure may be obtained. Urine flow less than 1.5 mL/kg/h
postoperatively. should be considered as a warning of a less-than-optimal
state although it is important to remember that neonates may
not produce urine in the first 24 h or so after birth [213].
Monitoring Blood Glucose
Acknowledgment The authors thank Mario, C.D. Kurth, and John
Perioperative hypoglycemia or excessive hyperglycemia McAuliffe for their contributions to the previous edition of this
should be avoided in the neonate. Intermittent tests using a chapter.
hand-held glucometer are valuable to confirm normal levels
and require very little blood. However, the level of signifi-
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Metabolic Care of the Preterm and Term
Infants, Including Control of Body 8
Temperature
Gianluca Bertolizio, Pablo Ingelmo, and Jerrold Lerman
Key Definitions according to their birth weight. Moderately low birth weight
A full-term neonate is a fetus that has reached ≥37 weeks (1500–2500 g) neonates occur in 6.9% of births [1]. Very low
gestational age at birth, whereas a preterm neonate is birth weight (VLBW) neonates defined as a weight of 1000–
<37 weeks gestation at birth. Ninety percent of births are 1500 g occur in 1.4% of births, and extremely low birth
full-term, only ~10% are preterm. Preterm neonates are fur- weight (ELBW) neonates defined as a weight of <1000 g at
ther divided into early preterm (~2.7% of all births), those birth.
born <34 weeks, and late preterm infants (7% of all births), In the early postnatal period (for term and preterm neo-
those born between 34 and <37 weeks [1]. Each group car- nates), an initial but transient decrease in urine output (from
ries with its morbidity and mortality risks [2]. Small for ges- 12 to 48 h) is followed by a diuresis (excretion of water) and
tational age (SGA) infants, which comprise 2–10% of US natriuresis (excretion of sodium) defined by a urine output
births, is defined as being smaller than their expected weight >80% of the IV input [8]. By the 5th postnatal day, urine
(<10%ile for gestational age or <2 standard deviations below output stabilized and varied with the fluid intake.
the norm) or heel-to-crown length when measured either in
utero or as a neonate [3, 4]. Risk factors for having an SGA
infant include maternal factors, maternal medical history, eonatal Body Water Distribution
N
and pregnancy history. In contrast, intrauterine growth and Metabolism
restriction (IUGR), ~10% of US births, is defined as a neo-
nate that has deviated from the normal intrauterine growth At the time of delivery, programmed changes in the cardiore-
curve often as a result of malnutrition and/or in utero growth spiratory system bridge life from the fetal to extrauterine
compromise [5]. IUGR falls into two broad categories [6]: world. With birth, the first few breaths rapidly expand the
type 1 or asymmetric, which accounts for 70–80% of IUGR, lungs and decrease the pulmonary vascular resistance. The
is referred to as “head-sparing” and has been attributed to net effect is an increase in pulmonary venous return to the
uteroplacental insufficiency during the third trimester; and left atrium, which stretches the atrial walls (Fig. 8.1). As the
type 2 or symmetric, which accounts for 20–30%, begins in umbilical cord is clamped and the placenta removed from the
early pregnancy, possibly due to genetics or infection and circulation, systemic vascular resistance also increases,
carries a much worse prognosis. IUGR causes serious peri- applying strain on the left ventricle. Together, the atrial
natal morbidity and mortality ranging from difficult cardio- stretch and ventricular strain increase atrial natriuretic pep-
respiratory transition to metabolic and neurodevelopmental tide (ANP) levels, which dilate the renal vasculature and pro-
sequelae [7]. Overall, the causes of IUGR are numerous but mote an initial natriuresis [9, 10]. Although the posterior
can be classified into maternal, fetal, and placental or a com- pituitary gland secretes antidiuretic hormone (ADH) during
bination of these [6]. Healthy neonates are also grouped the early transition to extrauterine life, aquaporin-2 (AQP2),
the primary target of ADH in the kidney, is not expressed in
the early postnatal period, limiting the urinary concentrating
G. Bertolizio · P. Ingelmo (*) capacity of the kidney, particularly in preterm infants [11].
Department of Anesthesia, Montreal Children’s Hospital, Despite an intact renin–angiotensin system with normal/high
Montreal, QC, Canada
aldosterone levels, sensitivity to aldosterone is also limited,
further enhancing the natriuresis. Ductal steal (a left-to-right
J. Lerman
shunt across a patent ductus arteriosus (PDA)) decreases
Department of Anesthesiology, Oishei Children’s Hospital,
Buffalo, NY, USA renal perfusion, which increases renovascular resistance and

258 G. Bertolizio et al.
Fig. 8.1 Changes in fluid

homeostasis and regulation in
neonates (especially preterm Postnatal Increased pulmonary
neonates) lead to poor drop in venous return
concentrating capacity and pulmonary
urinary loss of sodium. vascular
Reduction in pulmonary Posterior
resistance pituitary
vascular resistance after birth
increases pulmonary venous Left atrial stretch
return to the left atrium,
thereby stretching the atrium.
Umbilical cord clamping and
removal of the placenta
increases systemic vascular Left
resistance and left ventricular ventricular
strain. Atrial stretch and strain ADH
PDA
ventricular strain increase left to
natriuretic peptide levels, right
which cause renal shunt
vasodilation and natriuresis. Natriuretic
Although ADH secretion is peptides
present, reduced aquaporins (ANP,BNP)
in the collecting duct limit the
urinary concentrating Renal
capacity, particularly in vasodilation
premature infants. Although High renal
the renin–angiotensin system vascular
is functional with normal/high resistance Low
aldosterone levels, partial (RVR) cortisol
aldosterone insensitivity
results in a natriuresis. Ductal Low
steal (left-to-right shunt Aquporins
across a patent ductus in collecting
Lower ducts
arteriosus—PDA reduces SHORT Renin
medullary
renal perfusion), increased IMMATURE
osmotic
renal vascular resistance, Poor NEPHRON
gradient
reduced medullary osmotic renal Aldosterone
gradient, short immature sodium
nephrons, and reduced reabsorption
cortisol concentrations act in
concert to limit the ability of
the preterm infant to conserve Partial
Poor urine aldosterone
sodium and water concentrating insensitivity
capacity
natriuresis
reduces the medullary osmotic gradient. With short, imma- The net decrease in total body water begins slowly post-
ture nephrons and reduced cortisol concentrations, the ability natally, with limited urine output (oliguric phase) during the
of the preterm kidney to conserve sodium and water is first 24–48 h, followed by a diuresis as described below [8,
severely compromised (Fig. 8.1). 14, 15]. The early oliguric phase is explained physiologically
Major shifts in fluid homeostasis and regulation occur in by low blood pressure, renal blood flow, and glomerular fil-
neonates and preterm neonates, with immersion into extrauter- tration rate (GFR). This oliguric phase is marked by a dimi-
ine life. Distribution of total body water as well as the distribu- nution in urine output to 0.5–1.5 mL/kg/h that lasts 12–36 h.
tion of water between the extra- and intracellular compartments Urine and stool outputs are scant; although >92% of preterm
change dramatically throughout gestation and continue to and term neonates pass their first urine and stool outputs by
change through the first 9 months of postnatal life (Fig. 8.2). 24–48 h [14]. If the neonate remains oliguric or anuric
Total body water comprises 85% of the body weight in the pre- beyond 36–48 h postnatally, congenital urological or gastro-
term neonate, 75% in the full-term neonate, and then decreases intestinal anomalies should be sought, particularly if cardio-
to 60% in older children and adults (Fig. 8.2) [12, 13]. respiratory variables and/or laboratory indices are abnormal
8 Metabolic Care of the Preterm and Term Infants, Including Control of Body Temperature 259
100 Weight loss can be attributed, in part, to both sensible and

insensible water losses: (1) sensible fluid losses induced by
(a) upregulation of ANP secondary to increased pulmonary
blood flow and stretch of left atrial receptors during the tran-
%
sition to extrauterine life, (b) tubular insensitivity to aldoste-
rone, and (c) stool losses that comprise about 7 mL/kg/day in
preterm infants and 10 mL/kg/day in term neonates; and (2)
80
insensible fluid losses are 10–15 times greater in 24-week
preterm infants than in term neonates during the first 24 h [9,
15, 19]. Thereafter, insensible fluid losses continue through
the first postnatal month and then decrease, such that the dif-
ference between term and preterm neonates dwindles to
2-fold at the end of the first month.
60 ostnatal Changes in Hypothalamic,

P
Per cent of body weight
Endocrine, and Renal Physiology
Hypothalamic–Pituitary–Adrenal Axis
The adrenal gland is essential for organ growth and matura-

tion both in utero and ex utero. Maturation of the HPA–adre-
40 nal gland and its ability to address stress in the fetus and
neonate are determined by two developmentally separate
hormone drivers: corticotropin-releasing hormone (CRH)
and adrenocorticotropic hormone (ACTH). These two driv-
ers inhibit the developing adrenal gland differently and
explain why both term and preterm neonates may be unable
to cope with stress.
CRH is produced by both the fetal hypothalamus the pla-
20 centa in utero [20]. The placental source of CRH increases
throughout gestation, stimulating the release of cortisol in
the fetus. However, in contrast to the hypothalamic source of
CRH, the placental source of CRH is not under a negative
feedback loop but rather a positive feedback loop such that
both CRH and cortisol levels in the fetus increase relent-
lessly throughout gestation until reaching maximum levels at
0 term [20]. These increased CRH and cortisol levels reset the
setpoints in the HPA and adrenal gland in the fetus, so that
0 3 6 9 0 3 6 9 I
when the placenta is removed and both CRH and cortisol
Lunar months months
levels decrease precipitously, the HPA and adrenal glands are
Fig. 8.2 Body water compartment changes during growth (used with relatively insensitive to the decreased CRH and ACTH lev-
permission from FriisHansen B. Changes in body water compartments els, and unable to mount an appropriate stress response for
during growth. In: Linneweh F, editor. Die Physiologische Entwicklung several days, leaving the stressed term neonate with transient
des Kindes. Berlin, Germany. Springer-Verlag. 1959)
adrenal insufficiency and circulatory instability. In most neo-
nates, this transient period of adrenal insufficiency is unno-
[16]. Once the diuretic phase begins, both diuresis and natri- ticed; however, in those who incur stress at birth, this
uresis occur with a tripling of urine output to 3–5 mL/kg/h deficiency may prove to be a challenge to treat.
for several days, accompanied by a total body weight loss In the preterm infant, the function of the adrenal cortex and
that is independent of fluid intake. The onset of the diuresis release cortisol varies with gestational age [21]: before
has been attributed to an increase in GFR and ANP [17, 18]. 30 weeks gestation, the response of the adrenal cortex to exog-
A total body weight loss of 5–7% can be expected during enous ACTH is muted. Before 30 weeks gestation, the fetus is
these first 5–7 postnatal days, although weight loss in ELBW unable to synthesize cortisol due to immature enzymes and
neonates may be much greater, reaching 10–15% [15]. relies primarily upon placental transfer of maternal cortisol as
its source of cortisol [20]. This maternal source of cortisol sup- throughout gestation, often exceeding maternal concentra-
presses the HPA axis, delaying maturation and in some cases, tions at birth. The activity of the renin–angiotensin–aldoste-
causing involution of the fetal adrenal gland, which may rone (RAA) system is inversely related to gestational age.
explain the inability of the ELBW neonate and the neonate Urinary excretion of aldosterone increases significantly in
with IUGR to respond effectively to stress in the peripartum late gestation, between 30 and 41 weeks [19]. In VLBW
period including developing respiratory distress syndrome, infants, the production of aldosterone and expression of
immaturity of the lungs, and persistent hypotension of the renal mineralocorticoid receptors [30] are reduced com-
early preterm infant [22, 23]. This occurs because the activity pared with that in full-term neonates predisposing VLBW
of 11β-hydroxysteroid dehydrogenase type 2 in the placenta is infants to an increased risk of hyponatremia and dehydra-
very low in early gestation, permitting maternal cortisol to tion. As aldosterone concentrations increase with gesta-
cross the placenta, but as the fetus matures, the activity of the tional age, distal tubular reabsorption of sodium increases,
dehydrogenase type 2 increases, converting the maternal cor- but even by term, healthy neonates exhibit partial albeit
tisol to cortisone before it reaches the fetus. With the suppres- transient, tubular unresponsiveness to aldosterone, resulting
sion of the fetal HPA waning around 30–33 weeks, fetal ACTH in an impaired ability to excrete large or acute sodium loads
begins to stimulate the adrenal cortex to secrete cortisol. [19]. In fact, at term, plasma concentrations of aldosterone
Beyond 33 weeks gestation, the adrenal gland and its function- and renin are increased compared with maternal values,
ality mature in parallel with gestational age, so that by term, despite the associated hyponatremia, hyperkalemia, and uri-
two- thirds of the circulating cortisol originates from fetal nary sodium loss [31]. The renin–angiotensin system is very
adrenal glands and one-third from maternal sources and pla- active in the first postnatal week, leading to increases in
cental transfer [21, 24]. However, only 27% of ELBW infants peripheral vascular tone and plasma concentrations of aldo-
and critically ill neonates are unable to triple their cortisol pro- sterone [31]. The increase in angiotensinogen and plasma
duction rate in response to stress (transient adrenal insuffi- renin activity concentrations has been attributed to the low
ciency of prematurity) [25]. This early relatively adrenal systemic blood pressure, renal blood flow, and serum
insufficiency in VLBW neonates may explain, in part, the per- sodium concentration, as well as a decrease in extracellular
sistent hypotension and cardiovascular instability in some pre- fluid (ECF) after birth.
term infants, who are refractory to fluids and inotropes [25–27] Aldosterone concentrations and the distal tubular
but responsive to ACTH and/or steroid therapy during the first responses to aldosterone normalize as renal function matures
15 postnatal days [20, 22, 27, 28]. Thereafter, the adrenal by the end of the first year of life.
gland stabilizes cortisol production and this issue dissipates.
The stress response in most preterm neonates >30 weeks ges-
tation is also directly related to urinary cortisol levels [22]. Atrial Natriuretic Peptides (ANPs)
In full-term and late preterm neonates, maximum cortisol
levels (4–5 times normal) are achieved during parturition and ANPs attenuate the renin–angiotensin–aldosterone axis and
in the first few postnatal hours [24]. Low cord concentrations suppress vasopressin (ADH) release. These peptides vasodi-
of ACTH, cortisol, and free triiodothyronine postnatally may late the systemic, pulmonary, coronary, and renal circula-
be associated with retention of lung fluid and transient tachy- tions, and promote natriuresis and diuresis [17, 32]. As
pnea of the newborn [29]. Moreover, most neonates whose stated, ANP increases in response to dilation of the atrial
cortisol plasma concentrations are suppressed at birth expe- walls and ventricular strain during the transition to extrauter-
rience an increase in plasma concentrations within the first 2 ine life. This suppresses ADH, aldosterone, and renin; vaso-
postnatal weeks [22]. dilates the pulmonary and systemic vasculatures; and lastly
Ex utero, cortisol holds important roles in maintaining promotes diuresis and natriuresis. In aggregate, these com-
blood glucose and electrolyte concentrations, free water bine to decrease the extracellular and pulmonary fluid and
excretion by the kidney, cardiovascular homeostasis, and the ANP concentrations.
vascular integrity in the presence of a systemic inflammatory The time course of circulating ANP in the peripartum
response. In terms of cardiovascular homeostasis, cortisol period is one in which the concentration during the ante-
modulates the activity of beta receptors and their sensitivity partum period is small but increases in term neonate (and
to catecholamines, nitric oxide synthase, and calcium flux. even greater in the preterm neonate), with the transition to
extrauterine life as described above. The concentration of
ANP peaks by 2–4 postnatal days and then gradually
Renin–Angiotensin–Aldosterone wanes to reach adults levels between 2 weeks and
2 months postnatally. In children with congenital heart
Synthesis of aldosterone in the fetal adrenal gland com- disease, ANP levels vary with the type and severity of the
mences by the 13th gestational week and increases steadily specific heart defect [33].
Antidiuretic Hormone Neonatal Renal Function
Antidiuretic hormone (arginine vasopressin (AVP), ADH) In the neonate, renal function is quite immature compared
increases at the time of delivery, especially in neonates with that in the older infant. The number of nephrons in the
delivered vaginally [34]. ADH secretion increases in fetus reaches adult numbers by 34–36 weeks gestation,
response to stress, such as during birth, asphyxia with although the nephrons are shorter and functionally immature
respiratory distress syndrome (RDS), positive pressure [40]. Renal function and the control of fluids and electrolytes
ventilation, pneumothorax, intracranial hemorrhage, and are thus impaired in preterm infants <35 weeks postmen-
other factors (see Table 8.1). Sensitivity of the volume strual age with both fewer and immature nephrons. Postnatal
receptors and osmoreceptors in neonates is similar to that renal maturation, however, is more a function of postnatal
in adults, although the tubular sensitivity to ADH is reduced age than gestational age. After birth, renal blood flow (RBF)
in preterm infants [36, 37], which augments the excretion increases in response to the increased systemic blood pres-
of hypotonic urine (see below), an effect that continues sure with a doubling in the GFR during the first 24 h of post-
postnatally for a brief period. natal life [42]. The increase in RBF is further augmented by
In utero, the renal response to ADH is attenuated closure of the PDA, which is a low pressure siphon of blood
because prostaglandin E2 signals the prostaglandin EP3 away from the systemic circulation to the pulmonary vascu-
receptor to inhibit adenyl cyclase activation, thereby lature. However, the kidney in the neonate is less efficient at
blunting the responsiveness of the collecting duct to ADH excreting an acute sodium or water load than the kidney of
[38]. This results in hypotonic amniotic fluid. However, an older infant or child due to the immature responses to
postnatally this function becomes superfluous as prosta- aldosterone and ADH, in addition to incomplete receptor
glandin levels decrease and ADH is no longer inhibited expression. SGA infants are at increased risk for renal insuf-
from binding to the V2 receptor on the basolateral mem- ficiency [43, 44]. The ability of the postnatal kidney to con-
brane of the collecting ducts. ADH binding to V2 recep- centrate urine depends on the increased sensitivity of the
tors upregulates AQP2 receptors, allowing those water AQPs to ADH, the level of maturity of the Loop of Henle,
channels to insert into the apical basement membrane of and the tonicity of the medullary interstitium.
the renal tubule, increasing the permeability of water from Neonates tolerate fluid restriction poorly and become
the collecting tubules into the cell membranes (Fig. 8.3) dehydrated rapidly as a result of large insensible fluid losses
[38–40]. AQP2 levels continue to increase steadily, reach- and the inability of the kidneys to concentrate urine. Factors
ing a peak by the 10th postnatal week. Expression of that contribute to this inability to concentrate urine include a
AQP2 is also enhanced by glucocorticoid administration. decrease in medullary osmotic gradient and a reduced water
In preterm neonates, AQPs expression is reduced at birth, permeability response of the collecting duct to ADH. The
peaks on postnatal day 3, and returns to the concentrations lack of a renal medulla osmotic gradient and the absence of
at birth by day 7 [41]. AQP3 and AQP4, which also exist medullary tubules limit the urinary concentrating capacity of
in the basement membrane of the collecting tubules, facil- the neonatal kidney (600 mOsm/kg in preterm infants and
itate the passage of water out of the membrane cells and 800 mOsm/kg in full-term neonates) to about half that of
into the interstitium, but likely play a minor role in modu- adult values (1200–1400 mOsm/kg).
lating the egress of water from the collecting tubules.
They are not upregulated postnatally.
Renal Blood Flow (RBF)
Table 8.1 Perioperative causes of Increased ADH release
In both preterm and full-term neonates, RBF is reduced at
Non-osmotic Osmotic birth primarily because the oxygen tension is reduced and
Pain Fasting the renal vascular resistance is increased, the latter attribut-
Inflammation Hypovolemia
able to upregulation of the renin–angiotensin system.
Stress, catecholamines Hypertonicity
Upregulation of the renin–angiotensin system is key to
Surgery; laparoscopic surgery Hypotension
Vomitting Renal insufficiency Hypoxia
nephrogenesis as angiotensin II is a potent growth factor for
Hypoxia Hepatic insufficiency the kidney and vasodilator of the efferent arteriole, which
Hypercapnia augments the GFR [18, 38]. Nephrogenesis is complete in
Medications (e.g., opioids, amiodarone, vincristine) term neonates, but incomplete in preterm infants <34 weeks
Respiratory diseases (e.g., asthma, pneumonia, atelectasis) gestation, resulting in reduced GFR at birth. In addition,
Central nervous system disorders (e.g., head injury, tumors) angiotensin II vasoconstricts the efferent arterioles and com-
Ref. [35] with permission bines with prostaglandin EP2 and prostacyclin to vasodilate
Fig. 8.3 Aquaporin (AQP) in

the human kidney. Modified
with permission from Ref.
[39]
the afferent arterioles to create suitable conditions for the Glomerular Filtration Rate (GFR)
immature kidney to produce glomerular filtrate. Renal vas-
cular resistance is inversely related to gestational age and Although the glomeruli and nephrons are anatomically com-
decreases gradually postnatally, although it exceeds that in plete in the term neonate, they are functionally immature,
adults. RBF increases throughout infancy, reaching adult with reduced GFR and the concentrating ability. The GFR in
rates by 2 years of age [38]. the term neonate is only 25–30% of that in the adult, after
During the first 12 h after birth, 4–6% of the cardiac out- adjusting for differences in size and surface area. The reduced
put perfuses the kidney. Renal perfusion increases to GFR in the neonate can be attributed to the small surface
8–10% of the cardiac output during the first week, com- area of the glomerular basement membrane, which limits the
pared with 25% in adults [38]. A similar pattern of increases amount of fluid that can be filtered [40]. This impairs the
in renal blood flow occurs in preterm infants older than neonate’s ability to excrete a water load. The GFR depends
34–35 weeks gestation, with a more gradual decrease in directly on the gestational age; in preterm neonates, the GFR
renal vascular resistance and a more gradual increase in is reduced but increases slowly compared with that in full-
GFR [45]. In infants, a greater proportion of RBF perfuses term neonates. At 40 weeks postmenstrual age, the GFR is
the juxtaglomerular (medullary) nephrons instead of the 1.5 mL/kg/min (20–40 mL/min/1.73 m2), increasing to adult
cortical areas, whereas in adults, the majority of RBF per- rates of 2.0 mL/kg/min (120 mL/min/1.73 m2) by 2 years of
fuses the cortical area and only 10% perfuses the medullary age. In ELBW infants, the GFR remains reduced until a full
area. Because the juxtaglomerular nephrons are more complement of nephrons has developed at 35 weeks. The
involved in the conservation rather than excretion of GFR doubles in the first 24 h postnatally, continuing to
sodium, this helps to explain the limited ability of the infant increase four-fold through the first 2 years of life before
to excrete a sodium load. reaching the adult rate.
Tubular Function Aquaporin Peptides
Despite a full complement of tubules by 34 weeks gestation, A full description of the role of AQPs in the kidney is beyond
proximal tubular resorption in the term neonate lags behind the scope of this book. However, in brief, 13 AQPs have been
that in the adult [46]. Indeed, renal tubular function reaches identified in mammals, of which only 4, AQP1–4, are
adult levels by 1 year of age. Resorption of solutes such as expressed in the human kidney (Fig. 8.3) [39]. These trans-
organic solutes, glucose, and bicarbonate occurs extensively membrane protein tetramers consist of four water hour-
in the proximal tubule primarily with the help of active trans- glass-shaped channels that are lined with charged moieties to
port. Resorption of sodium occurs via the Na+K+ ATPase limit the transit of most molecules, except water [15]. These
transporter [47]. Na+K+ ATPase activity is decreased in the bidirectional pores allow the passage of water, along osmotic
neonate, along with smaller tubular resorptive surface area, or concentration gradients in the kidney [48]. AQP1, which
fewer solute transporters, and altered control of H+ transport has been detected in the human fetus by 24 weeks gestation,
compared with older infants. For example, Na+-K+ ATPase is primarily found in the apical and basolateral membranes
activity increases 5–-10-fold postnatally, resulting in resorp- of the proximal tubule and the descending loop of Henle, as
tion of most sodium filtered by the glomerulus through the well as in the Vasa recta. AQP1 facilitates the resorption of a
proximal tubule. Most other secretory and absorptive tubular majority of the water from the glomerular filtrate into the
processes, although immature, are relatively well-developed vasculature (Fig 8.3). AQP2 is the second most common
by term. Along with the solutes, water follows the osmotic AQP in the human kidney, which is found primarily in the
gradient via AQP1 channels out of the tubule to ensure iso- collecting duct, apical membranes of storage vesicles, and
osmolarity throughout the extra- and intracellular fluid com- principal cells. ADH-activated V2 receptors in the principal
partments in the body (see below). cells in the ducts activate exocytosis of the AQP2-containing
The ascending loop of Henle confers a special role in cre- vesicles and their subsequent incorporation into the apical
ating hypo-osmolar urine. The ascending loop reabsorbs 25% cell wall to resorb water in the collecting duct region of the
of the filtered sodium chloride but is impermeable to water, renal medulla, thereby concentrating the urine. Pathological
resulting in a hypo-osmolar urine. Although transporters for conditions such as congestive heart failure, in which ADH is
solutes including sodium are immature, the neonate excretes upregulated and AQP2 expression is increased, result in
hypo-osmolar urine at term, with an osmolality as low as increased water resorption from the collecting ducts [48].
50 mOsm/kg, similar to that of adults [46]. The sodium trans- The expression of AQP2 in the fetal kidney is limited, even
porter in this section of the tubule is blocked by diuretics such during the latter half of gestation, which is consistent with
as Lasix. In contrast to the ascending loop, the distal convo- the limited ability of the neonate to concentrate urine [39].
luted tubules resorb ≤10% of the sodium in the glomerular Water is resorbed from the collecting ducts via AQP2 into the
filtrate. However, in similarity with the ascending loop, the cells and exits into the interstitium via AQP3 and AQP4
distal convoluted tubule is impervious to water. Thus, sodium, channels. AQP3 and AQP4 in the human kidney have not
potassium, magnesium, chloride, and several other ions are been fully described.
actively resorbed from the ascending loop tubule, further
reducing the osmolality of the filtered urine [46].
ADH is upregulated in the presence of an increase in Maintenance Fluid Therapy
serum osmolarity and hypovolemia [46]. It acts directly on
the collecting ducts to resorb free water and increase the Water Requirement
osmolarity of the filtrate. The minimum urine osmolarity in
both neonates and adults is 50 mOsm/kg, reflecting the abil- Normal fluid requirements vary markedly in both low birth
ity of the kidney to excrete free water. However, at the other weight and full-term neonates, as well as throughout infancy
extreme, the neonate is severely restricted compared with the (Table 8.2). This variability has been attributed to differ-
adult, with a maximum osmolarity of 500–700 mOsm/kg in ences in caloric expenditures, growth rate, evaporative
neonates, one-half that in adults, 1200–1400 mOsm/kg. losses, and progress of renal function maturation and pro-
Infants maximize their urine concentrating ability by portion of total body water at different ages [50]. Full-term
1 year of age. Glycosuria and aminoaciduria are commonly neonates require 60 mL/kg/day of fluid on day 1, with
detected in neonates (and in preterm infants in particular) requirements increasing steadily to 150 mL/kg/day by
because of immature active transport pumps in the proximal 1 week postnatally [51]. Preterm neonates have larger sur-
tubule. The rate-limiting step in the neonate’s ability to con- face areas relative to their body weights, less subcutaneous
centrate urine is the failure of ADH to upregulate AQP2 pep- fat, and greater insensible water losses than full-term neo-
tides and incorporate them into the basement member of the nates [15, 51]. In the case of VLBW infants, their surface
collecting duct to facilitate the resorption of water. area-to-weight ratios are approximately three times greater
Table 8.2 Average fluid requirements of LBW infants (mL/kg/day) adult levels (<1%) within the first few days [42]. In preterm
during the first postnatal week [49] neonates, the FE Na + is as high as 6–7% before 28 weeks ges-
Postnatal Source of tation, decreasing slowly over the first postnatal month pos-
days water loss Body weight (g)
sibly to 2% [42, 54]. This can lead to negative Na+ balance,
750– 1001– 1251– 1501–
1000 1250 1500 2000
hyponatremia, neurologic disturbances, and poor growth
1 IWL 65 55 40 30 unless sodium is administered at a rate of 3–5 mmol/kg/day
Urine 20 20 30 30 [40]. Preterm neonates demonstrate a greater negative
Total 85 75 70 60 sodium balance than term neonates, which may persist for
2–3 IWL 65 55 40 30 many weeks after delivery because of decreased Na+K+
Urine/stool 40 40 40 45 ATPase activity (i.e., limited resorption of sodium), increased
Total 105 95 80 75 ECF volume, and reduced tubular aldosterone sensitivity.
4–7 IWL 65 55 40 30 The diagnosis of hyponatremia in neonates remains con-
Urine/stool 65 65 65 65
troversial. Most recommend maintaining the serum sodium
Total 130 120 105 95
concentration between 135 and 145 mEq/L. Hyponatremia
IWL Insensible water loss, LBW Low birth weight
has been defined as a serum sodium concentration either
<135 or <130 mEq/L [54]. In one study, the frequency of
than those in full-term neonates, resulting in greater insen- hyponatremia occurred in 4.3% neonates, using a definition
sible fluid losses. These losses, combined with the greater in neonates of <130 mEq/L. Of those who were hypona-
urinary excretion of solutes and reduced tubular concentrat- tremic, 70% were preterm and 90% of the hyponatremia was
ing ability, further increase the obligatory fluid losses in due to iatrogenesis [55]. Hyponatremia was associated with
these neonates [51]. Under normal conditions, a Cochrane a greater mortality, although the mortality was not due to the
review concluded that careful water restriction to maintain hyponatremia itself, but to the underlying cause. Extremely
normal physiological needs without dehydration in preterm preterm infants who become hyponatremic most likely do
infants limits the risk of sequelae such as necrotizing entero- not have reduced total body sodium, which would permit
colitis (NEC) and a PDA [52]. increasing their sodium intake. These infants require a reduc-
Energy expenditure and fluid requirements may also sig- tion in total fluid intake. Conversely, the preterm infant is
nificantly increase during stressful situations such as with unable to rapidly respond to a sudden sodium load and initi-
surgery (up to 30% increase), severe sepsis (up to 50% ate a natriuresis.
increase), fever (10% per degree over 37 °C), and cardiac Clinically, important disturbances in acid–base status are
failure (up to 25% increase). These conditions may increase unusual in full-term neonates unless protein intake is exces-
the need for augmented feeds, whether oral, gavage, or total sive. Factors that may contribute to metabolic acidosis in
parenteral nutrition (TPN). preterm neonates, who received TPN in the first postnatal
Sodium is often omitted or severely reduced in the fluids week, include gestational age, initial base excess, and amino
administered to neonates in the first 24–72 h. Four factors acid and lipid intake [56]. Plasma bicarbonate (HCO3−) con-
modulate the fractional excretion of sodium: renin–angioten- centrations depend on the renal HCO3− threshold, which is
sin–aldosterone system, ANP, prostaglandins, and catechol- reduced in the full-term neonate (19–23 mEq/L) and even
amines [53]. It is in the distal tubule that these factors interact less in the preterm neonate (18–22 mEq/L), and very low
to maintain Na+/K+ concentrations and fluid balance. birth weight (<1300 g) infants (14–18 mEq/L) [38, 40]. The
Judicious administration of sodium and fluids in the early reduced renal HCO3− threshold (physiological renal tubular
postnatal period will prevent complications from hypo- or acidosis—RTA) may be caused by the physiologic volume
hypernatremia as well as fluid overload or dehydration. The expansion in the preterm neonate and the relative immaturity
serum sodium can be an accurate marker of the hydration of the tubular transport mechanisms [57]. Sodium bicarbon-
status of the neonate with hyponatremia from fluid overload ate or more commonly sodium or potassium acetate supple-
and hypernatremia resulting from dehydration. ments of 1–2 mmol/kg/day are generally recommended for
very small preterm infants depending on the defect identi-
fied. Infants with normal anion gap metabolic acidosis
Sodium and Electrolyte Requirements secondary to renal immaturity may have a greater require-
ment for alkali (acetate) in their parenteral nutrition.
Immediately after birth, both full-term and preterm infants Most tubulopathies that occur in neonates are associated
are in negative sodium balance due to the physiologic natri- with an unexplained metabolic acidosis. In terms of the acid–
uresis stimulated by ANP changes with birth [30]. The high base balance, term and preterm neonates have a low thresh-
fractional excretion of Na+ ( FE Na + ) in term neonates (3.5%) old for spilling bicarbonate, although even preterm neonates
decreases rapidly over the first 24 h postnatally, reaching can retain sufficient bicarbonate to manage an acid load. The
normal plasma bicarbonate is 20–22 mmol/L in term neo- neonate, hepatic gluconeogenesis appears insidiously and
nates and 18–20 mmol/L in preterm neonates. Tubular disor- only after birth; in the preterm and IUGR neonates, gluco-
ders that impact the acid–base status of a neonate can be neogenesis is severely impaired due to immature enzymes
traced to a defect in either bicarbonate resorption in the prox- and insufficient precursors [58]. The placenta is permeable
imal and/or distal tubule or acid excretion in the distal tubule. to triglycerides, free fatty acids, and glycerol, and insulin
Tubular acidosis in neonates is usually inherited and stimulates fatty acid synthesis in the liver and glucose uptake
involves either the proximal or distal tubules [57]. Proximal by adipose tissue, resulting in triglyceride synthesis. During
renal tubular acidosis (RTA type 2) is associated with a ten- the third trimester, fat is stored in adipose tissue, which com-
dency to spill bicarbonate in the urine, presenting as a non- prises 16–18% of body weight at term. The accumulated fat
anion gap hyperchloremic metabolic acidosis [57]. The amounts to an energy reserve of approximately 5000 kcal in
bicarbonate that is spilled in the proximal tubule is partially the neonate.
reabsorbed in the distal tubule in exchange for potassium,
hence hypokalemia is common. RTA type 2 is treated with
oral alkali, water resuscitation, and potassium. In contrast, Endocrine Response at Birth
distal renal tubular acidosis (RTA type 1) results from a
defect in hydrogen ion excretion in the collecting ducts [57]. Birth is associated with an endocrine stress response that is
This results in a non-anion gap hyperchloremic acidosis, characterized by a massive increase in plasma catechol-
severe hypokalemia, and dehydration. In RTA type 1, the amine, glucagon, and cortisol concentrations and a decrease
urine pH always exceeds 6.2. Distal renal tubular acidosis in insulin levels. The large ratio of glucagon to insulin
(RTA type 4) is the only RTA that is associated with hyper- induces hepatic glycogenolysis, lipolysis, and gluconeogen-
kalemia, which arises from a deficiency in aldosterone. The esis, effects that are also stimulated by increased concentra-
latter results in hyperkalemia, hyponatremia, and hypoten- tions of circulating catecholamines at birth. Nonetheless,
sion, with similar laboratory findings to RTA type 1 except blood glucose concentrations in neonates decrease physio-
for the hyperkalemia. If RTA persists uncorrected and logically immediately after birth, reaching a nadir by 1–2 h
untreated, chronic renal tubular acidosis or alkalosis can (concentration: 20–25 mg/dL) (1.1–1.4 mmol/L) and
impair growth as well as calcium metabolism [57]. Early increase slowly thereafter, stabilizing by postnatal days 2–4
correction of RTA defects is imperative to prevent serious [58, 59]. The neuroendocrine responses during this transition
bone and growth defects. period have been characterized as a hypoketotic, hypoglyce-
mic response to incomplete suppression of insulin combined
with increased glucagon and epinephrine release [60].
Glucose During this transition period, the brain ensures adequate
energy sources by increasing cerebral blood flow and trans-
Insulin is first detected between 10 and 12 weeks of gesta- port of glucose in addition to using other sources of energy.
tion, and it regulates organ growth such as skeletal and car- The risk of all degrees of hypoglycemia in the term neo-
diac muscles, liver, and adipose tissue. The fetal effects of nates is ~18% when neonates of diabetic mothers, small for
excessive insulin, such as that seen in fetuses of diabetic gestational age, and late preterm infants are included [61].
mothers, result in macrosomia. However, by 20 weeks, the Hypoglycemia occurred significantly more frequently in late
fetal pancreas begins to respond to fluctuations in the glu- preterm infants than in infants of diabetic mothers, large and
cose and amino acid concentrations by secreting insulin. small for gestational age neonates [61]. Of these preterm
However, insulin remains relatively inactive until the onset infants, 2.4% exhibited symptomatic hypoglycemia.
of corticosteroid activity in the second trimester, after which Variability in the incidence of hypoglycemia can be attrib-
it begins to regulate the expression of enzymes related to gly- uted to different thresholds used to define hypoglycemia and
cogen storage and lipid synthesis. As a result, glycogen stor- the timing of the glucose concentrations related to birth and
age does not begin to accumulate (in the liver >> heart > the last feed [61]. Factors that increase the risk of hypoglyce-
skeletal muscle) until 27 weeks gestation and increases mia in preterm neonates include prematurity, gestational age
steadily thereafter until 36 weeks, after which it increases (the less the gestational age, the greater the risk (<33 weeks)),
very quickly (at a rate of 50 mg/g of tissue) until term [58]. and maternal hypertension, whereas factors that decrease the
This reserve, less than 5% of the body weight, is rapidly risk include antenatal magnesium sulfate and labor [62]. In
depleted if a source of energy is suddenly needed (glucose-6- another study, prematurity, macrosomia, improper feeding,
phosphatase is present only in the liver to release glycogen gestational diabetes mellitus, and hypothermia, but not ges-
rapidly as an energy source for the neonate) [58], which is tational hypertension, were also associated with hypoglyce-
why a neonate, and a preterm neonate to a greater extent, is mia [63]. Hepatic synthesis of glucose through glycogenolysis
prone to hypoglycemia during prolonged fasts. In the term and gluconeogenesis is the only source of glucose until feed-
ing or parenteral nutrition is established. Estimates of glu- <32 weeks, with hypoglycemia defined as <47 mg/dL
cose kinetics in full-term neonates suggest that healthy (<2.6 mmol/L), was similar to those without hypoglycemic
neonates produce glucose at the rate of 5–8 mg kg/min (or episodes, although surprisingly, those with a large variability
28–45 μmol kg/min), of which 50–70% is contributed by in the glucose concentration, and consistently >54 mg/dL,
gluconeogenesis. Liver glycogen stores (50–5 mg/g tissue) experienced worse neurosensory impairment [70]. In a fol-
may be depleted within 12 h of birth, after which energy low-up neurocognitive assessment for 15 years, the same
requirements are supported by oxidative fat metabolism until authors found no difference in IQ between the two groups,
feeding is established. The rate of lipolysis, as estimated by although IQ is a very crude and imprecise metric of cognitive
the rate of appearance of glycerol or fatty acid, corresponds function [70]. In the second study, hypoglycemic neonates
to 6–12 μmol kg/min. sustained worse executive and visual motor integration at
4.5 years of age than non-hypoglycemic neonates [71].
Children who had the most severe, recurring, and/or asymp-
Hypoglycemia tomatic hypoglycemic episodes were the most impaired. No
difference in neurosensory impairment was detected.
There is no consensus on the precise definition of either Numerous explanations have been offered for these different
hypoglycemia or euglycemia in neonates [64], although findings [72, 73].
most clinicians acknowledge that neonatal hypoglycemia Hypoglycemia exists during two distinct periods: the first
can lead to seizures and poor neurocognitive outcomes. Most in the immediate 48 h postnatally and the second beyond the
experts define hypoglycemia as a blood glucose concentra- first 3 postnatal days. Transient hypoglycemia in the imme-
tion <47 mg/dL (<2.6 mmol/L) [62, 64, 65], although the diate postnatal period is usually self-limiting, may require a
basis for this threshold is curious at best [63]. According to temporary infusion of glucose, and usually resolves sponta-
AAP (American Academy of Pediatrics) guidelines, a glu- neously once feeds have commenced. The mechanism for
cose concentration between 25 and 40 mg/dL (1.39 and the hypoglycemia postdelivery is thought to be a relative
2.2 mmol/L, respectively) during the first 4 postnatal hours is hypoketotic, hyperinsulinism state that is independent of
actionable. These levels warrant feeding, IV glucose, and whether the neonate is SGA or appropriate for gestational
rechecking the blood glucose concentration depending on age [60]. There is a failure to adequately suppress insulin. In
the values [66]. Between 4 and 24 h postnatal, the threshold contrast, hypoglycemia beyond the first 2–3 postnatal days
to intervene increases to <35 mg/dL (1.9 mmol/L) [66]. For portends more serious glucose metabolic derangements
another perspective, the World Health Organization defined involving glycogen stores and fatty acids, insulin secretion
hypoglycemia as a blood glucose concentration <45 mg/dL disturbances, and neuroendocrine disorders of cortisol and/
(2.5 mmol/L) [67]. The physiologically optimal range for the or growth hormone [64, 72, 74]. Immature infants (e.g.,
blood glucose concentration is 70–100 mg/dL (3.9– ELBW or VLBW) or those who are ill (hypoxia, ischemia, or
5.6 mmol/L), with a minimal optimal concentration of glu- sepsis) may have higher glucose requirements and are more
cose, 60 mg/dL (3.3 mmol/L). vulnerable to the consequences of hypoglycemia. Other
The definition of hypoglycemia in the neonate is based on infants at risk for postnatal hypoglycemia include infants of
a 1988 study of 661 preterm infants (<1850 g) in which the diabetic mothers, those who are large for gestational age
more days the blood glucose concentrations were <47 mg/dL (LGA > 90‰) or small for gestational age infants (SGA),
(2.6 mmol/L), the worse the motor and cognitive develop- infants with Beckwith-Wiedemann syndrome or intrauterine
ment scores at 18 months of age [68]. In fact, the Bayley growth restriction (IUGR <10‰), post-asphyxiated infants
scores were 3.5-fold worse in those with neonatal hypogly- (APGAR <5 at 5 min), and those with G6PD deficiency [64,
cemia compared with those who had not. Radiologically, 66 73, 75, 76]. An infusion rate of glucose of 3–5 mg/kg/min
neonates with hypoglycemia (<2.6 mmol/L) that lasted 3 to will prevent hypoglycemia in infants of diabetic mothers, a
34 days and symptomatology (seizures, irritability) had rate of 4–7 mg/kg/min will prevent hypoglycemia for most
abnormal MRI findings with thinning of the white matter of full-term neonates, and an infusion rate of 6–8 mg/kg/min
the parietal/occipital lobes when compared to neonates with- will prevent hypoglycemia in ELBW and IUGR infants [74].
out hypoglycemia [69]. Interestingly, the abnormal MRI Serial monitoring of the blood glucose concentrations is
findings did not correlate with the severity but did correlate advisable to avoid missing an episode of hypoglycemia that
with the duration of hypoglycemia. Close monitoring and might lead to clinical sequelae such as seizures. In the oper-
evaluation of hypoglycemic neonates who were also hypoxic ating room, the blood glucose concentration should be moni-
and/or asphyxiated during the perinatal period is imperative tored as indicated, particularly if glucose is not administered
to evaluate for potential neurocognitive deficits. Two studies to a neonate during surgery.
evaluated cognitive outcomes after neonatal hypoglycemia. In the preterm neonates, the control of glucose is much
In the first study, executive function in preterm infants more “brittle” with both hypo- and hyperglycemia occurring
to greater extremes and more frequently in these neonates. with a doubling of the 28-day mortality and a reduction in
Hypoglycemia occurs because extreme prematurity limits mortality with insulin [82]. Glucose infusions had only a
the hepatic reserve of glycogen (glycogen accumulates pri- modest impact on the persistent hyperglycemia, leading
marily during the third trimester), and hyperglycemia occurs the authors to recommend closer monitoring of these pre-
because exogenous glucose fails to suppress endogenous term infants throughout their first postnatal month. Stress,
glucose production. In neonates <28 weeks gestational age, corticosteroids, methylxanthine therapy, and administra-
hypoglycemia is almost unavoidable in the first few hours tion of glucose at excessive rates could all induce neonatal
after birth if exogenous glucose is not administrated. These hyperglycemia. Glucose is usually infused at rates between
infants have limited glycogen stores, decreased availability 4 and 7 mg kg/min to ensure basal glucose requirements in
of amino acids for gluconeogenesis, and inadequate lipid neonates. However, hyperglycemia may develop if glucose
stores for the release of fatty acids and fat stores to maintain infusion rates exceed 8 mg/kg/min in neonates with birth
glucose balance. Ketogenesis is severely limited in preterm weights >1 kg and if moderate infusion rates of 4–8 mg/
neonates because they lack fat stores in adipose tissue (fat kg/min were administered to VLBW neonates with birth
represents <2% of total body weight). Depending on its weights <1 kg. Hyperglycemia, which usually occurs after
severity and the number of episodes or duration, hypoglyce- an abrupt increase in plasma glucose concentration (e.g.,
mia can produce devastating effects on the central nervous after a bolus of 25% or 50% dextrose IV), has been associ-
system (CNS) [77, 78]. Reduced blood concentrations of ated with a greater risk of intraventricular hemorrhage. In
glucose invoke a stress response and alter cerebral blood the presence of ischemia or hypoxia, the impaired metabo-
flow and metabolism. During hypoglycemia, brain glucose lism of excess glucose causes an accumulation of lactate
metabolism decreases by up to 50%, relying primarily on and a decrease in intracellular pH that subsequently
alternate energy sources such as fatty acids and lactate. severely compromises cellular function that may result in
Preterm neonates appear less capable of offsetting these cell death [77].
developments by providing alternative fuels and substrates
for the brain than term neonates. Even moderate hypoglyce-
mia can lead to an adverse neurodevelopmental outcome nteral Nutrition (Trophic Feeding or
E
including an increased risk of motor and developmental Minimal Enteral Nutrition)
delay, particularly in small for gestational age preterm neo-
nates [78]. Cerebral injury is caused not only by severe and The nutritional requirements in preterm neonates during the
prolonged hypoglycemia but also by mild hypoglycemia and first few days after birth are the greatest in the neonate’s life-
intermittent episodes when it is combined with mild hypoxia time. During this period, the large nutritional demand is
or ischemia. MRI detected white matter abnormalities in needed to double the preterm neonate’s weight to ensure
more than 90% of full-term neonates with symptomatic adequate postnatal growth. Other factors that may increase
hypoglycemia (blood glucose level <45 mg/dL or the metabolic requirements include chronic hypotension,
2.6 mmol/L) [30, 31]. MRI evidence of the CNS manifesta- acidosis, hypoxia, sepsis, and surgery. Feeding is less effi-
tions of hypoglycemia has been documented in the parietal cient in some late preterm compared with full-term neonates
and occipital lobes [69, 79, 80]. Factors that were associated because the former fatigue quickly and have immature feed-
with abnormalities on the MRI included the number of days ing skills (poor suck and swallow coordination). Additionally,
of and prolonged/recurrent hypoglycemia, but not a lower these preterm neonates often have intestinal dysmotility,
blood glucose concentration than those with normal MRI reduced intestinal enzyme activity, and may be receiving
findings. The minimum blood glucose concentrations, how- corticosteroids, all of which may lead to feeding intolerance
ever, were less in those who developed seizures [69]. with associated anesthetic implications. Finally, some infants
require a longer-than-normal interval between feedings
because of delayed gastrointestinal motility and gastric emp-
Hyperglycemia tying [83]. Together, these may lead to the need for oral tro-
phic gavage (tube) feeding until effective full oral feeding is
Hyperglycemia (defined as blood glucose concentration possible [84]. The results of several Cochrane reviews and
greater than 125 mg/dL or 7 mmol/L or plasma glucose smaller studies on the effects of when to start first feeds,
concentration greater than 150 mg/dL or 8.25 mmol/L) is increasing feed rates, and the mortality and risk of develop-
commonly observed during the first week of life in preterm ing NEC in VLBW neonates concluded that trophic feeds
neonates <30 weeks gestational age [81]. In a study of 580 can begin before the 4th postnatal day, feed rates can be
preterm infants, <27 weeks gestation age at birth, hyper- advanced to ≥24 mL/kg/day, and the risk associated with
glycemia occurred in 30% of the neonates was associated NEC is not increased [85].
inimal or Small Volume Enteral Nutrition

M Total Parenteral Nutrition
(Trophic Feeding)
The smaller the infant, the greater the need for parenteral
Minimal enteral nutrition, minimal enteral feeds, or trophic nutrition and the greater the urgency to initiate it to provide
feeding refers to the practice of introducing early enteral adequate nutrition for growth and development [90]. In the
feeding with small volume feeds in preterm neonates. Several case of infants with birth weights <1500 g, total parenteral
interchangeable terms for this type of feeding each hold a nutrition (TPN) starts on postnatal day 2 or 3 when the fluid
different implication: “trophic feeding” is based on the feed- and sodium balance has stabilized. Infants require
stimulating intestinal growth, “priming feeding” refers to the 90–105 kcal/kg/day of TPN to achieve adequate growth;
feed-stimulating varied aspects of gut function, and “non- 40–50 kcal/kg/day is required just for the resting metabolic
nutritive feeding” means that these feeds are not intended to rate in a thermoneutral environment [90]. When supplement-
provide either the sole or primary source of calories and ing orogastric feeds, the TPN may be increased to 150–
nutrition for the neonate [86]. Starting volumes vary from 5 160 mL/kg/day as tolerated to provide adequate calories for
to 25 mL/kg/day with benefits noted at less than 1 mL/kg/ growth. The composition of TPN should be allocated accord-
day (priming). Minimal trophic feeds (either by bolus or ing to the energy source: 30–35% of the energy from dex-
continuous infusion of 10 mL/kg/day) in the first week of life trose, 10–15% from proteins, and 25–40% from lipids [90].
stimulate the gut by increasing the activity of various Current practice in many NICUs is to initiate TPN with
enzymes, inducing mucosal growth, promoting motility, and 2–3.5 g/kg/day of amino acids on the first postnatal day
preventing translocation of bacteria across the gut wall—a using “starter” or “vanilla” TPN solutions that are stocked in
significant concern in VLBW infants [86]. Human breast the NICU, increasing to 4 g/kg/day by the end of the first
milk (HBM) (colostrum) is preferred because it contains gas- week. In both HBM and formulae, lipids contain the essen-
trin and prokinetic hormones; positive results have been tial fatty acids, linolenic acid, and linoleic acid [90]. The pri-
reported with donor milk supplementing formula feeding in mary reason for including parenteral lipids is to provide the
reducing NEC [86–88]. Feeding volumes are kept small, essential fatty acids, which are important determinants of
regardless of the size of gastric residuals, with volumes membrane lipid composition and central nervous system
<20 mL/kg/day. Minimal enteral nutrition is often instituted development. ELBW infants usually receive their dietary fat
in any scenario associated with gut hypoxia or decreased via parenteral lipid emulsions. There are concerns that lipid
intestinal blood flow (asphyxia, hypoxemia, hypotension) infusions in preterm neonates may confer adverse effects
and/or marked diastolic steal (e.g., a PDA). such as impaired oxygenation, increased risk of lung disease,
impaired immune function, and increased free bilirubin lev-
els. TPN may cause early and late adverse events including
Normal Enteral Feeds cholestatic liver disease for which there is some evidence
that reduced lipid infusion rates and switching to fish-based
Maturation of the gastrointestinal tract with increases in the fat sources have been salutary. Lastly, central-line infections
intestinal length and surface area including villus and micro- have been serious complications in preterm infants whose
villus growth occur during the last trimester of pregnancy. TPN has been infused, necessitating anesthesia and anesthe-
HBM is the first choice for preterm and term neonates as it sia for line changes in some instances [90].
provides substantial benefits to the health of infants includ-
ing reduced infections, inflammation, and enhanced neuro-
cognitive development [89]. However, if unfortified, HBM Fasting and Preoperative Oral Fluids
may not provide adequate nutrients to meet the demands of
preterm neonates, particularly in light of large variations in Fluid management in the neonate who is undergoing major
the protein and fat content of HBM. HBM from mothers of surgery is complex, influenced by gestational age, postnatal
preterm neonates contains more protein than the milk from age, physiological maturation of organ systems, type of sur-
mothers of term neonates; initially, the HBM has a protein gery, concomitant illness, and blood loss. Furthermore, pre-
content of approximately 2.5–3 g/100 mL (colostrum), maturity exacerbates these challenges as organ systems are
which decreases to approximately 1.5–2 g/100 mL soon after immature and body fluid composition differs from that of a
birth (transitional milk), and finally stabilizes at 0.9– healthy, term neonate.
1.4 g/100 mL (mature milk). In general, increased concentra- Careful fluid and electrolyte management is essential in
tions of protein persist for the first month of lactation. the surgical neonate. Insufficient administration of fluids can
Thereafter, the protein content of preterm milk decreases and cause hypovolemia, hyperosmolarity, metabolic acidosis,
approaches the composition of full-term HBM. In contrast, hypotension, and renal insufficiency, whereas excess fluid
preterm infants receiving 150 mL/kg/day of fortified HBM administration can cause generalized edema, congestive
receive approximately 3.5 g/kg/day of protein. heart failure, and bronchopulmonary dysplasia (BPD). In the
VLBW infant, excess fluid administration may also be asso- quickly, reaching one-half the adult output by 5 months and
ciated with a PDA because the fluid overload stimulates the the full adult output by 2 years of age [92]. G cells, which
production of PGE2, which prevents the PDA from closing. produce gastrin, are present in the pylorus in the fetus
In the infant with a large PDA, aortic blood is shunted into between 12 and 18 weeks gestation [91]. Gastrin is both a
the pulmonary artery, reducing the proportion of blood flow potent trigger for gastric acid release and a trophic hormone.
to organs via the descending aorta. This then reduces intesti- In neonates, the circulating gastrin concentration exceeds
nal blood flow, which may lead to hypoperfusion, and isch- maternal levels for the first 4 months, although the surge in
emia and raise the possibility NEC. gastrin levels within 30 min of feeding (HBM or formula)
Readers are advised that much of the evidence regarding during the first 2 postnatal months is less than that in adults
the management of fluids in neonates and small infants is and without an increase in gastric acid secretion [94].
derived from studies in the critically ill neonate; thus, cau-
tion must be exercised in extrapolating these data to the
healthy neonate undergoing anesthesia and surgery. Gastric Fluid pH and Volume
Gastric fluid pH reaches 6–7 within minutes after birth in

Gastrointestinal Ontogeny term neonates, decreasing to 5.4 within the first hour, to 3.1
by 1–2 h, and then leveling off at a pH of 2.2 after 5–6 h
To understand gastric emptying and the risks thereof during where it remains into adulthood [95, 96]. The alkalinity of
anesthesia in neonates, a brief synopsis of the ontogeny of the gastric fluid immediately after birth has been attributed to
the upper gastrointestinal system is required. amniotic fluid that was swallowed during parturition (amni-
By 20 weeks gestation, the fetal stomach has both the otic fluid buffers the gastric juice) or reduced gastric acid
macro- and microscopic appearance of the stomach of the secretion as a result of reduced gastrin secretion in the post-
term neonate [90]. Gastric acid secretion is under the control natal period [92]. Gastric fluid pH in term neonates is less
of two mechanisms: endocrine (gastrin and histamine) acting after vaginal delivery and any labor state compared with
directly on the parietal cells and/or via enterochromaffin-like elective C-sections, and is most acidic after a precipitous
cells and vagal stimulation [91]. labor, possibly due to less amniotic fluid swallowed during a
Within the epithelium of the gastric rugae, four distinct stressful delivery. Within 2 h of birth, gastric acid secretion
cell types are present at birth, contributing to gastric secre- commences via gastrin, although acid production remains
tions: parietal, chief, endocrine, and mucosal cells [92]. Each meager for a while, increasing during the subsequent
cell type contributes specific and essential constituents to 4 months by 400% as the pH decreases dramatically [92].
gastric fluid. The parietal (oxyntic) cells secrete hydrochloric The gastric fluid pH on the first postnatal day becomes
acid and intrinsic factor (for Vitamin B12 absorption). The even more alkaline (>7) in preterm neonates <34 weeks ges-
chief (zymogen) cells secrete pepsin precursor, pepsinogen, tation than in term neonates. However, preterm infants as
that digests proteins. Endocrine cells secrete hormones that young as 24 weeks gestation are capable of acidifying the
regulate acid secretion through histamine-releasing gastric fluid to a pH <4 after the first postnatal day. The gas-
enterochromaffin- like cells and somatostatin-releasing D tric fluid pH in preterm infants 24–29 weeks gestation ranges
cells. These endocrine cells are present throughout the gas- from 1.8 to 3.7 after the first postnatal day (the gastric fluid
tric epithelium except in the region of the pylorus, where pH was <4 in 100% of infants) and decreases to 1.7–2.0 by
gastrin (G) cells dominate. Lastly, mucous cells secrete day 16 [91]. Gastric acid output reaches adult values between
mucous glycoproteins that protect the epithelium with a 6 months and 2 years [92, 97]. The greater gastric pH in pre-
thick lining. term neonates is independent of the nature of the delivery
Parietal cells are capable of secreting hydrochloric acid and may be explained by the lack of exposure to the surge in
by 19 weeks gestation, and of maintaining gastric fluid pH cortisol that occurs after 34 weeks gestation. Acidification of
<2 at 24 weeks gestation [91]. The density of parietal cells is the gastric fluid offers protection to the gut mucosa from
two- to three-fold greater in the epithelium of the neonate microorganisms, although it predisposes to mucosal erosion
than the adult, although the antrum may lack parietal cells in and the risk of ulceration and perforation. An off-setting
the majority of term neonates [92]. Intrinsic factor produc- effect is offered by prostaglandins, which in combination
tion begins during the first couple of postnatal days, reaching with epidermal growth factor increase bicarbonate secretion,
80% of adult values by 2 months postnatal age. The parietal reduce acid secretion, and render the epithelium more hydro-
cells in the neonate appear relatively insensitive to gastric phobic. HBM increases the gastric fluid pH >4 for 90 min,
stimulation [93]. Chief cells are present in fewer numbers in with q3h feeds offering protection against gastric epithelial
the neonate compared with the adult and secrete only 1/15th damage and perforation [91]. Exogenous dexamethasone
as much pepsin on the day 1 as does adult epithelium [92]. and indomethacin inhibit prostaglandin production and mor-
Thereafter, the pepsin production increases steadily and phine increases histamine release, each increases the risk of
gastric mucosal damage [91]. Although rare, gastric perfora- of the evidence published to date indicates that feeds includ-
tion in the preterm infant is devastating, carrying a 50% ing fluids empty from the stomach exponentially, that is, the
mortality. larger the volume the more rapid the elimination. Neonates
Swallowing is first detected in the fetus at 12–16 weeks feed every 2–4 h, and about 80% of neonates are fed HBM
gestation. At that time, the fetus swallows 2–7 mL/day but (not necessarily exclusively) in the United States [102]. In
the volume increases rapidly to 300–700 mL/day as term term and preterm neonates, the gastric emptying half-time
gestation approaches [92]. Fetal studies have tracked swal- after HBM is less than that after formula (Fig 8.4 and
lowing beginning at 24–26 weeks gestation and identified a Table 8.3) [88, 103, 104]. The gastric emptying half-times in
cyclical filling and emptying of amniotic fluid every 45 min. term and preterm neonates are: for water, ~15 min; for HBM,
Between 14 and 24 weeks gestation, irregular gastric peri- ~48 min; and for formula, ~78 min. Thus, the estimated 98%
stalsis occurs while the difference between the maximum gastric emptying times for these three feeds are 4× half-lives
and minimum gastric area is 3%. After 24 weeks, gastric or 1 h, >3 h, and >5 h, respectively, which correspond to the
peristalsis becomes regular and the difference in the gastric fasting times adopted by most societies of anesthesiology
area increases gradually such that by 32 weeks gestation the globally: 2 h for clear fluids, 4 h for HBM, and 6 h for for-
difference is 8%, signifying gastric volumes sufficient to per- mula (Table 8.4) [109–111]. Note: The APAGBI failed to
mit feeds [98]. Gastric fluid volume in the unfed neonate reach consensus regarding the duration of preoperative fast-
ranges from 0 to 10 mL [98, 99]. ing after HBM and formula [109] and the SSAI preoperative
Gastric Emptying Gastric volume remaining

100
The notion that all patients should fast before surgery holds
very different implications for neonates compared with older
infants and children. In part, because 50% or more of neona-
tal surgeries are urgent or emergent (bowel atresia, malrota- Term
Term
tion, or NEC), the neonates are often less than 48 h old and,
(%)
in many instances, have never been fed. IV dextrose solution 50

may be their only source of nutrition at the time of surgery. Preterm HBM Formula
For the remainder, the neonates are scheduled for elective
surgery, are older than 48 h, and have likely consumed HBM
or formula as their last and only feeds in this first postnatal Clear fluids
month. Accordingly, we restricted the discussion of fasting 0
in neonates clear fluids, HBM, and infant formula. 0 25 50 75 100
Time (minutes)
The gastric emptying time after clear fluids in neonates is
one-third that after HBM and one-fifth that after formula Fig. 8.4 Gastric emptying times for water, human breastmilk (HBM),
[100]. Gastric emptying times after clear fluids are slower and infant formula. The half-time for emptying water in neonates and
with an increased osmolality such as a greater dextrose con- young infants is 15 min, for HBM is 48 min, and for formula is 78 min.
centration. To date, evidence in children suggests that a fast- Data are adapted from Refs. [100, 103, 104]
ing interval of ~1 h after clear fluids had no effect on the risk
or frequency of aspiration, although none of the studies pub- Table 8.3 Gastric emptying half-time (minutes)
lished to date actually achieved a clear fluid fasting interval Term
of <1 h. Moreover, a very tight relationship exists between neonate Preterm neonate
the fasting interval after clear fluids and residual gastric fluid Water 15m
[100]
volume after clear fluids [101], that is, as the fasting interval
HBM 48 ± 15 25.1 ± 11.5 36 47 61 35
decreases, the residual gastric fluid volume increases expo- [104] [103] [87] [88] [105] [106]
nentially. Nonetheless, gastric fluid volume alone does not Formula 78 ± 14 51.9 ± 9.8 72 65 76 45
increase the risk of aspiration pneumonitis and evidence to [104] [103] [87] [88] [105] [106]
date indicates that clear fluid aspiration is usually well- 64 ± 7.1 34 ± 4.9
[99] [99]
tolerated. Gastric emptying studies after clear fluids in neo-
Casein vs 56.5 ± 15 vs
nates have not been forthcoming. whey- 65 ± 12.3
Although several techniques have been used to measure based [107]
gastric emptying after HBM and formula feeds in the past, formula
here we consider all of the techniques to have equipoise. Most HBM Human breastmilk
Table 8.4 Fasting guidelines
Year Duration of preoperative fasting (h) Additional recommendations for neonates
Reporting body Clear fluids HBM Solids Reference
Taskforce on Scandinavian preoperative 2005 2 4 6 Minimum 3 h fast breast milk [108]
fasting guidelines
APAGBI 2007 1 3 (<6 months) Formula [109]
4 (<6 months) 4 (<6 months)
6 (>6 months)
ESPA 2011 2 4 6 Healthy neonates [110]
Clear fluids 2 h;
HBM 4 h;
Cow’s milk 6 h
ASA Guidelines 2017 2 4 6 Healthy neonates <44 weeks PMA; [111]
HBM 4 h;
Infant formula 6 h;
Non-human milk 6 h
Swedish Guidelines 2018 0 4 6 Actively encourage HBM or formula 4 h preop [112]
APAGBI, ESPA, ADARPEF 2018 1 3 6 No specific recommendation [113]
8 Metabolic Care of the Preterm and Term Infants, Including Control of Body Temperature
Fasting guidelines recommended by the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI), the European Society for Paediatric Anaesthesiology (ESPA), and
L’Association Des Anesthésistes-Réanimateurs Pédiatriques d'Expression Française (ADARPEF)
HBM Human breastmilk
Solids include all non-human milk, formula milk, and any other solid food
271
fasting guidelines recommended age-specific guidelines for duced during metabolism [126]. They proposed that IV fluid
infants: a 4 h fasting interval for both HBM and infant for- therapy should be hypotonic instead of isotonic fluid and at
mula for infants <6 months of age [108, 114]. rates based on body weight rather as the neonate is unable to
During the first 3 postnatal months, 35–45% of those neo- excrete excess water and excess sodium. They estimated
nates who were breastfed received supplementation with that pediatric electrolyte requirement was a midpoint
infant formula [102], which complicates fasting guidelines between that received by consumption of HBM and that rec-
as formula is emptied from the stomach more slowly than ommended in adults and suggested that children need
HBM. Several factors slow the rate of gastric emptying of 2–4 mmol/kg/day of sodium and 1 mmol/kg/day of potas-
feeds: feeds that contain long-chain versus medium-chain sium. Their supposed ideal solution for maintenance con-
triglycerides, feeding with the neonate supine or in the left tained 30 mmol of sodium (4% dextrose and 0.18% saline or
lateral decubitus position, with brief intervals between feeds 4% and 0.2% saline) and is hypotonic [127]. This was the
and with smaller feed volumes, and the presence of concomi- standard pediatric intravenous solution until the late 1980s
tant diseases (such as acute respiratory distress) [83, 100, at which time a cluster of children developed hyponatremia,
115–119]. Other factors have minimal or conflicting effects seizures, aspiration, and brain damage upon emergence
on gastric emptying of feeds. These include the volume of from anesthesia after receiving large volumes of hypotonic
HBM, temperature, casein/whey ratio, and osmolality of the solutions during surgery [128]. It was at this time that a par-
feed, age of the preterm infant, phototherapy, and non- adigm shift in practice occurred to replace hyponatremic,
nutritive sucking [83, 107, 115, 117, 120, 121]. glucose-containing maintenance fluids for all children
Conservative recommendations for the fasting after admitted to the hospital, as well as those undergoing anes-
human and animal milk feeds (Table 8.3) are based, in part, thesia and surgery with isotonic solutions [129–131].
on the mean gastric emptying times, the large interindividual Opinion differs on whether any glucose is required in chil-
variances in gastric emptying for both HBM and formula, the dren >1 year of age to replace third space losses as hypogly-
exponential nonlinear gastric emptying curves, and the fact cemia and ketosis are exceedingly rare. In some countries,
that many mothers mix the two feeds (Fig. 8.4) [87, 104]. balanced salt solutions with 1–2% glucose have been devel-
Given the very low risk of regurgitation and aspiration pneu- oped for pediatric use in the perioperative period [132]. We
monitis should regurgitation occur, some have suggested that confine our discussion to the neonate, in which balanced salt
the fasting interval after milk products could be reduced, solutions are used to replace estimated extracellular fluid
based on preliminary data on gastric emptying [122]. A losses and hypotonic glucose/calcium solutions from the
model-based meta-analysis of gastric emptying studies also NICU are continued as maintenance solutions in the operat-
indicated only marginally smaller mean gastric residence ing room (Fig. 8.5). For elective surgery in neonates where
times after HBM compared with infant formula, although IV access has not yet been established and glucose is not
they too demonstrated enormous variances in the emptying infusing, isotonic or near-isotonic solutions with small con-
times [121]. Before considering abbreviating gastric empty- centrations of glucose (~2%) seem appropriate along with
ing times after milk-based feeds, it is important to appreciate serial serum glucose testing [133].
that the pulmonary effects of milk products are much more
injurious than clear fluids. In infant rabbit and mice models,
instillation of HBM and infant formula produced substantive Hyponatremia
lung injury, with physiological, cytokine, and histological
infiltrates in contrast to the lack of effect by clear fluid aspi- Hyponatremia, defined as a serum sodium <135 mmol/L,
ration [123–125]. Before reducing the fasting intervals after occurs in 9–24% of hospitalized children receiving hypo-
milk products in neonates, it is crucial to bear this evidence tonic intravenous solutions [130, 134–136]. Hyponatremia
and ensure that any perceived benefits are not outweighed by (<115 mmol/L) is primarily caused by extrarenal loss of
the well-known risks. electrolytes, in the presence of increased ADH activity and
the administration of hypotonic fluids [129]. Morbidity and
mortality associated with acute severe hyponatremia (Na
The Ideal Intraoperative Maintenance Fluid <130 mmol/L) results from acute cerebral edema, and may
include headache, lethargy, and seizures, and potentially
In 1957, Holliday and Segar proposed the 4–2–1 mL/kg/h even respiratory and cardiac arrest secondary to brain stem
formula to determine the rate of administration of mainte- herniation. Because of their greater brain/intracranial vol-
nance fluid for healthy hospitalized neonates, infants, and ume ratio, infants are at increased risk for these sequelae
children based on calorific requirements, insensible and uri- compared with adults. The original 4–2–1 IV fluid mainte-
nary losses, and an allowance for the water of oxidation pro- nance recommendation was never intended for use in the
Neonatal brain:
increased susceptibility to
hypoglycemic injury and
hypotension
Maintenance
solution (preferably PDA-
dextrose / amino acid risk of
TPN) at a set rate (~ 4ml/kg/h) increased
with glucose infusion rate of left to right
2-5 mg/kg/min to shunt with Replacement solution
maintain fluid overload (crystalloid such as
normoglycemia Ringer lactate or colloid
or blood product)
Rate - determined by
Lungs with BPD: intravascular volume,
sensitive to fluid fluid loss and blood
overload pressure
Renal immaturity
poor urine concentrating
Third-spacing
capacity (risk of intravascular
loss of large volume
dehydration)
of fluid, especially
impaired ability to excrete
with NEC/ gut surgery
excess water (risk of hyponatremia)
Fig. 8.5 Principles of intraoperative fluid management. Fluid therapy losses. Premature infants with bronchopulmonary dysplasia (BPD) and/
in the operating room consists of two components—maintenance and or a PDA are susceptible to fluid overload. The brain of the neonate is
replacement fluids. The maintenance fluid consists of a dextrose- particularly vulnerable to hypoglycemic injury. Cerebral circulation is
containing solution (preferably the same preoperative TPN solution) to pressure-passive with limited autoregulation and susceptible to hypo-
maintain normoglycemia. The maintenance fluid should be infused at tension. Abdominal surgery (especially NEC) is associated with
the same rate as preoperatively. The replacement solution should be a increased “third-space” losses into the gut requiring increased replace-
balanced salt solution such as Ringer’s lactate solution or a colloid ment fluid therapy. The immature kidney is unable to handle the
(albumin) or blood product and is administered to maintain adequate increased water load, thereby increasing the risk of hyponatremia. See
intravascular volume and pressure and to replace any deficit or ongoing text for details
operating room because the perioperative period is com- In 2007, the National Patient Safety Agency (NPSA) in
monly associated with markedly upregulated ADH levels the United Kingdom recommended that 0.18% saline 4%
and water retention [137]. Judicious restoration of euvolemia glucose be removed completely from general pediatric wards
(after 10 mL/kg isotonic solution boluses over 20 min and and replaced with 0.9% or 0.45% saline [139, 140]. When
repeated as needed) in infants and children (without cardiac treating conditions considered to be at high risk of hypona-
and renal dysfunction) in the perioperative period downregu- tremia (including serum sodium level in the lower normal
lates ADH (Table 8.1) and reduces the risk of developing reference range, intravascular volume depletion, and other
perioperative hyponatremia [35]. If ADH release is not conditions), the alert advised the use of isotonic solutions
quelled by reestablishing euvolemia, a surge in ADH will (e.g., 0.9% saline with or without glucose).
occur despite effective regional anesthesia or opioid dosing
to preclude a stress response as evidenced by normal blood
cortisol, insulin, and glucose concentrations [138]. The fluid Intravenous Solutions
status in the neonate should be assessed serially using hemo-
dynamic metrics to gauge when to cease or reduce the bal- A large number of isotonic intravenous solutions are now
anced salt to preclude a fluid and sodium overload, for which available for pediatric intravenous infusion (Table 8.5).
the neonate is ill-equipped to manage and which may Although some of these fluids are available in Europe, else-
increase morbidity. By downregulating the ADH levels, the where glucose-containing isotonic fluids are not commer-
risk of developing hyponatremia from the water load from cially available in the operating room. Thus, for neonates
the hypotonic maintenance solution and the isotonic bal- who arrive from home or who are not receiving 10% dex-
anced salt solution is diminished. trose infusions from the NICU, we prepare 1 or 2% dextrose
Table 8.5 Characteristics of common crystalloids compared with human plasma

Lactate,
Sodium Potassium Magnesium Calcium Chloride gluconate, Osmolality Osmolarity
(mmol/l) (mmol/l) (mmol/l) (mmol/l) (mmol/l) malate (mOsm/l) (mOsm/l) pH
Plasma 136–145 3.5–5.0 0.8–1.0 2.2–2.6 98–106 291 287 7.35–7.45
0.9% sodium 154 0 0 0 154 308 286 4.5–7.0
chloride
4% dextrose with 31 0 0 0 31 0 284 4.5
0.18% saline
Ringers Lactate 130 4 0 3 109 28 278 256 5–7
Hartmann’s 129 5 0 2 109 29 254 278 5–7
Lactate
Plasma-Lyte 148 140 5 1.5 0 98–106 27/23 295 271 7.4*
Sterofundin 145 4 1 2.5 127 24 309 Not stated 5.1–5.9
Ionosteril ISO 137 4 1.25 1.65 110 36.8 291 270 6.9–7.9
10% dextrose 0 0 0 0 0 0 278 3.5–5.5
4% albumin 130–160 0 0 0 130.160 310 250 7
*
Plasmalyte osmolarity varies depending on country of manufacture. Plasmalyte pH varies from 6.5 to 8.0 depending on country of manufacture.
Ionosteril manufactured by Fresenius Medical Care, Schweinfurt, Germany. Sterofundin manufactured by BBraun Melsungen, Germany.
Osmolality measures the number of osmoles in a weight (kg) of solvent. Osmolarity measures the number of osmoles in a volume (L) of solvent
solutions in the isotonic clear fluid in the operating room in Neonates require 4–8 mg/kg/min (approximately 300 mg/
100 mL buretrols by adding 2 or 4 mL of D50W in 98 or kg/h) of glucose to sustain brain development and preclude
96 mL of the isotonic solution, respectively. One hundred adverse neurocognitive outcomes [144]. The risk of hypo-
milliliter is usually sufficient maintenance fluid volume for glycemia in neonates increases with prematurity, perinatal
most surgeries in neonates. stress or asphyxia, small for gestational age infants, maternal
diabetes, and Beckwith-Wiedemann syndrome (see above
the “Hypoglycemia” section). Neonates who are treated with
Glucose-Containing Solutions TPN or glucose infusions are also at risk for hypoglycemia if
the infusion is stopped before or during anesthesia or the
Feeding the neonate after birth is essential for proper infusion rate is dramatically decreased. How much glucose
growth and development. Who to feed with what feed, by neonates require during the perioperative period remains
which route, how frequently, and when are questions that unclear. Neonates are capable of mounting a substantive neu-
beg answers [141, 142]. For the neonates, the answers are roendocrine response to both surgical stress and in the case
simple. After the glucose concentration stabilizes in the of preterm infants, reduced glycogen supply. This manifests
postnatal period, oral feeds are often initiated, unless the as an increase in plasma cortisol, glucagon, catecholamines,
neonate is diagnosed with a congenital anomaly that pre- and vasopressin, along with a decrease in circulating insulin.
cludes feeding. In the latter case, TPN may be needed to The result is an increase in the blood glucose concentration
provide nutrition either temporarily or for an extended through gluconeogenesis, fat mobilization, and protein
period. In the case of preterm neonates, immaturity of the catabolism. In VLBW neonates who are ventilated for pro-
sucking reflex requires the use of orogastric tube feeds in longed periods or septic, stress may trigger as a hyperglyce-
the interim provided that may be supplemented with TPN mic response even before surgery commences, e.g., in a
if insufficient nutrition can be delivered. These factors perforated bowel [145]. However, such compensation occurs
must be evaluated based on the gestational age of the pre- at the expense of valuable energy reserves, namely, glyco-
term infant and concomitant diseases. Nonetheless, some gen, fat, and proteins. In the case of preterm neonates, there
meta-analyses suggest that early gastric feeding is possible is a limited supply of glycogen, which increases the risk of
in select preterm infants and when the frequency and vol- hypoglycemia in this age group. Furthermore, if a stress-free
ume of the feeds are carefully titrated [85]. As the sucking anesthetic is administered or the neonate is severely preterm,
reflex and gastrointestinal system mature, TPN can be then the above neuroendocrine response may fall short of
phased out, the gastric tube removed, and oral feeds insti- mobilizing sufficient glucose to maintain euglycemia [138].
tuted. Evidence from a systematic review favors HBM in In a survey of pediatric anesthesiologists, 76% administer
VLBW to reduce the risk of morbidity in this population of glucose-containing solutions to neonates and 58% monitor
preterm infants [143]. the glucose perioperatively [146]. Accordingly, we recom-
mend maintaining the IV glucose solution (including TPN) Perioperative Fluid Management
rate during surgery; decreasing the infusion rate may result
in a disproportionately increased insulin level that could General Principles
cause hypoglycemia. If the infusion rate of glucose is
adjusted during surgery, then “at-the-bedside” plasma con- Current fasting guidelines recommend clear fluids 0–2 h pre-
centrations of glucose should be measured periodically as operatively, HBM 4 h, and infant formula 4–6 h, limiting the
clinically indicated. duration of the fasting period (Table 8.4) [109–111]. Infants
The results of two studies of the effects of continuing a who meet these criteria usually have only minor fluid deficits
10% dextrose solution at standard maintenance rates or that are generally not necessary to correct. However, if a neo-
switching to Lactated Ringer’s solution during surgery in nate is suspected of being dehydrated due to a prolonged fast
neonates demonstrated that the plasma glucose concentra- on the ward or if he/she is coming to surgery from the NICU,
tions increased at the end of surgery in both studies, although NICE guidelines recommend that the neonate should be
the glucose concentration doubled in the neonates who given 10–20 mL/kg of an isotonic (sodium concentration
received the glucose infusion but increased only modestly in 135–145 mEq/L) glucose-free solution over 10 min and then
the Lactated Ringer’s solution at the end of surgery [147, reassess for their volume status before considering a second
148]. Of greatest importance perhaps was the frequency of fluid challenge [109]. We routinely administer 10 mL/kg IV
hypoglycemia in the Lactated Ringer’s solution group, three- of Lactated Ringer’s solution before inducing anesthesia in
fold greater than in neonates who continued the glucose infu- neonates from the NICU and repeat the dose if blood pres-
sion. Furthermore, the increased blood glucose concentration sure wanes ≥25% systolic from baseline.
remained significantly greater than baseline for up to 8 h Continuing TPN with amino acids (but without lipids)
postoperatively. The authors attributed the increase in the before and during surgery is a common practice and has the
plasma glucose concentration to the metabolic and endocrine theoretical advantage of providing optimal nutrition while
responses to surgical stress, to an increase in counterregula- avoiding reactive hypoglycemia during catabolism associ-
tory hormones, primarily epinephrine, and glucagon and rec- ated with surgery. We routinely discontinue intralipid as the
ommended perioperative glucose monitoring to prevent large presence of lipid is a source of contamination if the intrave-
swings in plasma glucose concentrations. In 2007, the nous line is used to administer medications or other fluids
Association of Paediatric Anaesthetists of Great Britain and during surgery. If the intralipids are delivered through a sepa-
Ireland issued consensus guidelines for maintenance fluids rate line, then lipids may be continued during surgery. Three
in term neonates [109]. They recommended 10% dextrose at practical issues regarding the use of parenteral nutrition are
2–3 mL/kg/h in the first 48 h after birth, followed by 10% the following:
dextrose in N/5 saline at 4 mL/kg/h from the 3rd day onwards.
Children of low birth weight, prolonged surgery (more than 1. Partial parenteral nutrition with feeds: Many infants
3 h), or where the stress response is attenuated by regional undergoing semielective or elective surgery are receiving
anesthesia should have serial monitoring of blood glucose or partial feeds and partial parenteral nutrition
should receive a 1–2.5% dextrose-containing maintenance supplementation. The composition of partial parenteral
fluid. nutrition fluids may include a large concentration of elec-
Few studies have investigated the glucose, lipid metabo- trolytes (such as sodium, calcium, and potassium) and
lism, and hormone responses in neonates during anesthesia dextrose to compensate for low mineral content of oral
and surgery [132, 149, 150]. The studies were conducted on feeds (specifically HBM). When the infant’s oral feeds
neonates and infants, with the exception of neonates who are stopped for preoperative fasting, the partial TPN
required preoperative dextrose infusions, were preterm, or should not be increased to full volume. Instead, a new
were infants of diabetic mothers. Dextrose solutions between TPN solution with optimal glucose and electrolytes at full
1 and 4% were studied and the resultant metabolic responses volume (often 100–150 mL/kg/day) should be initiated.
to the infusions were compared postoperatively. Surprisingly, Alternately, the neonate’s feeds may be supplemented
the blood glucose concentrations 24 h postsurgery, as well as with a plain crystalloid solution such as 5% dextrose in
the incidence of hyperglycemia and the glucagon/insulin water (through a Y connector) to provide a partial TPN
ratio after 1% dextrose, were greater than those after 4% solution.
dextrose. Combined with the metabolic responses, the stud- 2. Parenteral nutrition is usually administered through a thin
ies supported a 2–4% dextrose infusion in the perioperative percutaneous or peripherally intravascular central cathe-
period in neonates. We believe that the data support 2% dexter (PICC line). These catheters have a small internal
trose infusions for neonates in the perioperative period to diameter (usually 1.9-Fr lines) and offer large resistance.
prevent hypo- and hyperglycemia and to ensure stable meta- They are not suitable for emergency fluid boluses and are
bolic indices. at a large risk of rupturing if small syringes (1–3 mL size)
are used to inject fluid volumes rapidly because of the amounts of both chloride and potassium before they are
great pressures that can build up within the catheter. scheduled for surgery.
3. Y-site compatibility of medications with parenteral nutri-
tion solution: In 2007, Roche laboratories updated their
prescribing information for ceftriaxone sodium to include Maintenance Fluids
a contraindication for the coadministration with calcium-
containing intravenous solutions in neonates due to Intraoperative fluid therapy can be optimally achieved with
reported fatal cases of pulmonary and renal precipitates two different types of fluids administered at different rates: a
(Rocephin package insert). Readers are referred to a dextrose-containing solution (preferably TPN) for mainte-
detailed review of which medications are compatible with nance fluids at a set rate (usually 100 mL/kg/day or 4 mL/
lipid- and non-lipid-containing parenteral fluids [151]. kg/h) and a separate solution to replace liquids (crystalloids
Table 8.6 highlights the compatibility of some commonly such as Ringer Lactate or colloids or blood products)
used medications with 2-in-1 (amino acids + glucose/ (Fig. 8.5 and Table 8.7). The APA consensus guideline on
electrolyte solution) and 3-in-1 (amino acids + lip- perioperative fluid management in children did not reach
ids + glucose/electrolyte solution) parenteral nutrition agreement on what type and volume of fluid to give a term
solutions. neonate after day 3 of life, but most neonatologists would
recommend that the maintenance fluid should be 10% dex-
trose with Na (3 mmol/kg/day) and K (2 mmol/kg/day) given
Perioperative Steroids at a rate of 4 mL/kg/h or 100–120 mL/kg/day [109].
Preterm infants are occasionally treated with courses of cor-

ticosteroids such as hydrocortisone or dexamethasone to The Myth of the Third Space
facilitate extubation, manage lung disease, or treat resistant
hypotension. Some of these infants may develop adrenocor- Third space refers to the sequestration of fluid to a nonfunc-
tical insufficiency with a suppressed HPA axis if more than tional extracellular space that is beyond osmotic equilibrium
an occasional pulse dose of steroids has been administered. with the vascular space [155]. During surgery, insensible
Adrenocortical insufficiency has been associated with circu- fluid losses (third space losses) vary widely depending on
latory collapse in the perioperative period, although it is ambient conditions. Preterm or low birth weight infants have
likely that these infants and children were hypovolemic and a greater surface area-to-weight ratio, lose more water by
that likely caused or exacerbated the circulatory instability. evaporation, and consequently require more replacement
Most of the reports predated current practices of fluid load- fluid. Fluid losses from the respiratory tract may be rather
ing neonates and infants before induction of anesthesia. With significant in small infants and influenced by the degree of
the difficulty in evaluating whether the HPA axis is intact, a humidification of the inspired gases.
stress dose of hydrocortisone is currently recommended Traditionally, “Third space” losses were replaced with
before surgery for these infants to attenuate the risk in crystalloid solutions at rates from 1 mL/kg/h for minor sur-
hypotension. gery to 10 mL/kg/h for large open surgeries in term neonates
to 50 mL/kg/h during surgery for NEC in preterm infants.
Third space losses are less when procedures are performed
Emergency Surgery laparoscopically.
More recently, the concept of the third space and fluid
For surgery that is emergent, neonates should be immedi- sequestration therein have been questioned. As a result, more
ately resuscitated with fluids. Abdominal emergencies (vol- restrictive fluid protocols were adopted in adults and associ-
vulus or pneumoperitoneum after NEC) are associated with ated with better outcomes. A Cochrane analysis of restricted
extravasation of fluid from the vascular space into the lumen. versus liberal water intake for reducing morbidity and mor-
Restoration of intravascular volume using crystalloids (iso- tality in preterm infants reported that cautious restricted
tonic saline or Ringer Lactate), colloids (albumin) or blood water intake while avoiding dehydration reduces the risk of
products (platelets, packed RBCs, or fresh frozen plasma) is PDA, BPD, NEC, and death [52].
important. Conditions associated with vomiting or aspiration
of gastric contents (such as pyloric stenosis, duodenal atre-
sia, or stenosis) are associated with abnormalities in serum Replacement of Intraoperative Losses
sodium, potassium, bicarbonate, and chloride. Infants with
pyloric stenosis present with hypokalemic alkalosis and There is currently no consensus on using isotonic solutions
require resuscitation with fluids that contain adequate as perioperative maintenance fluids in neonates, in part
Table 8.6 Y-site compatibility of medications with parenteral nutrition solution

Medication 2-in-1 TPN 3-in-1 TPN Comments
Acyclovir I I White precipitate forms immediately
Albumin C I
Alprostadil C –
Amikacin sulphate C Conflicting
data
Amphotericin B I I Yellow precipitate formation
Ampicillin Conflicting but administered in some
units
Atracurium C –
Bumetanide C C
Buprenorphine C C
Caffeine citrate C –
Cefazolin Incompatible if dextrose concentration is C
25%
Cefotaxime C C
Cefepime C –
Cefoxitin C C
Ceftazidime C C
Ceftriaxone I I
Dexamethasone C C
Diazepam C –
Diphenhydramine C C
Dobutamine C C
Dopamine C Conflicting
Epinephrine C –
Famotidine C C
Fentanyl C C
Furosemide ? Small amount of precipitate forms in 4 h in select
formulations
Heparin C I
Hydrocortisone C C
Insulin C C
Isoproterenol C C
Lorazepam C I
Meperidine C C
Methylprednisolone C C
Metronidazole C C
Midazolam I I White precipitate forms immediately in select
formulations
Milrinone C –
Morphine C ?
Norepinephrine C C
Ondansetron C I
Oxacillin C C
Penicillin G C C
potassium
Pentobarbital C I
Phenobarbital C I
Phenytoin I I
Propofol C –
Ranitidine C C
Sodium bicarbonate I Small amount of precipitate forms in 1 h in select
formulations
Vancomycin C C
Vecuronium C –
C compatible, I incompatible, – data not available, ? data not available, 2-in-1 (amino acids + glucose/electrolyte solution), and 3-in-1 (amino
acids + lipids + glucose/electrolyte solution)
278
Table 8.7 Consensus statements on fluids

Maintenance term Maintenance term
neonates postnatal neonates postnatal
Year Fluid deficit <48 h >72 h Intraoperative fluids Isotonic fluids Postoperative fluids Reference
APAGBI 2007 Third space losses 10% dextrose 10% dextrose Term and preterm 0.9% saline or [109]
1–2 mL/kg/h 2–3 mL/kg/h or 0.18% saline infants: no glucose Ringer’s lactate
peripheral surgery 40–80 mL/kg/day First 48 h of life solution unless solution
4–7 mL/kg/h thoracic 2–3 mL/kg/h already receiving
surgery glucose to continue
European Consensus 2011 Isotonic with 1–2.5% [152]
Statement glucose
Belgian Association for 2012 Hourly maintenance 0.9% saline 5% Isotonic with 1% Plasmalyte, Minor surgery: [153]
Paediatric multiplied by hours dextrose or 0.2% glucose full Hartmann’s isotonic with 1%
Anaesthesiology fasting and replace saline 5% dextrose maintenance volume solution, 0.9% glucose
50% first hour and saline Major surgery:
25% 2nd and 3rd hour isotonic with 5%
glucose
70% maintenance
volume
German Society 2017 Isotonic with Isotonic with 1–2.5% [154]
Anesthesiology and 1–2.5% glucose at glucose repeat boluses
Intensive Care Medicine 10 mL/kg/h 10–20 mL/kg
Preferred intravenous fluids for perioperative management in children. Available solutions vary by country (France: Polyionique: B66; Switzerland: Ringer Laktat mit glucose 1%; Belgium:
Hartmanns Glucose 2.5%; Austria: ELO-PAED 1% glucose; Germany: Electrolyt Infusionslosung 148 Glucose 1%; Holland: Kidialyte; sodium chloride 6.429 mg, potassium chloride 0.298 mg,
calcium chloride dihydrate 0.147 mg, magnesium chloride hexahydrate 0.203 mg, sodium acetate trihydrate 4.082 mg, glucose monohydrate 11.0 mg)
G. Bertolizio et al.
because large sodium loads are poorly handled by the imma- In most cases, fluid resuscitation should be undertaken
ture kidney and there is a lack of good evidence. Several with crystalloids that contain sodium in the range of 130–
recent studies support the use of an intra- and postoperative 154 mmol/L. Some use physiologically balanced solutions
IV solution containing close to physiological concentrations such as Hartmann’s solution, Ringer’s lactate solution, or
of sodium in children >6 months of age but there are fewer Plasma-Lyte 148 solution and some continue to use 0.9%
studies in children 0–6 months of age [132, 156, 157]. Mild sodium chloride. In the pediatric intensive care unit, a sur-
hyponatremia (serum sodium 133 and 134 mEq/L) has been vey of physicians revealed that the preferred solution to
reported in 12% of 34 neonates (0–7 days old) after a range treat hypotension in the presence of sepsis, trauma, trau-
of neonatal thoracic and abdominal surgical procedures matic brain injury, and acute lung injury was 0.9% saline,
[158]. The neonates received boluses of 10 mL/kg of normal whereas for postoperative cardiac surgery it was 4% albu-
saline or lactated Ringer’s solution with or without 1% dex- min—both fluids in a volume of 10 mL/kg [162]. In the
trose after induction of anesthesia, in response to poor urine operating room where repeated fluid boluses >10 mL/kg IV
output, blood loss, or hemodynamic changes. However, the may be required, we avoid using 0.9% sodium chloride
relationship between the change in serum sodium between because of the risk of developing hyperchloremic non-
postoperative and preoperative values and free water admin- anion gap metabolic acidosis.
istration did not support a relationship (r2 = 0.14) contrary to
the authors’ conclusions [158]. The serum sodium was not
<130 mEq/L in any neonate nor did sequelae occur. Judicious Colloids
use of lactated Ringer’s solution and normal saline in this
age group points to the need for serial serum sodium concen- There is no evidence that colloids are superior to crystalloids
trations and avoiding excess fluid administration [52]. in fluid expansion and resuscitation in neonates. Early vol-
Blood volume is estimated as 90–100 mL/kg in preterm ume expansion in preterm neonates, whether with colloid or
infants, 80–90 mL/kg in term neonates, and 70–75 mL/kg in crystalloid, has yielded no long-term improvement in either
infants >3 months of age. In cases of circulatory instability morbidity or mortality [163]. A meta-analysis of this subject
or blood loss, the goal of treatment is to restore and normal- by the Dutch Pediatric Society identified only one study in
ize the circulating blood volume rapidly. However, the choice neonates that reported no difference in serious outcomes
of which fluid to use for volume expansion remains conten- (death, intraventricular hemorrhage, or chronic lung disease)
tious. Anesthesiologists use intravenous balanced salt solu- between albumin and crystalloid solutions, but did note less
tions to replace the initial blood loss in a 3:1 volumetric ratio fluid retention in the crystalloid group at 48 h [164, 165].
in neonates; beyond that, a survey of French and British They concluded that isotonic saline should be the first-choice
anesthesiologists confirmed that the vast majority use albu- fluid to treat hypovolemia and hypotension in neonates.
min to restore euvolemia [159]. When prophylactic intravenous fresh frozen plasma, gelatin,
or glucose were compared in preterm infants (in a large
RCT), early morbidity and mortality and developmental out-
Intraoperative Hypotension come at 2 years were similar [166, 167].
Some pediatric anesthesiologists limit the role of crystal-
Hypotension is common in sick neonates, especially preterm loid to 30–40 mL/kg in neonates, expanding the circulation
infants. The definition of hypotension is, however, ill-defined, or treating oliguria from that point onward with a colloid,
especially in preterm infants. Systolic blood pressure (SBP) albumin being the first choice [159].
correlates poorly with systemic perfusion, and other measures
of regional perfusion have been advocated. Echocardiography
and assessment of SVC flow have been suggested and near- Albumin
infrared spectroscopy (NIRS) may provide noninvasive real-
time monitoring of cerebral and tissue perfusion in neonates Exogenous albumin solutions are biological products derived
[160]. There is a significant debate as to which fluid should be from pooled human donors. Many different types of com-
given to hypotensive infants: crystalloids, albumin, plasma, mercial albumin solutions are available. They are either
and gelatin-based substitutes are equally effective. hypo-oncotic (4%), iso-oncotic (5%), or hyper-oncotic (20%
Vasopressors may also have chronotropic and inotropic or 25%) and contain variable electrolyte concentrations, with
effects, which will have a complex effect on the neonatal cir- sodium concentrations ranging from 87 to 160 mmol/L and
culation and not necessarily result in increased organ perfu- potassium concentrations generally <2 mmol/L [168]. In
sion despite increased SBP. Newborns treated with dopamine hypotensive preterm infants, 4.5% albumin was demon-
have been shown to have the same mortality as those treated strated to be more effective than 20% albumin. This suggests
with albumin but have better SBP responses [161]. that the volume of albumin administered is more important
than its concentration to maintain or restore cardiovascular Table 8.8 Transfusion triggers in neonates
stability [169]. Side effects from albumin are rare; however, Transfusion threshold (g/L)
hemodilution with large amounts of albumin (25% hemodi- Postnatal Artificial Receiving oxygen/ Not receiving
lution of the blood volume) may produce a hypocoagulable age ventilation CPAP oxygen
state through inhibition of platelet aggregation or heparin- First 24 h <120 <120 <100
1–7 days <120 <100 <100
like effects on antithrombin III.
8–14 days <100 <95 <75–85
>15 days <85 <85 <85
Nonprotein Colloids
some studies warranting careful choice of the indications
Hydroxyethyl starches (HES) are modified polysaccharides for transfusion in this age group [175, 176]. The threshold
suspended in 0.9% NaCl, or more recently, a more iso- for red cell transfusion varies internationally as do the tim-
osmotic solution. HES solutions expand the plasma volume ing of the transfusion and “top-up” doses. In VLBW infants,
with effects lasting 2–6 h and are made of concentrations of physiologic anemia may reach a hematocrit of 24%,
3, 6, and 10% [170]. The high molecular weight/molar sub- prompting interest to transfuse these infants. However, dur-
stitution HES solutions are associated with hypocoagula- ing the first month of postnatal life, the erythropoietin lev-
bility due to the still-unknown effects on factor VIII, the els in these infants are two-thirds of adult levels despite the
von Willebrand factor, and platelets [171]. Adult studies presence of anemia [177]. Transfusions have been adminis-
suggest volume replacement with HES may be more risk tered to VLBW infants in the first 2 weeks of life to correct
than benefit but studies on the use of starches in pediatric the anemia, but these are not without complications [177].
patients, particularly those who are critically ill and/or have A systematic review reported that whether erythropoietin
renal dysfunction, are lacking [172]. In an open-labeled was administered before or after postnatal day 8, it did not
study of neonates and infants undergoing major noncardiac reduce the transfusion rate and actually increased the risk
surgery, morbidity, length of stay, and laboratory indices of retinopathy of prematurity in those who received it
(coagulation studies) with HES and albumin were similar [177]. Several studies that examined the immediate and
[173]. In neonates without cardiac, renal, or hemostatic long-term outcomes after restricted or liberal transfusion
abnormalities undergoing central-line placement, the use of practices in VLBW infants yielded similar results [176].
6% HES did not increase creatinine or bleeding when com- However, a recent MRI study of brain volume in graduates
pared with neonates receiving an equal volume of 5% albu- of the NICU who received either restricted or liberal trans-
min [174]. However, no improvement in cardiac output fusions reported a disturbing finding: less cortical and sub-
could be shown in hypotensive neonates with low cardiac cortical white matter volumes in females who received
output states after the administration of HES, isotonic liberal blood transfusions [178].
saline, or 5% albumin [174]. Large volume transfusion (defined as a circulating blood
Gelatins are polypeptides produced by degrading bovine volume of a neonate in 24 h), or 50% of the circulating vol-
collagen, which have a short duration of action because of ume within 3 h, may occur in some high-risk surgery such as
their rapid but transient passage into the interstitial space, NEC. In situations where >40 mL/kg blood loss occurs, pre-
rapid GFR, and enzymatic cleavage by proteases. The data mixing the packed red blood cells with fresh frozen plasma
supporting the use of gelatin in infants are limited. Animal may be appropriate [179]. Perioperative transfusions should
studies that evaluated capillary leak in septic shock indicate be considered in neonates if:
that gelatin and HES actually maintain plasma volume more
effectively than albumin. i. Acute blood loss >10% of the circulating blood volume;
ii. Hemoglobin <80 g/L in a stable neonate with symptoms
of anemia (including apnea, bradycardia, poor weight
Transfusion Triggers gain); and
iii. Hemoglobin <120 g/L in an infant with respiratory dis-
Neonatal transfusion guidelines for neonatal intensive care tress syndrome or congenital heart disease.
(NICU) are based on guidelines for VLBW infants as there
is limited evidence specifically for full-term infants. There
are no prospective studies in neonates that describe periop- Postoperative Fluid Maintenance
erative transfusion triggers, but transfusion thresholds dur-
ing the first 2 weeks postnatal age are shown in Table 8.8. With their revision of the approach to fluid administration
Transfusions in VLBW infants have been associated with in the intraoperative period, Segar and Holliday reduced
BPD, NEC, IVH, and ROP, and neurocognitive changes in the incidence of perioperative hyponatremia [180].
However, postoperative hyponatremia occurred [181] in Postoperative Metabolic Needs

part, because surgeons administered hypo-osmolar IV flu-
ids and with the multiple stimuli that upregulated ADH The stress response in full-term and preterm neonates differs
release [35]. Subsequently, Segar and Holliday revised both quantitatively and qualitatively from that of adults. The
their postoperative fluid guidelines to use isotonic or near- increases in stress hormones associated with surgery in the
isotonic solutions but at half of the previously recom- neonate exceed those measured in children and adults but
mended rates, 2 mL/kg/h for the first 10 kg, 1 mL/kg/h for under most circumstances return to baseline by 24 h [184].
the next 10 kg, and 0.5 mL/kg/h for the remainder [180]. Neonates <48 h old have a diminished stress response com-
The neonatal surgical patient remains at risk for increased pared with older neonates. One possible explanation for the
ADH, given that pain, stress, narcotics, hypovolemia, and/ latter difference may be the greater secretion of endogenous
or hemorrhage are associated with the postoperative period opioids in the perinatal period blunting the endocrine and
[35]. Adequate analgesia and control of the stress response metabolic responses [185, 186]. Resting energy expenditures
in children is insufficient to downregulate ADH release increase by only 20% in neonates undergoing major surgery
[138]. Non-osmotic stimuli of ADH secretion include posi- but return to normal values within 12 h. It has been suggested
tive pressure ventilation, stress, nausea and vomiting, that one reason critically ill neonates fuel the metabolic
hypoglycemia, fever, and decreases in intravascular volume stress response without increasing their resting energy
as a sequelae of illness or surgery (Table 8.1). Asphyxiated expenditure is that, unlike adults, neonates are still actively
infants may have increased circulating arginine vasopressin growing. Only approximately 65% of neonatal energy
(syndrome of inappropriate ADH, SIADH) and may be at requirements are necessary to meet resting energy expendi-
increased risk of cerebral edema. Their fluid intake should ture. The remainder is directed primarily to maintain growth
be restricted for 48–72 h, i.e., ≤60 mL/kg/day, or until sei- and to a lesser extent to regulate temperature and meet the
zures are no longer considered a problem. Several studies demands of other activities. The total energy needs of intra-
have suggested that the use of isotonic saline solution venously fed, full-term, surgical neonates are about 85 kcal
decreases the risk of hyponatremia in sick children [130, kg/day. Sick neonates stop growing, become lethargic, and
182]. Some surgical preterm neonates may require an addi- require nursing in a thermoneutral environment. Thus,
tional 30 mL/kg/day because of increased insensible fluid energy is available to supply the metabolic response to injury
losses and third space losses, and may also require addi- without any fluctuation in the resting energy expenditure.
tional sodium supplements (4 mmol/kg/day). Fluid man- Other factors such as sedation may further reduce the resting
agement practices after surgery for congenital heart disease energy expenditure, apportioning more energy for the meta-
vary widely. The most common prescribed fluids are iso- bolic response. This suggests that the routine administration
tonic (mainly 0.9% saline) but hypotonic fluids are fre- of excess calories may not be warranted in critically ill surgi-
quently prescribed. Most pediatric intensive care units limit cal neonates and also supports the hypothesis that neonates
fluid intake to 50% during the first 24 h post-cardiac sur- redirect energy, normally used for growth, to fuel the stress
gery. The most frequently used fluids for resuscitation is response [187].
0.9% saline (44%) or colloids (27%). Special attention must be directed to providing optimal
It is a common practice to resume TPN in neonates metabolic care in the postoperative period. Rates of survival
with a dextrose, electrolyte, amino acid, and lipid infu- for extremely low birth weight (ELBW) (<1000 g) infants
sion after surgery at 60–70% (usually 100 mL/kg/day) of have improved but delayed-onset growth failure is nearly
the preoperative rate, with frequent serial monitoring of universal. At the time of birth, only about 18% of ELBW
the serum electrolyte concentrations to preclude hypona- infants are less than the 10th percentile for weight and length.
tremia. Many postoperative infants gain considerable At 36 weeks corrected gestational age, as the neonates near
weight due to capillary leak and fluid administration in discharge from the NICU, most ELBW infants are less than
the perioperative period compromising respiration. Once the 10th percentile for weight and length. A 26-week gesta-
the preterm infant with BPD is hemodynamically stable, tion 1000-g birth-weight infant begins with body protein
diuresis (sometimes preceded by an infusion of albumin) stores of approximately 88 g compared with 250 g in a full-
is necessary to improve respiratory function and facilitate term infant. Without protein intake, the infant loses approxi-
extubation of the trachea. Institution of TPN is one of mately 1.5% of total body protein per day. After only 3 days
several factors that has improved morbidity and mortality without protein intake, body protein stores are reduced by
in preterm neonates after surgery for congenital bowel 5% from birth and are 10% less than a fetus of comparable
defects such as jejunoileal atresia [183]. Fluid restriction age. In contrast, after birth, most of the very preterm infants
as described below for postoperative management after are fed more lipid and glucose and fewer amino acids and
cardiac surgery may also be salutary in preterm infants protein than they need. Not surprisingly, therefore, very pre-
with BPD. term infants accumulate fat but remain relatively growth
restricted at term gestational age compared with those infants namic management may also be a contributory factor.
who grew normally in utero, and this postnatal growth Congenital heart disease increases cardiac and respiratory
restriction has long-term adverse growth, development, and work to a significant effect immediately after cardiac sur-
health consequences. gery. Adequate enteral nutrition may be difficult to achieve
early after cardiac surgery in neonates, but it is essential for
growth, wound healing, and the integrity of the immune sys-
Special Cases: Cardiac Surgery tem. Children with less complex cardiac lesions (e.g., VSD)
may need up to 50% more calories than healthy infants to
Infants undergoing neonatal cardiac surgery require special continue along a normal growth curve. Infants with single-
consideration and are an exception to the above recommen- ventricle repairs and aortopulmonary shunts may experience
dations. The optimal maintenance fluid infusion rate is often splanchnic ischemia due to the diastolic runoff from the
less than has been outlined above to manage borderline ven- shunt and are predisposed to NEC. In most cases, infants
tricular function or excessive pulmonary blood flow [51, who require neonatal surgery have substantive difficulty in
188]. Similarly, intraoperative fluids must be reduced as gaining weight postoperatively despite these adjustments to
fluid overload and renal dysfunction may significantly con- the caloric intake. Strategies to optimize the caloric intake
tribute to morbidity, e.g., after arterial switch surgery in and promote weight gain include the use of TPN in the early
neonates and infants [189, 190]. Furthermore, the use of postoperative period, the institution of nasogastric feeds, and
intraoperative balanced salt solutions that contain glucose the use of high-calorie enteral feeds [197].
during pediatric cardiac surgery remains controversial
because of possible associations with worsened neurologi-
cal injury compared with results when glucose was not Temperature Homeostasis
added. The use of glucose-free, balanced salt solutions dur-
ing pediatric cardiac surgery, however, may result in hypo- Core body temperature in adults is maintained constant
glycemia during the pre-bypass period. Moderate (±1.0 °C) within the body [198]. Temperature receptors
intraoperative glucose administration (2.5 mg/kg/min) will located in the skin and deep structures detect changes in tem-
not cause major hyperglycemia but just may prevent epi- perature (±0.4 °C) that are transmitted through the spinal
sodes of hypoglycemia. Tight glycemic control in pediatric cord to the preoptic nucleus of the hypothalamus. The hypo-
cardiac surgery may result in a 3% incidence of severe thalamus responds by activating autonomic and behavioral
hypoglycemia, which highlights the need to monitor blood changes to preserve core temperature. The skin contributes
glucose concentrations during neonatal cardiac surgery to between 20 and 50% to this response [199]. An active pre-
preclude swings in the plasma glucose concentrations [191]. capillary vasodilation sweating, arteriovenous shunt vaso-
Postoperative fluid restriction has also been widely constriction, and shivering are the primary autonomic
accepted as one of the important strategies to reduce the risk thermoregulatory mechanisms to maintain a constant core
of pulmonary edema and to improve respiratory function, temperature between 36 and 37 °C in humans [198, 199].
prevent intravascular volume overload, and reduce multi- Heat loss in neonates occurs by four distinct mechanisms:
organ dysfunction early after pediatric cardiac surgery, espe- radiation (39%), convection (34%), evaporation (24%), and
cially in low-weight infants [192]. After cardiopulmonary conduction (3%) (Fig. 8.6) [200]. Neonates have a large
bypass, sodium and water may be retained in response to the area/body mass ratio and less subcutaneous fat (less than half
systemic inflammatory response to bypass and surgery that that compared with adults), greater body water, and imma-
increase capillary permeability. Excess postoperative fluids ture skin, and hence they lose body temperature quickly
after cardiac surgery correlate significantly and indepen- [201]. The normal body temperature in the neonate ranges
dently with prolonged mechanical ventilation and poor out- between 36.5 and 37.5 °C. Neonatal hypothermia is divided
comes [193, 194]. For bypass cases, fluids are restricted to into three categories: mild or cold stress, 36–36.4 °C; moder-
50% of maintenance rates in the immediate postoperative ate stress: 32–35.9 °C; and severe stress, <32 °C [201, 202].
period, whereas in non-bypass cases, it is limited to 60% of The thermoneutral zone, defined as the ambient temperature
maintenance rates. This fluid regimen should continue until range that does not require energy above the basal metabolic
the infant’s airway is extubated, after which the fluid rate is rate to maintain, in the adult is 26–28 °C, whereas in the
increased by 10% per day [194, 195]. naked term neonate it is 32—35 °C and in the preterm infant
Growth failure and malnutrition are common in neonates 35 °C [201]. Two-thirds of the neonate’s heat production is
with congenital heart disease. The etiology of the growth devoted to basal metabolism, reducing the amount of energy
failure is multifactorial and most likely reflects a hypermeta- available to protect from cold stress [186]. A naked full-term
bolic state, inadequate caloric intake, malabsorption, and neonate, with no thermal protection exposed to an ambient
genetic factors [196]. Fluid restriction used for hemody- temperature of 25 °C, may lose up to 100 cal/kg/min, a
Fig. 8.6 This diagram illustrates the four mechanisms of heat loss in neonates include heating the operating room (to 28 °C) before the neo-
neonates: radiation (39%), convection (34%), evaporation (24%) and nate’s arrival and the use of a forced air warmer
conduction (3%). Effective strategies to mitigate these losses in most
decrease in core temperature by 2 °C, and a decrease in skin to bind to ATPase and produce energy [207]. Other hor-
temperature by 4 °C within 30 min [203]. In contrast, a mones are cofactors in activating non-shivering thermo-
warmed baby loses only 22–28 cal/kg/min in the same con- genesis including thyroid hormone, cortisol, leptin, and
ditions [204]. prolactin. During the first 2 weeks of postnatal life, cold-
induced non- shivering thermogenesis is replaced with
shivering thermogenesis [209].
Brown Adipose Tissue (BAT) Preterm infants <30 weeks of gestational age have mini-
mal BAT stores and thus cannot benefit from non-shivering
Brown adipose tissue (BAT) develops between 26 and thermogenesis to any large extent; as a result, they are at risk
30 weeks gestation and is the major energy source for heat of hypothermia for several months after birth. Moreover,
production in the neonate [205, 206]. Its brown color stems their glycogen stores are reduced. Heat loss via convection
from the concentration of mitochondria within the tissue. and conduction sources is increased in extremely low weight
BAT accumulates in discrete areas including the interscap- preterm infants because peripheral and arteriovenous shunt
ular, para-aorta, and perirenal/adrenal regions beginning vasoconstriction is impaired in the first 12–24 h after birth.
mid-gestation in the neonate, ultimately constituting about As a consequence, extremely preterm neonates may have
5% of the neonate’s weight at term [207, 208]. BAT is peripheral temperatures that are warmer than their core tem-
highly vascular, and innervated with noradrenergic fibers. perature [210]. Evaporative heat loss is predominant during
Heat production produced from BAT, also known as non- the first 10 days after birth in extremely preterm infants
shivering thermogenesis, is initiated by cold temperatures [211]. Preterm neonates have a thinner layer of keratin and
(≤23 °C in humans), which release norepinephrine [207]. little subcutaneous tissue, which predisposes them to
Norepinephrine, the neurotransmitter primarily responsi- increased heat loss through convective and evaporative
ble for BAT, in turn, activates uncoupling protein 1 (located mechanisms [201].
in BAT mitochondria membrane), which facilitates the The cutaneous vasomotor regulation along with shivering
transfer of protons generated by the electron transport are minimally active modalities in neonates. Sweating is
chain to preferentially transfer them into the mitochondria, impaired in the first 2 weeks after birth but could be activated
generating heat in the process, rather than allowing them for temperatures that exceed 37.9 °C [200]. Non-shivering
thermogenesis remains the primary mechanism for heat pro- Table 8.9 Strategies to prevent hypothermia in neonates during sur-
duction in neonates and infants until 6–12 months of age gery and MRI
[198, 205]. As the body temperature decreases to 35–36 °C, • Keep the neonate warm, particularly before transport and MRI
activation of the sympathetic nervous system initiates non- • Warm the operating room before arrival, ideally to 26–28 °C
shivering thermogenesis, along with a small contribution • Activate a forced-air heater (not MRI-compatible) using an
approved total body blanket for infants to 43 °C before the
from vasoconstriction to attenuate the decrease in tempera- neonate arrives in the suite. Use for all procedures.
ture. Non-shivering thermogenesis triggers energy produc- • Warm disinfectant solutions when possible
tion from BAT [212]. However, with the limited stores of • Warm fluids particularly if a large volume of IV fluid is
BAT, the source may become depleted within 24 h in a cold anticipated and warm all blood products (except platelets)
environment [204, 211, 213]. • Humidify inspired gases where possible
• Keep the skin dry
• Keep the operating room warm until the neonate is fully draped
• Monitor the core temperature of the neonate before, during,
Normothermia and Hypothermia and after surgery or MRI
• Reduce the room temperature for surgical comfort after
Core and axillary temperatures between 36.5 and 37.4 °C draping, to ≥21 °C
are considered normal in neonates and infants. The differ- • Increase the operating room temperature to 26 °C before
ences in temperature between full-term and preterm neo- undraping the neonate
• Cover the head, particularly preterm babies
nates and between rectal and axillary temperatures are
• Use the thermoneutral incubator, warming packs during
only several tenths of °C [214, 215]. Hypothermia has transport and ensure it is warm before transferring the patient
been defined as a core body temperature <36.5 °C, or a
skin temperature <36 °C. Severe hypothermia occurs when
the core and skin temperatures are <32 and <31.5 °C, the periphery. The core temperature decreases approximately
respectively [212, 216, 217]. 0.5 °C during the first 45 min of anesthesia but can be 1.5 °C
Hypothermia is a well-known independent risk factor of less by the end of the surgery without corrective interven-
morbidity and mortality in neonates and infants [201, 212]. tions [220, 224].
Cold stress at birth increases oxygen consumption by two- to In the NICU, the use of a radiant warmer, overhead heat
three-fold (up to 15 mL/kg/min) [205, 217] and norepineph- lamps, polyethylene wrap/vinyl bag/thermal mattress, and
rine release by 2.5 times [198]. A decrease in body tempera- prewarmed transport incubator prevents hypothermia.
ture of 1 °C increases mortality by four-fold, particularly in Additional techniques may include exothermic warming
the preterm infant and those <1500 g [201]. Hypothermia mattress, heating humifying inspired gases, along with
has been linked to respiratory distress, metabolic derange- occlusive wraps and radiant heat, and warmed polyethylene
ments, intraventricular hemorrhage, major brain injury, caps, which are also useful (Table 8.9) [201, 212, 225].
bronchopulmonary dysplasia, retinopathy of prematurity, In the operating room, two primary strategies prevent the
NEC, and nosocomial infection [212, 218, 219]. Hypothermia neonate from becoming hypothermic, and several secondary
has also been linked to hemodynamic instability, increased strategies may also be used [219]. The first one is to preheat
blood loss, and decreased metabolism of propofol and mus- the operating room temperature to ≥26 °C before the neo-
cle relaxants. However, transient mild intraoperative hypo- nate arrives. This attenuates but does not preclude hypother-
thermia may not be harmful to the neonate [220]. mia from developing [220, 222]. An operating room
temperature of 30 °C may prevent a decrease in the internal
temperature of 7.7 °C/h in a low-birth-weight neonate,
revention of Hypothermia in Infants
P whereas a forced-air device at 38 °C may prevent a decrease
Receiving Anesthesia of 5.0 °C/h. In the same clinical scenario, a mattress warmed
at 39 °C prevents a decrease of 1.5 °C/h, and the head tube
Anesthesia decreases vasoconstriction and shivering thresh- gauze only prevents a 0.4 °C/h. When combined, these mea-
olds by up 2 °C but has little effect on sweating [198]. sures may decrease the heat loss in a model of the neonate,
General anesthesia, both intravenous and inhaled, abolishes almost four-fold less than in a naked full-term neonate [226].
non-shivering thermogenesis and has little effect on the The second strategy is to use a forced-air body warmer
peripheral vasoconstriction threshold in neonates [221, 222]. under the neonate, prewarmed to 40 °C before the neonate
Curiously, in vitro studies demonstrated a dose-dependent arrives in the operating room and maintained throughout
suppression of BAT activity with inhaled agents, but not with induction of anesthesia and patient positioning, until the sur-
propofol or ketamine [223]. gical drapes are applied. A forced-air warmer is the single
Temperature decreases in the first 10 min after induction most effective strategy to maintain normothermia in the neo-
of anesthesia due to a redistribution of central core heat to nate [226–229]. Warmed intravenous and irrigation fluids are
secondary strategies especially with high flow infusions or and 37.5 °C), even after 80 min [239]. However, episodes of
extensive peritoneal lavage, although most fluid warming hypothermia have been reported, particularly in infants whose
strategies are impractical in neonates due to the large dead pre-scan body temperature is below normal [238, 239].
space of the warming devices. Other secondary strategies MRI scanners produce radiofrequency radiations between
including using humidified gases in the ventilator circuit, a 64 (1.5 Tesla) and 128 MHz (3 Tesla), which may be absorbed
radiant overhead warmer, and covering the neonate (during by the neonate, increasing their body temperature and, if it
the first 20 min of anesthesia) reduce heat loss [224, 230, continues for a protracted period, overheating them [239].
231]. Once the surgical drapes have been applied, the tem- Hyperthermia has been associated with cellular and organ
peratures of both the operating room and the forced-air damage, possible developmental abnormalities, and pro-
warmer may be adjusted to maintain thermoneutrality in the longed intubation, which should be avoided. MRI scans in
neonate and avoid hyperthermia [229]. infants should be maintained below the maximum allowable
The type of surgery and the ambient operating room tem- specific absorption rate (SAR) of 4 W/kg to reduce the risk
perature are key determinants of the severity of the hypother- of overheating [240]. Few studies in older children confirm
mia that may occur intraoperatively [224]. Neonates and that the body temperature increases from 0.2 to 0.5 °C during
infants undergoing cardiac, urologic, and ENT procedures MRI scans [241].
are at the greatest risk for hypothermia [232].
In contrast to adults whose temperature is only monitored
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General and Thoracoabdominal Surgery
Including Management of Conjoined 9
Twins
Kate Cross, Peter Carachi, and Sally Wilmshurst
Introduction surgery has been produced by the enhanced recovery after

surgery (ERAS) group [1]. This is a first step towards
Provision of safe anesthesia for the neonate undergoing tho- improving the care provided to neonates who require intesti-
racic or abdominal surgery presents several challenges for the nal surgery, and many of the principles can also be applied to
pediatric anesthesiologist. This is a diverse group of patients, preterm neonates, but the evidence for some aspects of care
encompassing the robust term neonate presenting for elective remains quite weak.
inguinal hernia repair to morbidly sick extreme low-birth-
weight neonates with necrotizing enterocolitis. This group
presents with a huge variation in size, from approximately General Considerations
500 g to 5 kg, and in the maturity of organ systems. Some will
be cared for at home, whereas others will be cared for in the Anesthesia complications are more common in the neonatal
neonatal intensive care unit (NICU). Several surgical special- period [2–4] and there remains concern about the safety of
ties may be involved in the care of the neonate including car- anesthesia on the developing human brain (see Chap. 18).
diothoracic, general surgery, hepatic surgery, and urology. For these reasons, only essential surgery should be carried
Comorbidities are common in this age group. Congenital out during this period. Wherever possible, this surgery
surgical lesions often coexist with other abnormalities such should be carried out in specialist units. Antenatal identifica-
as congenital heart defects; other organ involvement, e.g. tion of common or severe congenital abnormalities is usually
lung hypoplasia in congenital diaphragmatic hernia; and very reliable in developed countries, ensuring that delivery
midline defects as in VACTERL, which is an acronym for and postnatal care can be optimally planned during the ante-
vertebral, anal, congenital heart disease, trachea-esophageal natal period. Acute surgical conditions and unexpected con-
fistula, renal, and limb defects. Medical complications of genital anomalies can present to any hospital and may require
prematurity such as persistent pulmonary hypertension, that the neonate is stabilized and transferred to a specialist
respiratory distress syndrome, and hydrocephalus also need unit for further investigation and management.
to be considered. Multidisciplinary collaboration between the anesthesiolo-
This chapter aims to briefly outline some of the main gen- gist, surgeon, and, if relevant, neonatologist is vital to ensure
eral issues, describe specific thoracic and abdominal condi- the neonate is optimally prepared for surgery and has a safe
tions that require surgical or anesthetic intervention in the postoperative plan.
neonatal period, and describe the surgical and anesthetic Neonatal anesthesia requires several special anesthesia-
requirements for each. There are very few randomized con- related considerations:
trolled trials to guide management. Most strategies are based
on case reviews or expert consensus. A recent evidence- –– Immature organ systems, particularly the kidney, liver,
based guideline for full-term neonates undergoing intestinal and cardiovascular system
–– Altered drug handling
–– Rapidly changing fluid and electrolyte requirements
K. Cross (*) · S. Wilmshurst –– Feeding issues
Great Ormond Street Hospital for Children, London, UK
–– Blood result reference ranges and significance
–– Vascular access difficulties
P. Carachi
–– Regional anesthesia challenges
Children’s Hospital for Wales, Cardiff, UK
e-mail: [email protected] –– Prone to heat loss and poor heat retention

292 K. Cross et al.
–– Equipment difficulties such as ventilators and the significance of the absolute number is unclear and should
monitoring be managed based on the advice of the local hematologist,
–– Postoperative apneas but most authorities would recommend transfusing platelets
–– Parental anxiety if the concentration is <100 × 109/L [5].
A “group and save” (also termed a “group and reserve”)
should be prepared for all but the most minor surgery follow-
Preoperative Assessment ing local policies. If the need to transfuse packed red blood
cells seems likely, then a crossmatch of 1 unit of packed red
History and Examination blood cells should be performed. Blood products should be
Evaluation includes a detailed history of gestational age, available for moderate and major surgery, that is, safe in the
birth history, Apgar scores, issues in the perinatal and subse- presence of maternal antibodies. In practice, O-negative
quent period, the surgical complaint, how the baby is feed- blood is often prepared for neonates as the red cells have no
ing, known associated anomalies, administration of vitamin antigen surface receptors to react with circulating antibodies
K, presence or need for vascular access, any relevant family in the neonate.
history, and current medication history. It is useful to record
how well very sick or small babies handle their daily cares as
this can yield insight into how the neonate will tolerate trans- Logistical Issues
fer to theater, anesthesia, and positioning. If surgery is
required in the first few days of life, the mother may still be Emergency Status
hospitalized herself and unavailable to give a history. The Some thoraco-abdominal surgery needs to be performed as
father may be accessible to document the history and consent an emergency, for example, gastroschisis, necrotizing entero-
or surgery; otherwise, the information may be obtained by colitis with perforation, malrotation with ischemic gut, or
telephone. tracheoesophageal fistula that requires ventilatory support.
The examination should be relevant to anesthesia and Other procedures can be delayed until the neonate is stabi-
include an assessment of the airway, position of lines, and lized and a suitable theater slot is scheduled. These proce-
tubes (or potential sites for their insertion), fluid status, and dures include bowel obstructions or atresia without
an examination of the heart and lungs. The back and sacrum perforation, such as pyloric stenosis and anorectal malforma-
can be inspected if regional anesthesia or analgesia is tion, congenital diaphragmatic hernia, and cystic lung
planned. Cleft lip or palate, choanal atresia, or more chal- malformations.
lenging airway abnormalities such as Pierre-Robin sequence
can sometimes coexist with midline congenital abnormali- Surgery in the NICU
ties (e.g., VACTERL). Transfer of the critically ill neonate to a distant operating the-
ater, particularly extremely low-birth-weight [ELBW] infants,
Investigations increases morbidity and mortality (see Chap. 13). It can also
Congenital heart disease is more frequent in children with be technically challenging, especially if the neonate requires
other congenital abnormalities; therefore, an echocardio- inotrope infusions or additional intensive care support such as
gram should be performed preoperatively where possible. HFOV or inhaled nitric oxide (iNO). In these situations, it is
Abdominal ultrasound is useful to assess kidneys in the pres- important to assess whether surgery should instead be carried
ence of esophageal atresia or other midline abnormalities. out in the NICU. This was first described for PDA ligation
Cranial ultrasound may be performed in premature infants to and diaphragmatic hernia [6, 7]. It is now becoming common-
diagnose an intracranial hemorrhage. Spinal imaging may be place for NEC surgery. The risk-benefit of surgery on the
helpful if regional analgesia is planned. NICU varies from unit to unit depending on geography and
For major surgery or in hospitalized infants, blood testing personal preferences. Drawbacks and challenges of perform-
should include bilirubin levels, renal and liver function tests, ing neonatal surgery in the NICU include maintenance of ste-
full blood count, blood glucose concentrations, and the coag- rility, limited space, ensuring adequate access to the neonate
ulation profile. Both the prothrombin time and APTT is com- during surgery by the whole team, unsuitable lighting, anes-
monly prolonged in premature neonates. The significance of thesia monitoring, the availability of drugs, and equipment,
this is unclear in the absence of bleeding. These results temperature control, privacy, and in some centers, enlisting
should be interpreted in the context of the lab standards for the support of the NICU personnel. Most of these issues can
the hospital and in discussion with a hematologist and the be addressed through good communication, advance plan-
anesthesia and surgical teams. The concentration of platelets ning, and the use of locally agreed upon protocols among the
is often low, or even if the concentration is normal, platelet NICU, surgical, and anesthesia teams. Simulation exercises
function may be impaired in septic or sick neonates. Again with a setup plan and designated equipment trolley can help
9 General and Thoracoabdominal Surgery Including Management of Conjoined Twins 293
defuse obstacles, addressing practical issues and engaging the ues before induction of anesthesia may be a challenge in the
whole team’s participation [8]. A team brief should always be neonate who is constantly moving. After induction of anes-
performed preoperatively and should include members of the thesia and tracheal intubation, noninvasive blood pressure,
NICU team. Surgical and anesthesia consents should be ECG, capnography, and hemoglobin saturation are recorded.
obtained and the child’s ID confirmed as is standard local The skin can be easily damaged by adhesives used in moni-
practice. The availability and location of blood should be toring. End-tidal CO2 monitoring should be used except
checked before induction of anesthesia; a person should be when HFOV is used; in the latter case, transcutaneous CO2 is
designated to collect the blood from the blood bank (particu- preferred (see Chap. 7). Pre- and post-ductal saturations are
larly after hours when minimal staff is present). All blood helpful in the presence or suspicion of congenital heart dis-
products (see below) should be checked in the standard man- ease or persistent pulmonary hypertension. Invasive moni-
ner according to hospital guidelines. A standard blood warmer toring can be considered for major surgery or in the presence
requires a large volume for priming and is inappropriate for of congenital heart disease, sepsis, or when frequent blood
small volume transfusions as in the case of a neonate. sampling is needed. Umbilical lines may already be present
Accordingly, we filter 10–20 mL aliquots of blood through in a neonate whose lungs are ventilated. These vessels can be
small volume blood filters (Hemo-Nate® blood filter, Utah, useful for up to 5 days postnatally, although they are prone to
Midvale UT, USA) and either immerse the sealed syringes in disruption during abdominal surgery. If used, the tip of the
a warm water bath or warm them before use. UAC optimally should be located above the diaphragm at the
Anesthesia machines and scavenging equipment are T6–10 level and the UVC at the SVC/RA junction. Arterial
rarely available in the NICU. Consequently, an intravenous lines in neonates carry a significant risk of limb ischemia,
anesthetic technique is usually favored, which complements thrombosis, or long-term limb length discrepancies. For this
existing sedation/analgesia and paralysis strategies as well as reason, they should only be used when clinically indicated
sidestepping the issue of neurocognitive effects of anesthet- and the risks and benefits discussed with the wider team and
ics on the neonatal brain. Standard monitoring including the parents (see Chap. 7).
end-tidal or transcutaneous CO2 if oscillated should be func- If accessible, capillary refill can be regularly assessed
tional. Before the neonate is draped, the anesthesiologist during surgery. Bowel discoloration may be a sign of tissue
should ensure lines are accessible to administer medications, hypoperfusion. Near-infrared spectroscopy (NIRS) is
the monitoring is optimal, and that they are familiar with the increasingly used in neonatal cardiac surgery and can also be
ventilator and syringe pumps before starting. useful for monitoring cerebral and mesenteric perfusion in
the NICU, although access to the abdomen would be limited
eam Brief and Preparing the Theater
T during surgery [10, 11]. Monitoring urine output can be use-
A team brief should be performed for all cases including ful during long surgery although the neonate may not make
emergencies and regardless of the operating location [9]. The urine for the first 24 to 48 h after birth. If the neonate is mak-
theater should be pre-warmed to ~80 °F (or 27 °C). Thought ing urine, the volume could be monitored although it is usu-
should be given to the necessary anesthetic and surgical ally very small, and technically, measuring the volume can
equipment, surgical access, positioning, and warming the be difficult or impossible during certain surgeries such as
baby using forced-air warming during surgery, fluid warm- bladder exstrophy.
ing, and insulating wrapping material. Red blood cells and
blood products should be available in a nearby refrigerated Induction
location if required. Tracheal intubation is mandatory for neonates who require
thoracic and abdominal surgery. Laryngeal mask airways
(LMA) are rarely used in neonates, although they may be
Conduct of Anesthesia useful for rescuing a difficult airway or for bronchoscopy.
Obtaining and maintaining a good seal around the larynx is
Sedative premedication is rarely used in neonates. Occasionally difficult, although the I-gelTM LMA was effective during
glycopyrrolate or atropine may be useful if a difficult airway is neonatal resuscitation [12] and comparable to the Proseal 1
anticipated or if the use of the bronchoscope is planned during anesthesia [13]. However, most have frequent diffi-
although this practice has fallen by the wayside in many cen- culties seating the LMA, maintaining a patent airway, as well
ters; in North America few administer prophylactic anticholin- as challenges ventilating the lungs with sizes 1 and 1.5
ergics unless IV succinylcholine is planned. LMAs [14, 15]. Since most surgery in neonates is emergent,
a tracheal tube is the most appropriate airway.
Monitoring A feeding tube should be inserted into the stomach in neo-
Standard intraoperative monitors should be used following nates with full stomachs, or if an indwelling feeding tube is
national standards. Obtaining reliable cardiorespiratory val- already present, it should be aspirated after rolling the neo-
294 K. Cross et al.
nate to the left and right lateral decubitus positions while Vascular Access
aspirating the stomach contents. In some circumstances, it Choose a site and size of vascular access that is most appro-
may be necessary to remove the feeding tube to facilitate priate to the surgery. Venous access may already be present
laryngoscopy. It should be replaced once the airway is in neonates who are nursed in the NICU, but small size cath-
secured. eters such as a 24 gauge, while adequate for use in the NICU,
Where possible the neonate should be oxygenated before may be inadequate in the operating theater if the need arises
induction of anesthesia. It is often quite challenging to hold to rapidly transfuse packed red blood cells, to resuscitate
a facemask in place with a crying neonate. Not infrequently, large volumes of fluids/albumen, and/or to sample blood.
neonates desaturate during laryngoscopy and intubation Larger size venous access such as a 22 gauge or central line
despite our best efforts to pre-oxygenate, even in those with should be established if transfusion is a possibility. Venous
normal airways [16]. To minimize the risk of desaturation, access in the lower extremities is not uncommon in neonates
care should be taken to maintain preexisting CPAP or PEEP, as the saphenous vein is substantial, although in some cir-
to gently mask ventilate the lungs after induction of anesthe- cumstances, intra-abdominal surgery, in which the vena cava
sia, or to apply high-flow nasal oxygen during laryngoscopy or a tributary must be compressed or ligated, may render IV
to prevent desaturation [17, 18]. access in the lower extremities useless.
An intravenous or inhalational induction may be used in Femoral and jugular lines size 4 or 5F are appropriate for
neonates. An inhalational induction is very rapid in the neo- central venous access but surgical positioning may influence
nate, but increases the risk of aspiration if a full stomach is this choice. Caution should be exercised in neonates with
present, as is often the case in neonatal surgery. Nonetheless, congenital heart disease as a shunt (e.g., Blalock) may be
some centers routinely perform inhalational inductions in present from previous surgery or a left-sided SVC can
neonates even full stomachs without complications [19, 20]. directly communicate with the coronary circulation.
Inhalational inductions are useful when intravenous access Ultrasound will identify patent central veins for cannula-
has not been established before induction of anesthesia or a tion [31] and an interventional radiologist can often assist
difficult airway is suspected. An intravenous induction is with difficult access. If long-term vascular access is required
often more appropriate in neonates, but care should be taken for parenteral nutrition or antibiotics, a peripherally inserted
to give the agents slowly and titrate to effect wherever pos- central catheter (PICC) or midline catheter should be consid-
sible as even propofol has resulted in several case reports/ ered under the same anesthetic.
series of profound bradycardia and hypotension at induction
in neonates [21]. It must be appreciated that neonates, par- emperature Monitoring and Warming
T
ticularly VLBW infants, who are nursed in the NICU are Neonates are poikilotherms with limited ability to generate
managed relatively “dry” to reduce the risk of home dis- heat in a cold stress environment. They depend on
charge on oxygen, intraventricular hemorrhage, necrotizing norepinephrine- mediated non-shivering thermogenesis via
enterocolitis, and patent ductus arteriosus [22, 23]. However, brown fat to keep warm (see Chap. 8). To maintain normo-
when general anesthesia is induced in such neonates, hypothermia, neonates should be nursed in a thermoneutral envi-
tension may ensue [24]. Accordingly, neonates should be ronment between 36.3 and 37.3 °C [32]. Prolonged
pretreated with 10–15 mL/kg balanced salt solution before abdominal and thoracic surgery, during which body cavities
induction of anesthesia to attenuate any decreases in blood and viscera are exposed, is associated with profound heat
pressure with induction of anesthesia [25]. For those neo- loss in the neonate unless preventative measures are taken. It
nates who have been receiving sedative medications in the should be noted that an under-appreciated period when heat
NICU, supplemental boluses of the same sedatives may be loss can occur is during transport from the NICU to the oper-
sufficient to achieve a surgical depth of anesthesia. ating theater. Up to 50% of neonates who are transported
A classic rapid sequence induction may be an unsuitable from the NICU to MRI experience temperatures <36.5 °C
technique for neonates due to the speed they desaturate dur- (see Chap. 8). The use of heating pads in the transport incu-
ing apneic periods and the compressibility of the cricoid ring bator may offset heat loss during transport [33]. Active
when pressure is applied. Consequently, a “modified rapid warming strategies should be incorporated in the operating
sequence induction” includes gentle mask ventilation during theater protocol for neonates to prevent hypothermia from
induction of anesthesia, maintaining a low peak airway pres- developing. Such strategies should include preheating the
sure to avoid gastric insufflation until the airway has been operating theater (to 80 °F or 27 °C) before the neonate
secured with a tracheal tube and avoiding cricoid pressure arrives; the use of a forced-air warming blanket, heating
[17, 26–29]. An alternative to gentle mask ventilation may be fluids, and blood; use of a heat moisture exchanger in the
the use of “high-flow” nasal oxygen (at 8 L/min flow) to pre- ventilator circuit; and insulating the head and body parts to
clude desaturation during tracheal intubation; the results of minimize heat loss. Surgical irrigation fluids should be
this study are pending [30]. warmed and exposed bowel covered with warm wet towels
whenever possible [34]. Core temperature is the preferred Maintenance Requirements

temperature metric, although the choice of location depends The maintenance fluid requirements depend on the age of the
on factors such as the site of surgery and patient issues such neonate. Insensible losses are greater in premature infants
as the presence of an imperforate anus or other anomaly. than in full-term neonates and infants for several reasons: in
Core temperature is most reliably monitored in the neonate premature infants their skin is thin (with minimal subcutane-
in the esophagus (retrocardiac) or nasopharynx. ous fat), and they have a large body surface area to volume
ratio, ventilator requirements, and warming, which lead to
Positioning greater maintenance volumes. Serum ADH is increased,
Positioning depends on the surgical access required, includ- GFR is reduced, and urine concentration is limited by imma-
ing the prone or lateral position. Pressure areas need particu- ture renal tubular function early in the life of the neonate.
lar care and attention before commencing surgery and at Fluid and sodium requirements are least during this time
regular intervals during prolonged surgery. Also, care should (60% of normal) and dextrose-containing fluids are appro-
be taken to prevent accidentally leaning on the neonate. priate to prevent hypoglycemia, especially in premature
infants. Sodium is added to the fluids after the first few days
Fluid Management of life and the volume of fluids administered is liberalized
Managing fluids in the neonate and particularly in the prema- once the postnatal diuresis occurs [38–40]. Maintenance flu-
ture neonate is an area of ongoing debate (see Chap. 8). ids can be continued perioperatively using a syringe driver or
Controversy exists regarding the choice of fluid; balance salt mechanical pump for precise delivery. In some neonates and
solutions are used for most fluid replacement intraopera- most premature infants, the maintenance solution for neo-
tively, contrasting with albumin, which is widely used in the nates in the NICU consists of an electrolyte solution that
NICU. The reason for avoiding albumen is that it may worsen includes calcium and 10% dextrose to prevent hypocalcemia
postoperative edema [35]. Most techniques to monitor fluid and hypoglycemia. These solutions are infused at a volumet-
management in adults and larger children such as cardiac ric rate of 4 mL/kg/h for the first 10 kg [41].
output monitoring, echocardiography measurements, and Managing glucose-containing solutions during neonatal
esophageal Doppler are neither sufficiently miniaturized nor surgery has been controversial. Some clinicians continue the
validated for use in neonates [36]. Surrogate markers of vol- preoperative maintenance infusion rate out of fear that reduc-
ume status such as heart rate, blood pressure, central venous ing the rate may lead to hypoglycemia during the periopera-
pressure, capillary refill, base deficit, lactate, and urine out- tive period (from increased circulating insulin levels),
put are widely used instead, although none provide an whereas others reduce the infusion rate to limit the hypergly-
entirely accurate assessment of tissue perfusion. cemic response to the stress of surgery. Although there has
Fluid requirements in the perioperative period can vary been a dearth of evidence published to date on this issue, one
from trivial to massive. Fluid management should identify recent retrospective study reported that the postoperative
and correct the preoperative fluid deficit, continue mainte- glucose concentration in neonates within 4 h of surgery after
nance fluids and electrolytes, replace perioperative losses an intraoperative glucose infusion of 8.2 mg/kg/min was
(which can be considerable in thoracic and abdominal sur- 80% greater than that in neonates whose glucose infusion
gery), and optimize cardiovascular stability and blood sugar was 15% less, or 6.9 mg/kg/min [42]. To further define the
management. frequency of postoperative hyperglycemia, a retrospective
review concluded that reducing the infusion rate of glucose-
Deficit containing maintenance solutions in neonates by 50% intra-
Neonates nap 1–3 h at a time, after which they feed for 1–2 h. operatively (from 7.3 to 3.75 mg/kg/min glucose) decreased
This cycle continues for the first 4–8 weeks after birth. the risk of postoperative hyperglycemia without changing
Current preoperative fasting guidelines permit clear fluids the risk of hypoglycemia [43]. If the glucose infusion rate is
2 h preoperatively, breast milk 4 h, and formula 6 h. Although decreased during surgery, we strongly recommend that the
some advocate a preoperative fast of 1 h after clear fluids to serum glucose concentration be measured serially.
preclude prolonged fasts [37], such a proposal has no trac-
tion in neonates as their nap times and feeding regimens pre- Perioperative Losses
clude accumulating a fluid deficit. For neonates nursed in the Perioperative fluid losses can range from minimal as in a
NICU, continuous IV fluids avoid developing significant straightforward surgery such as hernia repair to considerable
preoperative fluid deficits. A sick, unstable surgical neonate during bowel surgery in which the bowel is exposed for long
or one with a delayed surgical presentation may present with periods. Large perioperative fluid losses require balanced
a large deficit and require resuscitation with 10–20 mL/kg salt solutions such as lactated Ringer’s solution up to vol-
(NICE) aliquots of a balanced salt solution such as Ringer’s umes of 50–75 mL/kg. Although volumes as large as 100 mL/
lactate to restore euvolemia. kg may not be unusual in this setting, these large volumes
296 K. Cross et al.
may herald the onset of a dilutional coagulopathy, notably (ideally fresh, irradiated, and washed pRBC within 6 h of
thrombocytopenia and possibly coagulation factors. washing) and it should always be warmed and administered
Furthermore, premature infants are often hypoalbuminemic with monitoring. When a massive transfusion (greater than
prompting the administration of 5% albumin once 50–75 mL/ half of the neonate’s estimated blood volume) is required, the
kg balanced salt solutions had been infused. In some institu- use of antifibrinolytics, clotting factors, and platelets should
tions, colloid is only introduced if normovolemia cannot be also be considered.
achieved with these balanced salt solutions and blood prod-
ucts are not indicated. Platelets and Blood Products
Platelet concentrations decrease during neonatal sepsis or
Glucose inflammation and are therefore often required periopera-
Neonates, particularly those with limited hepatic glycogen tively for emergency intestinal surgery. ABO group-
stores, are at risk of hypoglycemia. The latter is exacerbated compatible, Rh-identical, CMV-negative single donor
by prematurity, stress, asphyxia, maternal diabetes, or the platelets should be used where possible in a dose of
presence of certain syndromes such as Beckwith-Wiedemann 10–20 mL/kg. Fresh frozen plasma or equivalent products
or hyperinsulinism. Dextrose-containing fluids should be are used for DIC (disseminated intravascular coagulation)
considered for all neonatal surgery, avoiding hypotonic flu- and vitamin K deficiency coagulopathy or during massive
ids after the first few days of life. Neonates from the NICU transfusion. This can be group AB or ABO compatible and
often present with a dextrose maintenance infusion at the is administered at a dose of 12–15 mL/kg. Cryoprecipitate
time of surgery, whereas neonates who arrive from home is indicated if fibrinogen levels are <0.5 g/L preoperatively
may not have an IV. In the absence of an appropriate com- and should be maintained >1 g/L in the presence of bleed-
mercial glucose-containing balanced salt solution, we pre- ing [5].
pare a 2% glucose-containing lactated Ringer’s solution by
adding 4 mL of D50W to 96 mL of lactated Ringer’s solution Point of Care Testing
in a Buretrol [44]. Blood sugar should be closely monitored Access to blood sugar and blood gas monitoring is essential
as levels below 2.6 mmol/L (47 mg/dL) for a prolonged in all but the most straightforward neonatal surgery. Frequent
period and hyperglycemia are both associated with neuro- blood sampling is a common cause of anemia in the neonate
logical injury and poor outcomes [45]. so it should be kept to a minimum and the dead space rein-
fused. Thromboelastography may be useful for guiding
Transfusions blood product administration in term neonates if appropriate
Estimated neonatal blood volume is 90 to 100 mL/kg in the reference ranges are available.
preterm neonate and 80–90 mL/ kg at term. Although in
2014, the literature recommended transfusion in the NICU
when 10% of blood volume is lost or where Hb is <90 g/dL Minimally Invasive Surgery in Neonates
in an otherwise well neonate or <110 g/dL in a neonate with
congenital heart disease or respiratory distress [46], since In some centers, laparoscopic surgery has become the stan-
then the transfusion threshold in neonates has become less dard of care for many abdominal and pelvic procedures in
clear. Several studies in VLBW neonates (including ETTNO children of all ages including neonates. The benefits are well
and TOP trials) demonstrated that blood transfusions in this described and include quicker recovery times, reduced anal-
age group based on restrictive (7–8 g/dL) or liberal (9–12 g/ gesia requirements, and a reduced stress response [51].
dL) thresholds do not lead to neurodevelopmental impair- Perioperative anesthetic management can be challenging
ment later in early childhood [47, 48]. However, evidence however, mainly due to the cardiorespiratory effects of a
has emerged that suggests that neonates who received a pneumoperitoneum, positioning, and sometimes inevitably
blood transfusion within 48 h of surgery experience increased longer procedure times. These issues are exacerbated in
30-day morbidity and mortality (OR 1.53) [49]. This report neonates.
requires further clarification and validation to establish its Laparoscopic techniques have been described for:
veracity. In the meantime, either a liberal or restrictive trans-
fusion protocol may be followed in neonates. A transfusion • Inguinal hernia repair
of 4 mL/kg of packed red cells increases the hematocrit by • Pyloromyotomy
4% and the hemoglobin by 1 gm/dL. The effect of such a • Duodenal atresia repair
transfusion will be clinically useful after 15 min and sus- • Congenital diaphragmatic hernia repair
tained for 24 h in the absence of further bleeding [50]. • Malrotation and Volvulus/Ladd’s procedure
Neonates are susceptible to hypothermia, hypocalcemia, • Abdominal or ovarian cysts
hyperkalemia, volume overload, and coagulation factor dilu- • Anorectoplasty
tion after transfusion. “Newer” blood should be transfused • Pull-through procedures for Hirschsprung’s disease
hysiological Effects of Laparoscopic Surgery

P children, there are several options to achieve this; however, in
Insufflation of carbon dioxide to expand the intra-abdominal neonates there is no appropriately sized specialist equipment
cavity can cause a number of physiological effects that are (such as double-lumen tube or endobronchial blockers). The
detrimental to the surgical neonate. Cardiovascular effects remaining options are endobronchial intubation using a con-
include vagally mediated bradycardia, reduced venous return, ventional tracheal tube, or lung retraction by the surgeon. This
and increased systemic and pulmonary vascular resistance. is done either under direct vision or using gas insufflation via
These effects are exacerbated by extreme reverse Trendelenburg the thoracoscope [60, 61]. Use of a bronchoscope to facilitate
positioning or by the use of high insufflation rates and pres- an endobronchial intubation is difficult, since the smallest
sures and need to be appreciated in the presence of cardiac commercially available fiberoptic scope is 2.2 mm, has no
anomalies [52, 53]. Compared with older children, the neona- suction channel, and requires a tracheal tube size of 3.5 mmID
tal peritoneum has a relatively large surface area and the or greater to enable ventilation during the bronchoscopy. For
abdominal wall is more pliable; therefore, surgical access can this reason, the operative lung is often isolated by the surgeon
be achieved with lower abdominal pressures. It is recom- and a conventional tracheal tube can be inserted into the tra-
mended to use a slow rate of gas insufflation (<1 L/min) and a chea. This is a simple technique, but can result in inadequate
minimal IAP (intra-abdominal pressure) (6–8 cmH2O) to min- lung collapse, soiling of the healthy lung, and no facility to
imize complications and to avoid or discontinue nitrous oxide suction or deliver CPAP to the operative side.
as soon as possible after induction. Ensuring an empty stom-
ach using a nasogastric tube facilitates surgical access and Postoperative Care
minimizes the need for a tense pneumoperitoneum. It may be possible for a term neonate undergoing simple sur-
Because the neonatal peritoneum is thin and relatively gery to go home on the same day after a suitable period of
large and there is very little fat, clinically significant sys- cardiorespiratory monitoring. Most neonates undergoing
temic absorption of carbon dioxide occurs, especially in sur- abdominal or thoracic surgery are required to stay overnight or
geries of greater duration [54, 55]. Minute ventilation can be a period of care in the NICU because of the risk of postopera-
increased to offset the hypercapnia, but changes in lung com- tive apnea in premature infants as well as term neonates [62].
pliance due to diaphragmatic splinting, small airway closure, Postoperative apnea is primarily an issue for infants less than
and positioning can all affect ventilation. Use of a cuffed tra- 60 weeks post-conceptional age: the risk is greatest after gen-
cheal tube and hand ventilation can sometimes be useful. eral anesthesia and in the presence of anemia (Hb < 10 g/dL),
Where possible arterial carbon dioxide and acid-base status a history of preoperative apneas, neurological conditions, or
should be monitored during prolonged surgery and conver- chronic lung disease as detailed below [62–64]. Balanced
sion to an open procedure should be an option if acidosis is analgesia with local anesthesia and acetaminophen is suitable
profound or ventilation proves troublesome. for shorter procedures. An opioid-based technique is suitable
Transient oliguria may occur perioperatively due to IAP when prolonged monitoring or ventilation is planned. Detailed
effects on renal blood flow and increased antidiuretic hor- information on neonatal analgesia is covered elsewhere.
mone levels. Fluid requirements are usually reduced com-
pared with comparable open surgery. Bolus dosing of fluids
should be avoided in response to reduced urine output unless Specific Conditions
the neonate is exhibiting additional signs of cardiovascular
instability. Congenital Thoracic Malformations
Although port incisions are very small (3 mm), postopera-
tive pain can be significant if diaphragmatic irritation occurs. There are a number of congenital thoracic malformations
Good analgesia can usually be achieved with a combination that may require surgical intervention in the neonatal period.
of short-acting intraoperative opioids, paracetamol, and local Congenital thoracic malformations may represent a spec-
anesthesia, either as surgical infiltration or using a regional trum of disease rather than discrete entities. The three
technique such as caudal or transversus abdominis plane commonest pathologies are congenital cystic adenomatoid
(TAP) block (see below). malformation (CCAM), lung sequestration, and congenital
Thoracoscopy has been steadily gaining popularity as the lobar emphysema (CLE) [65].
approach for congenital thoracic lesions [56–58]. A review
and meta-analysis of published studies determined that tho-
racoscopic surgery is a reasonable alternative to thoracotomy ongenital Cystic Adenomatoid Malformation
C
in neonates [56, 59]. (CCAM)
One-Lung Ventilation This rare congenital lung lesion that occurs in 1:25–30,000
Thoracic surgery ideally requires good access to the diseased live births is the most common of the congenital thoracic mal-
lung and no risk of contamination of healthy lung. In older formations and the most common detected prenatally [66,
298 K. Cross et al.
Table 9.1 The Stocker classification of congenital cystic adenomatoid

malformation (CCAM)
Stocker type 0 (rare). This is a fatal defect in which the lungs do not
develop beyond the pseudoglandular level, resulting in small
hypoplastic lungs bilaterally with a bronchial airway. Also known
as acinar dysplasia
Stocker type I (macrocystic adenomatoid malformation) (60–70%).
Single or multiple large “cysts” (>2 cm diameter) are present, which
communicate with the proximal airways and distal lung
parenchyma. The lesion is relatively localized and most infants have
a good prognosis after cyst resection. Good prognosis
Stocker type II (microcystic adenomatoid malformation) (10–15%).
Multiple small spongelike cysts (<1 cm) replace the distal lung
parenchyma. This has a worse prognosis and is more commonly
associated with other anomalies, such as renal agenesis and cardiac
and chromosomal abnormalities
Stocker type III (solid cystic adenomatoid malformation) (5%). The
abnormality represents a severe end of the spectrum with multiple
airless cysts involving an entire lobe or even lung. This has a poor
prognosis, more commonly reported in stillbirths with CCAM
Stocker type IV (rare). This is an entirely alveolar pulmonary defect
Fig. 9.1 Congenital cystic adenomatoid malformation. Chest radio-
in which large cysts replace the numerous alveoli in the periphery
graph in a neonate with a left-sided amorphous cystic mass filling most
of the lung. Good prognosis
of the left hemithorax. The cardiac silhouette is shifted to the right. The
right hemithorax is slightly opacified
Stocker proposed a broader term for these defects: congeni-

67]. With advances in antenatal US and fetal MRI (accuracy tal pulmonary airway malformations (CPAM) [66, 73].
65–91%), we are detecting some lesions not identified previ- However, CCAM remains the primary acronym for these
ously and the true incidence may be greater. Congenital cystic defects. A simpler classification for this defect was proposed:
adenomatoid malformation (CCAM) is a multicystic pulmo- macrocystic or microcystic (solid), based on anatomy and
nary mass usually affecting only one lobe of the lung, more appearance on antenatal ultrasound, but Stocker’s classifica-
commonly on the left, but may occur bilaterally in 5–15% tion has persisted [66, 68, 72–74] (Table 9.1).
(Fig. 9.1). The etiology is unknown, although it may repre-
sent a hamartomatous process, focal pulmonary dysplasia, or Diagnosis
a bronchiolar developmental anomaly [68]. Identified growth The diagnosis is usually made by antenatal ultrasound at
factors (fGF-7) and genetic factors (Hoxb-5) have been impli- approximately 20 weeks’ gestation [75–79]. The lesions are
cated [67]. Anomalies associated with CCAM occur in up to monitored throughout gestation following one of three
18% of cases, involving renal agenesis and cardiac defects courses: increase in size, remain unchanged, or undergo spon-
(see type II below)[68]. The prognosis depends on the size of taneous resolution. In those with aggressive disease, the lesion
the CCAM and the cystic nature. Small lesions may be may respond to maternal steroids. A few specialist centers
asymptomatic, but large lesions may be associated with hypo- offer fetal interventions for high-risk cases causing hydrops
plasia of the normal lung and pulmonary hypertension and, in including thoracoamniotic shunt for isolated cysts, open fetal
severe cases, mediastinal shift causing cardiac compromise surgery, or an EXIT (ex utero intrapartum treatment) proce-
and nonimmune fetal hydrops [69, 70]. Fetal hydrops is the dure at delivery (see Chap. 14), depending on gestational age,
most serious harbinger of death [71]. The ratio of the CCAM the size of the cyst, and the health of the mother [68, 77, 79].
volume to the head circumference on the first antenatal ultra- Fetal MRI scanning is an excellent strategy to evaluate the
sound predicts the fetus’ perinatal course: a ratio <0.56 is volume of affected/unaffected lung and morphology of the
consistent with a good postnatal outcome, whereas a ratio lesion (T2 hyperdense lesion with cystic spaces).
>1.6 is consistent with developing hydrops [72]. Infants may present with symptoms of respiratory dis-
tress in the neonatal period, with tachypnea, increased work
Classification of breathing, and desaturation in 30% of cases, or occasion-
Stocker originally classified CCAM based on cyst size and ally with hyperinflation on the side of the CCAM. Some
postnatal histology, yielding three types. Subsequently type infants may be relatively asymptomatic. Ten percent of the
0 (tracheobronchial defect with small firm lungs and a bron- neonates present with recurrent pneumonia or pneumotho-
chial airway) and type 4 (an entirely alveolar defect) were rax in later childhood. A significant number of neonates
added to complete the current classification. Since types 1–3 remain completely asymptomatic and are only detected
are usually adenomatoid and types 1, 2, and 4 are cystic, incidentally.
CCAM may be evident on chest X-ray, especially if it is Classification

large. Microcystic lesions may be fluid filled, but macrocys- • Intralobar sequestration (ILS) (75%): the abnormal tissue
tic lesions are usually aerated and may be difficult to visual- is contained within normal lung predominantly within the
ize. A CT scan with contrast is usually performed to delineate lower lobes (often left sided). The child is generally
the limitations of the lesion. Ultrasound may be used to iden- asymptomatic but may present with hemoptysis, pneumo-
tify the blood supply and exclude an anomalous systemic thorax, or recurrent infections in later childhood. The
artery. All cases identified antenatally require clinical and venous drainage is often via the pulmonary veins. Right-
radiological investigation after birth even if asymptomatic to sided ILS may be associated with anomalous pulmonary
plan management. venous drainage characteristic of scimitar syndrome; care
must be taken to avoid ligating pulmonary veins during
Postnatal Management surgical resection.
Initial management involves respiratory support as needed and • Extralobar sequestration (ELS) (25%): the sequestration
imaging to confirm and define the extent of the lesion. Neonates is completely separated from the lung by visceral pleura.
with hydrops have a very high perioperative mortality as a Arterial supply is infradiaphragmatic in 20% of cases and
result of the pulmonary hypoplasia and pulmonary hyperten- the lesion itself is infradiaphragmatic in 3%. Venous
sion. These neonates should be medically stabilized before drainage is to the azygous system in the majority of cases.
embarking on surgical interventions [70, 79]. Surgery may be ELS affects males four times more commonly than
beneficial for neonates with significant respiratory signs and females and is more often associated with other anoma-
symptoms and/or compression of adjacent cardiac or major lies such as congenital diaphragmatic hernia (CDH)
vascular structures. Controversy exists regarding the appropri- (16%), CCAM (15%), congenital heart disease, chest
ateness and timing of surgery in asymptomatic or smaller wall abnormalities, and hindgut duplications.
lesions [69, 80–83]. Resection in infancy or early childhood is
increasingly advocated to preclude infectious complications Diagnosis
and malignant transformation (rhabdomyosarcoma, squamous These lesions may be detected on antenatal ultrasound or
cell carcinoma, bronchoalveolar carcinoma, and pleuropulmo- postnatal chest X-ray. The systemic blood supply must be
nary blastoma in 2–4% of cases) and to encourage compensa- delineated using ultrasound, CT, or MRI.
tory lung growth. Early surgery can also avoid the technical ELS is generally asymptomatic but is often detected earlier
difficulties associated with resection after infection with less than intralobar sequestrations. Both ILS and ELS may be
surgical complications [84]. If surgery is not undertaken, ide- detected antenatally and may resolve. Symptomatic infants
ally these neonates should be followed into adulthood to ensure with large sequestrations may present with respiratory distress,
a timely intervention should the lesion turn malignant [83]. feeding difficulties, or cardiac failure if the sequestered lobe is
associated with significant arteriovenous or left-to-right shunt-
Surgical Considerations ing [79]. Hydrops may result from severe cardiac failure in
The aim of surgery is to preserve viable lung tissue and utero, and pulmonary hypoplasia and pulmonary hypertension
reduce the mediastinal shift. The standard approach is pos- may be associated with large lesions, as in CCAM.
terolateral thoracotomy and lobectomy. Segmental resection
may be used for small lesions or multilobular disease but is Management
associated with a greater incidence of postoperative air leak. Respiratory support should be instituted as required, and the
The margins of the lesion can also be difficult to assess and systemic blood supply defined on imaging usually US or
residual lesion may remain [67]. Thoracoscopic resection is contrast-enhanced CT scan, as the first step. Surgical exci-
increasingly being performed but access may be difficult sion is generally advocated. The timing of surgery depends
with large cystic lesions [51, 57, 58, 85]. on the clinical situation. Complications such as infection and
cardiovascular compromise due to shunting should be treated
before resection.
Lung Sequestration
Surgical Considerations
This lesion consists of nonfunctioning lung tissue that does As for CCAM, thoracotomy is the standard approach for pul-
not have a tracheobronchial communication. There is anom- monary sequestrations. Thoracoscopic resection is a viable
alous systemic arterial supply, usually directly from the alternative due to the relatively smaller size of the lesions. A
aorta, with more than one vessel in 15% of lesions. laparotomy or laparoscopic approach is required for infradi-
Sequestrations may have a patent or non-patent connection aphragmatic lesions. Additional therapeutic interventions
to the gastrointestinal tract (bronchopulmonary foregut mal- have been reported anecdotally including radiofrequency
formations) [79]. ablation and coil embolization [86].
300 K. Cross et al.
The anomalous systemic vessels can be fragile elastic Diagnosis

vessels with significant blood flow. Careful dissection and CLE may be detected antenatally but is difficult to distin-
meticulous control are required to prevent hemorrhage. guish from CCAM. Postnatally, there is often early respira-
Control of the systemic blood supply during surgery is criti- tory distress and clinical signs suggestive of pneumothorax.
cal especially when the origin of the vessel is on the opposite A CXR may show lobar hyperinflation, mediastinal shift,
aspect of the diaphragm to the operative field (infradiaphrag- and flattening of the ipsilateral diaphragm. Ultrasound can
matic vessel for intrathoracic lesions). A loss of control can help distinguish from a tension pneumothorax, or if stable
result in retraction of the vessel out of the operative field and enough, CT or MRI scan will confirm the diagnosis. If the
catastrophic hemorrhage. A crossmatch should be available neonate is stable, then a preoperative echocardiogram should
for all of these neonates. be also performed to identify congenital heart disease.
Management
Congenital Lobar Emphysema (CLE) The primary treatment is lobectomy, which may be required on
an emergent basis before a full preoperative workup can be
Congenital lobar emphysema (CLE) is a rare obstructive overin- performed. More recently, segmental lung resection has proven
flation disorder, occurring in 1:20–30,000 live births with a sex successful in preserving lung without an increased incidence of
predominance in males, 3:1 [87]. CLE may be due to defective a recurrence [89]. Positive pressure ventilation worsens the
bronchiolar development. The affected lobe is hyperinflated and hyperinflation, and if respiratory support is required preopera-
may compress the adjacent normal lung. Hyperinflation becomes tively, then HFOV may be preferred. A chest drain should
progressive after birth, although neonates usually present with never be inserted as it may cause preferential ventilation of the
respiratory distress in the first few days of life. The left upper lobe abnormal lung leading to respiratory failure [88].
is involved in almost 50% of cases followed by the right middle
lobe (28%) and the right upper lobe (20%); bilateral involvement
is rare (Fig. 9.2). Cardiac anomalies are present in 20% of neonates nesthetic Implications for the Management
A
with CLE [79, 87, 88]. of Congenital Thoracic Malformations
Similar anesthetic principles and considerations exist for

these lesions; hence, their discussion is appropriate.
Thoracotomy and lung resection for CCAM are usually well
tolerated. Full invasive monitoring is required but one-lung
ventilation is usually not necessary. If the CCAM is con-
nected to the bronchial tree, hyperinflation may lead to a
ball-valve effect.
For infants have severe respiratory distress, HFOV (high-
frequency oscillatory ventilation) may be required preopera-
tively, although the neonate is usually weaned to conventional
ventilation early in the postop period [79]. Analgesia may be
provided by intravenous opioids or thoracic epidural analge-
sia via a caudal catheter [90].
Similar management exists for cases of lung sequestra-
tion. Neonates with severe pulmonary hypertension should
be medically managed before surgery. In general, pulmonary
sequestrations do not become hyperinflated [91]. The anes-
thesiologist should however prepare for the risk of major
hemorrhage as anomalous systemic blood vessel can have
significant blood flow. These vessels can be challenging
when the origin is on the opposite side to the operative field.
The airway may be secured with a tracheal tube after either
an inhalational or IV induction with propofol. The blood or
Fig. 9.2 Congenital lobar emphysema. Chest radiograph with hyperin-
flation of the left chest and displacement of the cardiac silhouette brain partial pressure of insoluble inhalational anesthetics
toward the right chest. A large gastric air bubble is present such as sevoflurane is substantially reduced by right-to-left
shunts. Furthermore, end-tidal concentrations of sevoflurane Table 9.2 EA/TEF classification and incidence in neonates
do not reliably predict the brain partial pressure. Thus, end- EA with distal TEF (80–85%)
tidal concentrations cannot be used to assess the depth of anes- Pure EA (5–7%)
thesia with sevoflurane in neonates with these lung lesions. Isolated TEF (“H”-type fistula) (3–6%)
Depending on the surgical approach and recovery, the anes- EA with proximal and distal TEF (3–5%)
thetic prescription should either ensure reversible anesthesia EA and proximal TEF (2%)
for extubation after a thoracoscopic approach or a combina-
tion of an inhalational agent and opioids (fentanyl is preferred) are based on the anatomical variations seen. It is therefore
to manage a thoracotomy and the chest wall pain that results. most appropriate to describe the conditions anatomically
In CLE surgery, all attempts should be focused to minimize [94, 95, 98] (Table 9.2; Fig. 9.3).
excessive positive pressure before opening the chest. Positive The length of the gap between proximal and distal esoph-
pressure can result in rapid inflation of the emphysematous agus is variable, as is the position of fistula (or fistulae)
lobe and cardiovascular compromise. Spontaneous ventila- within the trachea (see Fig. 9.3). These anatomical variations
tion, manual assisted ventilation, and titrated pressure support have important implications for surgical strategy and anes-
are strategies that may be used to minimize peak airway pres- thesia management. A long gap (type A or B or type C)
sures [92]. Nitrous oxide is replaced with air in these cases. where the fistula is at the carina makes a primary anastomo-
Once the chest is opened however, ventilation should be consis far more difficult and different management approaches
trolled to ensure adequate oxygenation and ventilation. may be needed. In one series, the fistula was mid-tracheal in
Although technically challenging, lung isolation may be 61%, at or just above the carina in 33%, cervical in 8%, and
requested to protect the diseased lung from overinflation bronchial in 1%. There was more than one fistula in 3% of
through endobronchial intubation or endoluminal insertion patients [98, 99]. In the “H”-type TEF, the fistula is typically
of a Fogarty catheter or bronchial blocker [61, 93]. Such in the cervical region, whereas in EA with a proximal fistula,
devices are prone to dislocation due to the neonate’s small the fistula is usually 1–2 cm from the blind-ending upper
size, surgical positioning, manipulation of the mediastinal pouch [96].
structures, and compression of the diseased lung. Neonates with EA/TEF are often born premature, with
Patient-specific multidisciplinary case discussion can low birth weight (Fig. 9.4) [95]. Approximately 50% of neo-
highlight concerns and a plan for emergency thoracotomy nates with EA/TEF have associated anomalies, an incidence
with surgeon/scrub team ready at induction of anesthesia. that increases with decreasing birth weight (<2500 g) and
with pure EA. In contrast, anomalies are less common in
those with an isolated H-type fistula [95, 96, 100, 101]. The
Esophageal Atresia/Tracheoesophageal Fistula most common anomalies associated with EA/TEF are car-
diac anomalies (29%), followed by duodenal atresia and
Esophageal atresia (EA) and tracheoesophageal fistula (TEF) anorectal anomalies (14%), genitourinary anomalies (14%),
occur in 1:3000–1:4500 live births [94–96]. The etiology is intestinal malrotation (13%), chromosomal abnormalities
believed to be due to a defect in the separation of the trachea (trisomies 21, 18, and 13q deletion) (4%), vertebral and skel-
and esophagus from a common foregut, which normally etal anomalies (10%), and specific-named associations (see
occurs after 4 weeks’ gestation. The etiology and exact embry- below). The most common cardiac defects are atrial or ven-
ology remain unclear, although the theories put forth include tricular septal defects or tetralogy of Fallot [101, 102]
failure of fusion of lateral tracheoesophageal folds or the tra- (Fig. 9.5) [103]. A right-sided aortic arch is present in 2.5–
cheoesophageal septum, imbalance in epithelial proliferation 5% of infants with EA/TEF [104].
and apoptosis, trifurcation of the lung bud, and a possible role Several disorders have been associated with EA/TEF
of the notochord. Animal evidence suggests a greater develop- [95]. The VATER/VACTERL association, an association of
mental role of the foregut in this defect as the fistula and distal unknown etiology, is defined by the presence of at least
esophagus may be respiratory in origin [66]. There is also evi- three of the following congenital malformations: vertebral
dence that specific targets in the molecular mechanisms defects, anorectal anomaly, cardiac defects, TEF, renal
responsible for complete separation of the trachea and the anomalies, and limb (radial) abnormalities [103, 105, 106].
esophagus may be responsible for EA/TEF defects [97]. Approximately 47% of neonates with EA have VACTERL
anomalies.
Classification VACTERL-H association is the VACTERL association
First classified in 1929 (Vogt), and modified in 1953 (Gross), with hydrocephalus, although hydrocephalus is often listed
five common types of EA/TEF have been described, which as a non-VACTERL anomaly (see above). CHARGE syn-
302 K. Cross et al.
Fig. 9.3 Classification of trachea-esophageal fistula according to Gross and Vogt. The incidence of the variants is depicted under the drawing [95]
drome is an autosomal dominant disorder caused by a muta- also associated with CATCH syndrome (22q deletion that
tion on chromosome 7. It is associated with TEF, coloboma, includes cardiac defects, abnormal facies, thymic aplasia,
cardiac defects, choanal atresia, neurocognitive and growth cleft palate, and hypocalcemia). Of the trisomy syndromes,
impairment, and genital, ear, and cranial nerve defects. EA/TEF is most often associated with Edwards syndrome
Potter’s syndrome, which is associated with renal agenesis, (trisomy 18). Feingold syndrome (dominant inheritance) is
pulmonary hypoplasia, dysmorphic facies, and Schisis asso- similar to VACTERL syndrome but features microcephaly
ciation, which is associated with omphalocele, cleft lip and/ and learning difficulties [95]. Other syndromes associated
or palate, congenital diaphragmatic hernia, and neural tube with EA/TEF include DiGeorge sequence, Pierre-Robin
defects, may also be associated with EA/TEF. EA/TEF is sequence, Fanconi syndrome, and polysplenia [66].
Diagnosis
EA may be suspected antenatally in the presence of polyhy-
dramnios with a small or absent gastric bubble or associated
abnormalities present in the fetus. Most cases, however,
present after birth. A history of polyhydramnios should
prompt the pediatrician to pass a size 8–10 Fr orogastric tube
immediately after birth. With EA, the tube cannot pass the
upper esophagus and will coil in the upper chest on XR. The
diagnosis is strongly suspected clinically in the first few
hours after birth if mucous that accumulates in the upper air-
way cannot be cleared by swallowing and an orogastric tube
cannot be passed. The neonate chokes or becomes cyanosed
if it attempts to feed. Aspiration pneumonia due to delayed
diagnosis was common decades ago but should now be
uncommon with good clinical awareness.
The diagnosis of EA/TEF should be confirmed on plain
X-ray of the chest and abdomen. A coiled nasogastric tube
will be identified in the upper third of the esophagus (level
T2–T4); air in the gastrointestinal tract indicates the pres-
ence of a distal TE fistula. A gasless gastrointestinal tract
Fig. 9.4 Esophageal atresia in a neonate. This chest radiograph depicts suggests the absence of a distal fistula, although a proximal
a multi-orifice orogastric tube (with side holes) ending at the mid-
thoracic level. A tracheal tube ends at the thoracic inlet. Umbilical vein
fistula remains a possibility. Other abnormalities such as ver-
and artery catheters enter radiograph from below; one terminates at T6– tebral anomalies (usually in the lower thoracic region) or the
T7 and a second at T8–T9. A gastric air bubble is not visible here “double bubble” of duodenal atresia can also be detected on
preoperative films. A thorough clinical examination is impor-
tant to exclude associated anomalies and the presence of
coexisting problems, such as respiratory distress syndrome
in premature infants. An echocardiogram is strongly recom-
mended before surgery to identify cardiac defects and the
position of the aortic arch. If the neonate has passed urine
(thus excluding bilateral renal agenesis), then a renal ultra-
sound can be delayed until after surgery.
An H-type TEF is infrequently detected in the neonatal
period but should be suspected with a history of recurrent
chest infection due to repeated aspiration.
Risk Stratification
It is helpful to stratify neonates with EA/TEF according to
risk. The original stratification by Waterson was based on
birth weight, associated anomalies, and the presence of
pneumonia [96]. Neonatal care has improved leading to a
Fig. 9.5 EA/TEF with situs inversus. Chest radiograph of a neonate current risk stratification that is based solely on birth weight
with EA/TEF. The multi-orifice orogastric tube (with side orifices) ends
and the presence of cardiac anomalies [101, 102, 108].
at T3–T4 reflecting EA. The cardiac silhouette and gastric bubble are
reversed, present on the right side. Echocardiogram verified the pres- Improved outcomes have resulted in survival rates exceeding
ence of a ventricular septal defect. The large gastric air bubble is con- 98% in neonates with birth weights >1500 g and without
sistent with a distal tracheoesophageal fistula major cardiac anomalies, 82% with birth weights <1500 g or
major cardiac anomalies, and 50% with birth weights
Non-VACTERL anomalies are being reported in asso- <1500 g and major cardiac anomalies [108]. A four-part clas-
ciation with EA/TEF with increasing frequency. Such sification has been suggested more recently, with prediction
anomalies include single umbilical arteries, genital of 100% survival in neonates with birth weights >2000 g
defects, digital defects, neurologic anomalies, and respi- without cardiac anomalies and 40% survival in high-risk
ratory tract defects [103, 107]. neonates with birth weights <2000 g with major cardiac
304 K. Cross et al.
anomalies [102]. The premature infant with a major cardiac Neonates with pure EA or EA with a proximal TEF often
anomaly remains a high risk. Parents of infants with signifi- have a long gap between proximal and distal ends of the
cant chromosomal anomalies (trisomy 18), unrepairable car- esophagus. A feeding gastrostomy is made via laparotomy
diac defects, bilateral renal agenesis, or other major which can be technically challenging as the stomach is usu-
complications of prematurity with very poor prognosis may ally very small. The length of the gap should be estimated
be given the option of nonoperative treatment. radiographically at the time of surgery with a probe or ure-
thral sound from the stomach and the Replogle tube in the
Medical Management proximal pouch both under gentle tension. If the gap is
Initial management of neonates with EA/TEF is to prevent greater than the vertical height of three vertebral bodies,
aspiration of oral secretions before definitive surgery. A 10 Fr upper pouch suction is continued postoperatively and
double-lumen oro-esophageal Replogle tube should be inserted delayed primary closure is usually possible by about
into the upper pouch and placed on continuous suction, or 12 weeks of age; if the gap is greater than six vertebral bod-
secretions should be cleared frequently by naso-esophageal ies, a cervical esophagostomy is often fashioned and the
tube suction. The neonate should be given maintenance intra- esophagus repaired at a later date. Esophageal replacement
venous fluids and nursed 30° head up or in the decubitus posi- surgery is often required in this situation although esopha-
tion. Blood should be crossmatched and available for surgery. geal lengthening procedures both open and thoracoscopi-
If preoperative ventilation is required, inspiratory pressures cally have been reported with varying success [96, 111].
should be kept to a minimum, if possible placing the tip of the An esophagoscopy or bronchoscopy should be performed
tracheal tube distal to the fistula (see below). Premature infants at the start of surgery to provide absolute confirmation of the
should receive surfactant according to standard protocols. diagnosis, to assess the position of the fistula if present, and
to exclude multiple fistulae [98, 99, 112, 113]. A variety of
Surgical Considerations techniques have been described to identify fistulae in neo-
The aim of surgery is to restore continuity of the esophagus nates: rigid bronchoscopy, esophagoscopy, or flexible fiber-
and ligate the TE fistula, if present. Surgery is usually per- optic bronchoscopy via the tracheal tube. The advantage of
formed on the first or second day of life if the neonate is using a small flexible bronchoscope is that the scope may
stable and does not require respiratory support. The opera- also be used to assess the position of the tip of tracheal tube,
tion should ideally be scheduled during daylight hours given to pass through the fistula to assist the surgeon in identifying
the complexity of both the surgery and anesthesia. Primary the fistula during surgery, and to assess the airway at the end
esophageal anastomosis is usually possible in EA with distal of surgery to exclude a residual blind-ending tracheal pouch
TEF unless a very wide gap is found with a low carina fis- and the severity of the tracheomalacia near the fistula [114].
tula. In a neonate with severe comorbidities such as a duct- The traditional approach to repair of EA/TEF is extra-
dependent cardiac anomaly or extreme prematurity, it may pleural via a right posterolateral thoracotomy with the neo-
be preferable to divide the fistula and place a feeding gastros- nate placed in the lateral decubitus position with a roll
tomy. Delayed primary esophageal repair can be performed under the chest to facilitate surgical access. The posterior
6–12 weeks after cardiac surgery or when the baby is more mediastinum is approached via the 4th and 5th intercostal
robust. This may also be possible if a wide gap is found. spaces with extrapleural dissection gently compressing the
Emergency surgery may be required if the child requires right lung. The approach is delicate and time-consuming
preoperative ventilation, as in the case of the preterm neo- but potentially reduces morbidity from an anastomotic
nate with respiratory distress syndrome. If the lung compli- leak, should one occur. If a right arch is confirmed on pre-
ance is poor, gas from the ventilator may preferentially enter operative echo, a left-sided approach should be considered
the gastrointestinal tract via the fistula. This may lead to gas- although repair is certainly still possible from the right and
tric distension, deteriorating cardiorespiratory status, and a double aortic arch may be approached via the standard
possible gastric rupture. Inadvertent intubation of the fistula right thoracotomy [104]. If the child becomes unstable, a
must be excluded in cases of severe gastric distention with transpleural approach may be used.
cardiorespiratory instability [109]. To prevent gastric disten- Thoracoscopic repair has become popular in specialist
tion from ventilation via the fistula, some have recommended centers in recent years and, in expert hands, has the same
clamping the distal esophagus as soon as the chest is opened surgical complication rate as open techniques, with compa-
[110]. Decompressive gastrostomy should not be undertaken rable blood gases and operating times, but with reduced time
as a primary intervention as it will lead to a torrential gas in intensive care postoperatively and length of stay [59, 114–
leak via the gastrostomy and worsening minute ventilation. 120]. Currently recommendations are based on large case
The child should undergo emergency transpleural ligation of series, since no randomized controlled trials have compared
the fistula, with consideration of delayed division of the fis- the two techniques [117, 118, 121]. For thoracoscopic repair,
tula and possible repair of EA within 8–10 days [96]. the child is placed semiprone with the right side of the chest
elevated at 45° so that the structures may be easily visual- are long-term issues centered around feeding difficulties,
ized. Lung deflation is produced by CO2 insufflation, and multiple painful procedures and surgeries, feeding, and air-
care should be taken to minimize hypercarbia, as described way issues.
previously.
Major concerns during open or thoracoscopic surgery Anesthetic Considerations
include accurate identification of anatomical structures and General anesthetic issues include principles in the neonate
cardiorespiratory instability due to OLV and distortion of the with a high incidence of comorbidity and those specific to
trachea. The anesthesiologist may be asked to push on the thoracotomy or thoracoscopic procedure. Anesthetic chal-
Replogle tube to help identify the proximal esophageal pouch. lenges for these cases include facilitating accurate identifica-
Test occlusion of the fistula is good practice to ensure that the tion of the anatomical structures, cardiovascular instability
right lung can still be inflated and that a vital structure (e.g., due to anesthesia, one-lung ventilation, and the effect of sur-
the pulmonary artery or a main bronchus) has not been gical manipulation of structures.
clamped in error. If the neonate does not tolerate OLV, sur- Selective OLV is not necessary as the surgeon can com-
gery may have to proceed with intermittent two-lung ventila- press the neonatal lung to access the fistula. The anesthesi-
tion once the neonate recovers. This requires good ologist may be asked to push on the Replogle tube or advance
communication between the anesthesiologist and surgeon. an appropriately sized tracheal tube to help identify the prox-
Increased FiO2 and hand ventilation may be required, but imal esophageal pouch.
respiratory compromise usually improves after ligation of the There has been evolution in the role of thoracoscopic
fistula. The integrity of tracheal repair can be checked by repair of TOF /OA repair. Concerns have been highlighted
instilling warm saline in the chest during a sustained inflation over the cardiovascular effects of prolonged thoracoscopic
to identify an air leak by the presence of air bubbles. The surgery, the need for high airway pressures resulting in
lower esophagus should not be aggressively mobilized in hypoxia and hypercarbia, and its effect on the newborn cen-
order to avoid devascularization, as this may cause later prob- tral nervous system. Recent reviews from centers experi-
lems with esophageal motility. A gas leak from the upper enced in this minimally invasive technique suggest similar
pouch during esophageal anastomosis should raise suspicion results but an increased incidence of stricture or anastomotic
of an upper pouch fistula. Dissection of the upper pouch helps breakdown in the thoracoscopic cohort [120].
to identify a proximal fistula, if one is present, and allows Preoperative ECHO is mandatory to identify the presence
mobilization of the esophagus to minimize tension of the of congenital heart disease ranging from PDA or ASD/VSD
repair. If there is significant tension at the anastomosis, the morphology to hypoplastic left heart syndrome. Failure to
neonate should remain paralyzed and the lungs ventilated correctly identify congenital cardiac lesions can result in
mechanically for approximately 5 days postoperatively [96]. catastrophic complications including hypoxia, hypotension,
A transanastomotic tube (TAT tube) placed under direct and irreversible cardiac arrest.
vision before the anastomosis is completed facilitates early Airway management and positioning of the tracheal tube
feeding in the absence of a gastrostomy and should be clearly in the presence of a fistula is extremely challenging.
marked to preclude accidental removal postoperatively. Anesthetic challenges include intubation of the fistula lead-
Early complications at EA/TEF repair include tracheo- ing to gastric distension and splinting of the diaphragm and
bronchomalacia (20–40%), anastomotic leak (15–20%), difficult ventilation [108, 125, 126]. The majority of compli-
anastomotic stricture (30–50%), and recurrent fistula (10%) cations occur with a large fistula occurring at the level of the
[122]. Tracheomalacia is due to abnormal cartilage in the carina.
region of the fistula and often produces a typical barking A variety of anesthetic techniques and airway man-
cough. In severe cases, the child may develop recurrent chest agement strategies have been described [96, 114, 125–
infections or “near death” episodes due to acute airway col- 128]. Most advocate inhalational or intravenous
lapse, and emergency aortopexy may be required in the first introduction according to personal preference, with mus-
few months after repair [96]. An early anastomotic leak may cle relaxant and gentle ventilation before intubating the
cause a tension pneumothorax; a chest drain should be trachea [114, 125–128].
inserted and the leak explored and repaired. Late complica- One technique popularized was to deliberately intubate
tions include gastroesophageal reflux (severe reflux in 40%) the right main bronchus, rotate the tube to position the bevel
and recurrent chest infections, probably related to gastro- towards the sternum, and then withdraw the tube until bilat-
esophageal reflux [95]. Long-term respiratory complications eral air entry is confirmed. This ensures the tube is below the
including bronchiectasis may result from aspiration, GERD, fistula but does not prevent intubation of a large carinal fis-
and chest wall abnormalities [123]. Both the parents and tula [109].
their neonate are at risk for psychological and traumatic A collaborative approach with ENT colleagues would enable
stress (including post-traumatic stress disorder) [124]. These a diagnostic MLB to delineate the anatomy of the airway,
306 K. Cross et al.
exclude laryngeal cleft, and facilitate positioning of the endotra- Neonates with cardiac disease have a greater incidence
cheal tube relative to the fistula. The distance between the fistula for critical events such as desaturation and need for new
and the glottis and carina, respectively, may be measured using inotropic support compared with those without cardiac dis-
rigid bronchoscopy [128]. This is facilitated with spontaneous ease as well as a 57% mortality during hospitalization for
ventilation and lidocaine topically applied to the larynx. those with ductal-dependent congenital heart disease [100].
Spontaneous ventilation is maintained until the fistula is ligated; These data underscore the need for preoperative ECHO and
after that, neuromuscular blockade can be safely administered. if a heart defect is present to discuss the need for central
If the fistula is mid-tracheal, the tip of the tracheal tube is venous access. Phenylephrine should be prepared to treat a
ideally positioned just below the fistula with bevel facing “tet spell” in a neonate with an unrepaired tetralogy of
anteriorly as the fistula originates from the posterior wall Fallot.
with gentle positive pressure ventilation. Provided the fistula
is small at the carina, the tracheal tube can be positioned mid
tracheal. It is imperative that the tracheal tube is fixed care- Congenital Diaphragmatic Hernia
fully and checked after positioning to ensure the dependent
lung remains ventilated. Congenital diaphragmatic hernia (CDH) occurs in 1:2,500
In the unusual situation of a large fistula at the level of the live births, with a slight predilection for males. There are two
carina resulting in preferential gastric ventilation, some authors major types: Bochdalek (posterolateral defect) (Fig. 9.6a, b)
suggest passing a 2/3 Fr Fogarty embolectomy catheter through and Morgagni (anterior) (Fig. 9.7a, b) [130]. The posterolat-
the fistula into the stomach via a rigid bronchoscope and eral defect accounts for 85–95% of cases of CDH and most
occluding the fistula through inflation of the balloon. The tra- are diagnosed antenatally. CDH is associated with herniation
cheal tube is positioned alongside the Fogarty catheter. This of the abdominal viscera into the affected hemithorax, with
may not be possible so a surgeon should proceed to thoracot- displacement of the mediastinum to the contralateral side
omy to ligate the fistula as quickly as possible. An alternative (Fig. 9.6a, b). The lung on the side of the hernia is hypoplas-
strategy may be thoracotomy and ligation of distal esophagus tic, whereas the lung on the contralateral side is usually nor-
below the fistula. If the stomach becomes very distended before mal (if survival is likely) or hypoplastic (if survival is
the fistula is ligated, the tracheal tube can be intermittently dis- unlikely). The degree of lung hypoplasia and associated pul-
connected to decompress stomach via airway. monary hypertension are the major determinants of outcome;
Analgesia may be managed using an opioid-based tech- surgical repair of the diaphragm has a relatively minor con-
nique such as fentanyl or remifentanil intraoperatively and tribution to the long-term outcome. Anomalies occur in
intravenous morphine postoperatively particularly for the 40–60% of neonates with CDH. These include cardiac, neu-
child with long-gap EA who will remain ventilated postop- ral tube, chromosomal, renal, and genital anomalies and pul-
eratively. Caudal catheters have been described and are most monary sequestrations, as well as malrotation and duodenal
suitable for low-risk infants who are candidates for early atresia [131, 132]. The anterior (Morgagni) defect accounts
extubation immediately postoperatively. Many pediatric sur- for only 2% of diaphragmatic hernias, located retrosternal (at
geons prefer a controlled extubation by the anesthetic team the level of the xiphoid) or anteromedially in the diaphragm
immediately postoperatively to reduce the need/risk for (Fig. 9.7a, b). These are often asymptomatic and may not be
emergency reintubation that may damage surgical closure or detected until adulthood or found incidentally with other
to leave the tube in place for several days to ensure adequate investigations such as CT scanning for cardiac anomalies
postoperative analgesia can be provided without the risk of [133].
respiratory distress and emergency reintubation.
Blood loss is usually minimal; intravenous crystalloid Embryology
such as Hartmann’s solution is ideal and a fluid volume of The diaphragm develops during weeks 4–8 from four embry-
10–20 mL/kg is usually required. Blood glucose monitoring ological elements. A Bochdalek hernia results from failure of
is essential. Broad-spectrum antibiotics should be adminis- closure of the pleuroperitoneal canals during early embryo-
tered before skin incision and continued as per the surgical nal life, often with early in-growth of the liver through the
discretion. defect. The exact cause for CDH remains unknown but may
Secure intravenous access should be established and be associated with genetic factors that lead to failure in cell
many anesthesiologists advocate for arterial access to facili- migration, myogenesis and formation of connective tissue,
tate beat to beat monitoring and arterial blood gas sampling or abnormalities of the retinoid signaling pathway, which is
during one-lung ventilation, although this is not necessary. important in the development of the diaphragm. CDH may
Cranial NIRS (near-infrared spectroscopy) may have a role occur as an isolated abnormality (often associated with a
in the continuous intraoperative monitoring as suggested mutation on chromosome 15q26) or occasionally associated
from the critical care environment although no studies have with syndromes such as Pallister-Killian, Fryns syndrome,
been forthcoming [129]. Cornelia De Lange, or Edwards syndrome [131]. Abnormal
a b
Fig. 9.6 Congenital diaphragmatic hernia (CDH): foramen of stomach in the left chest. The tracheal tube ends at the thoracic inlet.
Bochdalek defect. (a) This chest radiograph depicts a neonate with con- PICC line enters the right chest and ends in the superior vena cava. (b)
genital diaphragmatic hernia in the left (classic Bochdalek defect) chest A schematic of a neonate with a CDH with bowel present in the left
with stomach and bowel in the chest, displacing the heart to the right chest; the right lung is compressed and the heart is deviated toward the
chest. Note the multi-orifice orogastric tube (with side holes) in the right chest (Courtesy of Dr. Satyan Lakshminrusimha, Division of
esophagus, curving up and across the diaphragm and terminating in the Neonatology, Women and Children’s Hospital of Buffalo, Buffalo, NY)
a b
Fig. 9.7 (a, b) Congenital diaphragmatic hernia. Foramen of Morgagni of Morgagni). (b) This lateral chest radiograph depicts a loop of bowel
defect. (a) This AP chest radiograph depicts a neonate with congenital in the immediate retrosternal space (see arrow), rising above the anterior
diaphragmatic hernia with a loop of bowel that herniated through a aspect of the diaphragm (Courtesy of Dr. K. Valle, Division of Pediatric
defect in the anteromedial (retrosternal) area of the diaphragm (foramen Surgery, Women and Children’s Hospital of Buffalo, Buffalo, NY)
308 K. Cross et al.
karyotyping has been reported in 16% of neonates with Morbidity associated with CDH in the longer term includes
CDH, in 4% of those without anomalies, and 39% of those ongoing respiratory problems with recurrent infections and
with anomalies [134, 135]. reduced exercise capacity compared with age-matched peers,
neurocognitive defects secondary to neonatal hypoxia or intra-
Diagnosis cranial hemorrhage, and visual impairment and deafness, pos-
The diagnosis of CDH is made by antenatal ultrasound in sibly related to intensive care management. Gastroesophageal
~70% of cases, due to the presence of intrathoracic bowel reflux is common and may require medical or surgical inter-
loops or stomach, often signaled by a history of maternal vention. Recurrence rates of up to 50% are reported in CDH
polyhydramnios [133, 136]. All cases should be referred to especially if the initial defect is very large. Scoliosis and chest
a specialist center. The fetus should be screened for associ- wall deformity may also occur [131, 146, 147].
ated anomalies and the family provided with antenatal coun-
seling, particularly if there are features associated with a Antenatal Treatment
poor prognosis (see below) [137, 138]. Antenatal MRI scans Antenatal treatment for CHD has been trialed with varying suc-
may provide further prognostic information about lung vol- cess. The most promising treatment is fetal endoscopic tracheal
ume, liver herniation, left ventricular mass, and pulmonary occlusion (FETO) with a balloon for those with poor prognosis
diameter and is becoming more commonplace but not rou- based on lung measurements. FETO prevents the egress of lung
tine [131, 139]. fluid from the fetal lung and improves lung growth and reduces
Postnatally, the neonate may present with an exacerbation vascular resistance. The tracheal balloon is either removed
of their respiratory distress. Symptoms may range from mild before delivery, by EXIT, or punctured immediately after deliv-
to severe, depending on the severity of the CDH. The abdo- ery by tracheoscopy or percutaneous puncture [148, 149].
men is scaphoid as the intestine is in the chest, and breath Promising results have been reported, although the complica-
sounds are reduced on the affected side. The diagnosis is con- tion rate is relatively great and may include previously unrec-
firmed by X-ray of both the chest and abdomen, which helps ognized conditions such as tracheomegaly or bronchomegaly
differentiate from other chest pathologies such as CCAM. A and remains under review [150, 151]. Premature delivery con-
nasogastric tube should be placed before imaging as this may tributes to the poor outcomes of FETO [148]. In a randomized
lie or curl above the diaphragm if the stomach is in the chest. controlled trial of FETO, survival improved in neonates with
An echocardiogram should be sought to delineate associated isolated severe CDH [148, 149, 152].
cardiac abnormalities and to estimate the severity of pulmo-
nary hypertension [140]. Serial cranial ultrasound should be Medical Management
performed to exclude an intracranial bleed. Medical management of CDH has changed dramatically over
the last two decades, from a strategy of early emergency sur-
Outcomes gery with aggressive hyperventilation to reduce pulmonary
Despite the advances in the medical and surgical manage- hypertension to optimizing the cardiorespiratory status using
ment of this condition, the overall mortality remains at a “gentle ventilation” strategy to minimize barotrauma that
21–48%. However, specialist centers with a large number of includes minimum peak inspiratory pressures, maintaining
cases have better survival rates of up to 80% live births [141]. spontaneous ventilation and permissive hypercarbia followed
Mortality in non-syndromic infants is primarily related to by a planned, surgical intervention [153, 154].
pulmonary hypoplasia and pulmonary hypertension and, as Delivery should be planned at or near a center with pedi-
surrogate markers of severity, the need for ECMO/HFOV or atric surgical and NICU expertise so that the optimal postna-
for patch repair [142]. Right-sided, bilateral, or large defects, tal respiratory support and timely surgical intervention can
a lung to head ratio of 1.0 or less, and the presence of the be provided. The neonate should be allowed to mature to
liver in the chest portend worse outcomes, as do prematurity, term to permit maximum maturation of the lung. A nasogas-
chromosomal anomalies, severe cardiac defects (particularly tric tube should be passed after delivery to decompress the
transposition of the great arteries or single-ventricle physiol- stomach, central and arterial access obtained, and the warm-
ogy), and spinal anomalies [143, 144]. In an effort to estab- ing strategies commence with minimal handling. Pulmonary
lish a standardized scoring system, an international consensus surfactant has not been shown to be beneficial [155].
concluded that the size of the diaphragmatic defect (as a sur- The perinatal management of patients at delivery to opti-
rogate for the severity of pulmonary hypoplasia and hyper- mize outcomes is attracting increasing attention [156].
tension) and the severity of the cardiac defect may predict Interventions such as early intubation and ventilation require
outcome [145]. ECMO required for more than 2 weeks or further review as ideal practice is not clear. Initial ventilation
associated with renal complications or persistent pulmonary strategy (conventional or high-frequency oscillation) varies
hypertension for more than 3 weeks is also associated with among centers. The only randomized trial between conven-
high mortality [137, 138, 141, 142]. tional and high-frequency oscillation, the VICI-trial, found
no difference in mortality at 1 year of age or the frequency of >35 weeks’ gestation, have no lethal congenital abnormali-
bronchopulmonary dysplasia [157]. However, that study was ties, have no irreversible organ dysfunction (including neu-
terminated prematurely due to fiscal reasons resulting in a rological injury), and have no contraindication to systemic
power of only 44%. Hence, we cannot infer from these anticoagulation.
results that the two modes of ventilation have equipoise.
Optimal ventilation should aim for a pre-ductal SpO2 Surgical Considerations
85–95%, post-ductal SpO2 >70%, arterial pCO2 The objectives of surgery in the management of CDH are to
45–60 mmHg, and pH >7.25. If a conventional ventilation reduce the herniated contents safely into the abdomen and
strategy is used, the initial settings should include a peak repair the defect. Ideally, surgery should be delayed until the
inspiratory pressure (PIP) 20–25 cmH2O, positive end- neonate is stable, that is, off inotropes (with the possible
expiratory pressure (PEEP) 2–5 cmH2O, and a frequency exception of dopamine) for 24 h. Some have used “stability”
40–60 breaths per minute with minimum required inspired criteria to determine the neonate’s eligibility for surgery;
oxygen to maintain the threshold oxygen saturation [157, however, these criteria may be more appropriate for deter-
158]. Prolonged use of muscle relaxants is ideally avoided, mining the timing, rather than eligibility, for surgery [163].
and the neonate should be allowed to breathe spontaneously Surgical intervention is possible while the neonate is on
between assisted breaths. If HFOV is used, the initial settings ECMO, although studies suggest that the mortality was
should include a mean airway pressure 13–17 cmH2O, fre- increased because of a greater risk of bleeding [164]. Many
quency 10 Hz, amplitude (∆P) 30–50 cmH2O, and I/E ratio centers undertake surgery only after weaning the neonate
1:1 [157, 158]. Hyperinflation of the lungs should be avoided from ECMO and decannulation with possible improved sur-
(<8 ribs on unaffected side on chest X-ray). vival [164], although some have achieved improved mortal-
Echocardiography should be performed to estimate the pulmo- ity rates repairing CDH on ECMO by limiting the use of
nary artery pressure, direction of shunting across the arterial duct/ anticoagulants and using antifibrinolytics [163, 165]. For
foramen ovale, myocardial contractility, the presence of a congeni- large defects, a patch repair may be required which should be
tal heart/vascular defect, and the response to treatment. The oxy- fashioned as a dome shape rather than a flat repair. This extra
genation index (OI) should be calculated (OI = mean airway patch allows widening of the thoracic diameter with growth
pressure (cmH2O) × FiO2 × 100/PaO2 (mmHg)). iNO 10–20 ppm without the patch detaching and ideally minimizes the risk of
may be indicated if the OI is >20 or the pre-/post-ductal oxygen recurrence [166]. Surgery may be performed by using an
saturation difference is >10%. The use of iNO is controversial and open technique (usually laparotomy) or increasing a mini-
response should be assessed using echocardiography. Prostacyclin mally invasive technique [167].
or prostaglandin E1 (PGE1) should be considered if there is no Laparotomy via an upper abdominal transverse incision
response to iNO. Many units use PGE1 routinely to prevent clo- allows good access to the length of the diaphragm and can be
sure of the arterial duct and to off-load the right ventricle. Sildenafil extended easily if further access is required. The abdominal
or milrinone may be indicated if pulmonary hypertension is refrac- contents are reduced into the abdomen and the defect is iden-
tory to treatment or persistent, but may cause systemic hypoten- tified. The spleen may require gentle finger reduction rather
sion [159]. The early use of sildenafil in the management of than simple traction on the gastric and colonic attachments,
pulmonary hypertension has also been proposed and there is cur- to avoid damage and bleeding. A hernial sac, which is pres-
rently a trial underway comparing this to iNO [160]. ent in 10–20% of cases, is usually excised during surgery.
Endothelin receptor antagonists (bosentan) and tyrosine Pulmonary sequestrations may also be found, either supra-
kinase inhibitors (imatinib) are currently under investigation. or subdiaphragmatic, and these are also excised. The hypo-
Fluid boluses may be required if peripheral perfusion is poor plastic ipsilateral lung may be seen via the defect in the
or hypotension is present. If cardiovascular instability per- chest. The diaphragmatic rim should be mobilized and, if
sists, inotropes may be required to increase the mean arterial possible, a primary repair performed without tension using
pressure to the upper normal range in order to reduce right- nonabsorbable interrupted sutures. If the diaphragm is defi-
to-left shunting across the arterial duct. cient laterally, then the sutures should incorporate a large
Venoarterial extracorporeal membrane oxygenation bite of rib or muscle to prevent recurrence. If the defect can-
(ECMO) may be offered in some centers as temporary stabi- not be closed without tension or is very large, a patch repair
lization and support in cases of severe cardiorespiratory fail- is required, although this technique is associated with worse
ure [161]. Specific ECMO criteria vary between centers; short-term and long-term outcomes. A variety of nonabsorb-
current European criteria for ECMO include inability to able materials have been used, including Gore-Tex®,
maintain pre-ductal saturation >85% or post-ductal satura- Marlex®, Dacron®, and Silastic®. Nonabsorbable materials
tion >70%, respiratory or metabolic acidosis with a pH have the advantage of cost, reduced bleeding, and easy han-
<7.15, need for aggressive ventilation, or refractory systemic dling; however, they do not grow with the child and may
hypotension [162]. The neonate should be >2 kg and actually shrink over time. These materials are associated
310 K. Cross et al.
with adhesions, increased recurrence, gastroesophageal ations in these neonates. Surgical repair should only be per-
reflux, and chest wall deformities [168]. Newer biosynthetic formed in physiologically stable neonates, ideally when
patch materials such as collagen lattices with embedded inotropic support is no longer required and the neonate has
growth factors (Surgisis®, AlloDerm®) are under investiga- been weaned off ECMO, usually at 2–6 days after birth [141].
tion, although they may increase the risk of postoperative Surgery should be postponed if the child becomes unstable
small bowel obstruction and have higher longer-term failure during transport to the OR or before surgery begins. Transfer
and recurrence rates especially in large defects. Techniques of the neonate with severe CDH carries considerable risk of
that involve muscular flaps have been described, but they are complications. The team should be prepared for major cardio-
time-consuming and may be associated with increased bleed- respiratory problems with skilled staff and equipment imme-
ing and abdominal wall deformity. Myogenic patches may diately on hand. Some units perform surgery in the NICU, but
be developed in the future [168]. A chest drain is not used this remains a contentious issue (see Chap. 13) [168].
routinely as the underwater drain may cause overdistension A balanced anesthesia technique that includes opioids
of the hypoplastic lung. Such a drain may be inserted at a such as high-dose fentanyl 20–50 mcg/kg, muscle relaxants,
later date if a clinically significant effusion develops. The and an inhalational anesthetic should be used to preclude a
advantage of the abdominal approach is that a Ladd’s proce- pulmonary hypertensive crisis. Nitrous oxide should be
dure can be performed at the same time if the position of the replaced with air at an appropriate oxygen saturation.
duodenojejunal (D-J) flexure is consistent with malrotation The ventilatory strategy should be the same as in NICU
and there is the potential for volvulus. but logistical challenges often exist due to the quality of the
MIS for CDH has been reported using both laparoscopic theater ventilator compared with the NICU machine. A TIVA
and thoracoscopic approaches. The laparoscopic approach technique is required for the child receiving HFOV or who
enables better instrument handling for the diaphragmatic depend on ECMO. Central venous access should be femoral
repair. Reduction of contents against the pneumoperitoneum in origin aiming to preserve cervical vessels if ECMO is
and the subsequent lack of intra-abdominal space after indicated. Invasive monitoring should be continued from the
reduction can be challenging. The thoracoscopic approach is NICU, with transcutaneous carbon dioxide monitoring to
preferred by many and has the advantage that the pneumo- supplement direct measurement of arterial PaCO2, particu-
thorax encourages lung reduction and there is an excellent larly in MIS.
view of the diaphragm after reduction. The lateral suture Surgical repair is usually uneventful and blood loss is
placement can be very difficult due to the rigidity and shape usually limited. Special precautions are required if the child
of the thoracic cavity. Initial reports of thoracoscopic repair remains on ECMO. Hypotension usually responds to fluid
also suggested an early greater recurrence rate; however, boluses of 10–20 mL/kg balanced salt solution or an increase
recovery and other surgical complications such as adhesive in the infusion rates of inotropes. Hypotension in the pres-
bowel obstruction may be improved [169–171]. Right-sided ence of an increasing difference between the pre- and post-
CDH, CDH-associated liver herniation, and the need for ductal SpO2 values may indicate an intraoperative pulmonary
patch closure may be better suited for an open procedure. As hypertensive crisis. Simple interventions include increasing
for thoracoscopic repair, carbon dioxide absorption and aci- FiO2, increasing depth of anesthesia, opioid administration,
dosis can be problematic during MIS although the effect of and correction of the acidosis that are usually effective. iNO
this can be minimized with lower IAPs [55, 118, 172]. For should be available in the event of a pulmonary hypertensive
this reason, an open surgical approach may currently be pre- crisis unresponsive to these measures. Deteriorating oxygen-
ferred for neonates with CDH and congenital heart disease, ation intraoperatively requires exclusion of a pneumothorax
for those who required ECMO, or for those who have con- on the contralateral (good lung) side or endobronchial intu-
tinuing systemic right ventricular pressures or require sig- bation must be excluded. At the conclusion of surgery, the
nificant inotropic support [173]. neonate should be transferred back to the NICU; the duration
It is important to avoid a “flat” diaphragmatic repair during of postoperative ventilation is determined by the severity of
primary or patch repair. When the herniated chest contents are pulmonary hypoplasia and pulmonary hypertension.
reduced into the abdomen, the intra-abdominal pressures may
increase to cause abdominal compartment syndrome. If there
is evidence of significant venous congestion of lower limbs Abdominal Surgery
after closure, then an abdominal wall silo should be left as a
laparotomy at the site of the abdominal incision, as for gas- Inguinal Hernia
troschisis repair. This may be closed a few days later. Inguinal hernias occur commonly with a childhood inci-
dence of 0.8–4.4%. Males are affected 8–10 times more fre-
Anesthetic Considerations quently than females. Premature infants have an increased
Management of pulmonary hypertension and pulmonary risk of hernias with an incidence of 13% in neonates born at
insufficiency and the timing of surgery are primary consider- <32 weeks’ gestational age (GA) and 30% in infants <1 kg
birth weight [174]. This group also has an increased risk of Surgical Management
complications such as obstruction and incarceration. Inguinal Inguinal hernias require surgical closure of the PPV. In many
hernia is also associated with cystic fibrosis, connective tis- centers, hernia repair is performed as an open procedure via
sue disorders, and abdominal wall defects. an inguinal incision with ligation of the sac after separating
it from the vas and testicular vessels. Care must be taken to
Pathophysiology fully mobilize and ligate the sac to prevent recurrence while
Inguinal hernias result from the failure of obliteration of the preserving the vas and vessels with minimal surgical trauma.
patent processus vaginalis (PPV), which develops during tes- The duration of anesthesia and surgery for inguinal hernia
ticular descent. Up to 50–80% of neonates may have a PPV repair in neonates is greater than in older children. The risks
and remain asymptomatic until bowel or other intra- of recurrence or testicular atrophy are greater in neonates,
abdominal contents enter this sac. When that occurs, it is particularly if the hernia has become incarcerated.
classified as an inguinal hernia. The right side is more fre- Laparoscopic repair may also be performed with the clo-
quently affected (60%) than the left, with 10–15% of cases sure of the internal ring with a nonabsorbable suture. This
occurring bilaterally (with a greater incidence in infants). technique allows the contralateral side to be assessed and
repaired if indicated, which may be particularly beneficial in
Diagnosis infants as the incidence of bilateral hernia or contralateral
An inguinal hernia is diagnosed clinically with the history or PPV is 60% in this age group. There is less dissection of the
presence of a groin swelling (Fig. 9.8). This may extend into cord structures, which may result in less damage; laparo-
the scrotum on the ipsilateral side. The testis should also be scopic hernia repair in infants is a safe procedure with a
palpated during examination, to separate from a groin swell- small complication rate, although long-term outcomes are
ing. The hernia may contain bowel, omentum, or in the case not yet clear [175–177]. The laparoscopic approach is feasi-
of females, an ovary. Examination should ensure that the her- ble even in very small neonates, although the ability to toler-
nia is reducible; if the hernia is irreducible (i.e., incarcer- ate carbon dioxide insufflation is an important factor, and the
ated), then the hernia immediately becomes a surgical procedure may be more challenging technically in the very
emergency. The majority (60%) of incarcerated inguinal her- premature or low-birth-weight neonates. Instead of carbon
nias occur in the first 6 months of life. dioxide insufflation, some advocate gasless laparoscopy in
neonates, thereby obviating the cardiorespiratory effects of a
carboperitoneum [178]. There is no consensus in the litera-
ture as to the best surgical approach; however, delaying neo-
natal inguinal hernia repair until ready for same-day
discharge may be preferable [179].
Anesthetic Management
The timing of surgery in neonates who require hernia repair
remains controversial, particularly in premature neonates;
the younger the neonate, the more susceptible they are to
postoperative apneas as well as surgical complications. This
has to be balanced with the risk of incarceration if surgery is
delayed. Many centers plan surgery for premature infants
near the time of discharge from the hospital, and others delay
surgery until after discharge to reduce the potential for post-
operative apnea and the need for prolonged postoperative
ventilation [180].
An analysis of data from prospective studies of former
preterm infants undergoing hernia repair under general anes-
thesia in the mid-1980s and late 1990s suggested that the
probability of postoperative apnea in premature infants was
<1% at PCA 56 weeks, with negligible risk of postoperative
apnea at 60 weeks’ PCA. The risk factors for postoperative
apnea were gestational age at birth, postconceptional age,
ongoing preoperative apneas, and anemia (hematocrit <30%)
Fig. 9.8 Inguinal hernia in a neonate. Close-up of a right inguinal her-
nia (Courtesy of Dr. YH Lee, Division of Pediatric Surgery, Strong [64]. Factors that may reduce the frequency of apneas in pre-
Hospital, University of Rochester, Rochester, NY) mature infants after general anesthesia include regional
312 K. Cross et al.
block (spinal anesthesia) without sedation, an ilioinguinal/ although pyloric stenosis does occur in premature infants.
iliohypogastric nerve block, administration of intravenous The diagnosis may be confirmed by clinical examination
caffeine 10 mg/kg, and the avoidance of neuromuscular with visible gastric peristalsis and a palpable pyloric “tumor.”
blockade or potent opioids [63, 181]. Respiratory events These signs may be more clearly demonstrated with a “test
after sevoflurane and desflurane anesthesia occur with simi- feed.” The classical biochemical picture is one of dehydra-
lar frequencies in premature neonates [182]. Current practice tion with hypochloremic metabolic alkalosis due to loss of
guidelines recommend postoperative apnea monitoring for gastric acid. Total body potassium may be depleted due to
neonates/infants who are full term but less than 44 weeks’ renal compensation and tubular reabsorption of hydrogen
PCA and infants who were premature at birth (e.g., and sodium ions and water in exchange for potassium. If the
≤37 weeks’ gestation) and who are less than 60 weeks’ PCA, vomiting continues unabated, the neonates become dehy-
although it has been suggested that this guidance could be drated, prompting ADH to cause renal reabsorption of water
relaxed to 46 weeks for former preterm infants who are with- and sodium at the expense of hydrogen and potassium ions,
out other risk factors for postoperative apnea [183]. resulting in “paradoxical aciduria” in the presence of meta-
Spinal or caudal epidural anesthesia as a sole technique bolic alkalosis. However, mounting evidence suggests that
may be associated with fewer postoperative respiratory com- neonates with pyloric stenosis present earlier in their disease
plications than general anesthesia but spinal has a significant process, resulting in less severe electrolyte imbalance in the
failure rate [183, 184]. During the last decade, concern has past decade [194, 195]. As a result of the less severe electro-
increased regarding the possible neurotoxicity from general lyte imbalance and the increasing reliability of ultrasound to
anesthesia in neonates and infants (see Chap. 18). The GAS delineate both the thickness and length of the pylori (with a
study (general anesthesia versus spinal anesthesia for infants sensitivity of 100% and specificity of 98%), ultrasound has
undergoing hernia repair), a randomized multicentered trial, supplanted the electrolyte panel as the cardinal criterion for
completed neurodevelopmental follow-up at 5 years and diagnosis of pyloric stenosis [192–194, 196].
found no significant difference in psychomotor scores
between regional and general anesthesia [185, 186], although Medical Management
the infants were exposed to a single anesthetic for about 1 h. This disorder is a medical, not surgical, emergency. Initial
Since such an exposure reflects the median exposure to gen- management consists of rehydration and correction of any
eral anesthesia during surgery in infants, these results likely electrolyte imbalance. Depending on the severity of the fluid
support the safety of single anesthetic exposures in neonates and electrolyte derangements, 24–48 h preparation may be
and infants [187]. required, although affected neonates are reaching pediatric
surgeons earlier in the disease process currently, reducing the
Pyloric Stenosis time required to correct electrolyte disturbances, if they even
Pyloric stenosis occurs in 1–3:1000 births and is four to five develop disturbances at all [194, 195]. Surgical intervention
times more common in males than females and more com- should not be undertaken until the neonates have been stable
monly in firstborn males. The etiology of pyloric stenosis has medically and the plasma bicarbonate is <28 mmoL/L and
been elusive, although there is some evidence for a genetic plasma chloride >100 mmoL/L. Infants with severe dehydra-
basis for the disease, feeding practices, erythromycin expo- tion may require an initial fluid bolus of 20 mL/kg 0.9%
sure postnatally (or prenatally), sleeping position (prone saline, followed by maintenance fluid with 5–10% dextrose
increases the risk), and possibly infectious moieties [188– and 0.45% saline, provided the plasma sodium is in the nor-
191]. The age at which pyloric stenosis presents has been mal range. The stomach should be decompressed with a
gradually decreasing. Currently, most cases present at 2–5 nasogastric tube, and gastric losses replaced ml for ml with
postnatal weeks, after several days of projectile vomiting intravenous 0.9% saline and 10 mmol KCL per
[192–194]. Pathological hypertrophy of the inner layer of 500 mL. Potassium should be added to maintenance fluids
smooth muscle in the pylorus results in gastric outlet obstruc- only after the infant begins to pass urine [192].
tion, which leads to the projectile nature of vomiting.
Pyloric stenosis is usually an isolated defect. However, in Surgical Management
some cases, it is associated with genetic syndromes includ- The traditional operation for pyloric stenosis is Ramstedt’s
ing Cornelia de Lange and Smith-Lemli-Opitz syndromes as pyloromyotomy, an extramucosal longitudinal splitting of
well as chromosome 8 and 17 translocations and (partial) the hypertrophied muscle (Fig. 9.9). This was originally
trisomy 9 [189]. described using an upper midline incision but many centers
now use a supraumbilical approach to provide better cosme-
Diagnosis sis. Laparoscopic pyloromyotomy is also widely performed,
The classic symptom of pyloric stenosis is non-bilious pro- with a randomized controlled study and early meta-analysis
jectile vomiting. Term infants are predominantly affected, demonstrating some benefits from this approach (reduced
Whether laparoscopic approach includes multiple incisions,

a single incision, or a microlaparoscopic (<2 mm diameter
instruments) approach [199], it would appear to be the evolv-
ing standard for pyloromyotomy.
Anesthetic Considerations
Surgery should only be scheduled after the fluid status and
electrolyte concentrations (including pH) have been normal-
ized; otherwise, the child will be at increased risk of postop-
erative apnea, arrhythmias, and circulatory instability.
Previously a nasogastric tube was routinely inserted as part
of medical management before arrival in the operating room.
It has been proposed that constant gastric drainage in the
absence of milk feeding may worsen electrolyte balance and
be unnecessary in the preoperative period [200]. Depending
on institutional practice, a nasogastric tube may be in situ
before arrival in the operating room. Regardless, the stomach
should be emptied by passing a large bore tube into the stom-
ach before induction of anesthesia to minimize the risk of
Fig. 9.9 Pyloromyotomy. The thickened muscle layer of the pylorus gastric fluid regurgitation and pulmonary aspiration. “Four
can be seen, incised down to the mucosa. To ensure the muscle has been quadrant” aspiration is an appropriate technique accom-
completely incised, laparoscopic alligators distract the walls of the plished by rolling the neonate to the left and the right while
muscle layer. Note the very thick muscular wall that has been peeled off
aspirating the NG tube. An index of suspicion should be
the pylorus. The liver edge is present immediately above the pylorus at
the top of the figure (Courtesy of Dr. K. Bass, Division of Pediatric maintained that the NG tube could be blocked or malposi-
Surgery, Women and Children’s Hospital of Buffalo, Buffalo, NY) tioned. Ultrasound assessment of gastric contents has been
studied in infants with pyloric stenosis, demonstrating that a
qualitative assessment of stomach contents can be made
quickly and easily before induction of anesthesia [201].
The traditional induction technique is a modified RSI,
avoiding cricoid pressure but gentle mask ventilation contin-
ues with 100% oxygen until laryngoscopy begins. Surveys of
experienced pediatric anesthesiologists reveal that fewer
than 50% apply cricoid pressure to infants with pyloric ste-
nosis [202]. There is in fact no evidence that cricoid pressure
actually prevents aspiration pneumonitis [203]. It has also
been demonstrated that cricoid pressure is difficult to apply
correctly in young infants and may distort the airway, com-
plicating laryngoscopy and tracheal intubation [28, 204].
The modified RSI as described is commonly practiced in
neonates and young infants with full stomachs to prevent
desaturation during the interval between loss of conscious-
Fig. 9.10 Laparoscopic insufflation of the abdomen. The neonate’s
ness and securing the airway.
head is at the top of the figure and the legs are at the bottom. During The anesthetic regimen for pyloric stenosis involves off-
laparoscopic pyloromyotomy, three ports are placed: the largest trocar setting two conditions: to facilitate rapid tracheal intubation
(5 mm Mini Step) is inserted through the umbilicus, whereas the two and recovery from anesthesia in ~30 min, the duration of sur-
smaller graspers are passed laterally through simple skin incisions. The
peritoneal cavity is insufflated with carbon dioxide to ~8 mmHg
gery. In preparation for tracheal intubation, a hockey-stick
pressure curve to the tracheal tube (a 3.5 uncuffed or 3.0 Microcuff®
tube) molded with a stylet to maintain its shape ensures a
rapid and successful tracheal intubation, particularly in the
time to full feed and length of stay), without an increase in absence of a muscle relaxant.
postoperative complications although the debate continues Intravenous induction with propofol can be used in com-
regarding the superiority of the laparoscopic over the open bination with opioid and a muscle relaxant. With the black
approach for pyloric stenosis [6, 197, 198] (Fig. 9.10). box warning by the Food and Drug Administration in the
314 K. Cross et al.
USA, many clinicians avoid succinylcholine in male infants iting as a sign of an incomplete repair or complication [218].
and young children. If a nondepolarizing relaxant is used After the pneumoperitoneum is released, the inspired con-
(most commonly rocuronium), then a small dose is often centration of desflurane is reduced to ~3%. When the skin
administered to preclude difficulty when antagonizing with incisions are closed and dressed, all anesthetics are
an anticholinesterase after brief surgery [205, 206]. discontinued.
Alternately, sugammadex can be used to antagonize neuro-
muscular blockade with rocuronium (in a dose of 2–4 mg/ Intestinal Atresias
kg) even in neonates [207, 208], although it is expensive, not Congenital intestinal atresia or stenosis can occur at any point
available in every country, and not approved for use in neo- along the gastrointestinal tract. The neonate presents with
nates in many countries. intestinal obstruction, the timing, and specific presenting fea-
Balancing the hesitation to use a nondepolarizing muscle tures relating to the level of the obstruction [219–221].
relaxant when the surgeon can complete the surgery rapidly,
other regimens may be considered. A short-acting IV opioid Pyloric Atresia
such as fentanyl 1–2 mcg/kg or remifentanil followed by a Pyloric atresia is an extremely rare condition (1:100,000 live
large induction dose of propofol (3–5 mg/kg) has been used births) representing 1% of intestinal atresias. Up to 30% of
to secure the airway. Alternately, others administer sevoflu- patients have other associated anomalies including epider-
rane in oxygen while preoxygenating the neonate [209], molysis bullosa, aplasia cutis congenita, and esophageal
judiciously timing a bolus of IV propofol (2–4 mg/kg) ± a atresia. Presentation is with non-bilious vomiting with a sin-
short-acting opioid, to provide optimal intubating gle gastric bubble on abdominal X-ray and no distal gas.
conditions. Surgery involves a laparotomy to either excise the obstruct-
Delayed emergence after pyloric stenosis is a common ing membrane or perform a bypass procedure (gastroduode-
and perplexing problem. This has been attributed to several nostomy or gastrojejunostomy) to restore intestinal
causes including the intraoperative use of opioids. Although continuity. The practical considerations are similar to those
some insist on administering a short-acting opioid such as for duodenal atresia.
fentanyl or remifentanil, infiltrating the laparoscopic
wounds with local anesthetic is quite effective [210, 211]. A Duodenal Atresia
regional block such as a rectus sheath block or epidural has Duodenal atresia or stenosis occurs in 1:5,000–1:10,000 live
also been effective after open pyloromyotomy [212, 213]. births with a male preponderance. Half of the patients have
IV or rectal acetaminophen also provides mild pain relief associated anomalies, commonly trisomy 21 (30–40%), mal-
perioperatively, without delaying emergence [214]. Despite rotation (30–40%), and cardiac anomalies (20%). Anorectal
avoiding opioids entirely, many continue to experience a and genitourinary anomalies, esophageal atresia, and
very slow emergence from anesthesia and time to extubation Meckel’s diverticulum are also associated with duodenal
after this surgery. Other possible causes for the delayed atresia and, more rarely, biliary anomalies. Up to 45% of
emergence include the use of nondepolarizing muscle relax- babies are born prematurely [219]. Duodenal atresia may be
ants, although one retrospective study disputed this claim, classified as follows (Table 9.3).
noting that 0.7 mg/kg rocuronium minimally delayed the
time to transport to recovery compared with succinylcho- Embryology
line, after a propofol/sevoflurane anesthetic [205, 206, 215]. Duodenal atresia may be due to abnormal embryological
Insufflating the abdomen in neonates and infants does not development of the duodenum, pancreas, and biliary tree.
require the use of a nondepolarizing muscle relaxant, Proposed mechanisms include failure of recanalization of
although it does require a deep level of anesthesia, which the duodenum during the 8–10th week and altered rotation of
often implies large concentrations of inhalational agents and the ventral analogue of the pancreas resulting in an annular
controlled ventilation. Pharmacokinetically, desflurane with pancreas. The obstruction is distal to the ampulla in the
or without nitrous oxide is the optimal maintenance inhala- majority of patients (60–85%). An alternative theory com-
tional anesthetic to facilitate a rapid emergence and extuba- mon to all atresias is the possibility of a vascular accident
tion after pyloromyotomy (editor’s note) (see Chap. 3) (see jejunoileal atresia below).
[216]. At least one MAC of desflurane is required during
insufflation, which corresponds to an end-tidal desflurane
concentration of 9.6% in this age group [217]. To reduce the Table 9.3 Classification of duodenal atresia
concentration of inhalational anesthetic required, remifent- Type I—mucosal diaphragmatic membrane
anil may be added [210]. Antiemetics are not indicated in Type II—short fibrous cord connecting two ends of the atretic
neonates as the incidence of postoperative vomiting in this duodenum
age group is very small and surgeons may use ongoing vom- Type III—complete separation of the two ends of the duodenum
Diagnosis rotation should be checked and malrotation corrected if

Polyhydramnios occurs in 33–60% of pregnancies and antena- present. The gall bladder should be visualized for bile.
tal ultrasound may demonstrate a “double bubble.” Cardiac Some surgeons choose to leave a transanastomotic tube in
abnormalities may also be detected at this time. Postnatally the situ although full enteral feeds are usually achieved with-
baby develops bilious vomiting in the majority, although vom- out this maneuver.
iting may be non-bilious if the atresia is proximal to the
ampulla. Abdominal X-ray shows the characteristic double Anesthetic Considerations
bubble with an absence of gas distally. Distal gas may occa- Anesthetic considerations relate mainly to anesthesia for lap-
sionally be seen if the atresia is periampullary with the main arotomy in the presence of upper gastrointestinal obstruction
pancreatic and accessory duct opening on either side. Gas can and coexisting abnormalities, especially complex cardiac
then travel via the biliary tree into the distal intestine. The ante- anomalies, and prematurity. If the child is otherwise well, the
natal and abdominal X-ray findings are less clear in duodenal aim should be to extubate at the end of the procedure.
stenosis, which may present later depending on the degree of
obstruction. The differential diagnosis of duodenal atresia is Jejunal/Ileal Atresia
malrotation and volvulus, which can have catastrophic conse- Small bowel atresia or stenosis is a common cause of neona-
quences if not detected. If there is any doubt about the diagno- tal intestinal obstruction occurring in 1:3,000 live births
sis, for instance, if there is distal gas or no antenatal history, an [220]. Stenosis is due to a localized narrowing of the lumen
urgent upper gastrointestinal contrast study should be per- without loss of continuity in the intestine or mesentery
formed to exclude malrotation. If doubt still remains, then an (Fig. 9.11). Small bowel atresias are classified into four
urgent laparotomy should be performed. major types [221, 223] (Table 9.4).
Types II and IIIa occur most commonly. There may be a
Management family history, especially in type IIIb atresia. Multiple atre-
The ultimate management for this congenital defect is surgi- sias are not uncommon, with up to 67% of jejunal atresias
cal, although the neonate should initially be resuscitated and
stabilized before proceeding. A nasogastric tube should be
passed, losses replaced, and maintenance fluids infused.
Preoperative workup includes a thorough clinical examina-
tion and echocardiography to exclude associated anomalies.
Outcomes
The mortality and morbidity associated with duodenal atre-
sia are small. Early operative mortality is less than 5%, pre-
dominantly due to complex cardiac anomalies, and long-term
survival is 90%. Morbidity associated with this condition
includes gastroesophageal reflux disease, delayed gastric
emptying, peptic ulcer disease, duodenal stasis, and blind
loop syndrome or megaduodenum, and adhesive small bowel
obstruction. These complications may not be apparent until
much later in life.
Surgical Considerations Fig. 9.11 Jejunal atresia. At laparotomy, normal jejunum is held up on
the right side of the photo. The jejunal lumen narrows at the atresia in
A laparotomy and duodenostomy (either end-to-side or the middle of the photograph, with a very small lumen thereafter. The
Kimura diamond anastomosis) are the primary procedures mesentery, which supplies blood to the bowel, is intact (Courtesy of Dr.
performed. Access is via a supraumbilical transverse or YH Lee, Division of Pediatric Surgery, Strong Hospital, University of
umbilical (Bianchi) incision. The minimally invasive lapa- Rochester, Rochester, NY)
roscopic approach is feasible and safe and is being used in
some centers, although liver retraction and exposure of the Table 9.4 Classification of small bowel atresias [221]
duodenum can be difficult especially in a small infant or in Type I—a membrane or web
the presence of hepatomegaly. The laparoscopic approach Type II—blind ends separated by a fibrous cord
may benefit earlier return to full enteral feeding and Type IIIa—disconnected blind ends
reduced analgesic requirements [222]. It is important to Type IIIb—absence of the superior mesenteric artery resulting in
check that a second duodenal web is not present (seen in the “apple peel,” “Xmas tree,” or “Maypole” abnormality
1–3% of cases), and there are no distal atresias. Intestinal Type IV—multiple segment atresia (“string of sausages”)
316 K. Cross et al.
and 25% of ileal atresias having further distal atresias. and maintenance fluids. Investigations should be per-
Chromosomal abnormalities are much less common in the formed as described above.
more distal atresias compared with duodenal atresia
although 12% of patients with ileal atresia will also have Surgical Considerations
cystic fibrosis. These patients should have genetic screening The most common surgical procedure to localize the atresia
and a sweat test performed at an appropriate time postopera- is a laparotomy. Once it has been identified, the atresia is
tively. There is an association between gastroschisis and excised with a primary anastomosis. There may be a signifi-
small bowel atresias. cant discrepancy in size between the proximal and distal
ends of the atresia, making an end-to-end primary anastomo-
Embryology sis challenging. Despite this, a 7:1 discrepancy can be
The most popular theory is that the atresia results from an accommodated with meticulous technique and 7-0 suture
intrauterine “vascular accident.” Interruption of the blood material. If bowel length is not a problem, then the dilated
supply results in sterile necrosis and resorption of affected bowel can be resected back to a more reasonable caliber. If a
segments. Multiple causes of vascular interruption have been type IIIb “apple peel” atresia is discovered, particular care
proposed including fetal intussusceptions, midgut volvulus, must be taken to avoid compromising the retrograde vascular
thromboembolic occlusions, transmesenteric internal her- supply from the marginal colic arteries to the remaining dis-
nias, and incarceration as the result of an abdominal wall tal small bowel. Problems with the absorption of feed and
defect. The use of methylene blue in amniocentesis for twin short bowel syndrome are also more common with this type
pregnancies has also been implicated. The insult is believed of atresia [225]. This has been attributed to the severity of the
to occur after week 11 of gestation. This is supported by the vascular insult. Given the high risk of multiple atresias, the
findings of bile, lanugo hair, and squamous epithelial cells continuity of the distal bowel should be confirmed by pass-
from swallowed amniotic fluid distal to the atresia. ing a small balloon catheter through the lumen and flushing
with either air or saline before the anastomosis is performed.
Diagnosis If the neonate is unstable or the distal bowel is significantly
Polyhydramnios may be present prenatally although it is compromised, then a proximal stoma and mucous fistula are
less common, the more distal the obstruction. Dilated preferred as a temporizing measure, with the restoration of
bowel loops may be present on antenatal scans. Postnatally, bowel continuity restored when the neonate has fully recov-
these lesions present with signs of intestinal obstruction ered. The remaining length of small bowel should be mea-
including vomiting (usually bilious), abdominal disten- sured and documented to help predict and manage neonates
sion, and failure to pass meconium. Respiration may be with possible short bowel syndrome.
compromised if the distension is severe, and the neonate
may require preoperative respiratory support (and hence Anesthetic Considerations
postoperative support). A plain abdominal X-ray will These are the same as for any neonate undergoing laparot-
show dilated bowel loops (number depending on the level omy. However, postoperative ventilation may be required
of the obstruction). A contrast enema may be performed after prolonged laparotomy and a significant fluid shift.
preoperatively to exclude the differential diagnoses of Long-term vascular access may be required for parenteral
meconium ileus, Hirschsprung’s disease, and coexisting nutrition.
more distal atresias. Ten percent of neonates present with
meconium peritonitis due to antenatal perforation; calcifi- Colonic Atresia
cation or meconium pseudocyst may be seen on abdomi- This is a very rare cause of intestinal obstruction and repre-
nal X-ray. sents <10% of all intestinal atresias. A vascular insult is the
likely cause of these atresias. These occur when closing
Outcomes abdominal wall defects especially gastroschises secondary to
The long-term survival for patients with jejunoileal atresia is localized vascular interruption. Applying the Grosfeld clas-
84% [224]. The primary cause of morbidity and mortality is sification, most are type IIIa or type I. Associated proximal
short bowel syndrome or intestinal failure requiring total atresias are common (22%), and right-sided atresias are
parenteral nutrition, with the associated risk of sepsis and associated with Hirschsprung’s disease.
liver disease.
Diagnosis
Medical Management Colonic atresia presents with symptoms of distal obstruction,
As with all neonatal intestinal obstruction, the initial goal including abdominal distension, failure to pass meconium,
is to stabilize the neonate by decompressing the stomach and bilious vomiting. Multiple loops of distended bowel on
with an NG tube, nil by mouth, intravenous resuscitation, plain abdominal X-ray confirm the presence of distal bowel
obstruction. A hugely distended loop of bowel is often pres- or meconium may be passed vaginally or be evident in a pat-
ent because of the closed loop obstruction in the presence of ent processus vaginalis in the scrotum. Calcification is often
a competent ileocecal valve. Contrast enema confirms the evident on a flat plate (X-ray) of the abdomen. Intestinal vol-
location of the most distal atresia. vulus or atresias may also occur.
Management Outcomes
Preoperative management is the same as for all neonates Outcomes are slightly more favorable in simple meconium
with intestinal obstruction. This has been discussed above. ileus with a 1-year survival of 92% compared with 89% in
Early surgical intervention is essential, as the mortality from complicated meconium ileus [226].
perforation may reach 100% if surgery is delayed for more
than 4 days. Management
The usual resuscitative measures should be performed in
Surgical Considerations conjunction with broad-spectrum intravenous antibiotics,
Surgical options are laparotomy with either formation of and the neonate should remain nil by mouth. If the diagnosis
decompressing colostomy or primary anastomosis. Although is consistent with simple meconium ileus, the obstruction
anastomotic leakage is frequent and sepsis has been reported may be relieved by nonoperative measures using a hyperos-
previously in neonates undergoing primary anastomosis, molar contrast enema (Gastrografin® or Omnipaque®), which
more recent reports support this approach. Hirschsprung’s may be repeated. Operative intervention is indicated for
disease should be considered if an anastomotic leak is enema failures and complicated meconium ileus.
detected. A stoma is preferred to direct anastomosis if resec-
tion to bowel with a more appropriate caliber results in short Surgical Considerations
bowel syndrome. As per jejunal/ileal atresias, the distal Surgical options include manual disimpaction at laparotomy
bowel must be assessed intraoperatively by flushing with air either via a proximal enterotomy or with the intraluminal
or fluid to identify additional atresias. injection of 4% N-acetylcysteine. A combination of these
two may be required to fully clear the impacted plugs. If this
Meconium Ileus is not possible, a distal loop or double-barreled stoma should
Meconium ileus results from the obstruction of the distal be performed, although this is rarely required. Primary lapa-
small bowel due to thick inspissated meconium. The major- rotomy is performed in complicated meconium ileus; the
ity (90%) of cases can be attributed to intestinal and pancre- options are resection and anastomosis or, alternatively, stoma
atic dysfunction secondary to cystic fibrosis (CF). Up to 25% formation. It is essential to ensure that the obstruction into
of neonates with underlying cystic fibrosis will present with the microcolon is relieved completely if a stoma is not per-
meconium ileus. Once the obstruction has been successfully formed. Additional N-acetylcysteine via a nasogastric tube is
treated, the infant must be tested for CF. The presence of sometimes advocated. The stoma should be closed as soon as
meconium ileus does not predict a worse, long-term outcome possible to avoid excessive sodium losses from the gastroin-
from CF, although almost all children with meconium ileus testinal tract and from sweat.
develop pancreatic insufficiency and will require pancreatic
enzyme replacement when feeds are introduced [226]. It is Anesthetic Considerations
important to involve the respiratory physicians early, even Management is the same as for any neonatal laparotomy
though clinical lung disease is very uncommon in neonates. including fluid resuscitation and respiratory support accord-
ing to clinical requirements. Hypertonic enemas increase the
Diagnosis risk of hypovolemic shock in neonates as fluid becomes
Simple meconium ileus presents with distal intestinal sequestered in the gut. Fluid may need to be replaced
obstruction. Plain abdominal X-ray shows multiple loops of throughout the intra- and postoperative periods to replace the
dilated bowel with a “soap bubble” appearance in the right preoperative and intraoperative fluid losses. A sweat test
lower quadrant (Neuhauser’s sign). This results from the should be performed early in the postoperative period to
mixing of air and the tenacious meconium. A contrast enema establish the diagnosis of CF. Fortunately, respiratory com-
will show a microcolon with pellets of meconium in the ter- plications are uncommon in the neonatal period.
minal ileum.
Complications occur in 50% of cases. Perforation may Malrotation and Volvulus
occur in the antenatal period if the proximal bowel becomes Malrotation is a congenital anomaly of the bowel in which an
ischemic or perforates secondary to a volvulus. This will abnormal position and fixation of the midgut shorten the
lead to meconium peritonitis and possibly a giant pseudo- mesenteric base, predisposing to a volvulus [227]. The inci-
cyst. The neonate may present with a large abdominal mass dence is 1:500–1:1000 based on postmortem studies. The
318 K. Cross et al.
derness or distension, diarrhea or constipation, and lethargy

present less commonly. Systemic compromise and blood in
the stools are later signs of volvulus in which significant
ischemia has already occurred. Abdominal X-ray may be
deceptively normal. The gold standard for diagnosis is an
upper GI contrast study, which demonstrates duodenal
obstruction when volvulus has occurred. The appearance is
that of a “bird’s beak,” coiled, or “corkscrew.” The normal
position of the D-J flexure is to the left of the midline, at or
above the level of the pylorus. For uncomplicated malrota-
tion in the absence of a volvulus, the contrast study demon-
strates the abnormal position of the D-J flexure to the right of
the midline. The position of the cecum is variable, rendering
it an unreliable sign of a malrotation. CT or ultrasound may
Fig. 9.12 Midgut volvulus. At the ends of the gloved fingers (center of demonstrate reversal of the normal position of the superior
the photo), a tightly twisted midgut (covered in yellow fat) volvulus is
evident (Courtesy of Dr. YH Lee, Division of Pediatric Surgery, Strong mesenteric artery (SMA) relative to the superior mesenteric
Hospital, University of Rochester, Rochester, NY) vein (SMV), with spiraling of these vessels if volvulus has
occurred. Ultrasound can be used to track the course of the
duodenum and D-J flexure. Urgent laparoscopy or laparot-
incidence based on symptomatic presentation is 1:6000 live omy is required if the diagnosis remains in doubt [228].
births or may be discovered incidentally. Other anomalies
associated with malrotation include intestinal atresias, such Outcomes
as duodenal web, abdominal wall defects, congenital dia- Malrotation with volvulus may lead to ischemic necrosis of
phragmatic hernia, imperforate anus, cardiac abnormalities, the entire midgut. Accordingly, it is essential that a pediatric
Meckel’s diverticulum, and trisomy 21. Males are twice as surgeon assess all neonates with bilious vomiting in a timely
likely to present in the neonatal period as females. Malrotation manner to prevent ischemia of the bowel. The mortality rate
with midgut volvulus constitutes a true surgical emergency is ≤10%. Short bowel syndrome (see Gastroschisis for fur-
as the consequences are potentially catastrophic with loss of ther discussion) occurs in 18% of neonates with volvulus.
the entire small intestine (Fig. 9.12). Complications of surgery include adhesive bowel obstruc-
tion in up to 20% and recurrent volvulus in 6% of neonates.
Embryology Those with malrotation may develop intestinal dysmotility at
The traditional theory of intestinal development has the a later date.
small bowel undergoing a counterclockwise 270° rotation
during the 6th–10th week of gestation as it returns to the Management
abdomen from the physiological hernia. During weeks A high level of clinical suspicion must be present when a
10–12, the bowel undergoes fixation. Failure of these pro- neonate presents with bilious vomiting. The outcome after
cesses is termed “malrotation.” This anomaly results in a volvulus depends on time so early diagnosis and intervention
shortened mesenteric base with the D-J flexure in an abnor- are critical. Initial resuscitation should be undertaken before
mal right-sided and low position, with a high position of the an urgent upper GI contrast study. Immediate surgical inter-
cecum, and a tendency of the small bowel to twist around the vention is indicated if malrotation with volvulus is diag-
mesenteric base (volvulus). This causes obstruction of the nosed. For those in whom malrotation without volvulus is
blood supply and lymphatic drainage to the small bowel (as confirmed or suspected, optimal management is controver-
well as luminal bowel obstruction), which can lead to isch- sial. Knowing there is a substantive risk for future volvulus,
emia to ischemia with necrosis of the entire midgut. It is many surgeons advocate a semi-urgent surgical procedure to
imperative that malrotation with volvulus is identified in a assess the mesenteric base and proceed to correction, if
timely manner and corrected before necrosis of the bowel appropriate.
occurs.
Diagnosis The classic surgical approach is Ladd’s procedure with dero-
The majority of neonates with malrotation present in the first tation of the volvulus. In this procedure, the duodenum is
month of life (50–75% of cases). The most common present- mobilized, the mesenteric base is widened, and the D-J flex-
ing symptom is bilious vomiting, although some may have ure and the small bowel are mobilized to the right of the abdo-
non-bilious vomiting. Other signs including abdominal ten- men and the cecum and large bowel to the left. If obstructing
peritoneal bands (Ladd’s bands) are identified, they are If the neonate is stable, maintenance of anesthesia can
divided. Many surgeons also perform an appendicectomy as include fentanyl or remifentanil or a low dose of inhala-
the cecum is abnormally located in the left upper quadrant. tional anesthesia. Deep inhalational anesthesia must be
Ladd’s procedure has been classically performed via laparot- avoided in critically ill neonates. The surgeon should
omy or more recently by laparoscopy, the latter providing a inform the anesthesiologist when the volvulus is about to
potentially less invasive means to assess the stability of the be reduced because derotation may lead to acute cardio-
mesentery. If technical factors preclude the latter approach, vascular instability due to the release of lactic acid and
then early conversion to an open technique must occur. The other vasoactive compounds. The anesthesiologist should
role of laparoscopy for correction of volvulus in a neonate be prepared to manage transient acidosis and hyperkale-
remains controversial; however, there is increasing evidence mia with IV calcium chloride (10–30 mg/kg), bicarbonate,
of the safety and benefits of this approach and this is becom- and occasionally salbutamol.
ing more commonly performed [228–231]. The long-term Reperfusion of the bowel is the primary goal. Adequate
outcomes for the laparoscopic approach however remain fluid resuscitation with warmed boluses of Hartmanns or
unclear. Despite a reduced risk of future adhesive bowel PlasmaLyte solution, albumin, or packed red cells is required
obstruction, the risk of recurrent volvulus remains uncertain. based on clinical assessment and monitoring. The fluid
Derotation of the bowel is often sufficient to restore the requirement may be substantial at this juncture; volumes as
blood supply to the midgut and the viability of the bowel. great as 50–100 mL/kg may be required. Inotropic support
However, if the diagnosis is delayed, the bowel may remain may also be required at this time to support the circulation,
ischemic after derotation, possibly the result of vascular active warming of the neonate, and patience and time to
thrombosis in the mesenteric vessels. The surgical options to assess recovery of the bowel.
address the ischemic/necrotic bowel include excision of the If malrotation is identified early, and the child is in good
necrotic segment, with or without anastomosis, or conserva- condition preoperatively, it is reasonable to consider extubat-
tive management with a “second look” laparotomy after ing the trachea at the end of surgery. The late-presenting
36–48 h to determine whether perfusion of the ischemic infant with necrotic bowel may remain critically ill even
bowel has improved. A technique that involves massage of after derotation, requiring full support in the intensive care
the mesenteric vessels after derotation (to break up clot), and unit until perfusion is restored. Long-term parenteral nutri-
systemic thrombolysis using tissue recombinant tissue-type tion may be required in some cases to bridge until the bowel
plasminogen activator (tPA), has been described in two neo- regains full functionality.
nates with severe intestinal ischemia due to thrombosis. This
resulted in dramatic restoration of bowel perfusion, with Hirschsprung’s Disease
subsequent complete recovery of bowel function [232]. If the Hirschsprung’s disease is congenital aganglionosis of the
small bowel is completely necrotic, then withdrawal of care bowel of variable length extending from the anus proximally
should be explored with the parents. [234]. This results in a lack of propagation of the intestinal
propulsive waves, failure of relaxation of the internal anal
Anesthetic Considerations sphincter, and functional bowel obstruction. It occurs in
These cases are critical surgical emergencies that must be 1:4,500–5000 live births with males affected more than
given priority over all other cases. Surgery must not be females. 80–90% of those with Hirschsprung’s disease pres-
delayed. Preoperatively, the status of the neonate may range ent in the neonatal period.
from relatively healthy to hypovolemic and/or septic shock.
In the latter condition, preoperative resuscitation should occur Embryology
concurrently with the preparation and transfer of the neonate Hirschsprung’s disease is one of the neurocristopathies with
to the operating theater. Group “O”-negative blood should be presumed failure of the craniocaudal migration of the neural
available if necessary. A nasogastric tube should be passed to crest-derived neuroblasts, which form the myenteric and
decompress the abdomen, and ventilatory support provided submucosal enteric plexuses (which should reach the rectum
as required. If the neonate is in shock or extremis, then anes- by week 12 of development). Other theories include failure
thesia should be induced using IV ketamine, fentanyl, and/or of neuroblast differentiation, defects in function, or cell
remifentanil, and the airway secured after with either death. Varying lengths of bowel are affected, the most fre-
rocuronium or atropine/succinylcholine [233]. Coagulopathy quent pattern being short-segment disease affecting the rec-
is common in the presence of necrotic bowel requiring plate- tosigmoid region (80%). Long-segment disease occurs when
lets and fresh frozen plasma. Inotropic support with dopa- aganglionosis extends proximal to the rectosigmoid region,
mine and/or adrenaline may be required. Invasive monitoring with total colonic disease in 3–8% of cases. Total intestinal
is very useful during this initial resuscitation phase. involvement is rare.
320 K. Cross et al.
Genetics tioning stoma into the ganglionic bowel. A stoma is indicated

Hirschsprung’s disease is a multigenic disorder with multi- if the neonate is unwell or has developed enterocolitis and
ple different genes and chromosomal loci implicated, with perforation and has a grossly dilated colon or suspected
new genes being continually identified [235, 236]. There long-segment disease. Hirschsprung’s enterocolitis is a
appears to be a dysfunction in one of two signaling path- potentially fatal complication that must be identified early
ways, which are critical in the development of the enteric and managed aggressively to reduce the risk of sepsis, intes-
nervous system. There is weak and sex-dependent pene- tinal necrosis, and perforation. Treatment with fluid resusci-
trance, with variable phenotypic expression. 10% of patients tation and broad-spectrum antibiotics is required.
have a family history (more common in long-segment dis- Definitive surgery consists of resection of the aganglionic
ease). The RET (receptor tyrosine kinase) proto-oncogene segment, either after initial stoma formation or ideally as a
mutation 10q11.2 is present in 50% of familial and 15–20% primary procedure. Several “pull-through” techniques have
of sporadic cases and 70–80% of long segment and up to been described, usually performed when the infant is approx-
38% of short-segment disease [235–237]. Currently, genetic imately 3 months of age, 5–6 kg weight [239]. The timing
profiles are not widely available to assess the disease risk in and exact procedure performed varies among centers and
individuals; however, a further understanding of the complex according to the length of abnormal bowel. Each technique
genetic interplay may lead to novel new treatments including can be performed completely open, or with laparoscopically
stem cell therapy [236–238]. assisted intra-abdominal dissection and biopsies, or entirely
Hirschsprung’s disease occurs in isolation in 70% of laparoscopically [239, 240].
cases, but it may be associated with trisomy 21 (5–15% of
cases of Hirschsprung’s disease), other neurocristopathies Surgical Procedures
(Waardenburg-Shah syndrome (SW4), congenital central The first surgical procedure described to address
hypoventilation syndrome, multiple endocrine neoplasia Hirschsprung’s disease was the Swenson procedure. This
(MEN) type 2, neuroblastoma, and neurofibromatosis I), procedure is a low anterior resection of the rectum and agan-
other syndromes such as Shprintzen-Goldberg and Smith- glionic bowel, with a low anastomosis performed by prolaps-
Lemli-Opitz, and congenital anomalies such as cardiac, gen- ing the bowel outside the anus.
ital, and gastrointestinal anomalies, facial dysmorphism, and The Duhamel procedure was the first alternative opera-
cleft palate [234]. tion proposed in which the native rectum remains unchanged
and a side-to-side anastomosis is stapled to the ganglionic
Diagnosis bowel, which is mobilized and brought down to the presacral
In neonates, the most common presenting symptoms are space. This requires less rectal dissection and offers a better
bile-stained vomiting with failure to pass meconium in the chance of continence in the long term. It is often the pre-
first 24 h of life (94% of normal term infants pass meconium ferred technique for long-segment disease. A retrospective
<24 h). This may be associated with poor feeding, abdominal review of open and laparoscopic approaches yielded similar
distension, and vomiting. Rectal examination may result in operative time and outcomes [240].
explosive stool and may temporarily relieve the symptoms. The Soave procedure further minimizes rectal dissection
Signs of enterocolitis (fever, abdominal distension, and diar- by performing a mucosal dissection in the rectum and leav-
rhea) may also be present. Differential diagnoses include the ing a rectal muscular cuff. The original description has been
other causes of neonatal distal bowel obstruction discussed modified to include a formal anastomosis just above the level
in this chapter. An abdominal X-ray may show dilated loops of the dentate line.
of bowel with an absence of air in the rectum. A distal con- A pure “transanal” pull-through without a laparotomy or
trast study may show dilatation of the proximal colon with a laparoscopy has also been reported for Hirschsprung’s dis-
change in caliber (transition zone) to normal bowel, but this ease but may not be appropriate for longer-segment disease.
is not reliable. Rectal biopsies provide a definitive diagnosis Long-segment disease is not always suspected preopera-
for Hirschsprung’s disease; the diagnosis is confirmed by the tively, potentially complicating this approach. Other opera-
absence of ganglion cells, with altered acetylcholinesterase tions have been described, although less frequently reported.
staining with hypertrophied nerve trunks. It is performed There is a paucity of prospective studies that compare the
using a suction rectal biopsy in the neonatal period or open different techniques. Retrospective reviews and meta-
biopsy in older children. Anorectal manometry is not usually analysis show comparable results with no “gold standard”
performed in neonates. identified [241, 242].
Management Outcomes
Initial management aims to relieve the functional bowel Appropriately managed, Hirschsprung’s disease is associ-
obstruction either with warm saline washouts or a defunc- ated with low mortality, although up to 50% of patients
undergoing surgery develop a complication such as constipa- urethra, vagina) and rectum. Anorectal anomalies occur as
tion, fecal incontinence, or enterocolitis. Enterocolitis, the the result of the failure of this separation and usual subse-
most severe complication, can occur in all patients with quent degeneration (apoptosis of the membrane) resulting in
Hirschsprung’s disease, both before and after surgery. It a wide range of clinical abnormalities.
occurs more frequently in those with long-segment disease
and those with trisomy 21. Enterocolitis is the primary cause Classification
of mortality in children with Hirschsprung’s disease and The Krickenbeck classification of anorectal anomalies is shown
must be identified and managed aggressively. Constipation in Table 9.6 [245]. In males, imperforate anus with rectoure-
occurs more frequently after the Duhamel pull-through, thral fistula is the most common defect followed by rectoperi-
whereas incontinence occurs more frequently after the Soave neal fistulae (Fig. 9.13). In females, the most common defect is
and Swenson procedures. To date, there are no prospective imperforate anus with rectovestibular fistula [245].
randomized controlled trials that compare the outcomes
from the different surgical techniques, although overall com- Diagnosis
plication rates appear to be similar among all approaches. Anorectal anomalies are diagnosed clinically, requiring a
thorough inspection of the perineum, sacrum, and buttocks
Surgical Considerations to identify the anatomy. If the neonate’s clinical condition
The transition zone between ganglionic (normal) and agan- permits, it is important to wait 16–24 h after birth to diag-
glionic (abnormal) bowel can vary in length (>20 cm) and nose a fistula, especially in males, as it may take this time for
demonstrate an irregular margin [243]. It is important to per- meconium to reach the rectum [246]. Associated anomalies
form an anastomosis between bowel segments with normal should be sought and further investigations may be required
ganglion cells without tension or vascular compromise. Time such as an echocardiogram, abdominal X-ray, and renal
must be allowed regardless of procedure for intraoperative ultrasound. An “invertogram” was previously advocated, but
frozen section results of serial biopsies at ascending levels to this is not routinely performed in many centers.
accurately assess the extent of affected bowel and also assess
the anastomotic donut. If long-segment disease is discovered Outcomes
unexpectedly, then many recommend that the pull-through Short-term complications after reconstructive surgery
procedure be delayed until formal histology is available. include anal stenosis, which may require repeated dilatation
or formal revision and wound infection. Pelvic sepsis can
A complete preoperative history should be completed includ-
Table 9.5 Conditions associated with anorectal anomalies [244]
ing a history of existing syndromes and anomalies that are
associated with Hirschsprung’s disease. Definitive surgery, Genitourinary (renal dysplasia, vesicoureteric reflux, undescended
testes, vaginal abnormalities)
either open or laparoscopic, may take 1.5–4 h in experienced
Spinosacral (sacral agenesis, vertebral anomalies, tethered cord)
hands [240]. The anesthetic prescription should be designed
Cardiac (septal defects and tetralogy of Fallot)
to ensure tracheal extubation at the end of surgery. For the Gastrointestinal (esophageal atresia, intestinal atresias,
laparoscopic approach, the neonate is supine but positioned Hirschsprung’s disease)
in steep Trendelenburg. All of the airway fittings should be Chromosomal (trisomy 21, VACTERL association, Currarino triad)
manually tightened and IV access points extended such that
they are reachable once the neonate is draped. Blood loss is
usually minimal, obviating the need for blood transfusion. Table 9.6 Krickenbeck classification of anorectal anomalies [245]
Caudal/epidural regional analgesia is well suited for periop- Major clinical groups
erative analgesia after this surgery. Postoperatively, rectal • Perineal (cutaneous) fistula
analgesia is contraindicated. • Rectourethral fistula (prostatic, bulbar)
• Rectovesical fistula
• Vestibular fistula
Anorectal Anomalies
• Cloaca
Anorectal anomalies occur in 1:4,000–1:5,000 neonates with • No fistula
a slight male preponderance [244]. Associated abnormalities • Anal stenosis
are present in 30–60% of cases; the most common associa- Rare/regional variants
tions are listed below (Table 9.5). • Pouch colon
• Recta atresia/stenosis
Embryology • Rectovaginal fistula
During weeks 4–6, the pouch at the caudal end of the hindgut • H fistula
(the cloaca) is separated into the urogenital sinus (bladder, • Others
322 K. Cross et al.
of males. In the remaining males, a combined abdominal

approach is required to mobilize the rectum.
It is important to avoid damage to pelvic structures and their
innervation during surgery. A muscle stimulator is essential
to identify the sphincter complex and ensure correct place-
ment of the neo-anus. For muscle function to be stimulated,
muscle relaxants are avoided after induction of anesthesia.
Dissection should be adequate to bring the rectum to the
perineum without tension in order to minimize retraction
after the repair and anal complications.
An understanding of the associated anomalies, particularly
cardiac and spinal anomalies, is important. Stoma formation
is a relatively minor procedure in the neonatal period, and a
Fig. 9.13 Imperforate anus. A close-up photograph of the perineum in single-shot caudal epidural provides excellent perioperative
a male. Note that immediately inferior to the normal penis and scrotum, analgesia for primary anoplasty (provided there are no sacral
one observes the outline and pigmentation of the imperforate anus abnormalities). Reconstructive surgery is usually performed
(Courtesy of Dr. YH Lee, Division of Pediatric Surgery, Strong Hospital,
University of Rochester, Rochester, NY) in the prone position (PSARP) or occasionally as a combined
abdominoperineal or laparoscopically assisted procedure.
Intravenous access should be placed in the upper extremities
occur as a life- and continence-threatening early complica- to ensure that the fluids are infused into the circulation, not
tion of surgery, especially if a diverting stoma has not been the surgical field. Blood transfusion is rarely required for this
performed. surgery. These reconstructive surgeries are usually several
Constipation is the most common long-term complication hours in duration, with the neonates in the Trendelenburg
of anorectal surgery, occurring in 18–62% of infants. Fecal position. As a result, tracheal intubation is usually required.
incontinence is a second long-term complication, occurring The anesthetic prescription should be designed to extubate
in 25% of infants. Social continence can often be achieved the trachea at the end of surgery. Perioperative analgesia can
with a combination of modalities including antegrade ene- be achieved with a continuous caudal/epidural infusion of
mas via an antegrade colonic enema (ACE) stoma. Urinary local anesthetics (e.g., bupivacaine, ropivacaine, or chloro-
dysfunction may also occur, being attributable to the under- procaine) [247–250] or IV morphine infusion with or with-
lying urinary tract anomaly rather than the surgery. out a transversus abdominis (TAP) block if central neuraxial
is contraindicated [251–253].
Management
Initial management is supportive with intravenous fluids and Cloaca
gastric decompression with a nasogastric tube. Associated This type of anorectal anomaly is uncommon, occurring in
anomalies should be excluded and time allowed to detect a 1:50,000 live births.
fistula, if clinically appropriate. Surgical decompression and
reconstruction are required. Depending on the anatomy and Diagnosis
associated anomalies, the neonate may undergo a primary Careful clinical examination will reveal a single perineal
anoplasty (“low” anomalies) with or without a diverting opening. Further imaging studies such as contrast studies
colostomy and distal mucous fistula or formation of colos- and CT scan with reconstruction can be very useful, as well
tomy/mucous fistula with later reconstructive surgery at as assessment of the common channel and structure via
1–2 months of age (“high” anomalies). Several operative cystoscopy.
approaches have been proposed for reconstruction including
posterior sagittal anorectoplasty (PSARP), an anterior sagit- Management
tal approach, sacro-perineal procedure, abdomino-sacral Initial management is supportive as for other anorectal
pull-through, abdominoperineal pull-through, and anomalies. Of note, hydrocolpos can result in urinary
laparoscopic-assisted pull-through techniques. PSARP is the obstruction and pyocolpos can result in perforation. Both of
most common procedure, suitable for most females and 90% these conditions may require urgent drainage.
Outcomes
The long-term results for cloacal repair in terms of conti-
nence are worse than for lower anorectal anomalies. Only
10% of neonates with a common channel >3 cm in length
will be continent.
Recognition of the anomaly is important as a more proximal
transverse colostomy is required to allow for adequate length
for the reconstruction procedure. Assessment of the length of
the common channel before reconstructive surgery is impor-
tant for both prognostic reasons and to assess the need for a
combined intra-abdominal approach.
Abdominal Wall Defects
Gastroschisis
Gastroschisis occurs in 1:4,000 live births, affecting males
and females equally, and incidence has continued to increase
over the past 20 years. Gastroschisis is strongly associated Fig. 9.14 Gastroschisis. In this preterm neonate, the thickened, red
with maternal age <20 years, smoking, use of recreational bowel from gastroschisis lays open and exposed. Note that gastroschisis
arises from an anterior abdominal wall defect on the right side, lateral
drugs, low maternal weight, maternal genitourinary infec- to the intact umbilical cord (Courtesy of Dr. YH Lee, Division of
tion, and low socioeconomic status [254–258]. Pediatric Surgery, Strong Hospital, University of Rochester, Rochester,
NY)
Pathophysiology
Gastroschisis is usually a small, right-sided (<10% left) defect of a sac, and an intact umbilical cord differentiate gastroschi-
in the abdominal wall lateral to the intact umbilical cord, sis from omphalocele.
through which the intestines protrude, uncovered, and unpro-
tected (Fig. 9.14). The exact embryological mechanism for this Management
anomaly is still unclear. In utero, the eviscerated bowel floats Antenatal diagnosis allows prenatal planning and transfer of
uncovered and exposed in the amniotic fluid. This may contrib- the parturient to a center where surgical management of the
ute to the thickening of the bowel wall and fibrinous “peel” that gastroschisis and a level-3 nursery are available [261]. There
is often present on the bowel at delivery. The abdominal wall is insufficient evidence to determine the optimal manage-
defect can narrow later in pregnancy, resulting in obstruction ment of these fetuses, for example, the age at which the fetus
and ischemic changes to the gut. Associated anomalies are should be delivered and the delivery technique [258, 262]. A
infrequent with this defect, but when they occur, they are usu- survey of maternal-fetal medicine practitioners in Canada
ally gastrointestinal in origin. For example, intestinal atresias suggested that preterm (<36 weeks) delivery of fetuses with
occur in 10–15% of cases. The liver rarely herniates. gastroschisis was associated with more complications, i.e.,
greater time requiring parenteral nutrition and greater length
Diagnosis of stay in NICU, whereas delivery of fetuses ≥38 weeks was
The majority of neonates with gastroschisis are diagnosed on associated with increased bowel matting and a meta-analysis
routine antenatal ultrasound. Blood testing shows increased was unable to provide further clarity [263, 264]. There is no
maternal serum concentrations of alpha-fetoprotein in the evidence that cesarean section improves neonatal outcomes,
absence of myelomeningocele. “Complicated gastroschisis,” although early induction of labor (from gestational week 36)
as in the case of gastroschisis with intestinal atresia, may be may avoid the unexplained late fetal deaths that can occur
predicted by the presence of dilated bowel on antenatal ultra- with this condition.
sound [259]. Approximately 30–70% of neonates have intra- Initial management at delivery is supportive, avoiding hypo-
uterine growth retardation or small for gestational age. The thermia, hypovolemia, and sepsis. The exteriorized bowel
mechanism for this latter effect is unclear but may be due to should be wrapped in clear plastic film and supported in the
enteric loss of proteins or inadequate supply of fetal nutrients midline to minimize venous engorgement or placed in a pre-
[260]. After delivery, the laterality of the defect, the absence formed silo. Above all, care must be taken to avoid damaging
324 K. Cross et al.
the exposed bowel. A servo-controlled warm incubator should A staged closure is required if primary closure is not
be used. Large volumes of intravenous fluids may be required to appropriate or possible. A hand-sewn Prolene mesh silo is
offset the large evaporative fluid loss from the exposed bowel. applied surgically under general anesthesia or using a pre-
Broad-spectrum antibiotics should be given. A nasogastric tube formed spring-loaded silo. For neonates with uncomplicated
should be placed to decompress the stomach and bowel. gastroschisis who do not have significant viscero-abdominal
disproportion, the preformed silo can be applied in the neo-
Outcomes natal unit without the need for general anesthesia or tracheal
Survival with gastroschisis is reported to be 90–95%, with the intubation [270]. These techniques allow gradual compres-
majority of deaths due to massive bowel resection or necrosis sion of the bowel into the abdomen over a period of days and
[265]. Intestinal function may be slow to recover after closing facilitate early extubation. The neonate undergoes planned
the defect, necessitating a long period of parenteral nutrition. surgical closure 3–5 days later, or closure of the defect using
A review of a gastroschisis database indicated that the time to adhesive strips once the bowel is fully reduced, depending on
achieve independence from parenteral nutrition, reduce the the silo technique used [270]. The use of the preformed silo
length of stay, and achieve freedom from infection was opti- may be associated with reduced ventilator days in the NICU,
mized when enteral feeds were withheld for at least 7 days but this approach may also be associated with specific tech-
after closure of the defect [266]. However, these findings nical complications that could lead to venous congestion of
should be interpreted in the context of the neonate’s status. the intestine resulting in bowel ischemia [271].
Intestinal dysfunction and short bowel syndrome complicate
gastroschisis. Gastroschisis accounts for approximately 20% Anesthetic Considerations
of the cases of short bowel syndrome, with the incidence of Some centers do not use anesthesia for closure of gastroschi-
the latter inversely proportional to birth weight [267]. Surgical sis if a sutureless or preformed silo technique is used,
short bowel syndrome is defined as the need for parenteral although others recommend routine anesthesia with paraly-
nutrition for >3 months. Current advances in management sis to facilitate every attempt to reduce the bowel. An
strategies that involve a multidisciplinary team approach, par- operative technique is required for complicated gastroschi-
enteral nutrition, prophylaxis from infection, and ongoing sis. A combination of general anesthesia with epidural anes-
surgical consultation have dramatically improved bowel thesia provides good postoperative analgesia and may reduce
function and survival in these neonates [267, 268]. the need for postoperative ventilation [272]. The child must
be kept warm and well hydrated with fluid blouses of 20 mL/
Surgical Considerations kg Ringer’s or albumin. Arterial access is useful for monitor-
The primary objective of surgery is to cover and protect the ing complex procedures. In neonates with otherwise uncom-
bowel. The secondary objective is to effect a staged return of plicated gastroschisis, enteral feeding usually begins
the bowels to the abdomen, without causing an abdominal 7–10 days after delivery. In those who require long-term par-
compartment syndrome. The latter is often identified by the enteral nutrition, it is important to preserve veins for chronic
onset of respiratory distress, ischemic or necrotic bowel, and catheters for long-term parenteral feeding. Some units advo-
renal insufficiency. For monitoring strategies to identify cate placement of a tunneled feeding line at the time of initial
abdominal compartment syndrome, see Anesthetic surgery [273].
Considerations below. The major concern that may arise during closure is the
The surgical treatment of gastroschisis remains contro- development of abdominal compartment syndrome. If the
versial. Primary closure may be undertaken in neonates with reduction is performed under general anesthesia, care should
small-size gastroschises using general anesthesia in the oper- be taken during face mask ventilation to minimize the peak
ating theater. Complications such as intestinal atresia, perfo- inspiratory pressure to avoid gaseous distention of the stom-
ration, necrosis, or volvulus may be addressed at the same ach and small intestine, and nitrous oxide should be avoided.
time. Before attempting a primary closure, rectal decompres- Intra-abdominal pressures should be maintained <20 mmHg
sion with possible rectal washouts may decrease intralumi- during primary closure of the defect; otherwise, excess pres-
nal contents and facilitate a smooth reduction. Good sure may limit venous return and/or bowel and renal vascular
long-term outcomes have also been reported using a “suture- insufficiency [274]. Some centers use a balloon-tipped cath-
less ward reduction” protocol with morphine sedation for eter in the bladder or stomach, central venous pressure, or
carefully selected neonates with uncomplicated gastroschi- PETCO2 to track serial changes in intra-abdominal pressure
sis. The bowel is inspected carefully for intestinal anomalies during closure [275, 276]. If the intragastric pressure >20 cm
and the neonate remains conscious during the procedure. H2O or the PETCO2 >50 mmHg the attempted closure, then
The reduction should be abandoned if the neonate develops primary closure should be halted and a staged closure con-
respiratory distress or the surgeon perceives the abdominal sidered—similarly, if the ventilator settings should be noted
pressure is excessive [269]. at the start of the procedure and followed throughout to iden-
tify any decreases in tidal volume due to upward movement Diagnosis

and splinting of the diaphragm. During closure, the bowel As in gastroschisis, the diagnosis of exomphalos is con-
must be constantly assessed for signs of venous congestion. firmed antenatally using ultrasound imaging. Exomphalos is
Urine output can be used to reflect the adequacy of renal per- a midline abdominal wall defect with a sac that contains the
fusion after completing the surgery. After closure but before herniated visceral contents. Antenatal chromosome testing is
leaving the operating room, the lower limbs should be exam- recommended. After delivery, the defect in the umbilical ring
ined for evidence of venous compromise and pulses. is visible, usually with an intact sac. It can be difficult to
visualize externally whether the liver is herniated.
Exomphalos (Omphalocele)
Exomphalos occurs in 1:4000 live births, affecting males 1.5 Outcomes
times more frequently than females. It can be classified as The mortality rate in neonates with exomphalos, 10–30%, is
major, minor, or giant, depending on the size of the defect substantively worse than it is for gastroschisis. However,
and the presence of liver herniation. Major defects are greater unlike gastroschisis in which the severity of the bowel dys-
than 4 cm in diameter or contain a herniated liver. Giant function and ischemia determines the morbidity and mortal-
defects are greater than 6 cm in diameter or contain a herni- ity in that condition, the severity of the associated anomalies
ated liver. Associated anomalies are common, occurring in determines the morbidity and mortality in exomphalos.
more than 50% of neonates, particularly those with a minor There is increasing recognition of the pulmonary complica-
defect. Anomalies associated with exomphalos include chro- tions in exomphalos especially exomphalos major or giant
mosomal abnormalities (30%) such as trisomies 13, 18, and exomphalos due to as-yet-unexplained pulmonary hypopla-
21, other midline defects (pentalogy of Cantrell, bladder and sia or pulmonary hypertension [277].
cloacal anomalies), and cardiac and musculoskeletal abnor-
malities. Beckwith-Wiedemann syndrome, an abnormality Management
found on chromosome 11 associated with gigantism, macro- Supportive management is the initial priority. If the sac
glossia, exomphalos, pancreatic islet cell hyperplasia with remains intact, then the bowels are protected and urgent sur-
hyperinsulinism, organomegaly, and hemihypertrophy, gical intervention is unnecessary. The sac and its contents
occurs in 12% of cases. Pulmonary hypoplasia is associated should be supported depending on its size. Time can be taken
with exomphalos major. to delineate and stabilize the associated anomalies before
proceeding with reduction. If the sac has ruptured, then sur-
Pathophysiology gical intervention becomes more urgent as in the case of
Exomphalos is a central defect of the umbilical ring. The gastroschisis.
herniated organs are covered with a membrane (sac) continu-
ous with the umbilical cord (Fig. 9.15). This is thought to Surgical Considerations
represent the failure of the intestines to retract into the Primary reduction of the contents with excision of sac is
abdominal cavity from the umbilical stalk after the period of usually achievable for small defects, but a staged closure is
rapid growth of the intestines early in embryogenesis. generally required for larger defects. A hand-sewn surgical
silo is placed under general anesthesia, leaving the sac
intact, with serial reductions performed in the neonatal
unit, including after extubation. Once the visceral contents
have been reduced, the silo can be removed and the defect
formally closed in theater. The likely success of primary
closure should be assessed by gentle compression before
excising the sac. If not favorable, then the sac should be left
intact for silo placement. If the sac is excised, care must be
taken superiorly to avoid damaging the hepatic veins, which
may cause a significant hemorrhage. Neonates with giant
exomphalos are occasionally treated conservatively, par-
ticularly if there is marked disproportion between the vis-
cera and the size of the abdominal cavity (typical “scaphoid”
abdomen). The intact sac is allowed to epithelialize, with
topical application of antibacterial sclerosing agents such
Fig. 9.15 Omphalocele. In this midline defect, the herniated bowels
as povidone-iodine or silver sulfadiazine, although sys-
are covered by a thick membrane (Courtesy of Dr. YH Lee, Division of
Pediatric Surgery, Strong Hospital, University of Rochester, Rochester, temic absorption of iodine or silver may themselves create
NY) a problem [278].
326 K. Cross et al.
Anesthetic Considerations ment of a multidisciplinary team. Previously a commonly

The preoperative assessment should include an echocardio- fatal condition, the dramatic advances in neonatal care have
gram and appropriate investigations to fully define the sever- transformed the outcome from this defect to almost 100%
ity of any other anomalies present. Otherwise, the anesthetic survival beyond the neonatal period, although long-term
prescription is similar to that for gastroschisis repair. Neonates issues relating to the function and psychological outcomes
with exomphalos major are particularly at risk for abdominal remain.
compartment syndrome. Reduction of the liver into the abdo-
men can compress the inferior vena cava, acutely decreasing Management
venous return and cardiac output. Intra-abdominal pressure After delivery, care should be taken to avoid damage to the
can be monitored using either a bladder or gastric pressure bladder plate. Moist nonadherent dressings should be applied
transducer (see above) to provide an objective metric upon before transfer of the child to the specialist center, and the
which to stage the reduction. As in gastroschisis, close and umbilicus tied rather than clamped. In cloacal exstrophy,
clear communication between the surgeon and anesthesiolo- exomphalos is managed using the techniques described
gist will ensure a successful reduction. above.
Bladder Exstrophy/Cloacal Exstrophy Surgical Considerations

Bladder exstrophy occurs in 1:30–50,000 live births affect- The long-term aims of surgery are the reconstruction of the
ing males four times more frequently than females. Antenatal bladder for social urinary continence, treatment of vesico-
diagnosis occurs in only 25% of cases [279]. This defect in ureteric reflux, reconstruction of the genitalia to allow for
the anterior bladder and abdominal wall exposes the bladder cosmetic appearance, sexual and urinary function, and, in the
and urethra as part of the exstrophy-epispadias complex case of cloacal exstrophy, reconstruction to obtain fecal con-
(Fig. 9.16). tinence. As a result of the wide diastasis of the pubic bones,
Cloacal exstrophy occurs four to five times less frequently pelvic osteotomies are often required in order to close the
than bladder exstrophy, in 1:200,000 live births. It occurs pelvic brim anteriorly and reduce the risk of wound dehis-
equally in both males and females. Cloacal exstrophy is a cence and bladder prolapse.
lower abdominal wall defect with two hemibladders sepa- Surgery may be performed in staged procedures: the blad-
rated by a midline cecum, exomphalos, and imperforate der is closed early in the neonatal period with or without
anus. Spinal malformations such as myelomeningocele may pelvic osteotomies, depending on surgical preference; the
occur as part of the omphalocele-exstrophy-imperforate genitalia is repaired at 3–6 months of age, in some centers
anus-spinal defect (OEIS) complex. with a radical bladder neck reconstruction at this stage (Kelly
procedure) and a secondary hypospadias procedure at
Outcomes 3 years; and finally, bladder augmentation and ureteric reim-
Optimal outcomes for these rare conditions are obtained by plantation are performed if required in later childhood. If the
centralizing the care to specialist centers, with the involve- bladder closure and osteotomies are performed in a single
procedure, a multidisciplinary approach involving anesthe-
sia, urology, and orthopedics is the prescription for success.
In this case, the anticipated duration of surgery will be quite
prolonged (see below). A single-stage procedure of bladder
closure, bladder neck reconstruction, and epispadias repair
in the neonatal period has been described (Mitchell proce-
dure), although concerns that urethral blood flow may be
compromised with this technique must be considered [280].
The complication rate after single-stage repair is reportedly
similar to those after a staged repair, although soft tissue
defects may be more common in the former [281].
Neonates with bladder exstrophy are usually born at term
without other associated anomalies. Surgery for primary
bladder closure is ideally performed in the first few days of
Fig. 9.16 Bladder exstrophy. This congenital defect in the anterior
life, while the pelvic bones remain malleable. Blood loss is
abdominal wall reveals the bladder wall, malformed genitalia, and wid-
ened pelvis with an absent symphysis pubis (Courtesy of Dr. RJ. Banchs, significant if pelvic osteotomies are performed, and a blood
Children’s Hospital, University of Illinois. Chicago, Ill) transfusion is often required. A plaster cast or external fix-
ator may be applied at the end of surgery for support. Anesthetic Considerations
Although systolic blood pressure remains a reliable metric Cystoscopy and resection of PUV during the neonatal period
for detecting hypovolemia in neonates, central venous is a minor procedure that requires a brief general anesthetic.
access may be a useful adjunct measure to monitor fluid sta- Nonetheless, most prefer to secure the airway in these neo-
tus during this surgery as urine output is not easily quanti- nates with a tracheal tube (rather than a supraglottic device)
fied. Intravenous access should be placed in the upper because the neonate may be positioned either cross-table or
extremities (or neck) to retain access to the lines and to at the end of the operating room table and the duration of
ensure that all fluids remain in the circulation. With the pro- surgery is somewhat unpredictable, dependent on the extent
longed duration of surgery and the need to monitor blood of the pathology. Significant comorbidities such as pulmo-
pressure, perform laboratory tests (hemoglobin, electrolyte, nary hypoplasia and renal dysfunction must be considered
and glucose concentrations), and respond to sudden blood when planning the anesthetic prescription. Antibiotic pro-
loss, arterial access should be considered. Surgery may be phylaxis is essential. A single-shot caudal epidural block can
prolonged (4–6 h or greater). A combination of general provide excellent perioperative analgesia depending on the
anesthesia and epidural anesthesia allows many neonates to extent of the surgery.
be extubated at the end of surgery. Some units advocate the
use of tunneled epidural catheters to facilitate immobiliza- Sacrococcygeal Teratoma
tion and reduce wound complications [282]. Sacrococcygeal teratoma occurs in 1–2:40,000 live births,
representing 35–60% of all teratomas [285]. Females are
Posterior Urethral Valves more commonly affected than males by a 3–4:1 margin
Posterior urethral valves (PUV) are the most common cause (Fig. 9.17). These tumors arise from an embryonic cell line
of lower urinary obstruction in males, occurring more com- in the pelvis that contains cells in different proportions from
monly in non-Caucasians at a rate of 1:5000 live births. the ectoderm, mesoderm, and endoderm [286]. Structurally,
Other less common causes of lower urinary obstruction sacrococcygeal teratomas are classified as cystic, solid, or a
include prune-belly syndrome and urethral stenosis or atre- combination of the two. Cystic teratomas comprise 15% of
sia. PUV are usually an isolated finding that causes severe all sacrococcygeal teratomas, have more differentiated cells,
obstructive uropathy, with 20–60% of these neonates devel- and are usually benign. The majority of sacrococcygeal tera-
oping chronic kidney disease in childhood and 11–51% pro- tomas are solid or mixed (Fig. 9.18). The more solid the
gressing to end-stage renal failure in their lifetime [283]. composition of the teratoma, the more likely it is to be
Severe obstruction and oligohydramnios during lung devel- malignant.
opment (16–24 weeks’ gestation) may cause pulmonary Perinatal mortality in neonates, whose tumors are diag-
hypoplasia leading to substantial fetal and perinatal mortal- nosed antenatally, is 25–37%. Mortality is more likely in
ity (33–75%) [284]. fetuses with rapidly growing vascular teratomas that act
Diagnosis
PUV are frequently identified from the appearance of bilat-
eral hydronephrosis during routine antenatal ultrasound
(accounting for 10% of cases of antenatal hydronephrosis),
although many do not present until later in childhood, with
urinary tract infection, failure to thrive, or continence. Late
diagnosis is associated with less severe renal impairment and
a better long-term prognosis. At birth, renal ultrasound dem-
onstrates a thick-walled bladder and hydronephrosis and pro-
vides an assessment of the degree of renal cortical damage.
The urethral valves can be demonstrated in a voiding cysto-
urethrogram or directly at cystoscopy.
Management
The definitive treatment for PUV in neonates is the relief of
the obstruction by catheterization and antibiotic prophylaxis,
with cystoscopy and transurethral ablation. The results of Fig. 9.17 Sacrococcygeal teratoma. This tumor was located on the
outside of the sacrum, completely external to the pelvis. Consistent
antenatal treatment with vesicoamniotic shunt have been dis-
with the greater incidence of sacrococcygeal teratomas in females, this
appointing to date. Long-term follow-up is required, with neonate was a female (Courtesy of Dr. W. Pegoli, Division of Pediatric
active management of bladder dysfunction and reflux. Surgery, Strong Hospital, University of Rochester, Rochester, NY)
328 K. Cross et al.
Table 9.7 The Altman classification of sacrococcygeal tumors [290]

Type 1—tumor is predominantly external with minimal presacral
component
Type II—tumor presents externally, but with substantial intrapelvic
extension
Type III—tumor is present externally, but the bulk of the tumor is
intrapelvic with extension into the abdomen
Type IV—presacral tumor with no external component
assessment of the external and internal elements of the tera-

tomas (Table 9.7) [290].
Management
Complications associated with sacrococcygeal tumors relate
to their vascularity, size, and position. In utero, the fetus
Fig. 9.18 Excised sacrococcygeal teratoma. The tumor appears to be should be monitored for the development of hydrops and
multiloculated, but mostly solid in this case placentomegaly. These occur in rapidly growing vascular
teratomas that cause a vascular steal syndrome, which in turn
may precipitate high-output cardiac failure necessitating an
physiologically as arteriovenous malformations. These urgent in utero intervention to prevent premature delivery
malformations lead to hydrops, polyhydramnios, high- and/or death. These interventions may include amnioreduc-
output cardiac failure, preterm birth, and death. Two vari- tion, cyst aspiration, radiofrequency ablation, shunts, and
ables suggest a greater risk for a poor prognosis: the ratio surgical debulking [291, 292]. Outcomes after in utero
of the tumor volume to the fetal weight >0.11 determined interventions are similar to those who did not undergo inter-
before 32 weeks’ gestation and tumor morphology <60% ventions, despite the worsened features present in the inter-
cystic [287, 288]. vention group, with a mortality between 25% and 45% [292,
At delivery, 90% of sacrococcygeal teratomas are benign; 293]. Cesarean section is indicated for large tumors, that is,
the minority is malignant. However, the malignancy rate for those larger than the neonate’s biparietal diameter [285].
increases dramatically from 10% at birth to 75% by 1 year of Vaginal deliveries are best avoided in neonates with large
age and 100% by 5 years of age if the tumor is not resected. tumors as the latter may rupture causing the neonate to rap-
Hence, early detection and antenatal intervention or surgical idly exsanguinate. Rectal examination should be performed
excision of the tumor at birth is crucial to achieving long- with great care to avoid rupturing the tumor. Imaging tech-
term survival. niques including abdominal X-ray, echocardiogram, ultra-
The Currarino triad, which is comprised of a presacral sound, and/or MRI will help to define the anatomy, location,
tumor, anorectal malformation, and sacral anomaly, fol- and vascularity of the tumor. Tumor markers should be mon-
lows an autosomal dominant familial inheritance pattern itored (alpha-fetoprotein and beta-HCG): alpha-fetoprotein
from a genetic defect on chromosome 7. Urogenital anom- increases in the presence of a malignancy. These should be
alies have been identified in females with sacrococcygeal followed postoperatively to detect a malignant recurrence.
teratomas and should be suspected in any female with
voiding difficulties [289]. Outcomes
If the sacrococcygeal teratoma is identified as an incidental
Diagnosis finding during the antenatal period, the expected survival
Sacrococcygeal teratomas are often detected antenatally rate is 90%. Mortality approaches 60% in complicated preg-
using ultrasound. Differential diagnoses include meningo- nancies and 100% in the presence of hydrops or placento-
cele, lymphangioma, lipoma, or taillike remnant. At delivery, megaly, which reflects high-output heart failure due to
85–95% of these teratomas are external midline sacral shunting through the vascular teratoma.
masses. The skin covering the mass is usually normal, The prognosis in terms of malignancy depends on the
although hemangiomas, ulcers, and evidence of necrosis tumor type, stage, location (Altman classification), and com-
may be present [285]. Investigations should be performed pleteness of excision, in addition to the child’s age at the
preoperatively to define the borders of the mass within the time of the operation. If the initial resection is performed
pelvis. In older children, the tumor may be entirely intrapel- after the neonatal period, the risk of a recurrence increases
vic, without external evidence of the tumor. The Altman clas- substantially, especially if the serum alpha-fetoprotein con-
sification of sacrococcygeal tumors is based on the postnatal centration is increased. Up to 7% of tumors recur, mostly
within the first 3 years. These tumors recur locally, although tumor, in the context of a neonate who may be premature and
metastases are possible. The long-term prognosis in these have pulmonary hypertension, renal and hepatic impairment,
children, including those with a malignant sacrococcygeal and a coagulopathy associated with high-output cardiac fail-
teratoma, exceeds 80% due to platinum-based multimodal ure. Access to the neonate may be compromised if surgery is
chemotherapy [285]. performed in the prone position. It is essential to make prep-
Poor functional outcomes are becoming increasingly arations for major blood loss with crossmatched fresh blood
recognized with an increased rate of urological and bowel and blood products. Intraoperative cardiac arrest has been
functional issues being identified in >50% of patients. reported from hyperkalemia and hypocalcemia associated
Patients require focused follow-up in this regard and it is with a rapid, massive transfusion, especially when transfused
not clear whether this represents a tumor or surgery effect rapidly through a central venous catheter, and hyperkalemia
[291, 294, 295]. has been associated with surgical manipulation of a necrotic
tumor [296]. Fresh pRBC is preferable and should be trans-
Surgical Considerations fused slowly after warming, preferably through a peripheral
Once the airway is secured, monitoring and vascular access IV rather than a central line. Activation of the major hemor-
(including arterial access) are established, and the bladder is rhage protocol or massive transfusion protocol for neonates
catheterized, the neonate is turned prone (Fig. 9.19a, b). The enables a balanced coordinated approach to a major blood
coccyx should be removed with the tumor for complete exci- loss. Several protocols have been published with proposed
sion of the tumor. If the tumor has a small intrapelvic com- massive transfusion protocols in pediatrics (according to the
ponent, it should be resectable in this position. A combined infant’s weight) including the Starship Massive Transfusion
posterior and abdominal approach may be indicated for protocol from Auckland, New Zealand (https://www.star-
larger intrapelvic tumors or in cases where early vascular ship.org.nz/guidelines/massive-t ransfusion-p rotocol/,
control is required. Bleeding is the major risk for this condi- Accessed April 4, 2021) although these protocols are only
tion and preoperative IR embolization has been advocated in empirical [297–299].
some instances. At the conclusion of surgery, the neonate should be trans-
ferred to the intensive care unit in the prone position. The
Anesthetic Considerations bladder catheter remains in situ for 24 h. The serum concen-
Excision of sacrococcygeal teratoma is a high-risk proce- tration of alpha-fetoprotein should be monitored on a regular
dure, with significant perioperative morbidity and mortality. basis to assess the risk of a malignant recurrence.
In some cases, it may be prudent to have two experienced
anesthesiologists to provide anesthesia for these cases as Biliary Atresia
sacrococcygeal teratomas have been known to hemorrhage Biliary atresia (BA) is the progressive obliteration and
suddenly and massively. The perioperative risks relate pri- sclerosis of the extra- and intrahepatic bile ducts leading
marily to a major hemorrhage from the highly vascular to liver fibrosis, cirrhosis, and death if untreated, occur-
a b
Fig. 9.19 Sacrococcygeal teratoma. (a) Caudal view. (b) Lateral view. the neonate (Courtesy of Dr. W. Pegoli, Division of Pediatric Surgery,
The neonate was anesthetized, the tracheal intubated, and the neonate Strong Hospital, University of Rochester, Rochester, NY)
positioned prone for surgery. Note the large size of the tumor relative to
330 K. Cross et al.
ring in 1:10,000–15,000 live births. Its etiology is Management

unknown; however, environmental and genetic/develop- Once the diagnosis has been made, any coagulopathy should
mental aspects have been proposed [300]. It is associated be corrected and surgery planned. Being a rare condition,
with other anomalies in 15–20% of cases. Biliary atresia best outcomes are usually obtained when these neonates are
splenic malformation syndrome (BASM) occurs in 10% referred to a specialist center. In the UK, children with BA
of cases, with polysplenia or asplenia, cardiac abnormali- should be referred to one of three national specialist centers.
ties, situs inversus, malrotation, preduodenal portal vein, Long-term prognosis is linked to the timing of operative cor-
and absent vena cava [301]. rection of bile flow, so ideally, surgery should be performed
as soon as possible, usually at age 1–2 months. Jaundice usu-
Classification ally clears early in 50–60% of patients. These children have
BA is classified according to the level of obstruction of the a good 5-year prognosis, although liver transplantation may
extrahepatic bile ducts (Table 9.8). Type III is further subdi- be required for those with persistent jaundice or clinically
vided according to the pattern of obstruction of the common significant portal hypertension. Long-term survival is
bile duct (CBD) and distal ducts. The most common type of expected in 90% of cases, although neonates may have
BA is type IIIb. significant long-term morbidity that is related to hepatic cir-
rhosis or the effects of immunosuppression after liver
Diagnosis transplantation.
The key feature of BA is prolonged jaundice (conjugated
hyperbilirubinemia) beyond the first 2 weeks of life with Surgical Approach
signs of biliary obstruction (pale stools and dark urine), in an The initial surgery consists of an open Kasai procedure.
otherwise healthy term neonate [301]. Infants who present Laparoscopic techniques do not appear to offer advantages
later may show signs of failure to thrive due to fat malab- such as fewer adhesions, over the open approach [304–308].
sorption, with coagulopathy due to failure to absorb vitamin The Kasai procedure involves resection of the extrahepatic
K, hepatosplenomegaly, and ascites [302]. The initial meco- biliary tree including the portal plate and the fashioning of a
nium is usually colored, as obstructive jaundice develops Roux-en-Y jejunal anastomosis at this level to restore bile
postnatally. Diagnosis of BA is usually made by liver biopsy flow to the intestinal tract. If the diagnosis is not clear before
or occasionally laparoscopic cholangiogram with the direct the laparotomy, then an intraoperative cholangiogram can be
puncture of the gall bladder, or radioisotope scan to detect performed before dissection [301]. Factors that predict suc-
bile acid in the intestine (hepatobiliary iminodiacetic acid cess after a Kasai procedure include preoperative direct bili-
(HIDA) scan) [301, 303]. rubin <2, absence of liver fibrosis, and limited episodes of
The differential diagnosis of BA includes the choledo- cholangitis [302].
cal cyst, inspissated bile syndrome, and other infective/
metabolic causes of neonatal hepatitis, which should be Anesthetic Considerations
excluded with a TORCH screen, metabolic screen, and Coagulopathy should be corrected preoperatively using vita-
ultrasound. Choledocal cyst is a cystic disorder of min K. Platelets and fresh frozen plasma may occasionally be
unknown etiology affecting the pancreatobiliary system. required as well. Oral neomycin and clear fluids should be
Children may present with jaundice and an abdominal given for 24 h preoperatively. Broad-spectrum prophylactic
mass at any age from birth to adulthood. Without treat- antibiotics are essential before skin incision and for 5 days
ment, this disorder may progress to cholangitis or cirrho- postoperatively to prevent cholangitis (e.g., gentamicin and
sis. The anesthetic considerations are similar to BA, cefoxitin). Isotonic maintenance fluids containing dextrose
although the underlying hepatic function is usually nor- are required to avoid intraoperative hypoglycemia, e.g., 1–5%
mal, apart from obstructive jaundice. dextrose in lactated Ringer’s solution or 5% dextrose in
PlasmaLyte. Transfusion is usual, although massive blood
loss is uncommon. Hepatorenal syndrome has not been
Table 9.8 Classification of biliary atresia
reported in this age group. Ascites is uncommon, but if it
Type I—obstruction at common bile duct (5% of cases)
develops, losses should be replaced with 5% albumin. Active
Type II—obstruction at the common hepatic duct (2% of cases)
warming and invasive access are required as surgery usually
Type III—obstruction of the porta hepatis (>90% of cases)
Subtype a. Patent CBD, atrophic gall bladder takes 2–4 h. An opioid-based/muscle relaxant technique is
Subtype b. Fibrous CBD, atrophic gall bladder ideal, avoiding nitrous oxide to prevent bowel distension. The
Subtype c. Absent common hepatic duct, mucocele of gall surgeon may kink the inferior vena cava during mobilization
bladder of the liver resulting in unexpected hypotension, which may
Subtype d. Miscellaneous require the immediate infusion of additional intravenous flu-
ids or vasopressor infusion to maintain circulatory homeosta- Early signs include feeding intolerance, bilious vomiting
sis. At the end of the surgery, the tracheas of most neonates or increased nasogastric aspirates, abdominal distension with
can be extubated. These neonates are best managed in a high- or without tenderness, hemodynamic instability, and blood
dependency unit with morphine analgesia [309]. per rectum (Fig. 9.20). Thrombocytopenia, coagulation
abnormalities, and increased inflammatory markers such as
Necrotizing Enterocolitis C-reactive protein are common. Radiological investigations
Necrotizing enterocolitis (NEC) is the most common surgi- are often helpful in confirming the presence of
cal neonatal emergency affecting up to 0.5% of all live births NEC. Pathognomonic findings of NEC on abdominal X-ray
and 10% of low-birth-weight (<1500 g) live births [310]. The include distended loops of bowel, pneumatosis intestinalis,
overall incidence of NEC, both medical and surgical, appears and portal venous gas with or without free perforation
to be steadily decreasing, along with the mortality rates (Fig. 9.21). The value of ultrasound and other imaging modal-
[311]. Advances in neonatal care have improved survival ities as diagnostic or prognostic tests has yet to be established;
rates for premature and low-birth-weight infants, as well as however, US may be a useful adjunct [317]. Recent labora-
those affected by this disease. tory investigations have identified several biomarkers that
herald the onset of NEC/sepsis [318, 319]. Such insights may
Pathogenesis provide the basis for future studies to identify biomarkers that
The etiology of NEC remains unclear although risk factors will identify a neonate’s risk of developing NEC.
include prematurity, early formula feeding, cardiac disease,
low birth weight, transfusion in the preceding 48 h (transfusion- Outcomes
associated NEC), and sepsis [312, 313]. Breast milk appears Despite early and aggressive therapy and support, the mor-
to be protective, likely due to transferred immunoglobulins. tality from NEC remains substantial, in our local series rang-
Multiple gut factors predispose to the development of NEC in
preterm neonates including dysmotility, abnormal microbiota,
reduced mucin barrier, increased gut permeability, decreased
immunoglobulins and gut immunity, increased risk of isch-
emia, and slow gastric emptying [314, 315]. This in turn may
facilitate bacterial translocation across the bowel wall trigger-
ing an inflammatory cascade that results in ischemic damage
to the bowel. The pathological organisms are often endoge-
nous bowel flora, suggesting an imbalance in the defensive
mechanisms rather than a specific virulent organism, although
clusters of cases have been known to occur.
Diagnosis
NEC is primarily a clinical diagnosis [310]. It is classified
according to the criteria described by Bell (Table 9.9) [316].
Table 9.9 Bell classification for diagnosing NEC [316]

Stage IA—suspected disease: temperature instability, increased
aspirates, mild distension; radiology normal or dilated loops
Stage IB—as above, with bright red blood per rectum
Stage IIA—proven NEC, mildly ill: as above with absent bowel
sounds, ± abdominal tenderness; radiology shows intestinal
dilatation, ileus, pneumatosis intestinalis
Stage IIB—proven NEC, moderately ill: mild metabolic acidosis,
mild thrombocytopenia, absent bowel sounds, abdominal tenderness
+/− redness of abdominal wall or abdominal mass; radiology shows
portal vein gas +/− ascites
Stage IIIA—advanced NEC, severely ill: as above with
hypotension, bradycardia, metabolic acidosis, disseminated
Fig. 9.20 NEC in a premature neonate. This neonate developed NEC
intravascular coagulation, neutropenia, generalized peritonitis,
and a distended abdomen. Note the “rectus muscle-sparing” lines sepa-
tenderness and distension; radiology as above with definite ascites
rated from the erythema of the anterior abdominal wall (Courtesy of Dr.
Stage IIIB—advanced NEC, severely ill with perforation: as above YH Lee, Division of Pediatric Surgery, Strong Hospital, University of
with pneumoperitoneum on abdominal X-ray Rochester, Rochester, NY)
332 K. Cross et al.
Definitive studies for managing NEC once it has occurred

are lacking, and treatment has been determined by expert
consensus and the neonate’s clinical condition [329]. The
first-line treatment is medical, targeting sepsis and prevent-
ing further intestinal damage. The neonate is kept nil by
mouth for 7–10 days, with a nasogastric tube in situ to
decompress the stomach, intravenous broad-spectrum antibi-
otics, and appropriate cardiorespiratory and hematological
support. Nutritional challenges can be addressed using total
parenteral nutrition (TPN).
It is important to appreciate a little known risk of red cell
hemolysis when considering to transfuse with fresh frozen
plasma or blood products with plasma [330]. The T antigen,
also known as the Thomsen-Friedenreich (or T) c ryptantigen,
is a naturally occurring but concealed red cell antigen
(cryptantigen) that becomes activated when bacteria (e.g.,
streptococcus, pneumococcus, and Clostridium perfringens)
carrying neuraminidase activate the T antigen. Transfusion
of plasma that contains immunoglobulin M anti-T antigen
Fig. 9.21 Lateral radiograph of a neonate with NEC. The neonate was
binds this activated T antigen causing polyagglutination and
positioned in the left lateral decubitus position with a multi-orifice gas- red cell hemolysis. Activated T antigen is present in approxi-
tric tube in the stomach. Free air is evident against the right (upper) mately 11–27% of neonates with NEC, with a greater fre-
lateral abdominal wall, outlining the liver and falciform ligament quency in more severe NEC (category III NEC 30% vs. II
(Courtesy of Dr. YH Lee, Division of Pediatric Surgery, Strong Hospital,
University of Rochester, Rochester, NY)
4%) [331, 332]. The magnitude of the risk of T antigen in
neonates with NEC is unclear, although many clinicians
avoid transfusing plasma-rich blood products to these neo-
ing from 30% to 90% with pan-intestinal disease [320]. In a nates and many blood banks screen plasma for antibodies to
large prospective study, perioperative mortality was 30% for T antigen and release only plasma with low or no titers of T
all neonates with NEC, compared with 6% in those managed antigen to neonates with NEC. Nonetheless, any child with
medically [320, 321]. The mortality rate in neonates who NEC who develops hemolysis after a transfusion should be
were treated with primary peritoneal drainage alone was investigated to identify the cause, not overlooking the possi-
50%. A multicenter retrospective review between 2006 and bility that activated T antigen is the putative agent [333].
2017 in the USA suggested mortality from NEC has been Surgical intervention is required in 10–20% of neonates
steadily decreasing along with the incidence of NEC, as well with NEC, increasing to 50% in very low-birth-weight neo-
as the mortality from any primary peritoneal drainage, now nates. The indications for surgery include serial examina-
at 35% [311]. Significant morbidity occurs in up to 25% of tions that indicate worsening physiological parameters or
operative neonates, including stricture formation and failure failure of medical treatment. The precise indications for sur-
to thrive, and in those who require extensive resection, short gery remain controversial; ideally, surgery is indicated for
bowel syndrome, and long-term requirement for parenteral the presence of gangrenous bowel, before it has perforated
nutrition with the associated risk of liver disease and sepsis [310]. However, there are no reliable metrics to define such a
[322]. Neonates with NEC may also experience worse neu- clinical scenario. Absolute indications for surgery include
rological outcomes, particularly those with advanced disease evidence of perforation, clinical deterioration despite maxi-
that require surgical intervention [323]. A recent review has mal medical therapy, an abdominal mass with persistent
confirmed poor outcomes including high mortality support- obstruction or sepsis, and the presence of an intestinal stric-
ing ongoing research into this condition [324]. ture. Relative indications include abdominal tenderness, dis-
tension or discoloration where the clinical diagnosis may be
Management in doubt, the finding of portal venous gas on plain abdominal
The primary approach to NEC is to adopt strategies that pre- X-ray, a fixed intestinal loop, and thrombocytopenia.
vent the disorder. Such strategies include standardized enteral
feeding, exclusive use of human breast milk and milk-based Surgical Approach
fortifiers, minimal antibiotic exposure, minimal gastric acid The surgical objectives are to control sepsis, to excise
blockade therapy, and the use of high-quality probiotics, if the necrotic bowel, and to preserve intestinal length [310, 322].
preceding measures fail [314, 325–328]. A laparotomy remains the mainstay approach for most neo-
nates with NEC. In the very low-birth-weight group tory instability, DIC, and sepsis requires meticulous prepara-
(<1000 g) with evidence of perforation, peritoneal drainage tion. In the operating theater, anesthesia may be induced
has been proposed as either an interim or definitive alterna- using an opioid such as fentanyl in incremental IV doses of
tive to laparotomy, although a systematic review suggested 5–10 mcg/kg up to 12.5–25 mcg/kg and/or ketamine 2–4 mg/
that this was associated with increased morbidity and should kg and rocuronium [336]. The clearance of fentanyl decreases
be used as an interim approach only [334]. The clinical insta- with decreasing gestational age in neonates with normal
bility of these neonates warrants consideration of surgery on intra-abdominal pressure [337]. Inhalational anesthetics are
the NICU to avoid iatrogenic deterioration. Surgical options infrequently used in neonates with NEC as these surgeries
at laparotomy include resection with enterostomy, resection are often performed in the NICU without access to anesthe-
with primary anastomosis, a proximal diverting jejunostomy sia workstations and because these neonates are often hemo-
for extensive disease, and “clip and drop” or the watch and dynamically unstable. A balanced salt solution (10–20 mL/
wait with possible “second look” laparotomy [310, 322]. The kg) should be administered before induction of anesthesia to
extent of the disease, the stability of the neonate, and the prevent hypotension as anesthesia is induced. More recently,
surgeons’ experience/preference will determine which of remifentanil has been investigated in preterm neonates [338,
these options are undertaken. For a stable neonate with focal 339]. The duration of action of remifentanil in premature
or multifocal disease, a resection with anastomosis is appro- neonates between 24 and 41 weeks’ gestation is similar to
priate. For an unstable neonate in whom the viability of the that in full-term neonates, 5–10 min. This has been attributed
distal bowel is uncertain, a stoma may be fashioned. In the to the similar activity of nonspecific tissues esterases
presence of pan-intestinal disease (>75% of the small and throughout gestation [340]. Animal evidence also suggests
large bowel involved), either a proximal diverting jejunos- that remifentanil may effectively attenuate ischemic-
tomy or the “clip and drop” approach requiring a repeat lapa- reperfusion injury in the intestines [341]. If true in humans,
rotomy in the next few days is performed. NEC is responsible remifentanil may provide a salutary effect in neonates with
for one-third of the cases of surgical short bowel syndrome potentially ischemic bowel. Before anesthesia is discontin-
in NICU. Although mortality has been substantial in these ued, a longer-acting opioid should be administered to pro-
neonates, a multifaceted approach to resting and preserving vide postoperative analgesia.
bowel function, nutrition, infectious prophylaxis, and surgi- Surgery may be performed in the operating room or in
cal consultation dramatically improved survival [267]. A the NICU (see Anesthesia Outside the OR, Chap. 12).
general guide for the ability of the gut to support enteral Indications for surgery in the NICU include minor proce-
feeds long term is the presence of 30 cm of bowel with the dures (insertion of a peritoneal drain); a very small, unstable
ileocecal valve or 50 cm without [310]. In extreme cases neonate; and ventilation with HFOV. For anesthesia in the
where the entire intestine is necrotic, withdrawal of care may NICU, a TIVA technique is required. In such cases, incre-
be an important consideration. mental doses of IV fentanyl (10–20 mcg/kg) or a remifent-
The neonatal liver is fragile and often enlarged in these anil infusion, together with ketamine and rocuronium,
infants. Aggressive perioperative resuscitation can result in should provide hemodynamic stability and adequate surgi-
hepatic engorgement and may result in capsular rupture and cal conditions. The extent of the procedure depends on the
life-threatening hemorrhage. Surgical handling can also have hemodynamic stability of the neonate, and close coopera-
similar catastrophic consequences. The laparotomy incision tion among the surgeon, neonatologist/intensivist, and anes-
may be performed more caudally or obliquely especially in thesiologist is required at all times.
extremely low-birth-weight infants, to lie below the liver Inotropic support (dopamine, dobutamine, epinephrine,
edge. Strict avoidance of liver instrumentation can help or norepinephrine) is often required, in neonates with
decrease the risk of hemorrhage. In the face of uncontrolled NEC. In order to accurately monitor the responses to this
bleeding, ice and pack compression of the abdominal cavity support, arterial pressure monitoring is highly recommended.
should be considered. The inotropic support should be tailored to the neonate’s
Laparoscopy may be used as a diagnostic tool in NEC if requirements and titrated to the desired endpoint [342]. In
the neonate is stable, if there are signs of obstruction, and if addition, venous access large enough to rapidly deliver blood
the diagnosis is uncertain. Some have attempted gasless lap- products should be secured. Albumin 5%, blood, platelets,
aroscopic surgery to diagnose and manage NEC in neonates and clotting factors may be required before or during sur-
with limited success [335]. gery. Warmed IV fluid boluses of 10–20 mL/kg should be
given depending on the clinical condition of the child and
Anesthetic Considerations measured losses, guided by the results of arterial blood gas
Laparotomy for NEC in a premature neonate <1000 g pro- estimation. Since these neonates are often of very low birth
vides a significant challenge for the anesthesiologist. The weight, their albumin levels are reduced. Balanced salt solu-
potential for rapid blood loss in a neonate with cardiorespira- tions may be used to replace small fluid shifts but are best
334 K. Cross et al.
limited in volume administered to preclude exacerbating pre- Table 9.10 Conjoined twin variants
existing hypoalbuminemia and dilutional coagulopathy. If Type of Incidence of
large volumes of fluid are required (up to 50 mL/kg), it is conjoined twin variant (%) Anatomical description
prudent to switch from balanced salt solutions to albumin Thoracopagus 42 Face to face, joined thorax to
umbilicus, always involves the
and blood products early to maintain the hematological and heart
coagulation profile. At the same time, care must be taken to Omphalopagus 5.5 Umbilicus, never involves the heart
avoid over-transfusing the child, as this could open a ductus Pygopagus 1 Sacrum and perineum
arteriosus or risk catastrophic bleeding from a distended Ischiopagus 1.8 Joined at the lower abdomen and
liver. The neonate may remain critically ill after surgery has duplicated fused pelvic bones
requiring full intensive care support. Mild controlled hypo- with external genitalia and anus
always involved
thermia may be a therapeutic option in neonates with multi-
Craniopagus 5 Joined at the skull and share
ple organ dysfunction [343]. meninges, does not include the face
and trunk
Parapagus 2.9 Extensive side-to-side fusion, lower
Conjoined Twins abdomen and pelvis ± thorax; two
subvariants as shown in Fig. 9.10:
diprosopus refers to duplication of
Introduction the face (partial or total) and
Conjoined twins present an extreme clinical, logistical, and dicephalus refers to duplicate heads
ethical challenge for both the surgical and anesthesia teams. Rachipagus Extremely Dorsally fused and may involve
rare, 1 cervical vertebrae and occipital
Successful management of these children requires a multidis-
bone
ciplinary team in a close working relationship. Antenatal Cephalopagus 5.5 Head to umbilicus—extensive
diagnosis is usually possible to prepare and meticulously plan anomaly usually unsurvivable.
for surgery at an experienced center. There is often a need for Overall, fusion is predominantly on
surgery to be performed after the first few months of life. the ventral side (87%), less
commonly dorsal (13%)
Occasionally however, emergency procedures or investiga-
tions that require anesthesia may be required in the neonatal
period, or very rarely can present unexpectedly after birth. natal period. After birth and assessment, conjoined twins are
divided into three groups based on their survival and urgency
Epidemiology of surgery (Table 9.11)
Conjoined twins occur in 1.47 per 100,000 live births. Emergency procedures that may be anticipated for con-
Stillbirth is common with these defects. Females outweigh joined twins include those carried out to defunction bowel or
males by a factor of about 3 to 1 and are more likely to sur- relieve gastrointestinal or urinary tract obstruction. Rarely
vive birth. Approximately 35% of live births die within 24 h emergency separation is considered when severe cardiac
of birth, with 18% surviving beyond this. Conjoined twins defects require it or when one twin is dying. Such surgery
occur sporadically. The pathogenesis of conjoined twins is carries a high mortality of 40–80%.
most likely from abnormal splitting of the blastocyst after Larger defects are usually internally more complex. If
the 12th day of gestation. organ function allows, they are separated closer to 1 year of
Conjoined or symmetric twins (as opposed to parasitic age when the infant has grown in relation to the size of the
twins) are classified by their site of attachment. A commonly defect. Cardiac involvement is associated with a poor prog-
used classification system with eight subtypes was described nosis. Conjoined twins may also present for anesthesia in the
by Spencer as listed in Table 9.10 [344] and illustrated in neonatal period for vascular access, for investigations for
Fig. 9.22. A worldwide incidence of each type has also been surgical planning, or for separation of very minor defects.
reported [345–347].
Management
Presentation The management of conjoined twins is complex and chal-
Conjoined twins can be identified on antenatal ultrasound as lenging. Ethical, legal, and potentially psychological chal-
early as 8 weeks’ gestation, although false positives are com- lenges are ever present for the team, patients, and families in
mon before 12 weeks. When the diagnosis has been con- addition to the anatomical and physiological issues. Not all
firmed, further antenatal imaging can assist with delineating conjoined twins are amenable to surgery; many are unsuit-
the anatomy, including fetal MRI, echocardiography, and able for separation because of ethical considerations or unfa-
ultrasound. Delivery is ideally undertaken close to term in or vorable anatomy. Safe management of conjoined twins
near to a center with expertise in managing and separating requires a multidisciplinary team approach involving sur-
conjoined twin. Surgical planning can start during the ante- gery, anesthesia, radiology, intensive care, pediatric medi-
Ventral conjunctions
Rostral
cephalopagus Thoracopagus Omphalopagus
Caudal Lateral Lateral

Ischiopagus Parapagus diprosopus Parapagus dicephalus
Dorsal conjunctions
Craniopagus Rachipagus Pygopagus
Fig 9.22 Pictorial illustrating each of the eight variants as described by Spencer, with two subvariants of parapagus [With permission. Pattanaik
HP, Parida S, Mohapatra M Conjoined twin: review with a case report. Medico-legal update, October-December 2020, Vol 20, No.4]
336 K. Cross et al.
Table 9.11 Results of treatment of conjoined twins ing and can be lost during successive cannulations for inves-
Group 1—unsurvivable or not for surgery tigations. Thoraco-omphalopagus twins will not have
Group 2—planning for elective surgery umbilical vessels that can be used for emergency neonatal
Group 3—requiring emergency surgery access. Central access is optimal for major surgery, both
intraoperatively and in the postoperative period. This should
cine, cardiology, ethics and legal team, nursing and other be jugular for thoracic and abdominal surgery. If necessary,
therapies, as well as the hospital communication or media interventional radiology can place longer term lines for nutri-
team to support the family and to maintain confidentiality. tion, antibiotics, and sampling postoperatively, but these usu-
Ideally there should be a designated team leader and the ally have narrow lumens and may be unsuitable for theater.
team should begin meeting as soon as a set of twins are iden-
tified in the event that urgent surgery is required during the Preoperatively Assessment
neonatal period [348, 349]. Each twin should have a dedicated consultant anesthetist
The anatomical challenges relate primarily to the area of who will attend planning MDTs and undertake a detailed
fusion and shared organs. Delineating the extent of organ preoperative assessment of “their” twin. Counseling and
involvement often requires detailed radiological investiga- consenting the parents need only be done once.
tions, some of which may require general anesthesia. These Useful preoperative investigations include complete blood
can include radionuclide tests, MRI, CT, angiography, ultra- count, coagulation profile, U&E and liver function tests (and
sound, and echocardiography [350]. Relatively new technol- other assessments of renal and hepatic function), fasting
ogies such as 3D imaging and printing can assist surgical blood sugar, crossmatch, chest X-ray, and echocardiogram.
planning. Despite detailed preparation, unexpected issues
are commonly encountered intraoperatively and the team Theater Setup
need to be prepared for this. As part of the preoperative planning, the anesthesia team
should understand the surgical steps, which personnel will
Anesthesia Issues be involved and at what stage, and what positioning will be
Anesthesia may be required in the neonatal period for elec- required. Care should be given to the setup of the equipment
tive procedures, for emergency surgery, or rarely for full in the operating theater including the position of the anesthe-
separation [351]. sia machines and ventilator tubing and lines. The surgical
team need good access to the babies and the anesthesia team
Logistics need to have secured the airways and any IV lines and be
Two distinct anesthesia teams will be required for each and able to easily access these wherever possible. Theater lights
every anesthetic until after separation. Two anesthesia and equipment such as diathermy, suction, or cell salvage
machines and two sets of equipment will be required at every will need to be considered for both twins.
location. Some remote areas such as imaging suites will not Simulation with the full team can be extremely useful
be well set up for this and alternative arrangements need to with a “dry run” including the use of mannequins for all
be considered beforehand. Labeling or color coding machines steps from ward transfer through induction, operative proce-
and equipment are very helpful. Having personnel with con- dures, and positioning to transfer postoperatively, being very
joined twin expertise is vital, but sharing knowledge for suc- helpful for planning and familiarity with the setup prior to
cession planning is also very important since these cases are surgery. This can also allow potential trouble points to be
rare even in larger centers. identified. Two full teams of staff (anesthetic, anesthetic
assistants, surgeons, scrub staff, runners) are required for
Airway each twin and must be allocated. The use of different colored
The orientation of conjoined twins can result in challenging theater caps or similar can help identify each team’s mem-
airway management, particularly when face to face or where bers [352].
there is high thoracic involvement or neck abnormalities. For separation surgery one twin will require transfer to a
Supraglottic airway devices can be useful for rescue man- separate operating table after separation for the reconstruc-
agement or for anesthesia for imaging. Information about tion and will therefore usually be transferred to an adjacent
airway management for separation surgery can be gathered theater. It is important to set this area up in advance and to
during anesthesia for pre-separation investigations. If neces- decide which twin will move and how sterility will be main-
sary, videolaryngoscopy, ENT assistance, or elective trache- tained on transfer. The twin with the more robust cardiovas-
ostomy can be considered. cular circulation and physiology is often the designated twin
to be moved which should be planned in advance.
Vascular Access and Blood Loss Holding a thorough team brief on the day is vital so that
Separation surgery is long and can be associated with large the whole team can introduce themselves, establish roles,
fluid shifts and blood loss. In addition, veins can be challeng- outline the plan for surgery, and discuss what may go wrong.
In the event of emergent surgery it may not be possible to secured and every lumen should be accessible and all clips
follow all these steps but it is helpful for the whole depart- opened. Peripheral access is preferable in the upper limb
ment to know that a set of conjoined twins are in the hospital since lower body blood vessels may be damaged or ligated
and to know who to call if there is an emergency. A verbal intraoperatively.
“dry run” in an emergency planning meeting is usually still
possible even in truly emergent situations. Monitoring
Usual anesthetic monitoring should be applied before
Conduct of Anesthesia induction of anesthesia. An arterial line is inserted in both
Conjoined twins share a circulation and shunting from one twins after tracheal intubation. This enables close hemody-
twin to another occurs. Sometimes this is very apparent pre- namic monitoring and regular blood sampling to check
operatively and sometimes this becomes apparent during fluid and acid-base status. Electrocardiographic monitoring
anesthesia and surgery. It is rarely predictable from preop- may be difficult because of surgical access. Urine output
erative imaging, except where one twin has a cardiac defect. can be difficult to monitor in the presence of pelvic abnor-
The degree of shunting can affect the rate of onset of anes- malities, during renal tract surgery, and because of the
thesia and the response to medications. Differing heart rates small size of the babies, but it should be recorded where
are common. possible or documented as being present. Temperature
Despite this shared circulation, it is safest to consider should be monitored and NIRS may be useful depending on
each twin as an individual and the anesthetic management the site of conjoining.
should proceed with that in mind.
Fluids and Blood
Induction Emergency neonatal abdominal surgery has been described
Induction usually occurs in the operating theater unless the elsewhere in the chapter. Fluid loss can be considerable.
babies have already required intubation and sedation on the Fluid will need to be warmed and electrolytes and acid-base
NICU. It can be helpful to ask other personnel to leave dur- measured to assess adequacy of fluid replacement. Hourly
ing anesthesia to avoid distractions since good communica- maintenance fluid will also be required. Hypoglycemia is
tion is absolutely vital. common in neonates and a dextrose-containing fluid should
Despite the shared circulation, induction should occur be infused throughout.
simultaneously. Drug doses are calculated as half of the com- Surgery to separate the neonates is often quite prolonged,
bined weight but each baby may show a different response. often exposing large sections of bowel and abdominal vis-
Either inhalational or IV induction is suitable but nitrous cera for extended periods. Blood loss is common. Blood
oxide should be avoided as it may distend the bowel. After should be crossmatched for each twin and administered sep-
securing venous access, neuromuscular blockade should be arately to each twin as a gold standard, despite part or all of
administered simultaneously. their circulations are shared. This can be bypassed in an
emergency and the same unit of blood safely administered to
Airway either baby before separation. As a result of shunting, one
Intubation should occur one after another. If there is diffi- neonate may show an exaggerated response to blood or fluid
culty maintaining an airway with a bag and mask, adjuncts administered compared with the other or have a diuresis.
should be used or an LMA can be inserted. Once the first of Massive transfusion can be an issue. The neonatal myo-
the twins is stabilized, the second twin should be positioned cardium is sensitive to hypocalcemia and this should be
for tracheal intubation. On occasion, this will involve consid- immediately treated and coagulopathies corrected.
erable manipulation of the first twin. Short handle laryngo-
scopes and videolaryngoscopy can be helpful. Prone Antibiotics
positioning is likely at some stage so a reinforced or nasal These should be administered according to surgical request
tracheal tube is preferred; the nasal route is often preferred and local policy and are continued into the postoperative
for long-term ventilation postoperatively. Both tubes should period. Usually more than one dose will be required during
be well secured and auscultated in a range of positions. long separation surgery.
Lines Inotropes and Resuscitation

As mentioned previously, large bore venous access is neces- Surgical separation causes profound changes in shunting
sary for fluid and blood administration and for monitoring. affecting preload and afterload. Inotropes are often required
Inotropes are commonly required in the presence of intracar- and these can include adrenaline and milrinone. Knowledge
diac shunting and cardiac management. Vasodilators may be of any coexisting cardiac defect may influence inotrope
required for hypertension after separation. Lines should be selection.
338 K. Cross et al.
In the unfortunate event of a malignant arrhythmia, cardio- Postoperative Care

version of one twin may result in an arrhythmia in the other; Postoperatively the neonates will be best managed in an ICU
therefore, two defibrillators should always be available. setting, even after relatively simple bowel defunctioning
surgery. After separation surgery, the trachea remains intu-
Surgical Considerations bated, and the lungs ventilated. On occasion, the neonate
The surgical principles should follow a similar approach to may remain paralyzed to allow recovery and ongoing fluid
those for anesthesia with both twins considered separately. management. Large wounds are usually closed with syn-
The anatomical arrangement will determine practicalities of thetic polyethylene or polypropylene material and require
surgery. Twins with cardiac involvement, which would not serial “tucks” to achieve full skin closure.
allow separation or with a single portal system, are not con-
sidered separable.
The specific surgical team will be determined by the Summary
organs involved and for those with abdominal and pelvic
fusion will involve the general surgeons, the urologists, plas- Neonatal anesthesia for conjoined twins is very rare and usu-
tic surgical team, and potentially orthopedic surgeons. The ally carried out at a specialist center for investigations and
exact surgical procedures which may be required can be par- emergency surgery. Excellent communication, planning, and
tially planned from the imaging although it can be difficult to multidisciplinary teamwork are essential as logistical chal-
ascertain the exact level of bowel involvement and fusion lenges exist at every stage. Airway management, vascular
until surgery. The initial incision for separation will usually access, and blood loss are major considerations even for the
be from the “back” through skin and muscle, requiring the most experienced anesthesiology team.
patients to then be turned over while maintaining sterility
(with careful preservation of vascular access and the air-
ways) to allow further incision, exploration, and proceeding References
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332. Hall N, Ong EGP, Ade-Ajayi N, et al. T cryptantigen activation is 351. El-Elah KA, A. Management of conjoined twins during neonatal
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laparotomy as initial surgical treatment for perforated necrotiz-
Neurosurgery and Ophthalmology
10
David N. Levin and Sulpicio G. Soriano
Introduction Primary neurulation occurs when the neural plate forms the
ectoderm folds and fuses dorsally. The walls of neural tube
The central nervous system (CNS) and visual system undergo give rise to the brain and spinal cord. The neural canal
extensive structural and physiological changes during the develops into the ventricles and central canal of the brain
first year of life. Neonates have unique features in cranial and spinal cord. Fusion of the cranial neural folds and clo-
bone development, cerebrovascular physiology, and congen- sure of the cranial neuropore give rise to the forebrain, mid-
ital lesions, which impact the conduct of anesthesia. Neonates brain, and hindbrain. Closure starts near the cervical spine
are at greater risk than any other age group for morbidity and region and extends cephalad and caudad. Closure of the
mortality during the perioperative period due to respiratory neural tube begins at 22–23 days of gestational age, with
and cardiac-related events [1]. This risk is increased further complete closure around days 26–27. Failure of the anterior
when the indication for surgery includes neuropathology [2]. neuropore to close results in anencephaly and dermoid/der-
Therefore, an organ system-based evaluation, detailed in mal sinus tracts, whereas posterior defects lead to encepha-
preceding chapters, must be performed to rule out congenital loceles and myelomeningoceles. Most defects occur along
anomalies or coexisting pathology that may impact the con- the lumbosacral region but can arise at any level, including
duct of anesthesia and outcome. the thoracic and cervical segments. Secondary neurulation
starts after primary neurulation is completed and forms the
lower sacral and coccygeal segments. Derangements in this
evelopment of the Central Nervous
D progression can lead to closed spinal dysraphism (spinal
and Visual System bifida occulta and tethered cord). The incidence of neural
tube defects is approximately 2–5/1000 live births.
Embryology Outcome studies reveal increased perioperative morbidity,
mortality, and cognitive deficits in neonates with congenital
The development of the central nervous and visual system neurological lesions [2, 6–8].
occurs in parallel early in gestation [3]. Derangement in this Eyes develop between the 3rd and 10th week of gestation.
process leads to congenital lesions of the CNS and eye [4]. The retina, iris and ciliary body epithelia, optic nerve, smooth
Therefore, a basic understanding of embryology will provide muscles of the iris, and a portion of the vitreous humor arise
insight into a majority of neurosurgical and ophthalmologi- from the cephalic region of the neural tube ectoderm. Surface
cal lesions. ectoderm gives rise to the lens, conjunctival and corneal epi-
Neurulation is the fundamental process where the neural thelia, eyelids, and the lacrimal apparatus. The remaining
plate folds and bends dorsally to form the neural tube [5]. ocular structures arise from the mesenchyme.
D. N. Levin Cerebrovascular Physiology

Hospital for Sick Children and University of Toronto,
Toronto, ON, Canada Cerebral autoregulation is fully developed in the healthy
term neonate. However, in the neonate with coexisting dis-
S. G. Soriano (*) ease such as prematurity, hypoxic brain injuries, intracranial
Boston Children’s Hospital and Harvard Medical School,
hemorrhage, traumatic brain injury, neurovascular anoma-
Boston, MS, USA
e-mail: [email protected] lies, inflammatory processes, and congenital heart, cerebral

348 D. N. Levin and S. G. Soriano
hemodynamics may be seriously impaired. Although the Metapic

theoretical autoregulatory range of blood pressure in infants Coronal
is lower than that in adults due to the relatively low cerebral
metabolic requirements and blood pressure in infancy, recent
Sagittal
evidence demonstrated heterogeneity in the lower limit of Squamous
autoregulation in pediatric patients [9]. Furthermore, cere-
bral autoregulation may be absent and replaced by pressure-
passive CBF in critically ill, premature, low gestational age,
and/or low birth weight neonates [10]. Systolic arterial blood
pressure is a poor indicator of cerebral perfusion pressure in Lambdoidal
these patients, and the diastolic closing pressure may be a
better surrogate [11]. Extremes in blood pressure can lead to
Normal cranial sutures in infancy
cerebral ischemia and/or intraventricular hemorrhage and
dictate rigorous control of hemodynamics.
Cerebral blood flow (CBF) in the healthy neonate is sig-
nificantly less than that in adults and doubles in the first
2 days of life in parallel with increases in cardiac output [12].
intracranial pressure
Cerebral metabolic requirement for oxygen (CRMO2)
increases with gestational age [13]. However, non-invasive
indices of CRMO2 demonstrate that neonates with birth inju-
ries have significantly greater cerebral requirement for glu-
cose (CMRGlu), which continues to increase with gestational
age. These ontological changes in CRMO2 and CMRGlu are
reflected in CBF values derived from brain perfusion CT
scans [14]. The variance in these values is as great as those in
the CBF and the lower limit of autoregulation noted above.
intracranial volume
Thus, population-based averages are poor surrogates for indi-
vidual target values and requirements. Cerebrovascular reac- Fig. 10.1 Compliant and open sutures and fontanelles permit slow
tivity to carbon dioxide appears to be normal in healthy expansion on the intracranial volume and gradual increases in intracra-
neonates, but may be deranged in the setting of perinatal nial pressure. Intracranial hemorrhages or obstructed cerebrospinal
fluid flow led to life-threatening elevations of intracranial volume and
asphyxia or prematurity [15]. Inspired concentrations of oxy-
pressure
gen (FIO2) have an impact on CBF [16]. Premature neonates
are also vulnerable to the detrimental effects of high FiO2 due
to liberation of reactive oxygen species leading to broncho- sutures leads to a variety of craniosynostoses, which are best
pulmonary dysplasia and retinopathy of prematurity [17]. surgically corrected early in infancy with endoscopic tech-
niques or cranial vault remodeling at a later age [20, 21].
Neonates are also distinguished in that their calvarium
Anatomy of the CNS and Eye remains open after birth. This allows parenchyma and ven-
tricles to grow without increasing pressure within the skull.
Cranium Fontanels oscillate with the heart rate, which reflects intra-
The intracranial space in neonates is compliant. The compli- cranial volume expansion with each cardiac cycle. The
ance stems from the presence of open fontanelles and fibrous arachnoid villi begin to develop after birth, playing an impor-
unfused sutures. The posterior and anterior fontanelles close tant role in resorbing CSF in adults [2]. Premature neonates
in sequence, the former from 0 to 4 months and the latter and those with underlying calvarial or parenchymal pathol-
from 12 months to 18 months, respectively. Therefore, grad- ogy exhibit abnormal dural compliance and may be more
ual increases in intracranial mass due to hydrocephalus, susceptible to increased ICP [3]. Between 50% and 80% of
hemorrhage, and tumor may not cause symptomatic increases the cerebrospinal fluid (CSF) surrounding the brain and spi-
in ICP due to compensatory distension of the fontanelles and nal cord is secreted by the choroid plexus, which lines the
widening of the cranial sutures (Fig. 10.1). However, given floor of the lateral ventricles and the roof of the third and
the diminutive neonate and infant intracranial volume, acute fourth ventricles. Up to 30% of the CSF can be formed in
increases in cranial content due to blood or cerebrospinal other sites such as ependyma, brain parenchyma, and endo-
fluid can still result in life-threatening intracranial hyperten- thelium of cerebral capillaries. The CSF produced by the
sion [18, 19]. Conversely, premature ossification of the choroid plexus flows from the lateral ventricles, through the
10 Neurosurgery and Ophthalmology 349
interventricular foramen of Munro into the third ventricle ered with sterile, saline-soaked gauze in order to keep the
and then into the cerebral aqueduct of Sylvius to the fourth lesion moist and clear and the neonate is positioned prone to
ventricle. It emerges from the interior of the brain through avoid direct pressure on the defect.
the two lateral foramina of Luschka and the single medial
foramen of Magendie to enter the subarachnoid space. The
CSF is absorbed by the arachnoid villi. The mean production Cranial Dysraphism
rate of CSF in children is about 0.35 mL/min. CBF and CBV
are much more important determinants of ICP than is the Cranial dysraphisms or encephaloceles are characterized by
volume of the CSF. a sac-like calvarial defect that arises anywhere from the nose
to the occiput. The former can manifest as nasal polyps that
Spine protrude through the cribriform plate. Cranial meningoceles
The spinal cord and CSF are contained within the cylindrical contain cerebrospinal fluid and meninges. The presence of
vertebral canal. The spinal cord is the caudal continuation of neural elements in the meningocele classifies this cystic
the brainstem. Its caudal tip reaches the intervertebral space lesion as meningoencephalocele. Encephaloceles are classi-
of L3 at birth and then slowly migrates to the adult level of fied by their location on the cranium, with sincipital lesions
L1–L2 by 8 years of age, though there is a wide interin the frontal calvarium and occipital encephaloceles sited
individual variability [1]. Incomplete development of the posteriorly. Primary encephaloceles are often diagnosed in
spinal canal (spinal dysraphisms) leads to tethered cord utero by fetal ultrasonography, with large encephaloceles
syndromes. delivered by elective cesarean section. Most small encepha-
loceles have minimal neurological deficits, whereas those
Eye with large lesions may present with cranial nerve abnormali-
The neonatal visual system is comprised of the sclera, uvea, ties and subsequent developmental and growth delay, poor
and retina. These structures develop between the third and feeding, blindness, and seizures.
tenth week of gestation. During the sixth or seventh weeks of Preoperative diagnostic imaging is essential to delineate
gestation, the mesenchyme evolves into an inner, vascular the content and margins of the lesion. Sedation or general
layer that forms the choroid and an outer fibrous layer known anesthesia is required for computed tomography (CT) and
as the sclera. The sclera is the outer layer of the eye, with the magnetic resonance imaging (MRI) scans. Encephaloceles
transparent anterior portion delineating the cornea. The uvea can be associated with hydrocephalus and other craniofacial
is the vascular middle layer that contains the iris, ciliary and brain abnormalities such as anencephaly, microcephaly,
body, and choroid. It has multiple functions that include ataxia, Meckel’s, and amniotic band syndrome.
immunity, nutrition, oxygen and carbon dioxide exchange, Encephaloceles will continue to enlarge after birth. Surgery
light transmission, production of aqueous humor, and visual can be delayed and performed in stages, if the overlying skin
accommodation, most of which are controlled by the auto- is intact. Innovations in neonatal care and surgical techniques,
nomic nervous system. The neural tube ectoderm differenti- including image guidance and multidisciplinary reconstruc-
ates into the retina, with the posterior outer layer producing tion techniques, have improved the outcome for patients.
the pigmented layer and the posterior inner layer producing Sincipital encephaloceles usually contain fibrous tissue,
the neural layer of the retina. which can be safely transected at the level of the skull and the
defect closed primarily. Nasal or sphenoethmoidal encephalo-
celes are rare. They are characterized by a skull base defect
Neurosurgery around the sella turcica. Large lesions may obstruct the airway
and compromise pituitary function, whereas smaller lesions
Congenital Anomalies may be undetected throughout infancy. Other defects includ-
ing midline nasal masses including nasal polyps, dermoid
Congenital CNS anomalies typically occur as midline sinus cyst, and tumors should be included in the differential
defects. These neural tube defects may arise anywhere along diagnosis. Image guidance based on 3-dimensional image
the neural axis from the head (cranial dysraphism) to the reconstructions and radionuclide ventriculography is useful.
spine (spinal dysraphism). It may be relatively minor and The resection and closure can be difficult during transpalatal
affect only superficial bony and membranous structures, or it surgical approaches due to exposure and inadequate soft tissue
may include a large segment of malformed neural tissue. for closure. Other surgical procedures include transcranial,
These lesions are associated with type II Chiari (Arnold- subfrontal, and endoscopic transnasal approaches. The post-
Chiari) malformations, hydrocephalus, and neurologic defi- operative course may be complicated by CSF leaks, meningi-
cits. Cervical cord and brainstem compression are possible tis, visual impairments, and endocrine derangements.
in infants with concomitant type II Chiari malformations. Occipital encephaloceles may contain functional brain
After birth, the cervical and spinal defects are usually cov- tissue that needs to be preserved. Most encephaloceles with
substantial neural tissue herniating through large cranial of the antenatal history, birth history, prematurity, comor-
defect require an expansion cranioplasty and a plastic sur- bidities, and other congenital anomalies should be completed
geon to create split thickness calvarial grafts. When primary prior to surgery (Chap. 2). Some neonates with encephalo-
closure is not possible, a staged secondary repair is an option. celes may have tenuous respiratory function due to direct
Large occipital encephaloceles may be associated with twist- airway obstruction or impairment of the pontomedullary
ing of the brainstem, lobar herniation, and hydrocephalus. respiratory control center. Depending on the size of the
lesion and extent of the surgical procedure, significant blood
loss should be anticipated during both the intra- and postop-
Spinal Dysraphisms erative period.
Spinal dysraphisms are lesions in which the dorsal midline Intraoperative Management
structures fail to fuse during embryogenesis. Spina bifida Positioning the neonate for induction of anesthesia can be
aperta is easily identifiable by the sac-like lesion containing challenging. Anesthesia can be induced with a propofol, but
meninges (meningocele) or neural tissue and meninges hypotension with resultant cerebral ischemia might ensue
(myelomeningocele). Spina bifida occulta has an intact skin due to the lack of surgical stimulation [23]. Reducing the
surface but a small gap in the bony spine, with spinal cord dose of propofol and adjuvant opioids for induction and add-
and nerve root usually uninvolved. These spinal defects can ing a concurrent intravenous fluid bolus can mitigate the
occur anywhere along the vertebral column, although lumbar hypotension. In most cases, tracheal intubation can be per-
and low thoracic defects are most common. Rachischisis is formed with the neonate in the supine position with the
the most severe form of dysraphism where the posterior neu- defect supported with foam or gel head rings so there is no
ropore fails to fuse. A protruding membranous sac contain- direct pressure on the lesion. Manipulation of these lesions
ing meninges, CSF, nerve roots, and a dysplastic spinal cord should be limited because of the risk of rupturing the thin
often protrudes through the defect in meningocele or myelo- membranes. For very large defects, it may be necessary to
meningocele. These congenital lesions are surgically closed place the infant in the lateral decubitus position for induction
during the neonatal period. However, residual lesions and and tracheal intubation. The left lateral position is the pre-
scar tissue can manifest as tethered cord syndrome (TCS) ferred position so the tongue can fall to the left away from
due to traction on the spinal cord. This may lead to perma- the side of the mouth where the laryngoscope blade is
nent neurological deficit distal to the lesion, and requires sur- inserted. The Miller blade is inserted into the mouth via the
gical untethering when symptoms persist. right commissure for direct laryngoscopy. Intubation may be
Prenatal ultrasonography affords early diagnosis and more difficult in the lateral position (only use the left lateral
planning for elective cesarean delivery and expeditious clo- decubitus) in some neonates, requiring the use of a flexible
sure of meningomyeloceles. These lesions may also be fiberoptic bronchoscope or video laryngoscope.
repaired in utero at specialized fetal surgery centers [22]. In Encephaloceles are associated with compromised airways
order to minimize the risk of infection, meningomyeloceles to varying degrees. Effective mask ventilation may be
undergo primary closure of the defect within the first 24 h of impaired by protruding lesions of sincipital encephalocele
life. These lesions are often associated with a type II Chiari and may hinder effective mask ventilation. In these patients,
malformation where both the cerebellum and brain stem tis- difficult airway precautions and techniques should be applied
sue protrude into the foramen magnum. during induction of anesthesia [24]. Gigantic encephaloceles
Since type II Chiari (Arnold-Chiari) malformations pre- may prohibit proper positioning of the neonate for tracheal
dispose patients to hydrocephalus, insertion of a ventriculo- intubation. Some fluid-filled encephaloceles can be decom-
peritoneal shunt may be combined with the initial surgery. pressed by aspirating cerebrospinal fluid with a sterile needle
Alternatively, a ventriculoperitoneal shunt may be inserted a and syringe under ultrasound guidance. Alternatively, giant
few days later – or deferred if there is no evidence of hydro- occipital encephaloceles can be suspended through a pediat-
cephalus. Patients with thoracic lesions may have poor auto- ric horseshoe headrest. Mask ventilation may be difficult in
nomic control below the level of the defect. this position, so an assistant can support the head as the anes-
thesiologist applies a mask seal.
Surgical repair is performed in the prone position so the
Anesthetic Management patient’s face should be well supported by padded foam on
a horseshoe headrest to prevent direct pressure on the eyes
Preanesthetic Evaluation and mouth. Since the airway will be inaccessible during
Cranial and spinal dysraphisms are heterogeneous lesions repair of occipital encephaloceles, nasotracheal intubation
and mandate an individualized approach based on the sever- may be more secure and minimizes the risk of dislodging
ity and location of the defect. Therefore, a thorough review the tube. Prone positioning for the surgery requires careful
padding to prevent increased abdominal pressure and to pro- preferable to recover the patient in the prone position to
tect eyes and other pressure points. We recommend nasotra- avoid pressure on the incision. The patient will often con-
cheal intubation, fixing the tube with tape that would remain tinue to lose blood into the surgical site and require ongo-
sealed in the presence of any liquid prep solutions and ing monitoring and treatment for anemia during the
Mastisol or a similar adhesive. It is paramount to support the postoperative period.
breathing circuit with tape to the horseshoe when the neo-
nate is positioned prone as any downward pull may dislodge
the tube from the trachea. Hydrocephalus
Ensuring adequate oxygenation delivery to the develop-
ing brain is the cornerstone of neonatal neuroanesthesia and Hydrocephalus is the most common affliction of pediatric
critical care [25, 26]. Typically, blood loss during surgery is neurosurgical patients [27]. It has been defined as “an active
not significant enough to necessitate blood transfusions. distension of the ventricular system of the brain related to
However, the risk of bleeding and venous air embolization is inadequate passage of CSF from its point of production
greater in those with larger cranial defects. Therefore, mul- within the ventricular system to its point of absorption into
tiple intravenous lines and an arterial catheter should be the systemic circulation.” [28] Hydrocephalus is primarily
inserted when a large blood loss is anticipated. Occasionally, due to an accumulation of CSF within the ventricular system
rotational or myocutaneous flaps may be required for closure of the CNS by congenital lesions, tumors, or secondary
of large defects. Respiratory parameters and oxygenation injury. Multiple etiologies and classifications exist—all of
should be carefully monitored during primary closure of which promote the concept that all ventriculomegaly is
large defects because tight skin closure may compromise “obstructive” in the sense that CSF absorption can be
tidal volume and reduce venous return. Significant hypoten- impaired by structural blockage or reduced physiological
sion is typically due to blood and cerebrospinal fluid losses, transport at the arachnoid membrane and its granulations,
but also can be a manifestation of hypothroidism, adrenocor- cranial nerve lymphatics, and capillaries of microvessels.
tical deficiency, or diabetes insipidus. Neonates who develop Two subcategories for hydrocephalus are recognized:
diabetes insipidus should be treated with a vasopressin infu- obstructive or communicating. Obstructive or non-
sion and urinary output replaced with crystalloid. A Foley communicating hydrocephalus is an obstruction within the
catheter and an arterial line should be considered for any ventricular system or at the fourth ventricular outflow.
complex lesions or prolonged surgery. If the risk of a postop- Communicating hydrocephalus results from impaired circu-
erative CSF leak is substantive, a ventricular drain may be lation through the subarachnoid spaces (e.g., when the flow
inserted. With any flap-based closure on a vascular pedestal, of CSF is blocked downstream of the ventricles) or dimin-
meticulous fluid management aimed at maintaining perfu- ished absorption into the venous system.
sion while limiting edema needs to be employed. Similarly, Pathological increases in CSF production or decreases in
vasopressors may be implicated in failed graft viability and reabsorption can also lead to hydrocephalus. Congenital and
should be discussed with the surgical team if and when their neonatal hydrocephalus can be attributed to several develop-
use is contemplated. mental abnormalities or insults including neural tube defects,
infection, intraventricular hemorrhage, trauma, and tumors.
Postoperative Management Hydrocephalus occurs when CSF cannot be absorbed at a
Since most of these patients are neonates, postoperative rate sufficient to prevent its accumulation within the ventric-
observation should be in a neonatal intensive care unit ular system, forcing the cerebral ventricles and occasionally
(NICU) setting. The decision to extubate the trachea is dic- the subarachnoid spaces to expand. In addition, hydrocepha-
tated by the degree of blood loss, fluid and blood adminis- lus can occur as a result of the overproduction of CSF, as
tration, and neurological status of the neonate. Patients seen with choroid plexus papillomas.
with large sincipital encephaloceles should go to an inten- Hydrocephalus is ideally managed by ameliorating the
sive care unit postoperatively to be closely monitored for underlying problem. If this is not possible, however, surgical
adrenal cortical deficiency, diabetes insipidus, and airway implantation of a drain or shunt may be necessary. The most
obstruction. Mild sedation may be required for some pedi- common place to drain CSF through an implanted shunt is
atric patients should tracheal intubation and mechanical the peritoneal cavity, but the right atrium or pleural cavity
ventilation be continued. has also been used. Although implantation of a ventriculo-
Persistent CSF leaks may occur in repaired encephalo- peritoneal shunt is relatively straightforward, periopera-
celes and may be confused with normal sinus drainage. tively, patients may be at increased risk for aspiration of
Some patients may need additional surgery or have a ven- gastric contents caused by the combination of altered mental
triculostomy drain placed. In some complex occipital status and recent peritoneal manipulation. Venous air embo-
encephalocele and large myelomeningocele repairs, it is lism (VAE) may occur during placement of the distal end of
a ventriculo-atrial shunt if the operative site is above the level Neuroendoscopic techniques have been utilized for
of the heart. treatment of hydrocephalus and tumor biopsies [33, 34,
Premature neonates can develop hydrocephalus second- 36]. Precise insertion of ventricular shunt catheters can be
ary to intraventricular hemorrhages [29, 30]. The severity of facilitated with endoscopy as well. Despite the relative
post-hemorrhagic hydrocephalus is assessed by serial head safety of this procedure, hypertension, arrhythmias, and
ultrasounds. Accumulated CSF can be temporarily drained neurogenic pulmonary edema have been reported in con-
by placement of a ventricular reservoir or ventriculo- junction with acute intracranial hypertension due to lack of
subgaleal shunt in very premature neonates [31, 32]. A egress of irrigation fluids and/or manipulation of the floor
ventriculo-subgaleal shunt diverts CSF through a small of the third ventricle.
gauge tube from the ventricle into subcutaneous tissue.
Diversion of CSF is the permanent treatment for hydroceph-
alus. However, placement of a ventriculoperitoneal shunt is Tumors
limited by the size of the patient and increased risk of shunt
failure. The distal end of the shunt will also migrate as the Brain tumors in neonates are rare and develop during the
child grows. Hence, temporary shunts are used in the small- perinatal period [37]. Fewer than 2% of brain tumors occur
est of neonates with permanent diversion of CSF via a ven- in neonates and develop slowly during the antenatal period.
triculoperitoneal shunt reserved for older infants. Most of these tumors are infratentorial, comprised of cell
Infants with hydrocephalus can be treated with endo- types that differ from brain tumors in older children: [38]
scopic ventriculostomy on the floor of the third ventricle fol- teratomas comprise about one-third of the tumors, with the
lowed by cauterization of the choroid plexus to attenuate remainder being choroid plexus tumors, embryonal tumors
excessive production of cerebrospinal fluid [33–35]. Recent (including medulloblastoma), and astrocytomas [39]. These
advances in endoscopic techniques are being used to perform lesions are initially detected during antenatal ultrasounds
endoscopic third ventriculostomy (ETV) with the option of and subsequent fetal magnetic resonance imaging (MRI) for
cauterization of the choroid plexus to moderate cerebral spi- greater detail. Clinical presentation of these lesions includes
nal fluid production [33–35]. macrocephaly, bulging fontanelles, hydrocephalus, cranial
nerve palsies, seizures, and lethargy. These neonates should
be admitted to the NICU for cardiorespiratory monitoring.
Anesthetic Management Imaging modalities should be utilized early once the neonate
is stabilized. Initially cranial ultrasound and CT of the head
The common symptoms of hydrocephalus include a rapid are indicated with MRI to delineate the tumor and the adja-
increase in head circumference, irritability, sleepiness, nau- cent structures and rule out vascular malformations and
sea, and vomiting, and downward deviation of the eyes parenchymal hemorrhages [40]. Most neonates will tolerate
(known as “setting sun phenomenon”) due to paresis of CT and MRI procedures with swaddling after a “feed and
upward gaze is observed in 40% of children with obstructive sleep” approach. However, sedation or general anesthesia
hydrocephalus. Acute obstruction of a ventricular shunt may be required for more extensive protocols. The risk of
requires urgent treatment because an acute increase in intra- surgery and anesthesia is great in the neonate. Therefore, rig-
cranial pressure in the relatively small cranial vault of the orous surgical planning that includes managing hydrocepha-
infant and child can have devastating neurologic and cardio- lus and possible congestive heart failure in large vascular
respiratory consequences. tumors is indicated. Endoscopic techniques to biopsy the
The anesthetic management of these patients depends on tumor to determine the tumor type and temporize the hydro-
the acuity of the patient’s symptoms. Intravenous access is cephalus should be considered to minimize morbidity.
typically in place in the NICU and induction of anesthesia However, gross total resection of low-grade tumors is associ-
and tracheal intubation is facilitated with propofol and a non- ated with more favorable survival rates [41].
depolarizing muscle relaxant. Judicious dosing of propofol is
essential because it can cause prolonged hypotension in an
unstimulated neonate [23]. Venous air embolism may occur Anesthetic Management
during placement of the distal end of a ventriculo-atrial shunt.
Technological advances in minimally invasive surgery Hemodynamic stability during intracranial surgery requires
entered the realm of pediatric neurosurgery. These tech- careful maintenance of the patient’s fluids and electrolytes
niques include endoscopy and stereotactic guided insertion and careful dosing of anesthetics to preserve adequate cere-
of intracranial devices. Given the relatively small size of the bral perfusion pressure. Since the lower limit of cerebral
cranial vault in pediatric patients, life-threatening intracra- autoregulation in neonates is unknown, they are at risk for
nial hypertension can occur insidiously. cerebral hypoperfusion especially when they are deeply
anesthetized during periods of massive blood loss. Given the taining cardiac output and systemic perfusion during this
risk for significant blood loss associated with many neuro- vulnerable period. The massive blood transfusion protocol
surgical procedures, consideration should be given to site of your institution should be activated in order to engage
two large bore intravenous lines (22ga) and radial arterial the blood bank. Transfusion of 10 mL/kg of packed red
access (Chap. 7). Central venous pressure access is rarely blood cells can be expected to increase hemoglobin con-
warranted in the superior vena cava distribution as any line in centration by 2 g/dL. Neonates are susceptible to dilutional
a major vessel may obstruct venous drainage, resulting in thrombocytopenia and hypocalcemia in the setting of mas-
increased intracranial pressure. Femoral venous access may sive blood loss and blood product transfusions. The hypo-
be used in its stead. A Foley catheter is particularly important calcemia is a result of the exogenous citrate used as
if a diuretic is planned. Serial measurements of the hemato- anticoagulant in many blood products. Washing red cells
crit should be collected to assess for insidious blood loss. can theoretically mitigate hypocalcemia, although the
Typed and cross-matched blood should be available for all citrate content of plasma exceeds that in packed red blood
major craniotomies. A greater percentage (up to 25%) of car- cells. Administration of 5–10 mL/kg of platelets can be
diac output is directed toward the head. Therefore, normo- expected to increase platelet count by 50,000–100,000 cells/
volemia should be maintained throughout the procedure. mm3. Fresh frozen plasma and cryoprecipitate should also
Normal saline is commonly used as the maintenance fluid be administered to replenish clotting factors. The routine
during neurosurgery because it is mildly hyperosmolar use of the antifibrinolytic agent, tranexamic acid, has been
(308 mOsm/kg) and it theoretically attenuates brain edema. shown to decrease blood loss [44].
However, rapid infusion of a large amount of normal saline
(30 mL/kg per hour) is associated with hyperchloremic met-
abolic acidosis [20]. Balanced crystalloids have been shown Vascular Anomalies
to prevent hyperchloremic acidosis when compared with
normal saline [21]. Preoperative glucose-containing solu- Intracranial vascular anomalies are rare in neonates but may
tions may be included intraoperatively, especially in prema- be late clinical manifestation of insidious perinatal lesions.
ture neonates since hepatic glucose stores may be inadequate The most severe lesions are high-flow arteriovenous shunts
to maintain euglycemia. Preferably, serial glucose concen- that predispose afflicted neonates to high-output CHF [45].
trations should be monitored as hyperglycemia may exacer- These lesions are initially managed with endovascular tech-
bate a neurologic injury should it occur during tumor niques (EVT), which entail catheter-based angiography and
resection. Acute hyperventilation and careful patient posi- embolization of neurovascular lesions [46]. Indications for
tioning to maximize cerebral venous drainage can minimize therapeutic neuro-interventional procedures include emboli-
brain swelling [22]. Should these maneuvers fail however, zation of intracranial vascular anomalies, such as arteriove-
mannitol can be given at a dose of 0.25–1 g/kg intravenously. nous malformations (AVM) or arteriovenous fistulae and
This agent transiently alters cerebral hemodynamics and aneurysms, targeted injection of intra-arterial chemotherapy
increases the serum osmolality by 10–20 mOsm/kg [23]. for tumors, and pre-surgical embolization of both AVMs and
However, repeated dosing can lead to extreme hyperosmolal- tumors of the head and neck. Observation and medical man-
ity, and renal failure and exacerbate brain edema. Furosemide agement of mild CHF can delay these treatments until the
is a useful adjunct to mannitol for decreasing acute cerebral patient is 5–6 months of age. However, urgent perinatal
edema and has been shown in vitro to prevent rebound swell- interventions are indicated if the neonate has refractory CHF,
ing caused by mannitol [24]. Hypertonic saline (3%) pulmonary hypertension, or pulmonary edema.
decreases ICP and maintains cerebral perfusion pressure in
pediatric traumatic brain injury and recently was shown to
more favorably affect cerebral hemodynamics than mannitol Perinatal Stroke
[42, 43]. However, all diuretics interfere with the ability to
use urine output as a guide to intravascular volume status. The causes of perinatal strokes in decreasing order of inci-
Massive blood loss should be aggressively treated with dence include arterial ischemic infarction, cerebral sinove-
crystalloid and blood replacement as well as vasopressor nous thrombosis, and intraventricular hemorrhage [47]. The
therapy (e.g., dopamine, epinephrine, norepinephrine). In initial management of presenting symptoms—seizures,
essence, massive blood loss during resections of tumors hemodynamic instability, and respiratory compromise—is
and vascular malformations (see below) predisposes the paramount. Sedation or general anesthesia may be required
neonate to high-output congestive heart failure (CHF) dur- for MRI studies in order to delineate the extent of the lesion.
ing rapid infusion of blood products and crystalloid. These neonates are primarily monitored and managed
Therefore, background infusion of an inotrope, dopamine expectantly for symptoms of seizures, hydrocephalus, and
or epinephrine, with vigilant titration is essential in main- intracranial hemorrhage.
Vein of Galen Malformation nical difficulty in positioning the endovascular catheters,

patient immobility is paramount. The procedure may require
Vein of Galen malformations (VOGM) are congenital arte- frequent apneas and transient cardiac arrest to aid in imaging
riovenous malformations between choroidal arteries and the catheter placement and angiography [50]. Embolization with
precursor of the vein of Galen [48]. Patients with VOGM ethylene vinyl alcohol copolymer glue (Onyx, Covidien,
may present with high-output CHF, pulmonary hyperten- Plymouth, MN) can induce bradycardia and asystole [51].
sion, and/or hydrocephalus. Given the complex and unstable Catastrophic vessel perforation can lead to massive blood
nature of this lesion, a multidisciplinary team composed of loss, intracranial hemorrhage, and symptomatic increases in
neonatologists, neuro-interventionalist, neurosurgeons, and ICP. Frequently, staged partial occlusion of these pathologic
anesthesiologists should work together to develop a compre- vessels will be performed. Furthermore, embolization of
hensive management strategy [49]. large high-flow low-resistance arteriovenous malformation
can provoke a hypertensive episode which can precipitate
Preoperative Management bleeding. Therefore, contingency plans for an emergency
Since the most severe presentations of VOGM are accompa- craniotomy for evacuation of hematoma and ligation of
nied with high-output CHF and respiratory failure, preproce- bleeding vessels are mandatory. A thorough preoperative
dural optimization of these conditions should be managed in anesthesia consent should include discussion of catastrophic
the neonatal or pediatric intensive care unit (NICU/PICU). and permanent injury, including death.
Titration of inotropic support with dopamine or epinephrine
and intravenous fluids should be guided by invasive blood Postoperative Management
pressure monitoring via an arterial catheter. The neonate Given the prolonged nature of these endovascular procedures
may require tracheal intubation and mechanical ventilation and the fragile cardiovascular function of these neonates, postop-
as the CHF worsens. erative observation in an ICU setting should be routine. Often,
mechanical ventilation will require sedation. Sedation should be
Intraoperative Management intermittently halted in order to perform a neurological examina-
General anesthesia is mandatory for neuro-interventional tion. These patients are still at risk for swings in blood pressure,
procedures in these vulnerable neonates. Hemodynamic and intracranial hemorrhages, and seizures. Unpredictable hemody-
respiratory support established in the NICU/PICU should be namics post-embolization increase the risk for hemorrhage,
continued in the interventional radiology suite. Given the especially in partial embolization procedures [52].
diminutive size of the neonate, the use of the NICU ventila-
tor can assure more reliable and efficient ventilation during
the procedure. A total intravenous anesthetic (TIVA) tech- Ophthalmology
nique (opioid and nondepolarizing muscle relaxants) will
optimize cerebral metabolic coupling while accomplishing Neonates are susceptible to both congenital and acquired
the goal of keeping the patient immobile. Propofol at high lesions that require anesthesia for ophthalmological therapy
doses may have cardiovascular depressant effects and should [53]. Given the vulnerability of the surgical neonate, the
be administered judiciously [23]. The interventionalist will urgency of the surgery needs to be gauged against the risk of
use liberal amounts of crystalloids, heparin, and contrast the anesthesia. Most of these neonates will require an exami-
media as part of the procedure. Therefore, any fluids admin- nation under anesthesia/sedation (EUA). Therefore, the side
istered by the anesthesia provider need to account for the effect of ophthalmic drugs and potential anesthetic interac-
total fluid intake in order to minimize volume overload, tions should be acknowledged. These interactions are delin-
especially in the setting of preexisting CHF. Given the tech- eated in Table 10.1.
Table 10.1 Eye drops commonly used in neonates and their possible complications
Drug Action Side effects
Cyclopentolate Anticholinergic (similar action to atropine, but faster onset Grand-mal seizure [54–56]; psychotic reactions [57–60];
of action and shorter half-life) gastro-intestinal toxicity [61]
Phenylephrine Sympathomimetic/adrenergic Hypertension
Tropicamide Anticholinergic/para-sympatholytic Gastro-intestinal (more pronounced in children) [62]
Atropine Anticholinergic/para-sympatholytic (anti-muscarinic) Tachycardia [62]; gastro-intestinal [62]; atropine flush/
fever, acute confusion/psychosis
Homatropine Anticholinergic/para-sympatholytic, similar effects to
atropine but weaker
Table 10.2 Common neonatal congenital lesions of the eye Birth trauma can also lead to retinal hemorrhages. These
Congenital lesion occur in 26% of normal vaginal deliveries, 43% of vacuum
Coloboma Incomplete closure of the choroid fissure extractions, and 52% of combined forceps and vacuum deliv-
Glaucoma Abnormal iridocorneal angle eries. 83% of these lesions resolved in 10 days [68].
Cataracts Opaque lens due to infection
Detached retina Persistence of intraretinal space Summary
Microphthalmia Underdeveloped small eye
The approach to the neonates with neurological and ophthal-
Peter’s anomaly Persistent lens stalk
mological lesions is based on fundamental understanding of
the surgical lesion and implications of maturational changes
Congenital Ophthalmologic Lesions of the developing organ systems. Neonatal surgery is associ-
ated with increased perioperative morbidity and mortality,
Congenital lesions in the neonate primarily require sedation including persistent cognitive deficits [2, 6–8]. Therefore, a
or general anesthesia for a complete and thorough examina- comprehensive preoperative evaluation, meticulous intraop-
tion of both eyes. The principles noted above and elsewhere erative care, and close postoperative observation are indi-
in this book should be applied. Many of these congenital cated in this vulnerable patient group.
lesions may be syndromic and are mostly managed conser-
vatively until 6 months to 1 year when the risk associated
with surgery and anesthesia is reduced. Common neonatal References
congenital lesions are listed in Table 10.2.
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Cardiac Surgery
11
Wanda C. Miller-Hance, Erin A. Gottlieb, and Pablo Motta
Introduction Cardiovascular Physiology
Cardiac surgery in the neonate is usually indicated to correct An understanding of the important features of the fetal and
or palliate congenital malformations of the cardiovascular neonatal circulations is essential for those who care for the
system. Extremely rare in this age group is the need for sur- neonate with heart disease. These include the differences in
gical intervention for pathologies such as endocarditis, car- blood flow patterns and distribution of blood flow, changes at
diac tumors, or pericardial disease. Thus, the focus of this birth, and the transition of the circulation. Familiarity with
chapter is on anesthesia for cardiac surgery in the neonate the clinically relevant developmental aspects of cardiac
with congenital heart disease (CHD). A brief overview of the physiology is key as well. The section that follows provides
cardiovascular physiology of the fetus and neonate is pre- a brief review of our current understanding of these subjects.
sented, followed by a discussion of CHD that includes epide- It should be noted that much of the data regarding the fetal
miology, clinical features, and diagnosis in the neonate. circulation has been derived from studies in the fetal lamb,
Selected anomalies of particular relevance that occur in this with the information extrapolated to the human fetus.
age group are reviewed, with emphasis on anatomic features,
pathophysiology of the defect, perioperative management,
and specific considerations during anesthetic care. This is Types of Circulation
followed by an in-depth discussion of pertinent aspects of
anesthetic practice in the neonate with CHD undergoing car- Fetal Circulation
diac surgery. Finally, several specific perioperative problems The placenta is the organ of oxygen and carbon dioxide
and concerns in the neonate are highlighted. exchange between the fetus and the mother, serving the
role in utero of the postnatal pulmonary system. It is also
the site of nutrient uptake for the developing fetus.
Oxygenated blood from the placenta reaches the fetus via
W. C. Miller-Hance (*)
a single umbilical vein. This blood has the greatest oxygen
Department of Anesthesiology, Perioperative and Pain Medicine,
Arthur S. Keats Division of Pediatric Cardiovascular tension (pO2) in the fetus (range, ~30 to 35 mmHg). Blood
Anesthesiology; Department of Pediatrics, Lillie Frank from the umbilical vein courses through the liver; the left
Abercrombie Division of Pediatric Cardiology, Baylor College of lobe receives blood from the umbilical vein, and the right
Medicine and Texas Children’s Hospital, Houston, TX, USA
lobe receives blood from both the umbilical and portal
venous systems. A majority of umbilical venous blood
E. A. Gottlieb
(~50 to 60%) bypasses the liver by midterm gestation and
Pediatric Cardiac Anesthesiology, Dell Children’s Medical Center,
The University of Texas at Austin, Austin, TX, USA enters the inferior vena cava (IVC)-right atrial (RA) junc-
tion through the ductus venosus. Thus, blood in the IVC
Surgery and Perioperative Care, Dell Medical School, The
University of Texas at Austin, Austin, TX, USA during fetal life originates from the liver, the lower body,
e-mail: [email protected] and the placenta (via the ductus venosus). Approximately
P. Motta 30% of IVC blood is directed across the foramen (or fossa)
Department of Anesthesiology, Perioperative and Pain Medicine, ovale into the left atrium (LA) (Fig. 11.1). Preferential
Arthur S. Keats Division of Pediatric Cardiovascular streaming blood flow patterns in the fetal heart direct the
Anesthesiology, Baylor College of Medicine and Texas Children’s
more oxygen-saturated blood from the umbilical vein (via
Hospital, Houston, TX, USA
e-mail: [email protected] the ductus venosus) and left hepatic vein to be diverted

360 W. C. Miller-Hance et al.
Fetal Circulation Table 11.1 Characteristic features of the fetal and neonatal

circulations
Feature Fetal circulation Neonatal circulation
Arrangement of the In parallel In series
circulation
Shunts Present (essential) Absent
DA
Pulmonary vascular High Low
resistance
AO
Cardiac output Low High
SVC
Site of gas exchange Placenta Lungs
MPA
RA FO LA
blood ejected from the RV courses through the ductus arte-

riosus into the descending aorta (Desc Ao). Desaturated
blood from the Desc Ao reaches the placenta via the
umbilical arteries. Thus, the pattern of the fetal circulation
provides extremely efficient gas exchange in the placenta.
IVC
In summary, the fetal circulation is characterized by
LV parallel circulations, the presence of intracardiac and
RV
Occuring below extracardiac shunts, and an increased pulmonary vascular
the level of
the liver resistance (Table 11.1). Although CHD can be associated
with hemodynamic alterations and abnormal blood flow
Blood patterns in the fetus, the presence of these shunts compen-
from
placenta sates to a great extent for these changes, ensuring survival
© 2015 Texas Children’s Hospital until delivery in most cases.
Fig. 11.1 Illustration of the circulation in the fetal heart. The oxygen-
ated blood reaching the right atrium (RA) from the placenta via the The Transitional Circulation
umbilical vein and ductus venosus is preferentially shunted across the At birth, three major changes in the circulation occur with
foramen ovale (FO) into the left heart. In the left atrium (LA), blood ligation of the umbilical cord: (1) the placenta is excluded
mixes with the small amount of pulmonary venous return and is ejected from the circulation and the lungs assume the function of
by the left ventricle (LV) into the aorta (AO). A portion of the oxygen-
ated blood in the RA mixes with deoxygenated blood from the inferior gas exchange, (2) the lungs expand, greatly reducing the
(IVC) and superior vena cava (SVC) and courses into the right ventricle pulmonary vascular resistance and increasing pulmonary
(RV). Most of the RV output is shunted from the main pulmonary artery blood flow, and (3) systemic vascular resistance increases
(MPA) across the ductus arteriosus (DA) into the systemic circulation. as the low-resistance placental vascular bed is removed,
Reproduced with permission from Texas Children’s Hospital
leading to an increase in LV afterload and a decrease in the
volume of blood returning to the IVC. After birth, the
into the LA across the limbus of the foramen ovale. Thus, shunts between the pulmonary and systemic circulations
this communication is an important site of shunting in the during fetal life [ductus venosus, foramen ovale, and duc-
fetal heart. The direction of blood flow across the foramen tus arteriosus] normally close. The ductus venosus usually
ovale in utero is normally from the RA to the LA. In the closes within 24 h of birth. The mechanisms involved in
LA, blood mixes with the small amount of pulmonary this process are incompletely understood, but believed to
venous return and is ejected by the left ventricle (LV) into rely primarily on a passive process. Postnatal functional
the ascending aorta (Asc Ao). This relatively “highly” closure of the foramen ovale occurs when the LA pressure
oxygenated blood is distributed to the coronary arteries, exceeds the RA pressure. LA pressure increases as a con-
cerebral circulation, and upper extremities. The remaining sequence of the marked augmentation of the pulmonary
blood from the IVC [mostly from the lower body and liver] venous return associated with the increased pulmonary
mixes in the RA with blood from the superior vena cava blood flow. RA pressure decreases in parallel with the con-
(SVC) and coronary sinus, which has a relatively low pO2 comitant decrease in IVC pressure/flow. Patency of the
(~12 to 14 mmHg). Mixed blood then courses across the foramen ovale facilitates shunting at the atrial level, the
tricuspid valve and enters the right ventricle (RV; pO2 ~ 18 direction of which depends on the relative atrial pressures
to 19 mmHg), where it is ejected into the main pulmonary and other factors. It is not unusual for occasional right-to-
artery (MPA). A state of high pulmonary vascular resis- left shunting or bidirectional shunting to occur across the
tance associated with the airless collapsed lungs and fetal foramen during the first few hours or days after birth; this
low pO2 limits pulmonary blood flow, and most of the normally has no hemodynamic consequence. A change in
11 Cardiac Surgery 361
the direction of shunting across the ductus arteriosus bolic requirements of the neonate, with associated signifi-
occurs from right to left in fetal life to left-to-right in post- cant increases in blood flow to the lungs, kidneys, and
natal life. This change in the direction of the flow provides gastrointestinal system; the LV output increases to approxi-
the ductus arteriosus with blood with a greater pO2, which mate that of the RV.
stimulates closure of this communication. Constriction of
the ductus arteriosus is attributed to a local effect of the
increased pO2 plus a reduction in the plasma concentra- Developmental Aspects of the Myocardium
tions of circulating prostaglandins that ensues at birth.
Functional closure of the ductus arteriosus occurs within The fetal myocardium is structurally and functionally imma-
10–25 h after birth, whereas complete obliteration of the ture and has limited potential to increase cardiac output [4].
ductal lumen occurs within the first few weeks after birth These features are suited to a low-pressure system with a low
[1]. If the normal increase in the arterial pO2 does not systemic vascular resistance. The main energy substrates for
occur because of either pulmonary or cardiac disease, or the fetal heart are lactate and glucose. As the mitochondria
the constrictor response to oxygen is diminished (i.e., premature, the energy substrates transition from carbohydrates
maturity), the ductus arteriosus may remain patent. to fatty acids [5].
It is important to recognize that the changes that take The ultrastructure of the neonatal myocardium is poorly
place at birth, which are essential to normal physiology, organized. The neonatal heart has fewer myocytes, the
may significantly compromise the circulation of the neonate arrangement of the myofibrils is relatively poor, and the pro-
with a congenitally malformed cardiovascular system [2]. portion of contractile elements is less than those in the adult
Limited or lack of shunting across anatomic fetal structures myocardium [6]. In essence, the neonatal heart operates with
in the neonate with CHD postnatally, for example, can be an incompletely developed contractile system. Additional
catastrophic unless and until these communications are characteristics of the neonatal myocardium include: (1) con-
re-established. trol of contractility depends to a greater extent on circulating
catecholamines and adrenal function than on direct auto-
nomic influences, (2) the sarcoplasmic reticulum, the pri-
Postnatal Circulation mary source of calcium storage for excitation-contraction
coupling, is poorly developed, and (3) a deficiency in T
In the neonate, the adult pattern of blood flow through the tubules results in a significant dependence on transmem-
heart is established; RV output (pulmonary blood flow) and brane calcium fluxes. Thus, the neonatal heart is ill-equipped
LV output [systemic blood flow] are equal, and, normally, no to increase contractility in the face of an increased demand.
shunts are present. In summary, in contrast to that of the Other properties of the neonatal myocardium that limit its
fetus, the circulation in the neonate operates in series, lacks ability to augment cardiac output include: (1) less compliant
shunts, and is characterized by a progressive decrease in pul- ventricles that are less able to increase stroke volume, result-
monary vascular resistance (Table 11.1). ing in a greater dependence upon the heart rate to increase
cardiac output, (2) limited tolerance to changes in preload sec-
ondary to less ability to recruit the Frank-Starling mechanism,
Cardiac Output and Distribution of Blood Flow (3) less ability to significantly increase the contractile state,
and (4) poor compensation for changes in afterload. An impor-
In the fetus, both the RV and the LV eject blood into the tant aspect of neonatal cardiac function is the ventricular inter-
systemic circulation; thus, the cardiac output of the two dependence. Failure of one ventricle will impact the filling and
ventricles is in parallel. The total volume of blood ejected hence the function of the other. These characteristics dictate
by both ventricles in the fetus is referred to as the combined some of the important principles of perioperative neonatal car-
ventricular output (CVO). The RV contributes two-thirds of diac management including the frequent indication for inotro-
the CVO, whereas the LV ejects only one-third. A small pic support, the value of calcium boluses or infusions, and the
amount of the CVO, in the range of 5% to 10%, reaches the use of cardiac pacing. These characteristics also explain the
pulmonary circulation, and 55% to 60% courses through greater sensitivity of the neonatal myocardium to anesthetic
the ductus arteriosus into the Desc Ao. Approximately 3% drugs [7]. The major differences between the neonatal and
of the CVO reaches the heart and 22% the upper body. Only adult myocardium are summarized in Table 11.2.
10% of the CVO courses through the Ao arch isthmus into Postnatal cardiac development is accompanied by the loss of
the Desc Ao. Throughout gestation, a gradual reduction fetal regenerative capacity of cardiomyocytes within the first
occurs in the fraction of CVO that is distributed to the pla- few days after birth. The loss of fetal hyperplastic growth is
centa as the ventricular output increases to meet the replaced with postnatal hypertrophic growth of the myocar-
increased demands of developing fetal organs [3]. Cardiac dium. The mechanism for this loss in regenerative capacity is
output increases immediately after birth to meet the meta- incompletely understood in humans and widely variable
Table 11.2 Summary of major differences between neonatal and Table 11.3 Annual birth prevalence of congenital cardiovascular
mature myocardium defects in the USA
Parameters Neonatal heart Mature heart Rate per 1000 Estimated number (variable
Physiology Type of presentation live births with yearly birth rate)
Contractility Limited Normal Fetal loss Unknown Unknown
Heart rate dependence High Low Invasive procedure 2.4 9200
Contractile reserve Low High during the first year
Preload tolerance Limited Better Detected during the 8 36,000
Afterload tolerance Low High first yeara
Ventricular Significant Less Bicuspid aortic valve 13.7 54,800
interdependence From Benjamin et al. [9], with permission
Ca++ handling a
Includes stillbirths and pregnancy termination at < 20 weeks of gesta-
Predominant site of Sarcolemma Sarcoplasmic tion; includes some defects that resolve spontaneously or do not require
Ca++ flux reticulum treatment
Dependence on High Lower
normal iCa++
Circulating High Lower countries. Interestingly, for simple lesions (e.g., septal defects)
catecholamines the prevalence is increasing possibly due to improved diagno-
Adrenergic receptors Downregulated Normal β1 sis. In contrast, the birth prevalence of complex left-sided
insensitive β2, β1 predominant
predominant
obstructive lesions (e.g., hypoplastic left ventricle) is decreas-
Innervation Parasympathetic Complete ing, probably due to diagnosis in utero and, in industrialized
predominates; countries, the decision to terminate the pregnancy [12].
sympathetic To further complicate the epidemiology of CHD in neonates,
incomplete large regional variations in the prevalence have been reported
Cytoskeleton High collagen and Lower collagen
water content and water content
[13]. The prevalence of CHD in preterm infants is twice that in
Cellular elements Incomplete SR, Mature SR, infants born at full term [14]. Approximately 16% of infants
disorganized organized presenting with CHD were premature at birth. Updated epide-
myofibrils myofibrils miological data suggest that 20–30% of CHD has an identifi-
Ca++ calcium, iCa++ ionized calcium, SR sarcoplasmic reticulum able underlying etiology, with the proportion of CHD
From Andropoulos DB, Yuki K, and Koutsogiannaki S. Physiology and attributable to single gene disorders of 3–5%, chromosomal
cellular biology of the developing circulation. In Andropoulos DB,
Mossad EB, and Gottlieb EA editors. Anesthesia for Congenital Heart
anomalies of 8–10%, and pathogenic deletions/duplications of
Disease, fourth Ed, Hoboken: Wiley-Blackwell; 2023; with 3–25% [15]. CHD may also be associated with a genetic pattern
permission of inheritance (10%) (e.g., trisomy 18, 21, 4p deletion, and
22q11 deletion) and epigenetic and/or a syndromic pattern (as
among large animal models. There is emerging evidence that in omphalocele and Holt-Oram syndrome) [15]. Maternal
the cardiac microenvironment transforms with changes in rubella infection is also known to predispose the fetus to CHD.
the extracellular matrix composition associated with the The predominant cause of death in the first year of life is
development of the immune system [5]. The ability to arrest CHD [16]. Without treatment, the condition is fatal in a sub-
the decline in the capacity for regeneration would open stantive number of neonates, with increased mortality
potential therapies for neonatal CHD [8]. observed in preterm infants [14]. Twenty-five percent of
infants with CHD require intervention in the first year of life
in order to limit mortality [17]. Neonates account for ~17–
Epidemiology of Congenital Heart Disease 22% of patients included in the Society of Thoracic Surgeons
Congenital Heart Surgery Database who undergo cardiotho-
CHD is the most common birth defect in humans. In the USA racic surgical interventions each year (7,531 of 33,513
CHD affects approximately 8 out of 1000 live births patients as per report of the period ending 06/30/2022,
(Table 11.3) [9]. The worldwide prevalence of CHD has mostly from North American Centers). This fact emphasizes
increased substantially over time, from <1 per 1000 live births the need to appreciate the considerations for anesthesia care
in 1930 to 9 per 1000 live births in recent decades, corre- for neonates who require cardiac surgery.
sponding to 1.35 million worldwide live births affected with Despite many advances in the care of neonates with CHD, a
CHD every year [10]. The prevalence may be even greater number of factors including the late detection of critical pathol-
than previously thought as a study in a large cohort of neo- ogy contribute to the early morbidity and mortality in these
nates undergoing echocardiographic screening revealed a live infants. In an effort to address this increasing problem and to
birth prevalence of CHD of 26.6 per 1000 [11]. The reported improve the early diagnosis of critical CHD in the neonate, pulse
birth prevalence of CHD globally is increasing steadily due to oximetry (SpO2) has been adopted in several countries, includ-
the availability of diagnostic techniques in lower-income ing the USA [18–21]. Mandatory policies for such screening
have been introduced in some states before it was adopted In the neonate with suspected CHD, the physical exami-
nationwide. This resulted in a significant decrease in infant car- nation should include four extremity blood pressure deter-
diac deaths between 2007 and 2013 in the states that adopted minations and pre- and post-ductal SpO2 measurements. A
such screening compared with those without these policies [22]. hyperoxia test may be performed in an effort to distinguish
The pulse oximetry screening recommendation of the cardiac disease from other causes of cyanosis. This consists
American Academy of Pediatrics (AAP) for critical CHD is of the sequential administration of room air or 100% oxy-
to measure the oxygen saturation after 24 h of age on both gen while measuring the arterial oxygen tension (PaO2) in
their right hand and one foot simultaneously. Criteria sugges- the right radial artery (pre-ductal site) and in a lower
tive of CHD include any one of the following: (1) oxygen extremity/umbilical artery (post-ductal site). If the cyanosis
saturation of <95% in both extremities on three serial mea- is related to pulmonary disease, supplemental oxygen
surements, (2) saturation is ≤90% in either extremity, or (3) a should increase the PaO2 > 150 mmHg. In contrast, if the
difference between the saturations of ≥3% [23]. It should be cyanosis is related to CHD, supplemental oxygen will have
recognized that neonates with a negative screen may still have little or no effect on the PaO2, the value remaining
critical CHD due to the fact that hypoxemia may only be pres- <100 mmHg. This response in the neonate with CHD is
ent intermittently in some defects. referred to as failure of the hyperoxia test. Additional stud-
ies such as a chest radiograph and a complete electrocar-
diogram that includes right-sided chest leads (V3R and
linical Presentation and Diagnosis
C V4R), and in some cases a posterior chest lead (V7), are
of Congenital Heart Disease in the Neonate routinely obtained. Echocardiography is the primary imag-
ing modality for the initial evaluation and serial assessment
The presentation of CHD in the neonate depends upon the of most types of CHD. It is diagnostic in most neonates. In
nature and severity of the pathologic abnormalities [24]. only rare cases are additional studies such as chest com-
Although in many cases CHD is detected during fetal ultra- puted tomography, cardiac magnetic resonance, or cardiac
sound screening or immediately after birth, in some instances catheterization and angiography required to further delin-
the diagnosis is made at a later age. A particularly ominous eate the anatomical or functional abnormalities.
presentation is that of the apparently healthy neonate who
develops life-threatening symptoms after discharge from the
nursery, requiring urgent medical attention. Early recognition Classification of Congenital Heart Disease
and appropriate management of the infant with critical CHD
are essential to optimize outcome. Numerous classification schemes have been proposed for
The neonate with significant CHD varies in his/her clinical CHD [25, 26]. These categorize malformations based on (1)
manifestations from no signs or symptoms immediately after complexity of the lesion as simple versus complex disease,
birth to the gradual onset of signs or symptoms as their physi- (2) presence or absence of cyanosis, (3) whether pulmonary
ology changes (i.e., ductus arteriosus closure, alterations in blood flow is increased or decreased, (4) whether an obstruc-
pulmonary vascular tone). The most common clinical fea- tion is present affecting the RV or LV, and (5) the direction of
tures of CHD in the neonate are respiratory distress, cyanosis, shunting patterns (i.e., left-to-right, right-to-left). Other clas-
a heart murmur, and signs of reduced cardiac output [24]. sification systems are based on the underlying physiologic
Respiratory distress (i.e., tachypnea, labored breathing, inter- alterations or common features of the anomalies. An alternate
costal retractions) is usually associated with defects that approach that facilitates a differential diagnosis in the neonate
result in an increase in LA volume/pressure. These symptoms with CHD considers the clinical presentation and categorizes
may reflect pulmonary over-circulation (left-to-right shunts), defects based on the presence of cyanosis, congestive heart
obstructed pulmonary venous drainage, or pathology that failure, or a heart murmur [27]. Yet a third scheme relevant to
leads to an increase in LV end-diastolic volume/pressure. neonatal screening for CHD suggests three main categories in
Clinical cyanosis is usually apparent when the concentration terms of clinical significance as follows [28]:
of reduced hemoglobin exceeds 5 g/dL. Although often due
to lung disease, cyanosis may also indicate cardiac disease • Life-threatening congenital heart defects: those in which
secondary to reduced pulmonary blood flow, right-to-left cardiovascular decompensation or collapse is likely (e.g.,
shunting, or a mixing physiology. The presence of a heart transposition of the great arteries, coarctation/interrupted
murmur in the neonate is sometimes, but not always, associ- aortic arch, aortic stenosis, pulmonary atresia, and hypo-
ated with CHD. Conversely, serious CHD can be present in plastic left heart/mitral atresia).
the absence of a murmur. Hypotension may indicate impend- • Clinically significant congenital heart defects: those with
ing or frank hemodynamic decompensation and often implies effects on heart function but where collapse is unlikely
serious cardiac pathology that requires immediate interven- (e.g., ventricular septal defect, complete atrioventricular
tion to stabilize the infant and prevent vital organ damage. septal defect, atrial septal defect, tetralogy of Fallot).
• Clinically insignificant congenital heart defects: those tant, may not present with major hemodynamic manifesta-
with no functional clinical significance (e.g., small tions within the first few weeks of life and is less likely to
ventricular septal defect only detectable by echocar- necessitate urgent care. Defects considered clinically insig-
diography and requiring no treatment). nificant have little to no potential of impacting the physiol-
ogy in the neonate.
This third categorization is useful for determining the Although any cataloging system has limitations, a patho-
gravity of the situation and the immediate action needed physiologic classification is particularly helpful in the prac-
once the diagnosis is made. Life-threatening lesions, often tice of anesthesia, as it allows for the formulation of
because of ductal dependency for pulmonary or systemic hemodynamic goals based on the main consequences of the
blood flow or other reasons, require prompt attention defect. One such classification system of CHD is presented in
(Table 11.4). Clinically significant CHD, although impor- Table 11.5 [29].
Table 11.4 Ductal-dependent congenital heart disease in the neonate

Ductal-dependent lesions for pulmonary blood flow Ductal-dependent lesions for systemic blood flow
Critical pulmonary stenosis Coarctation of the aorta
Pulmonary atresia with intact ventricular septum Critical aortic stenosis
Complex lesions associated with severe pulmonary outflow tract obstruction or Hypoplastic left heart syndrome
pulmonary atresia
Severe form of Ebstein anomaly with anatomic or functional pulmonary atresia Interrupted aortic arch
d-Transposition of the great arteriesa Complex lesions associated with systemic outflow
tract obstruction or aortic atresia
a
Patency of the ductus arteriosus in d-transposition increases pulmonary blood flow and augments pulmonary venous return, leading to stretching
of the interatrial communication and enhancing intercirculatory mixing
Table 11.5 Physiologic classification of congenital heart defects and respective salient features
Lesions characterized by volume overload
• Due to communications at the atrial, ventricular, and/or arterial level.
• Frequently the result of physiologic left-to-right shunting.
• If the communication is proximal to the mitral valve (e.g., atrial septal defect, partial anomalous pulmonary venous return, or unobstructed
total anomalous pulmonary venous return), right heart dilation is present; if the shunt is distal to the mitral valve (e.g., ventricular septal
defect, patent ductus arteriosus), dilation of left-sided cardiac structures is seen.
• Symptoms related to the magnitude of the shunt and pulmonary to systemic blood flow ratio.
• Shunting influenced by the pulmonary vascular tone and relationships between the pulmonary and systemic vascular resistances.
• Diuretic therapy and, in some cases, afterload reduction are main medical management strategies.
Lesions characterized by obstruction to systemic blood flow
• Include those with ductal-dependent systemic blood flow (e.g., critical aortic stenosis, severe aortic coarctation, aortic arch interruption,
hypoplastic left heart syndrome, aortic atresia).
• Prostaglandin E1 therapy required to maintain ductal patency allowing for systemic blood flow until an intervention is undertaken.
• Diuretic therapy and manipulation of the systemic and pulmonary vascular resistances may be required to control increased pulmonary
blood flow and optimize systemic output.
• Inotropic and/or mechanical ventilatory support frequently necessary.
Lesions characterized by obstruction to pulmonary blood flow
• Include those with ductal-dependent pulmonary blood flow (e.g., critical pulmonary valve stenosis and pulmonary atresia with intact
ventricular septum).
• Prostaglandin E1 therapy is indicated for the treatment of arterial hypoxemia until obstruction can be relieved or alternate sources of
pulmonary blood flow are established.
Parallel circulation
• Classic lesion is that of d-transposition of the great arteries where the pulmonary and systemic circulations run in parallel.
• Associated with cyanosis.
• Intercirculatory mixing is essential for survival.
Single ventricle lesions
• Include those with atrioventricular valve atresia (e.g., tricuspid atresia), severe ventricular hypoplasia (e.g., hypoplastic left heart
syndrome), or anomalies where a biventricular repair is not feasible (e.g., unbalanced atrioventricular septal defect, double inlet left
ventricle).
• Common among these lesions is complete mixing of the systemic and pulmonary venous blood at the atrial or ventricular level, and aortic
or pulmonary outflow tract obstruction, accounting for the presence of cyanosis.
• An important goal of early management involves optimization of the balance between the pulmonary and systemic circulations.
ongenital Cardiovascular Anomalies

C
of the Neonate: Anatomy, Pathophysiology,
and Management, with Anesthetic Patent
Considerations Ao
ductus
SVC arteriosus
The remarkable advances in perioperative care during the
last several decades have refined congenital heart surgery
in the neonate, resulting in increased survival rates and PA
greatly improved outcomes [30]. These advances have per-
mitted new approaches for many defects: early corrective
surgery now being preferred over initial palliation and
LA
later repair. The rationale for early correction is based on
the premise that by restoring the anatomy and physiology
towards normal early in life, subsequent morbidity can be RA
minimized, allowing for the most favorable long-term out-
comes. As a result, the volume of corrective surgery during
LV
the neonatal period has markedly increased. The section
that follows addresses selected congenital cardiovascular
defects reviewing relevant aspects of the anatomy and
physiology, highlighting pertinent medical and surgical
management, and focusing on considerations regarding
anesthesia care.
Patent Ductus Arteriosus

RV
Anatomic Features
The ductus arteriosus is a vascular communication between IVC
the MPA and the Desc Ao (Fig. 11.2). This structure is an
essential component of fetal life, serving as a conduit to Fig. 11.2 Graphic representation of a patent ductus arteriosus. The
communication between the aorta (Ao) and pulmonary artery (PA) is
direct RV output into the Desc Ao. In some cases, the ductus shown. The usual direction of shunting, from left-to-right, in the iso-
arteriosus fails to close after birth, resulting in persistent lated lesion is noted. IVC inferior vena cava, LA left atrium, LV left
patency. Prematurity and respiratory distress syndrome are ventricle, RA right atrium, RV right ventricle, SVC superior vena cava
risk factors for persistent patency known as patent ductus
arteriosus (PDA). This lesion affects nearly a 33% of infants
<1500 grams at birth. A PDA occurs with increased fre- Pathophysiology
quency in certain genetic disorders (e.g., Holt-Oram syn- Communication at the level of the great arteries permits
drome), in association with in utero viral infections [Rubella] shunting between the systemic and pulmonary circulations.
and maternal drug ingestion (sodium valproate) [1]. Two factors determine the direction and magnitude of the
A PDA can be found in isolation or in association with shunting: the relative resistances of the pulmonary and sys-
other forms of CHD. In the isolated form, it accounts for temic vascular beds and the size of the communication. The
nearly 10% of all congenital heart defects. In some cardiopulmonary vascular resistance significantly affects the direc-
vascular malformations, ductal patency may be essential for tion of shunting. As the resistance decreases postnatally, the
either pulmonary or systemic blood flow and, therefore, neo- typical direction of blood flow through an isolated PDA is
natal survival. The discussion that follows addresses the iso- left-to-right, resulting in increased pulmonary blood flow
lated defect. and volume loading of the heart.
The clinical manifestations of a PDA depend on the mag- older infant or child [43, 44]. It is of interest that very low-
nitude of the shunt and the cardiopulmonary responses to the birth-weight infants who had percutaneous catheter closure of
shunt. Some ductal communications are restrictive (small their PDA did not experience post-ligation syndrome (see
diameter) in nature and limit the blood flow to some extent. below) and had less escalation of respiratory support com-
Other more sizeable communications permit a substantial pared with infants who underwent surgical ligation [45].
amount of blood flow from the Ao to the PA. In the latter
case, the neonate may develop signs of pulmonary over- Anesthetic Considerations
circulation (tachypnea, labored breathing, radiographic evi- The need for intervention in the full-term neonate for a hemo-
dence of increased interstitial lung water, LA/LV dilation, dynamically significant PDA is quite unusual and is more
cardiomegaly) and overt congestive heart failure. The pre- likely to occur if other coexisting disease is present. Infants
term neonate is particularly vulnerable to the hemodynamic undergoing transcatheter closure may be at risk for vascular
effects of a left-to-right shunt, which can lead to pulmonary injury, rhythm disturbances, and hemodynamic instability.
edema [31]. Frequently, a hemodynamically significant PDA These problems result from factors such as difficulty with
is associated with respiratory impairment, a requirement for vascular access, catheter manipulations, or blood loss. Other
mechanical ventilatory support, and/or failure to wean from procedural complications include device embolization and/or
the ventilator. A PDA in the preterm infant is considered a malposition. In the neonate undergoing surgical ductal liga-
risk factor for complications such as bronchopulmonary dys- tion, standard anesthetic practice for thoracotomy procedures
plasia, necrotizing enterocolitis, and intracranial hemor- in the small infant should be followed. The use of regional
rhage. The diastolic runoff (left-to-right shunt), also called anesthesia techniques can contribute to perioperative pain
pulmonary steal, can cause hypoperfusion of systemic management as discussed in a later section.
vascular beds leading to end-organ dysfunction (i.e.,
If the preterm infant requires surgical closure, a left thora-
impaired myocardial perfusion, gut ischemia, renal injury) cotomy is performed in the neonatal intensive care unit
[32]. The lack of significant ductal restriction and the (NICU) in many centers. This avoids the need to transport
increased pulmonary blood flow leads to pulmonary hyper- the critically ill neonate to the operating room, thereby
tension, imposing a further pressure load on the RV. decreasing the risk of problems such as hypothermia and
accidental tracheal extubation. This approach is particularly
Management useful if the infant requires high-frequency oscillating venti-
The goals of medical therapy are designed to control pulmo- lation. An opioid-muscle relaxant-based intravenous anes-
nary over-circulation and ventricular volume overload. In thetic technique is the most common practice.
most cases, this includes supportive treatment, which consists
of fluid restriction and diuretic therapy [33]. The administra- Specific Issues
tion of indomethacin or ibuprofen to promote ductal closure • Intravascular volume. Fluid restriction and diuretic ther-
in the preterm infant in clinical practice is well-established apy in the neonate with a PDA deplete the intravascular
[34]. In a recent multicenter, randomized study, paracetamol volume in the presence of congestive symptoms. This
was less effective than ibuprofen to close the ductus arterio- problem alone or in combination with surgical manipula-
sus (52% versus 78%), although the constriction rate and the tions that impair ventricular filling can predispose the
need for surgical closure of the ductus with the two drugs infant to hemodynamic instability during the surgical pro-
were similar [35]. Pharmacological therapy to close a patent cedure, necessitating intravenous fluid administration or
ductus may be less successful in very low- birth-
weight other acute interventions.
infants. Non-steroidal anti-inflammatory agents may also be • Ventilation. Ductal ligation requires manual manipulation
contraindicated due to side effects affecting renal, gastroin- of thoracic structures and retraction of the non-dependent
testinal, and cerebral perfusion. Ongoing debate continues lung to achieve optimal surgical exposure. These maneu-
regarding the management of a PDA in extremely preterm vers can further impair gas exchange. Therefore, vigi-
infants [36, 37]. A percutaneous catheter-based procedure to lance is of outmost importance combined with monitoring
occlude the PDA is an option in some infants and this type of of the arterial saturation measured by SpO2 continuously
approach has been used even in extremely preterm neonates and assiduously. Preoperative placement of additional
[38–40]. The experience thus far using an approved device “reserve” oximetry probes should be considered. End-
for ductal closure in preterm neonates appears encouraging tidal CO2 monitoring, routinely used in the operating
[41]. Surgical therapy of a PDA in the neonate usually con- room setting, may also be available for use if the surgical
sists of placing a clip or ligature around the communication, procedure takes place in the NICU. Adjustments to the
most commonly via a small posterior lateral thoracotomy ventilatory parameters, guided by variables being moni-
[42]. Although ductal closure using video-assisted thoracos- tored to optimize gas exchange, may be necessary.
copy has been reported in the neonate and even in preterm • Pulmonary blood flow. An important hemodynamic objec-
infants, this approach is more likely to be considered in the tive before surgical ligation of the PDA is to minimize fur-
ther increases in pulmonary blood flow that can tilatory support due to sudden decreases in pulmonary
compromise systemic output or myocardial function. compliance after surgical ligation [50].
Although limiting the inspired oxygen concentration is
desirable in this instance, in addition to the concern of the
risk of retinopathy of prematurity, this objective should be Coarctation of the Aorta
balanced with that of providing adequate systemic oxygen
delivery during the procedure (see Chaps. 2 and 17) [46]. Anatomic Features
• Blood loss. Even a small amount of blood loss can have a Coarctation of the aorta (CoA) represents 5% to 8% of all
major hemodynamic impact in the preterm or term congenital cardiovascular defects. The anomaly is character-
neonate due to their relatively small blood volume. Thus, ized by narrowing of the lumen of the thoracic Ao near the
as in any major vascular surgery, appropriate vascular region of the ductus arteriosus or ligamentum, resulting in
access and immediate availability of blood products are obstruction to the systemic blood flow. The constriction can
imperative. Blood loss is usually minimal, but life- be discrete [Fig. 11.3] or diffuse. In the neonate, this lesion
threatening hemorrhage can occur. can be part of a complex disease with hypoplasia of the
• Anemia. Many preterm neonates have underlying anemia, transverse Ao arch and isthmus (anatomic region between
which increases the risk of congestive heart failure. Red the left subclavian artery and aortic end of the ductus arterio-
cell transfusion to correct anemia will significantly improve sus) [51]. This constellation of findings is uncommon in
the cardiac status in many cases. Blood should be readily older infancy or later life.
available during surgical ligation, regardless of site where Associated pathology in CoA may include a PDA, bicus-
the procedure is being undertaken. The need for preopera- pid Ao valve, aortic stenosis (AS), subaortic obstruction, and
tive red cell transfusion should be considered in anemic
neonates to increase the margin of safety of the procedure.
• Inadvertent ligation of other structures. Unintentional
ligation of adjacent thoracic structures such as the left
pulmonary artery (LPA), left mainstem bronchus, and Coarctation
Ao
Desc Ao represents potential complications associated SVC
with ductal ligation. Pre-ductal (right upper extremity)
and post-ductal (lower extremity) monitoring with a
SpO2/blood pressure cuff may allow for early recognition
PA
of complications. Ductal closure should narrow the pulse
pressure and increase the diastolic and frequently, the sys-
tolic blood pressures. Confirmation of these changes dur-
ing ductal ligation is reassuring. LA
• Postoperative problems. Other important issues poten-
tially associated with ductal ligation deserve mention. If a RA
significant pneumothorax develops, it can be catastrophic.
Another concern is the possibility of nerve injury and
related morbidity. The recurrent laryngeal nerve courses LV
around the ductus arteriosus and can be injured during the
procedure, resulting in vocal cord paralysis. Diaphragmatic
paralysis secondary to phrenic nerve injury leading to ven-
tilator dependency also has been reported [47]. Chylothorax
due to thoracic duct injury is a rare complication. Other
concerns after ductal ligation in the preterm infant relate to
the effects of obliteration of the left-to-right shunt on car-
diopulmonary function. In some cases, the acute increase
in LV afterload can significantly compromise myocardial RV
performance, particularly in the presence of preexisting
ventricular dysfunction, which can manifest as a low car- IVC
diac output state and hypotension [31, 48, 49]. This is
referred to as post-ligation cardiac syndrome. A similar Fig. 11.3 Graphic representation of a discrete aortic coarctation. The
posterior shelf in the descending thoracic aorta (Ao) in this lesion is
picture of transient ventricular dysfunction can be seen shown. IVC inferior vena cava, LA left atrium, LV left ventricle, PA
following transcatheter closure. In some neonates, there pulmonary artery, RA right atrium, RV right ventricle, SVC superior
may be an immediate need for increased mechanical ven- vena cava
ventricular septal defect (VSD). Aortic coarctation also can Catheter-directed endovascular balloon dilation to reverse
be one of the defects present in the Shone complex, in a segment of arterial narrowing as in CoA has been per-
addition to subaortic obstruction, parachute mitral valve, and formed in the neonate, even in those with significant trans-
supravalvar mitral ring [52]. verse arch hypoplasia [54]. Percutaneous stent placement
(using a coronary artery stent) has been demonstrated to be a
Pathophysiology feasible bridging therapy in infants <1500 grams [55].
This lesion varies in severity, as is the case in many other However, surgical treatment yields better immediate and
forms of CHD. Presentation in a neonate usually implies midterm results compared with balloon angioplasty. The for-
more severe obstruction or the presence of coexisting anom- mer is the preferred intervention in most centers [56].
alies [53]. The hemodynamic consequences of CoA result
from the obstruction of the systemic blood flow and inade- Anesthetic Considerations
quate distal perfusion. When the PDA provides most or Adequate vascular access is essential. Ao cross-clamping
essentially all of the entire distal systemic perfusion via the may cause acidosis and end-organ dysfunction (spinal cord,
RV, CoA is a ductal-dependent lesion for systemic blood kidneys, gut) due to hypoperfusion. This concern is greater
flow. Constriction of the ductus arteriosus will have profound in the neonate than in older children because of the lack of
repercussions in this setting. In the case of less severe time to develop collateral circulation. Several strategies have
obstruction, ductal closure increases LV afterload and end- been applied in the neonate to minimize the potential for spi-
diastolic pressure and increases myocardial work and wall nal cord injury. Passive cooling or inducing mild hypother-
tension, which may lead to myocardial ischemia. Increased mia to 34–35 °C before applying the Ao clamp is utilized at
LA pressures can lead to left-to-right shunting at the atrial some centers. However, the incidence of spinal cord injury in
level and increased pulmonary blood flow. Pulmonary hyper- the absence of intraoperative hyperthermia is exceedingly
tension results from increased pulmonary venous pressures rare [57]. Hemodynamic changes during CoA surgery via
related to LA hypertension and from the increased pulmo- thoracotomy include hypertension upon application of the
nary blood flow. Coexistent defects can also contribute to the Ao cross-clamp and hypotension associated with its release.
volume or pressure load on the ventricular myocardium. Paradoxical or rebound hypertension may occur after the
repair is complete and neonatal coarctation may be followed
Management by hypertension in later life. This latter problem has been
Neonates with severe obstruction frequently require treat- linked to altered baroreceptor responses and abnormalities in
ment for congestive heart failure and possible ventricular the renin-angiotensin system [58]. Data also suggest that
dysfunction. If poor cardiac output as manifested by underlying pathological adjustment of autonomic cardiovas-
decreased peripheral perfusion, metabolic acidosis, lactic cular homeostasis occurs in these infants [59].
acidemia, renal insufficiency, poor ventricular function, or
shock is present, the situation is more ominous. This situa- Specific Issues
tion requires immediate intervention with tracheal intubation • Arterial pressure monitoring. The selection of monitors
and mechanical ventilation in addition to prostaglandin E1 (sites and types) varies according to the surgical plan
[PGE1] therapy to re-establish/maintain ductal patency and and specific approach (e.g., lateral thoracotomy versus
improve systemic perfusion. Additional care may include median sternotomy; resection with end-to-end repair,
inotropic support and, potentially, cautious afterload reduc- extended Ao arch repair, Ao arch advancement, and the
tion. In most cases of moderate to severe aortic narrowing, need for cardiopulmonary bypass (CPB)). Monitoring
surgical relief of the obstruction is the treatment of choice. blood pressure during these cases is critical. Right
Selection of the surgical approach, median sternotomy ver- radial artery pressure is standard practice although
sus lateral thoracotomy (discussed later in the chapter), is monitoring of arterial blood pressure at sites proximal
influenced by the associated pathology, particularly the pres- and distal to the obstruction may also be considered.
ence of aortic arch hypoplasia. The goal of the surgical pro- Additionally, monitoring blood pressure in a lower
cedure, regardless of the details of the specific technique or extremity using a blood pressure cuff or intravascular
approach, is to resect the narrowed segment and remove cannula is also common.
adjacent ductal tissue. This can be part of the pathology and • Cerebral oximetry monitoring. Monitoring cerebral oxy-
carries the potential for recurrence of the obstruction. Aortic genation using bilateral near-infrared spectroscopy
continuity is preferably established by using native tissue. (NIRS) may assess the adequacy of brain perfusion dur-
Associated significant Ao arch hypoplasia requires more ing the procedure and confirm a satisfactory aortic clamp
extensive reconstruction. position [60]. The left carotid artery might be occluded
during the period of cross-clamp [61]. Occasionally, the

position of the cross-clamp can also affect flow to the
innominate artery. The latter can be detected by an attenu-
ated tracing of the right radial arterial line or right-sided Ao
NIRS monitoring. A NIRS probe over the flank region can SVC PDA
be used as a somatic monitor to assess regional oxygen-
ation distal to the aortic clamp [60].
• Surgical considerations. As Ao arch hypoplasia requires PA
more extensive reconstruction to ensure the best long-
term outcome, CPB is often required and may include the ASD LA
use of special bypass techniques (e.g., antegrade cerebral flow
Coronary
perfusion or ACP). If so, additional monitors (e.g., neuro- arteries
monitors) may enhance the safety of the procedure.
RA
LV
d-Transposition of the Great Arteries
Anatomic Features
d-Transposition of the great arteries (d-TGA) accounts for
6% of all CHD. This malformation is identified in 10% of
neonates with critical heart disease and is the most common
cause of cardiac cyanosis during the neonatal period. Male
infants are more commonly affected.
In d-transposition, the Ao arises from the anatomic RV
RV
and the PA from the LV (Figs. 11.4). In most cases, the Ao is
situated anterior and to the right of the PA, in contrast to the IVC
normal position posterior to the PA. This malformation is
thought to result from abnormal rotation and septation of the Fig. 11.4 Graphic representation of d-transposition of the great arter-
conotruncus, resulting in discordant ventriculoarterial ies. Intercirculatory mixing occurs at the levels of an atrial septal defect
(ASD) and/or patent ductus arteriosus (PDA). The discordant connec-
connections.
tions between the ventricles and great arteries in this lesion are
In the most common form of the defect, an intact ven- depicted—the right ventricle (RV) ejects into the aorta (Ao) and the left
tricular septum or a very small VSD is present (Fig. 11.5a). ventricle (LV) into the pulmonary artery (PA). IVC inferior vena cava,
d-Transposition is associated with a larger VSD in 10% to LA left atrium, RA right atrium, SVC superior vena cava
25% of cases (Fig. 11.5b). In complex forms of transposi-
tion, a large VSD and various degrees of pulmonary stenosis
(PS) or left ventricular outflow tract (LVOT) obstruction is promised tissue oxygenation. Less commonly, a high
seen (Fig. 11.5c). Other anomalies include additional VSDs, pulmonary vascular resistance accounts for severe cyanosis
coronary artery variants, and Ao arch obstruction. despite ductal patency and an adequate anatomic interatrial
communication.
Pathophysiology Congestive heart failure is unlikely even in the presence
In d-TGA, the systemic and pulmonary circulations operate of a PDA, VSD, or CoA in the first few days of life.
in parallel rather than in series. This anomaly results in Concomitant shunts at the ventricular or ductal levels are
recirculation of blood, deoxygenated blood in the systemic limited by the relatively high pulmonary vascular resistance
circulation, and oxygenated blood in the pulmonary circula- which constraints significant shunt volumes.
tion. Intercirculatory mixing is essential for survival. The
typical presentation is that of cyanosis shortly after birth as Management
the ductus closes in an otherwise healthy-appearing neo- Without intervention, this defect is almost uniformly fatal.
nate. There is minimal or no response to the administration Preoperative management is determined by the adequacy of
of oxygen. A restrictive foramen ovale can result in poor mixing between the parallel circulations. PGE1 therapy
mixing and profound arterial hypoxemia, potentially pro- frequently is used to enhance intercirculatory mixing. The
gressing to metabolic acidosis and severe shock due to com- goal of maintaining ductal patency is to increase the pulmo-
a b c
d e f
Fig. 11.5 Panel a, graphic representation of d-transposition of the abnormal great artery relationship with an anterior and rightward
great arteries (d-TGA) with intact ventricular septum. Panel b: d-TGA aorta (Ao), and posterior and leftward pulmonary artery (PA) in a mid-
with ventricular septal defect (VSD) associated with shunting at the esophageal short-axis view (panel e), and the abnormal ventriculo-
ventricular level. Panel c, d-TGA with left ventricular outflow tract arterial relations with a parallel course of the great arteries in a
obstruction (LVOTO). Panels d–f, preoperative transesophageal echo- mid-esophageal long-axis view (panel f). Panels a–c reproduced with
cardiographic images displaying a large ASD with left-to-right shunt- permission from Texas Children’s Hospital. LA left atrium, LV left ven-
ing (white arrow) in a mid-esophageal four-chamber view (panel d); tricle, RA right atrium, RV right ventricle
nary blood flow and the volume of pulmonary venous blood root, closure of existing intracardiac communications, and
returning to the LA, which in turn increases the LA pressure repair of additional defects, as indicated. Early in the surgical
to the extent that it stretches the interatrial communication, experience, certain coronary patterns were considered to pre-
enhancing intercirculatory mixing. Balloon atrial septostomy clude this type of surgery, given the need to mobilize and reim-
is required to enlarge a restrictive foramen ovale if significant plant these tiny vessels. Today, however, the concern is much
hypoxemia is present. Some centers favor an elective atrial less, and, in fact, many centers do not or rarely regard abnor-
septostomy in the neonate to allow for improved atrial mix- mal coronary patterns a contraindication for the arterial switch
ing, discontinuance of PGE1, and later surgery after feeding is operation. Timing of the operation is important and it is under-
established and the pulmonary vascular resistance decreases. taken before pulmonary vascular resistance decreases. This is
The arterial switch operation (Jatene procedure) is the to prevent deconditioning of the LV, given that it will become
operation of choice for uncomplicated d-transposition the systemic ventricular chamber upon completion of the
(Fig. 11.6). The intervention achieves anatomic correction and operation. Hence, in most cases, the operation is performed
restores normal physiology. The surgical procedure involves within the first few weeks of life while the LV afterload [PVR]
transection of the great arteries above their semilunar valves, remains persistently increased due to the normally elevated
anastomotic connections to their appropriate respective out- pulmonary vascular resistance. Beyond the neonatal period,
flows, translocation of the coronary arteries to the neoaortic the approach to this lesion depends on numerous factors, but
Fig. 11.6 Graphic
representation of the arterial
switch operation in
d-transposition of the great
arteries. Upper left panel, the
ductus arteriosus/ligamentum
is divided, and the great
arteries are transected above
the level of their native
semilunar valves and roots.
Coronary artery buttons are
then removed from the
usually anterior and rightward
aorta. Upper right panel, the
coronary arteries are
translocated to the posterior
“neoaortic” root (native
pulmonary root). Left lower
panel, the Lecompte
maneuver is performed
allowing for the main
pulmonary artery to be
mobilized in front of the
neoaorta. Right lower panel,
the aortic anastomosis is
completed, and after repairing
the defects in the native aorta
(“neopulmonary artery”)
where the coronary buttons
were removed, the pulmonary
arterial anastomosis is
completed
importantly on the ability of the LV to support the systemic hypoxemia. The main goal is to maintain hemodynamic sta-
circulation based on the presence or absence of associated bility while an atrial communication is enlarged or created.
defects and their impact on LV “preparedness.” Marked clinical improvement is seen with adequate atrial
mixing. Access to emergency equipment, medications, and
Anesthetic Considerations blood products is essential.
If a balloon atrial septostomy is required before corrective The use of intraoperative transesophageal echocardiogra-
surgery, it can be undertaken at the bedside, in the intensive phy (TEE) is the standard at many congenital heart centers
care unit, or in the cardiac catheterization laboratory. and may be used to confirm the anatomy (Fig. 11.5d–f) and
Frequently, the intervention is urgent due to profound arterial the post-repair assessment.
Specific Issues
• Myocardial ischemia. Translocation of the coronary arter-
ies involves manipulation, probing, and, in some cases,
potential stretching or distortion of the vessels. These
maneuvers in addition to other aspects of the repair can SVC AO
predispose the neonate to coronary artery spasm and/or
myocardial ischemia. Thus, these patients require careful
surveillance for compromise of myocardial blood flow PA
(electrocardiographic monitoring of ST segments, LA
pressure monitoring, regional wall motion assessment by
LA
TEE, examination of coronary Doppler blood flows).
Inadequate coronary perfusion may cause ventricular
dysfunction, failure of separation from CPB, or intracta- RA
ble ventricular arrhythmias. The post-bypass administra-
LV
tion of a nitroglycerine infusion after surgery for d-TGA
is routine in some centers.
• Left ventricular compliance. The LV in the neonate with
d-transposition is relatively “stiff” and noncompliant
immediately after surgery, which results in extreme sensi-
Pulmonary
tivity to the administration of excess volume, resulting in stenosis
a significant increase in LA pressure and a decrease in
cardiac output. Chamber overdistension is poorly toler-
ated, so fluids should be administered cautiously and
guided by LA pressure, systemic arterial blood pressure,
RV
and qualitative echocardiographic assessment of LV size.
• Pulmonary hypertension. Because surgical correction is Right ventricular
performed early in life before the normal decrease in pul- IVC hypertrophy
monary vascular resistance, pulmonary hypertension can
be a problem in the immediate post-bypass period and Fig. 11.7 Graphic representation of tetralogy of Fallot showing the
classic features of this lesion: ventricular septal defect, pulmonary ste-
postoperatively. If the case, strategies that support the RV, nosis, overriding aorta (AO), and right ventricular hypertrophy. The
as well as the use of pulmonary vasodilators, should be potential various levels of right ventricular outflow tract obstruction are
considered. noted (subvalvar, valvar, and supravalvar). The right-to-left shunt across
the ventricular septal defect (shown by the arrow) accounts for the pres-
ence of cyanosis in this defect. IVC inferior vena cava, LA left atrium,
LV left ventricle, PA pulmonary artery, RA right atrium, RV right ven-
Tetralogy of Fallot tricle, SVC superior vena cava
Anatomic Features
Tetralogy of Fallot (TOF) is the most common cause of cya- spectrum of clinical manifestations in tetralogy is due to the
notic heart disease in later childhood, accounting for approx- variable anatomic features, particularly the severity of the
imately 6% to 11% of CHD. The absence of cyanosis or the RVOT obstruction. Associated pathology includes an atrial
failure to recognize mild cyanosis immediately after birth communication, additional VSDs, a persistent connection
explains why TOF is often diagnosed beyond the neonatal from a left superior vena cava (LSVC) to the coronary sinus,
period and is not recognized as the most common cyanotic coronary artery anomalies, and variants of Ao arch laterality
heart defect in the neonate. or branching pattern. Concomitant lesions such as a com-
The four components of TOF in the classic lesion include plete atrioventricular septal defect can be present in some
a large VSD, right ventricular outflow tract (RVOT) obstruc- cases (colloquially referred to as “tet-canal” defect).
tion, Ao override, and RV hypertrophy (Fig. 11.7) [62]. Pulmonary atresia with a VSD is considered to represent an
Anterior and cephalad displacement of the infundibular sep- extreme form in the TOF spectrum.
tum during cardiac development, also referred to as malign-
ment of the outlet septum with respect to other portions of Pathophysiology
the ventricular septum, is considered the fundamental pathol- The obstruction to RV outflow in TOF, which is often found
ogy responsible for the defects in this lesion [63]. The wide at multiple levels, has variable dynamic and fixed compo-
nents. The dynamic obstruction occurs only in the muscular infants, a single-stage definitive repair consisting of closure
infundibular region. In contrast, the fixed components occur of the VSD, relief of the RVOT obstruction, and repair of
at the subvalvar, valvar, and supravalvar regions and/or the associated defects.
branch pulmonary arteries. Cyanosis is caused by decreased A meta-analysis of the outcomes after complete physi-
pulmonary blood flow and right-to-left shunting across the ologic repair of TOF in the neonatal and post-neonatal
VSD, with lower pulmonary to systemic blood flow. The periods reported that mortality rate increased threefold and
nonrestrictive nature of the VSD combined with the RVOT the hospital stay increased 47%, including an 18% greater
obstruction explains how the right and left ventricular pres- duration of intensive care stay when the defect was repaired
sures equalize in this lesion. Sudden increases in RVOT during the neonatal period compared with repair after the
obstruction combined with right-to-left intracardiac shunting neonatal period [65]. A large study querying 2363 children
herald the hypercyanotic episodes or “tet spells.” These can with TOF using the Pediatric Health Information System
lead to significant morbidity or even death, but fortunately database compared the outcomes of those who underwent
are very rare in the neonate. either complete repair in the neonatal period or staged
TOF has a spectrum of clinical presentations [64]. At one repair. They found that the cardiac complication rate in
end, the acyanotic neonate with TOF has a large VSD and hospital was greater and the risk of mortality at 7 to 30 days
minimal RVOT obstruction that shunt blood across the ven- and 2 years follow-up was greater during repair in the neo-
tricular communication typically in the left-to-right direc- natal period compared with a staged repair [66]. Early
tion. Some degree of heart failure from pulmonary morbidity and greater mortality rates with neonatal com-
over-circulation may be present subsequently as the pulmo- plete repair as compared with a staged approach continue
nary vascular tone decreases, accounting for the “pink” form to be reported [67, 68].
of TOF. At the other end of the spectrum, the cyanotic neo- Many technical aspects of the surgical intervention in TOF
nate with severe PS/near pulmonary atresia depends on a are variable and depend on the surgeon/institution [69, 70].
PDA and is in need of an intervention to ensure a stable pul- The relief of the RVOT/pulmonary obstruction can be accom-
monary blood flow after the ductus arteriosus closes. In the plished through transatrial and/or PA access and, in some
middle of this continuum is the “classic” form of TOF, char- cases, through a ventriculotomy. An incision across the pul-
acterized by moderate pulmonary outflow tract obstruction monary annulus and placement of a transannular patch is nec-
and mild to moderate cyanosis at rest (systemic oxygen satu- essary in some cases, usually related to annular h ypoplasia,
ration ~ 80% to 90%). This condition is the case in most which is more likely in younger infants. With regard to clo-
neonates, in whom increasing cyanosis can occur with cry- sure of the VSD, the approach can be a transatrial, transven-
ing, agitation, or pain. tricular, or combined, based on the surgeon’s preference.
A particular variant of TOF with potential significant clin- Although a ventriculotomy or the need for a transannular
ical implications in the neonatal period is that associated patch can impact the long-term outcome, some prefer pallia-
with absent pulmonary valve syndrome. This pathology is tion rather than correction in very young infants. Alternative
characterized by a dysplastic pulmonary valve, various medical temporizing measures at some centers include the
degrees of valvar stenosis, and regurgitation, in addition to use of beta-adrenergic receptor antagonists to minimize the
the usual findings in TOF. Massive dilation of the main and risk of infundibular “spasm” and associated hypercyanotic
branched pulmonary arteries in this defect results in abnor- events. In selected cases, cardiac catheterization procedures
malities of the tracheobronchial tree. These anomalies can such as percutaneous balloon pulmonary valvuloplasty or
result in severe respiratory compromise due to air trapping stenting of the ductus arteriosus or stenting of the RVOT can
and are frequently associated with significant morbidity be beneficial while the infant awaits corrective surgery [71].
related to poor pulmonary mechanics.
Management During anesthetic care, the main concern in the unrepaired
The favored surgical approach in the neonate or very young neonate with TOF is the potential for hypercyanotic episodes
infant with TOF associated with severe RVOT obstruction that can result in profound hypoxemia and significant mor-
and significant cyanosis varies among institutions. Some bidity [72]. These episodes can be triggered by crying, light
centers advocate initial palliation with a systemic-to-PA anesthesia, pain, hypovolemia, sympathetic stimulation (or
shunt, most frequently in the form of a modified Blalock- sympathomimetic drugs), or anesthetic-related decreases in
Taussig (mB-T) shunt (graft between a subclavian artery and systemic vascular tone with augmentation of the right-to-left
PA). This is performed via a lateral thoracotomy or median shunting. Immediate management of an acute spell usually
sternotomy approach and is followed by corrective surgery requires titration of a systemic vasoconstrictor drug (phenyl-
later in infancy. Other centers prefer, even in very young ephrine, norepinephrine, or vasopressin). Augmenting the
cardiac preload by administering fluids to facilitate forward • Aortic arch sidedness. During palliative surgery via thora-
flow across the obstructed RVOT can also help. Beta-blockers cotomy, Ao arch sidedness can influence the site of shunt
(e.g., esmolol or propranolol) can be given in an effort to placement and, hence, the surgical approach (right versus
decrease heart rate and enhance diastolic filling time, while left thoracotomy). Although Ao arch anatomy is deter-
also relaxing the dynamic RVOT, but should be used with mined preoperatively, it is a matter of consideration dur-
great caution in the neonate. A measure that is usually con- ing surgical positioning.
sidered once the neonate has been stabilized is blunting of • Coronary artery anomalies. These anomalies are present
the sympathetic tone by increasing the anesthetic depth by in 5% to 12% of patients with TOF and potentially impact
the administration of a sedative, opioid, or inhalational agent. the surgical procedure. The left coronary artery, for exam-
Carefully titrated inhalational agents are especially advanta- ple, can originate anomalously from the right coronary
geous in view of their cardiac depressant effects on the artery and course across the RVOT and near or at the loca-
RVOT. Halothane was ideal for the child with TOF but is not tion of a planned transannular incision, requiring a modi-
readily available now. Sevoflurane has largely replaced halo- fication in the usual surgical plan.
thane for induction. This agent does not increase the heart • Effects of surgery. It is important to highlight the impact
rate in doses <1.5 MAC and may be a better choice than of the surgical intervention on the physiology and influ-
isoflurane for maintenance [73]. Both agents cause the same ence on perioperative care as follows:
amount of vasodilation. During cardiac surgery, a hypercya- –– Transannular incision and patch augmentation during
notic episode is rarely refractory to treatment necessitating definitive surgical repair of TOF invariably lead to
emergent initiation of CPB. The main goals of anesthetic pulmonary regurgitation because the intervention
care of the neonate with TOF are to minimize the potential violates the integrity of the annulus and valve. In
for further increases in right-to-left shunting, promote for- some cases, the relatively “stiff” RV limits the regur-
ward pulmonary blood flow, and preserve myocardial func- gitant volume, and this restrictive physiology is well
tion. Even issues that are known to minimally influence the tolerated initially [74]. However, in other infants, the
physiology of other forms of CHD can impact that of the acute RV volume load exacerbates an underlying ele-
neonate with TOF. An example is the potentially detrimental ment of diastolic dysfunction. This issue, com-
effect of mechanical ventilation on intrathoracic pressure, pounded by some degree of systolic impairment
further reducing pulmonary blood flow. related to myocardial edema, ischemic time, mechan-
ical effects of the manipulations of the heart, and
Specific Issues injury to the anterior RV wall resulting from the ven-
• Pulmonary vascular resistance. In general, pulmonary triculotomy/transannular patch, can complicate the
vascular tone does not substantively affect the physiology postoperative course. This may be further com-
of this lesion, although the normally increased pulmonary pounded by the presence of residual lesions (i.e., ven-
vascular resistance in the neonate can impede forward tricular level shunting). The consequence is a low
flow across the outflow tract. It can have important impli- cardiac output state manifested in the first 24 h post-
cations regarding perioperative management and surgical operatively. In patients with severe low cardiac out-
decision-making as it complicates the assessment of the put syndrome, spontaneous or negative pressure
severity of the RVOT obstruction. Therefore, a reasonable pulmonary ventilation can improve cardiac output
anesthetic goal is to minimize acute increases in pulmo- and cerebral oxygenation [75, 76].
nary vascular tone. –– After complete repair, RV function can be impaired
• Arterial blood pressure monitoring. The presence of an as previously described, and inotropic support may
aberrant subclavian artery, a relatively common associ- be required. However, it should be emphasized that
ated finding, should be considered in the selection of inotropic agents can influence the postoperative
sites for arterial line placement. In this setting, insertion assessment of the adequacy of the repair, because
and manipulation of a TEE probe for intraoperative tachycardia and increased inotropy can exacerbate
imaging during complete repair can compress the retro- any residual RVOT gradient.
esophageal vessel leading to blunting or disappearance –– Pathology such as residual VSDs or RVOT obstruc-
of the blood pressure tracing. When palliation in the tion, or significant tricuspid regurgitation may not be
form of a mB-T shunt is anticipated, the arterial catheter well tolerated in this particular patient group.
must be placed in a site other than the one supplied by –– An intentional atrial communication, in the form of a
the vessel where the vascular graft is planned to allow patent foramen ovale or small atrial septal defect,
for uninterrupted assessment of arterial blood pressure might be created during corrective surgery to facilitate
throughout the case. postoperative care in anticipation of decreased RV
compliance. This communication allows for mainte- diverted to the RA. This anomaly is classified into several
nance of cardiac output at the expense of a small types according to the main path by which blood in the
amount of atrial level right-to-left shunting and a mild anomalous pulmonary veins drains (Fig. 11.8): supracardiac,
degree of arterial hypoxemia. via a vertical vein to innominate vein or right SVC; cardiac,
• Junctional ectopic tachycardia (JET). JET consists of a into the coronary sinus or RA; infracardiac, via a common
narrow QRS tachycardia (heart rate greater than 170 pulmonary vein into the portal system, from there through
beats per minute), atrioventricular dissociation, and a the ductus venosus to the IVC; or mixed, a combination of
ventricular rate faster than the atrial rate [77]. The loss of the various types. In two-thirds of cases, this is an isolated
the atrial contribution to ventricular filling and shortened lesion. In the remaining one-third of cases, TAPVD is associ-
diastolic filling time can have significant hemodynamic ated with other defects (VSD, CoA, and complex CHD such
effects in this vulnerable patient. This arrhythmia can as heterotaxy syndromes).
occur in the immediate postoperative period after surgery
for CHD, including TOF repair [78, 79]. Strategies to Pathophysiology
manage this arrhythmia include sedation (to reduce sym- Anomalous pulmonary venous return is well tolerated in the
pathetic tone), decrease in the level of inotropic support, fetus because of the limited pulmonary blood flow associated
surface cooling (32–34 °C), correction of electrolyte dis- with the normally high pulmonary vascular resistance. In the
turbances, various forms of pacing, and administration of first few days/weeks after birth, the presence or absence of
magnesium. Pharmacological treatment with intravenous obstruction along the pulmonary venous pathway plays a
agents (e.g., amiodarone, procainamide, sotalol) may be major role in the physiologic consequences of the defect. In
indicated in some cases [80, 81]. Over the last several the absence of pulmonary venous obstruction and high pul-
years increasing clinical experience with dexmedetomi- monary blood flow, plus a nonrestrictive ASD, it is associ-
dine suggests that an infusion of the drug after CPB ated with a relatively high systemic arterial oxygen saturation
decreases postoperative JET in pediatric patients [82, (SaO2) and adequate systemic cardiac output. Over time,
83]. Pretreatment with a beta-blocker may also reduce however, RV volume overload and congestive symptoms of
the incidence of this arrhythmia [84]. Extracorporeal CHF ensue. This physiology of TAPVR can result in a late
membrane oxygenation support (ECMO) and/or extra- presentation. In contrast, a restrictive atrial communication
corporeal cardiopulmonary resuscitation (ECPR) should leads to a greater degree of arterial hypoxemia and compro-
be considered in the management of hemodynamically mised systemic output. Pulmonary venous obstruction
unstable primary arrhythmias as an emergent lifesaving almost always is the norm in infradiaphragmatic TAPVR
procedure [85, 86]. secondary to constriction of the ductus venosus. This latter
• Restrictive physiology. Some neonates post-tetralogy condition is characterized by profound hypoxemia caused by
repair develop a syndrome referred to as “acute right decreased pulmonary blood flow and pulmonary venous con-
ventricular restrictive physiology.” This is characterized gestion, pulmonary hypertension, and respiratory compro-
by a low cardiac output state, need for inotropic sup- mise. Relative “pseudo-hypoplasia” of left-sided cardiac
port, and prolonged intensive care stay. Using echocar- structures can be seen in the affected neonate with TAPVR.
diography, the physiology of RV restriction is All forms of this lesion have complete mixing of systemic
manifested by Doppler evidence of antegrade pulmo- and pulmonary venous returns at the level of the RA. Right-
nary arterial flow in late diastole. The findings reflect to-left atrial shunting allows mixed blood to enter the LA,
transmission of atrial contraction into the MPA and the which is then ejected by the LV into the systemic circulation.
role of the RV as a passive conduit during this phase of The degree of hypoxemia depends on the severity of the pul-
the cardiac cycle [87, 88]. monary venous obstruction; it can be mild and mimic respi-
ratory distress syndrome, or profound, in which case the
infant will be moribund.
Total Anomalous Pulmonary Venous Return
Management
Anatomic Features Initial efforts are directed at stabilizing the neonate and estab-
Total anomalous pulmonary venous return (TAPVR) lishing respiratory/hemodynamic support as necessary. Chest
accounts for 2% of all CHD. It is characterized by drainage radiography can provide a clue as to the site of drainage and
of all pulmonary venous blood back into the pulmonary cir- likelihood of obstruction (Fig. 11.9), and in most cases, a defin-
culation through remnants of vascular connections normally itive diagnosis is established only by echocardiography. At
present during fetal life. The lesion represents an obligatory times chest tomography may be done to further define the anat-
shunt as oxygenated blood from the pulmonary veins is omy. Surgical intervention can be undertaken on an elective
a SVC Innominate Vertical b SVC

vein (cardinal)
vein
LA LA
PVs PVs
PVs PVs
RA RA
LV LV
RV RV
IVC IVC
c SVC
LA
PVs
PVs
RA
LV
Ductus venosus
IVC
Fig. 11.8 Graphic representation of total anomalous pulmonary venous veins (PVs) typically empty into the coronary sinus, draining into the
return. Panel a, supracardiac drainage. In this lesion the path of pulmo- RA. Panel c, infracardiac drainage. In this setting, PVs drain through the
nary venous drainage is from a vertical vein to the innominate vein into ductus venosus to the RA. Frequently this anomaly is associated with
the right atrium (RA). In most defects an associated atrial septal defect pulmonary venous obstruction. IVC inferior vena cava, LA left atrium,
is present. Panel b, cardiac drainage. In this pathology, the pulmonary LV left ventricle, RV right ventricle, SVC superior vena cava
be administered cautiously to prevent LV overdistension.

This can be guided by using LA pressure monitoring.
Specific Issues
• Pulmonary vascular reactivity. There is a propensity in these
infants to develop acute pulmonary hypertensive crises in the
post-bypass or postoperative period due to a reactive pulmo-
nary vascular bed. These episodes are prevented/managed by
deep sedation and measures to decrease pulmonary vascular
tone. The administration of pulmonary vasodilators, includ-
ing inhaled nitric oxide, is indicated as required. In cases at
risk, PA pressure monitoring via a surgically placed direct
transthoracic catheter can facilitate management.
• Echocardiography. Placement and/or manipulation of a
transesophageal probe can compress the pulmonary venous
confluence and compromise hemodynamics. Epicardial
echocardiography might be considered preferable for intra-
Fig. 11.9 Chest radiograph obtained in a neonate with obstructed operative imaging to assess the surgical results.
supracardiac total anomalous pulmonary venous return showing the
widened mediastinum due to the superior vena cava engorgement and • Partial anomalous pulmonary venous drainage.
pulmonary vascular congestion. A tracheal tube is present and an oro- Anomalous drainage of only one or two pulmonary veins
gastric tube is noted to be coiled in the esophagus is not uncommon in association with other forms of
CHD. Usually this is of little physiological consequence
basis if minimal or no pulmonary venous obstruction is present in the neonatal period.
and the infant is doing well clinically. Most cases with obstruc- • Postoperative pulmonary venous obstruction.
tion require urgent or emergent surgery due to the presence of Approximately 15% of infants develop postoperative pul-
severe hypoxemia [89]. The administration of PGE1 may be monary venous obstruction, typically within 6 months of
detrimental in the presence of severe obstruction as it further surgery [90]. This may be related to anastomotic stricture or
increases pulmonary blood flow, aggravating the obstruction to progressive intimal hyperplasia. The individual pulmo-
and worsening oxygenation. However, in some cases PGE1 nary veins can also develop stenosis. Interventions for man-
may be beneficial as it influences vascular smooth muscle tone agement range from balloon angioplasty to reoperation.
and may maintain the patency of the ductus venosus, thereby
alleviating the obstruction. Regardless of the details of the anat-
omy in TAPVR, the surgical correction aims to reroute the Truncus Arteriosus
drainage of the anomalous pulmonary veins into the LA.
Anatomic Features
Anesthetic Considerations Truncus arteriosus (TA) is a relatively uncommon malforma-
The main issues regarding the anesthetic care in these neo- tion, representing only 1% to 2% of congenital cardiac
nates before the pathology is addressed center around respira- defects. Approximately one-third of infants with this anom-
tory and hemodynamic support [90]. In the presence of aly have deletions of chromosome 22 (e.g., DiGeorge syn-
pulmonary venous obstruction and severe hypoxemia, rela- drome). In TA, also referred to as persistent truncus arteriosus
tively high ventilatory settings that include the use of high or common arterial trunk, a single arterial root emerges from
peak inspiratory and positive end-expiratory pressures usu- the heart, giving rise to the Asc Ao, PA, and coronary arteries
ally are required. The repair is frequently performed under (Fig. 11.10). An unrestrictive outlet VSD is almost always
deep hypothermic circulatory arrest (DHCA) or using low- present and the origin of the common arterial trunk charac-
flow perfusion. Upon separation from CPB, support of the RV teristically straddles the ventricular communication. This
with inotropic agents and pulmonary vasodilators is impor- defect is thought to be caused by failure of the normal pro-
tant in order to maintain cardiac output in the presence of an cess of conotruncal septation that results in two great
increase in pulmonary vascular resistance. This management arteries.
aims at limiting the likelihood of a negative effect of the RV There are several classifications proposed for TA [91–93].
on the LV (ventricular interactions). The LV in this lesion is In the most commonly used classification scheme described
relatively noncompliant and is subject to failure. Blood vol- by Collett and Edwards, TA is subdivided into several sub-
ume overload can reduce stroke volume. Thus, fluid should types (types I, II, III) based on the anatomical origin of the
pulmonary arteries from the arterial trunk [91]. The most

common variant is one somewhere between types I and II,
colloquially referred to as TA type 1½. Associated lesions
include truncal valve issues (abnormal number of cusps, dys-
SVC
Ao plasia, stenosis, regurgitation), abnormal origin and course
of the coronary arteries, and Ao arch anomalies (right Ao
arch and Ao arch interruption). The details of the anatomy
PA can be defined by echocardiography in nearly all cases
(Fig. 11.11).
LA Pathophysiology
Hypoxemia in TA is due to complete admixture of systemic
RA and pulmonary venous blood as it emerges from both ven-
tricles into the single arterial vessel. The hemodynamic
repercussions of the defect relate to the direct physical
LV communication between the systemic and pulmonary cir-
culations at the level of the truncal root. This arrangement
imposes a pressure and volume load to both ventricles fur-
ther exacerbated by truncal valve pathology (stenosis or
regurgitation), if present. The clinical features depend pri-
marily on two factors: the pulmonary vascular resistance
and the presence of any intrinsic stenosis in the pulmonary
arteries. These variables determine the volume of blood
that enters the pulmonary vascular bed from the truncal
root.
RV The neonate usually is well compensated immediately
after birth due to the normal relatively high pulmonary vas-
IVC cular resistance. As this decreases however, symptoms
related to pulmonary over-circulation and congestive heart
Fig. 11.10 Graphic representation of truncus arteriosus demonstrating failure emerge. In the presence of branched PA stenosis, the
the common truncal root with a biventricular origin. In this lesion, there
is obligatory mixing of the systemic and pulmonary venous returns. Ao
neonate can remain clinically stable to the degree that pul-
aorta, IVC inferior vena cava, LA left atrium, LV left ventricle, PA pulmo- monary blood flow is adequately restricted. If the obstruction
nary artery, RA right atrium, RV right ventricle, SVC superior vena cava is severe, cyanosis can be significant.
a b
Fig. 11.11 Transthoracic echocardiographic images in a neonate with two-dimensional and corresponding color Doppler (panel b). White
truncus arteriosus displaying the biventricular origin of the single arte- arrow shows the flow from the truncal root into the right pulmonary
rial root in a parasternal long-axis view (panel a). This is a type II artery (RPA). LA left atrium, LV left ventricle, RV right ventricle, TA
truncus arteriosus with normal caliber pulmonary arteries, arising sepa- truncal artery, LPA left pulmonary artery
rately from the left posterior aspect of the common trunk as shown by
Management restrict pulmonary blood flow and augment systemic output.

Therapy for CHF is indicated preoperatively in most cases As would be expected, this intervention is often followed by
including inotropic support. The preferred management systemic arterial desaturation, necessitating an increase in
approach is surgical repair during the neonatal period. This the inspired oxygen concentration.
consists of removing the PA(s) from the truncal root, repair-
ing the ensuing defect, patching the VSD closed, reconstruct- Specific Issues
ing the RVOT, and repairing any associated pathology that • Atrial level shunting. In some cases, a small interatrial
may include the truncal valve. Early correction is indicated communication is left patent or is created intentionally to
since pulmonary vascular obstructive disease can rapidly facilitate the postoperative course. In this setting, some
develop. There is a high incidence of a need for reinterven- degree of arterial desaturation is expected as a tradeoff
tion, which occurs frequently and has been attributed to benefit to the maintenance of cardiac output, particularly
problems with the RV to PA conduit and truncal valve [94]. at times when right-sided/pulmonary artery pressures
increase.
Anesthetic Considerations • Residual lesions. After surgery, volume loading on the
A major challenge in the perioperative care of the neonate LV, as imposed by a residual VSD or truncal valve
with TA pertains to balancing the pulmonary and systemic regurgitation, may be poorly tolerated. The post-repair
vascular resistances to achieve cardiovascular stability dur- TEE examination is invaluable in: (1) excluding hemo-
ing the pre-bypass period. A low pulmonary vascular resis- dynamically significant truncal valve stenosis, regurgi-
tance facilitates over-circulation that is associated with a tation, and RVOT obstruction, (2) interrogating for
steal phenomenon characterized by high systemic SaO2, atrioventricular valve regurgitation and, (3) evaluating
low diastolic arterial pressures, and a wide pulse pressure. ventricular function.
This steal leads to impaired systemic output, hypotension, • Pulmonary hypertension. Affected neonates are particu-
and compromised tissue oxygen transport. There is hypo- larly vulnerable to developing acute increases in PA pres-
perfusion of distal tissues, and the potential for myocardial sures during the post-bypass period and in the intensive
ischemia. Thus, the likelihood for morbidity and critical care unit. This vulnerability can lead to acute decompen-
events is high. TA is considered one of the congenital sation, significant morbidity, and even death. The surgical
lesions most associated with a very high risk of adverse placement of a PA pressure-monitoring catheter for peri-
perioperative events [95]. operative management may be useful and is a matter of
The anesthetic management of the neonate with unre- institutional preference. The perioperative management
paired TA therefore focuses largely on controlling pulmo- of pulmonary hypertensive crises is addressed in subse-
nary blood flow and maintaining adequate systemic output quent sections of this chapter.
[94]. Reducing the inspired oxygen concentration where
possible, to room air levels, and increasing arterial carbon
dioxide tension (PaCO2) to mild hypercarbic values are the Critical Aortic Stenosis
most common strategies used to limit pulmonary blood flow
by avoiding decreases in pulmonary vascular tone. Effects of Anatomic Features
the anesthetics, positive pressure ventilation, and changes in Congenital AS is present in 3% to 6% of all patients with
intravascular volume may pose challenges to managing pul- CHD; however, symptomatic disease in the neonate or infant
monary over-circulation during the pre-bypass period and accounts for fewer than 10% of cases of Ao valve stenosis,
systemic hypotension may occur (arterial blood pressure can consistent with the rare nature of the lesion. The valve in
decrease). Electrocardiographic changes suggestive of myo- critical AS is characterized by leaflet fusion, frequently
cardial ischemia can be present. Agents that depress the exhibiting a unicuspid appearance, or might be severely
myocardium or cause significant systemic vasodilation thickened and dysplastic (Fig. 11.12). The Ao annulus, root,
should be administered cautiously. In addition to limiting and Asc Ao typically display some element of hypoplasia. In
pulmonary blood flow, other strategies may be required to many cases, LV dilation in combination with poor systolic
address systemic hypotension including fluid volume expan- function and mitral regurgitation is present. This condition is
sion, increasing the hematocrit, and infusing inotropes and frequently associated with infarction and atrophy of papil-
vasoconstrictors for ventricular support as required. During lary muscles as well as endocardial fibroelastosis (EFE).
cardiac surgery, a temporary snare can be placed around the Various degrees of LV hypoplasia and mitral and Ao arch
MPA segment or one of the PA branches to mechanically hypoplasia also can be present in some infants.
pressure gradient even in the presence of severe obstruction.

The transvalvular pressure gradient must be considered
within the context of the systolic function of a ventricle.
Critical AS in the fetus can lead to hydrops caused by
SVC Ao ongoing subendocardial ischemia and severe myocardial
dysfunction. In most cases of critical disease in the neo-
nate, antegrade flow through the Ao is inadequate to main-
tain cardiac output, and right-to-left shunting through the
PA
ductus arteriosus accounts for most of the systemic blood
flow. In fact, retrograde flow through the aortic arch via the
ductus may in some cases be responsible for coronary and
LA
cerebral perfusion.
The neonate presents with signs of severe heart failure
RA
or frank shock, often temporally related to constriction or
closure of the ductus arteriosus. Clinical evidence of con-
gestive heart failure in the neonate includes tachypnea,
LV poor feeding, diaphoresis with feeds, failure to thrive, hep-
atomegaly, and a gallop rhythm. A low cardiac output state,
associated with severe ventricular dilation and dysfunction,
is manifested by poor peripheral perfusion, pallor, cool
extremities, and lactic acidemia. Papillary muscle infarc-
tion, usually associated with severe mitral regurgitation,
can be part of a grim presentation. Systemic compensatory
responses consist of tachycardia, systemic vasoconstric-
tion, and increased blood volume. The physiologic altera-
RV tions are complex and impact not only the cardiovascular
system but also other major organs.
IVC
Management
Fetal congestive heart failure and hydrops present a unique
Fig. 11.12 Graphic representation of critical aortic stenosis. Ao aorta,
challenge. Transplacental digitalization has been used to treat
IVC inferior vena cava, LA left atrium, LV left ventricle, PA pulmonary
artery, RA right atrium, RV right ventricle, SVC superior vena cava
fetal heart failure. Critical AS without intervention carries a
high mortality rate in the neonate. In recent years, fetal inter-
Pathophysiology ventions for critical AS have been performed at specialized
Obstruction to LV outflow due to a restricted Ao valvar ori- heart centers in an effort to alter the natural history of the
fice leads to increased LV systolic pressure, a transvalvular condition in utero, potentially obviating progression of the
pressure gradient, increased myocardial force, and LV wall disease [96, 97]. An analysis of the outcomes after in utero
stress. The hypertrophied myocardium is at risk for develop- aortic ballooning in a series of infants with AS at Boston
ing subendocardial ischemia as a consequence of an imbal- Children’s Hospital estimated the survival to be 80 ± 4% at
ance in the ratio of myocardial oxygen supply and demand. 1 year and 75 ± 5% at 5 years after ballooning. Outcomes
Left ventricular EFE results from compromised subendocar- were better in biventricular children with freedom from car-
dial oxygen delivery secondary to myocardial ischemia. diac death of 96 ± 4% at 5 years and 84 ± 12% at 10 years,
Fibrotic myocardial changes lead to severely impaired ven- respectively [98]. Long-term outcome studies are needed to
tricular function, resulting in marked increases in LV end- determine the impact of fetal aortic valve interventions on the
diastolic and LA pressures. The presence of EFE along with disease process. Prenatal maternal oxygen therapy has also
LV dilation and/or dysfunction carries a poor prognosis. A been attempted as a means to increase fetal pulmonary venous
large gradient across the Ao valve places a severe stress on return, promoting filling to left heart structures and changes
the function of the LV. When considering the degree of the in LV geometry and promoting antegrade aortic flow [99,
aortic valve stenosis, it should be recognized that a poorly 100]. Therapy with PGE1 maintains systemic perfusion and is
functioning LV may not be able to generate a significant life-saving. Concomitant therapy in the critically ill neonate
usually consists of mechanical ventilatory support to reduce the increased myocardial work and decreased ventricular fill-
the work of breathing, diuretic therapy, and infusion of ino- ing times associated with the use of inotropic drugs.
tropic agents to augment systemic output as needed. In some
cases, afterload reduction is used cautiously. Specific Issues
Treatments for the primary pathology in aortic stenosis • Transcatheter interventions. Complication rates for trans-
include percutaneous balloon aortic valvuloplasty and sur- catheter procedures in the neonate are greater than in
gery. Transcatheter balloon valvuloplasty can be performed older infants and children. Potential problems include
as a palliative procedure to relieve obstruction, permit recov- bleeding, arrhythmias, transient myocardial ischemia dur-
ery of LV function, and allow the patient to grow before sur- ing balloon inflation, development of or increase in the
gery. These catheter interventions may be favored in some severity of aortic regurgitation, and vascular compromise
institutions. The choice of surgical intervention is influenced related to access. Other complications such as cardiac
by factors such as size of the Ao annulus, aortic root, subaor- perforation and tamponade should also be considered and
tic area, adequacy of the mitral valve and LV dimensions, prepared for accordingly.
and coexisting defects. Surgical and medical approaches • Post-bypass problems. In the post-bypass period, major
include aortic valvotomy (open/closed), commissurotomy, issues include residual systemic outflow obstruction, aor-
aortic homograft placement, Ross procedure, Ross-Konno tic regurgitation resulting from or exacerbated by the
operation or other root-enlargement procedures, Damus- intervention, hemodynamic perturbations due to associ-
Kaye operation, and Norwood palliation. In some infants, ated defects, and myocardial dysfunction (preexisting and
cardiac transplantation may be the only feasible option at post-CPB).
any time during their clinical course. Mechanical circulatory
support may be considered at several points during the care
as a bridge to an intervention, for postcardiotomy failure, or Hypoplastic Left Heart Syndrome
while awaiting cardiac transplantation.
Anatomic Features
Anesthetic Considerations Hypoplastic left heart syndrome (HLHS) accounts for
The care of the neonate with critical AS can be extremely approximately 2% of CHD, but 23% of neonatal deaths
challenging. Important anesthesia management decisions [101]. The morphologic features of this malformation
include carefully considering the potential myocardial include aortic atresia or stenosis, mitral atresia or steno-
depressant effects of drugs, anesthetic agents, and other peri- sis, Asc Ao and arch hypoplasia, CoA, PDA, and an
operative interventions. Hemodynamic decompensation can atrial level communication (Fig. 11.13) [102]. The
occur during induction of anesthesia or at any time during a pathology represents one of the most common forms of
catheter or surgical intervention. Even the most careful anes- univentricular congenital malformation. Although HLHS
thesia induction can result in cardiovascular instability and is considered a spectrum of disease and the degree of LV
cardiac arrest as sedatives/anesthetic agents decrease sympa- hypoplasia and systemic outflow obstruction varies, the
thetic tone, which may be the primary compensatory mecha- LV in the classic lesion (aortic and mitral atresias) is sig-
nism. Cardiac massage may be ineffective because of the nificantly underdeveloped and the Asc Ao is markedly
restrictive Ao valve orifice; therefore, one should recognize hypoplastic [103].
the potential for untoward events and proceed extremely cau-
tiously. Having immediate access to emergency drugs and a Pathophysiology
defibrillator is vital. In addition advanced discussions regard- HLHS is usually diagnosed either in utero by fetal echocar-
ing the potential need for urgent circulatory support during diography or immediately or very soon after birth. Most
either the catheter-based intervention or the pre-bypass affected neonates are born at term and appear normal at
period should be documented. It is prudent for the surgery birth. Because right-to-left shunting across the ductus arte-
and perfusion teams to be immediately available during riosus provides for the entire systemic blood flow in the
induction of anesthesia and throughout the procedure, case of aortic atresia, it is considered a “ductal-dependent
whether catheter- or surgical-based. circulation”. The atrial communication allows for the
It is important to continuously optimize ventricular filling egress of pulmonary venous return into the RA, where it
and function without overlooking the potential detrimental mixes with the systemic venous blood entering the RV and
effects of volume overload in the failing heart. Consider also MPA.
presence of an intact atrial septum. On occasion, a decom-

pressing vein allows for passage of LA blood elsewhere into
the circulation. If this is not the case, the critically ill neonate
Ao
displays profound hypoxemia and acidosis requiring imme-
SVC diate attention. This condition represents a major clinical
PDA
problem and potentially a poor outcome.
Management
PA
The initial management of the neonate with HLHS should aim
to optimize the clinical status of the neonate and maintain duc-
ASD
flow
tal patency with an infusion of PGE1. Mechanical ventilation,
LA correction of acid-base status, and inotropic support may be
necessary. The mainstay of management is to adjust the ratio
RA
of pulmonary to systemic blood flow (Qp/Qs) and to optimize
oxygen delivery (Fig. 11.14) [104]. The neonate with a high
PaO2 caused by pulmonary over-circulation may have inade-
LV quate systemic blood flow. This condition will be associated
with metabolic acidosis and result in problems related to
decreased perfusion of metabolically active organs (e.g., nec-
rotizing enterocolitis due to impaired splanchnic blood flow).
Measures must be implemented to maintain a relatively
high pulmonary vascular resistance, in order to limit the pul-
monary blood flow and to increase the systemic blood flow. In
most cases, maintaining normocarbia or mild hypercarbia,
and/or limiting the fraction of inspired oxygen concentration,
RV will achieve this goal. The administration of added nitrogen to
deliver a hypoxic gas mixture also has been used. Carbon
IVC dioxide may be added to inspired gases to increase pulmonary
vascular tone and favor the balance of the Qp/Qs [105, 106]. In
Fig. 11.13 Graphic representation of hypoplastic left heart syndrome. a study that assessed the effects of inspired gas mixtures to
Note the small left-sided cardiac structures and direction of flow across reduce pulmonary over-circulation and improve systemic per-
the patent ductus arteriosus (PDA) (right-to-left shunting). The ductus
fusion, 3% inspired carbon dioxide improved cerebral oxy-
allows for antegrade blood flow into the descending aorta (Ao) and ret-
rograde flow around the aortic arch. An atrial communication allows for genation and mean arterial pressure, whereas a hypoxic
unobstructed egress of left atrial blood. ASD atrial septal defect, IVC mixture (17% inspired oxygen) affected neither [107].
inferior vena cava, LA left atrium, LV left ventricle, PA pulmonary Various approaches have been utilized to manage neonates
artery, RA right atrium, RV right ventricle, SVC superior vena cava
and infants with HLHS reflecting the ongoing challenges in
their care [101, 108–112]. Options include comfort care and
The clinical presentation in HLHS varies; some infants no intervention, in which case death is almost assured, a step-
display cyanosis and/or features of pulmonary vascular con- wise palliative surgical strategy; an initial combined catheter-
gestion and others present with ominous signs of low cardiac surgical approach (hybrid procedure) and subsequent step
output and impending or frank cardiovascular collapse. palliation; or cardiac transplantation [113, 114].
Acute decompensation is associated with ductal constriction The initial surgical strategy for HLHS during the neonatal
and hypoperfusion of systemic vascular beds, resulting in period is referred to as Stage I palliation or the Norwood
metabolic acidosis, lactic acidemia, and in some cases, a procedure. It involves (1) neoaortic reconstruction using the
shock-like picture. The shunted blood across the ductus arte- native pulmonary root and homograft material to relieve the
riosus not only serves as the entire source of systemic cardiac systemic outflow tract obstruction, (2) an atrial septectomy
output but also provides coronary blood flow because there is to allow for unobstructed drainage of the pulmonary venous
absent (aortic atresia) or virtually no antegrade flow through return into the RA, and (3) creation of a reliable source of
the Ao valve (critical AS). An aspect of the pathology that pulmonary blood flow through either a mB-T shunt
influences the clinical presentation is the degree of restric- (Fig. 11.15) or an RV to PA conduit (Sano modification,
tion across the interatrial communication or sometimes the Fig. 11.16; Brawn modification, Fig. 11.17) [115]. The RV
Cardiovascular Stability
Balance PVR
Relative to SVR
PVR PVR
Flow Thru
PBF PDA or Central Shunt
PBF
Hypoxemia SBF
PaO2
Metabolic Acidosis
Myocardial Depression Hypotension
and and
Cardiac Output Coronary Perfusion
Cardiovascular
Collapse
Fig. 11.14 Physiologic balance between the systemic and pulmonary plastic left heart syndrome: use of high-dose fentanyl in 30 neonates.
circulations required for hemodynamic stability in the infant with hypo- Anesth Analg 1986;65:127–132. PBF pulmonary blood flow, PDA pat-
plastic left heart syndrome prior to and following palliation. Reproduced ent ductus arteriosus, PVR pulmonary vascular resistance, SBF sys-
with permission from Hansen DD, Hickey PR. Anesthesia for hypo- temic blood flow, SVR systemic vascular resistance
thus becomes the chamber that supports both circulations. enlarged (via balloon atrial septostomy) usually during or
This operation is associated with potential significant periop- within a few days after this procedure to diminish the gradi-
erative morbidity and mortality [116]. In fact, the Norwood ent across the interatrial septum. The hybrid approach delays
operation represents one of the greatest risk interventions in Ao reconstruction until later in infancy and is considered of
congenital heart surgery. potential benefit, as the fragile neonate is not subject to CPB
The hybrid procedure for HLHS represents an alternate or associated techniques such as DHCA. Although it remains
palliative option to Stage I reconstruction during the neona- unclear which patients derive the most benefit from this strat-
tal period (Fig. 11.18) [117, 118]. This approach involves a egy, neonates with low birth weight may have increased sur-
combined catheter-based and surgical strategy wherein a vival when this approach is used instead of the Norwood
stent is deployed by the interventional cardiologist across the operation [119, 120]. In these infants, the subsequent
ductus arteriosus to maintain patency and bilateral bands are Norwood reconstruction is combined with the creation of a
placed across the PA branches by the surgeon to restrict pul- superior cavopulmonary connection or Glenn anastomosis
monary blood flow. The interatrial communication is (Stage II palliation), thus effectively merging the first two
Fig. 11.15 Panel a, graphic a © 2014 Texas Children’s Hospital

b © 2014 Texas Children’s Hospital
representation of the
Norwood procedure with BT
modified Blalock-Taussig BT
shunt (BT). Panel b, similar
graphic showing the direction
of blood flow after palliation Neo Ao Neo Ao
with shunting at the atrial
level and pulmonary blood
flow provided by the shunt.
Reproduced with permission
from Texas Children’s
Hospital. Neo Ao neoaorta, LA LA
RA right atrium, RV right
ventricle, LA left atrium, LV RA RA
left ventricle LV
RV
RV
Brawn
Shunt
Neo Ao
© 2014 Texas Children’s Hospital
Fig. 11.17 Graphic representation of the Brawn shunt modification of

the Norwood procedure. The arrows indicate the ring conduit shunt
Fig. 11.16 Graphic representation of the Sano modification of the from the right ventricle into the right pulmonary artery and the recon-
Norwood procedure with a right ventricular to pulmonary artery structed or neoaorta (Neo Ao). Reproduced with permission from Texas
conduit Children’s Hospital
stages of the palliative pathway. This is referred to as a com- approach is either reserved for high-risk neonates with
prehensive Stage II procedure. Although the operative mor- HLHS or used liberally as the favored strategy.
tality with this intervention was initially found to be
substantial, mortality has significantly decreased with time Anesthetic Considerations
as perioperative protocols became available [121]. Depending It is essential to establish absolutely reliable vascular access
on institutional experience and preference, the hybrid and ensure excellent function of all monitors at the outset of
the procedure. In the operating room, the management prin-
ciples discussed previously to maintain systemic output,
oxygen delivery, and balance of the Qp/Qs are maintained
[122]. Temporary partial occlusion of a branch PA by the
surgeon to mechanically limit pulmonary blood flow and
SVC Ao favor systemic blood flow is often very useful. Inhalational
anesthetic agents or an opioid/relaxant technique may be
PDA used as preferred.
RPA The use of an alpha-adrenergic blocking agent (e.g.,
phentolamine) has been advocated as a means to optimize
LPA peripheral vasodilation during the cooling phase of
CPB. Long-acting alpha-adrenergic blockade with phenoxy-
LA benzamine has also improved systemic oxygen delivery
RA [123]. This is secondary to minimizing regional variations in
SaO2-induced vascular resistance, thereby allowing the use
of greater oxygen concentrations to improve systemic oxy-
LV gen delivery in the postoperative period [124]. The use of
TEE is variable among institutions during Stage I palliation.
In addition to providing information on anatomy and func-
tion, it determines the adequacy of the atrial communication,
presence and degree of tricuspid regurgitation, and evalua-
tion of the surgical intervention (Fig. 11.19). It also serves as
IVC
an intraoperative monitoring tool.
RV
Specific Issues
• Surgical palliative approach. The choice of the surgical
Fig. 11.18 Graphic displaying hybrid palliation for hypoplastic left heart approach for Stage I palliation (systemic-to-PA shunt or
syndrome. The approach consists of ductal stenting, banding of both RV to PA conduit) and the perfusion strategy (DHCA or
branch pulmonary arteries, and enlargement of an interatrial communica-
ACP) depend on the surgeon and the center where the
tion. Ao aorta, IVC inferior vena cava, LA left atrium, LPA left pulmonary
artery, LV left ventricle, PDA patent ductus arteriosus, RA right atrium, procedure is performed [125]. These factors impact the
RPA right pulmonary artery, RV right ventricle, SVC superior vena cava selection of arterial blood pressure-monitoring sites and
a b c
Fig. 11.19 Transesophageal echocardiographic images in hypoplastic the same view (panel b), and the diminutive native aorta (Ao) and mod-
left heart syndrome showing a miniscule left ventricle (LV) in the mid- erately dilated RV giving rise the pulmonary artery (PA) in the mid-
esophageal four-chamber view (panel a), flow across the interatrial esophageal RV inflow-outflow view (panel c). LA left atrium
communication into the right atrium (RA) and right ventricle (arrow) in
may favor the use of cerebral physiologic monitoring. tone. At the same time, the deleterious effects of over-
Monitoring procedures must be adapted to the bypass transfusion and polycythemia should be considered, par-
strategy to be used. Whereas a mB-T shunt allows for pul- ticularly in view of the potential negative impact on blood
monary blood flow to occur throughout the entire cardiac flow across the systemic-to-PA shunt and patency of this
cycle (continuous forward flow), in a Sano connection, connection. If maneuvers that decrease the pulmonary
most of this flow occurs during systole. The narrower vascular tone are unsuccessful, administration of inhaled
pulse pressure and relatively greater diastolic blood pres- nitric oxide as a selective pulmonary vasodilator may be
sure due to the lesser diastolic runoff allowed by the Sano considered. If the SaO2 is greater than expected, it is rea-
conduit as compared with the mB-T shunt is regarded as sonable to reduce the inspired oxygen concentration and
an advantage for coronary and end-organ perfusion. The ensure normocarbia or mild hypercarbia. If there is evi-
Sano strategy is preferred by some to provide a more sta- dence of adequate systemic output and tissue perfusion, a
ble immediate postoperative course. This relatively more relatively high SaO2 may be acceptable. Tracking trends
favorable circulation is also thought to possibly limit the in cerebral oxygenation may facilitate these interventions.
rates of interstage mortality that occur in these infants A high oxygen saturation combined with a low systemic
while they await a second stage palliation [126]. However, pressure may also indicate too large an mB-T shunt.
the ventriculotomy required for conduit placement may • Mixed venous oxygen saturation monitoring. An approach
add to the risk of myocardial injury and the long-term proposed in the neonate with single ventricle physiology
rhythm disturbances. This is a possible disadvantage of after Stage I palliation to ensure systemic oxygenation is
this procedure. In a randomized clinical trial of shunt type the use of continuous mixed venous oxygen saturation
that included a large number of infants with HLHS under- (SvO2) monitoring, using transthoracic oximetric cathe-
going the Norwood procedure, the transplantation-free ters placed by the surgeon at the time of the intervention
survival rate at a year post-operation with the RV to PA [128, 129]. One strategy is to target an SvO2 value >50%,
shunt exceeded that of the mB-T shunt. After that time a mean arterial pressure over 45 mmHg, normocarbia,
period, the transplantation-free survival rate was similar and to administer oxygen as required to maintain the
in the two groups [125]. SpO2 within a desirable range. Relying on SvO2 as a met-
• Right ventricular optimization. With the RV operating as ric of systemic oxygen delivery has been associated with
the systemic chamber in HLHS, all efforts to maintain/ favorable outcomes in neonates with HLHS [128, 129].
enhance RV function during the perioperative period • Postoperative issues. Regardless of the surgical tech-
should be considered. Decreased initial stroke distance nique, patients with HLHS present major challenges of
(distance that blood travels with each heart beat) and car- bleeding, myocardial dysfunction, low cardiac output, and
diac output, as determined by echocardiography, are asso- hemodynamic instability during the post-bypass period.
ciated with later mortality or cardiac transplantation. It Other potential problems include renal dysfunction and
has been suggested that early evaluation of HLHS patients hepatic impairment [130]. As a result of these concerns,
should include an assessment of stroke distance. Future sternal closure may be delayed, and some neonates may
research should evaluate its value in the postoperative need postoperative mechanical circulatory support. Initial
management [127]. studies using signal-processing algorithms of ST segment
• Balancing the circulations. After separation from CPB, a report success with early detection of events that require
balance between the pulmonary and systemic blood flows rapid intervention to avoid cardiopulmonary arrest. These
should be optimized. A conventional management strat- events were not noticed by conventional ST analysis
egy has been to monitor the systemic SaO2 for this assess- [131]. Immediate extubation has been proposed to favor-
ment and to guide this balance by targeting a value ably impact outcomes when used judiciously after Stage I
between 75% and 80%. If this value is less than expected Norwood palliation; however, the experience with this
after separating from CPB and potential factors such as practice to date has been extremely limited [132].).
inappropriate shunt size and shunt occlusion/distortion • Hybrid procedure. Deferring the risks associated with the
have been excluded, steps are undertaken to decrease the Norwood operation to a later time in infancy, by perform-
pulmonary vascular resistance and increase the systemic ing a hybrid procedure, can offer potential advantages.
arterial blood pressure in order to improve the pulmonary Although caring for an infant with HLHS, outside the
blood flow. A relatively high hemoglobin concentration is typical surgical setting, can present major challenges, a
important in this setting to enhance the delivery of oxygen report on the anesthetic management of neonates sched-
and to prevent anemia-related low peripheral vascular uled for hybrid procedure documented relatively stable
intraoperative and early postoperative hemodynamics

[133]. Furthermore, most neonates did not require blood
transfusions or inotropic support. Performing endotra-
cheal extubation was feasible either at the end of the pro- PDA
SVC Ao
cedure or soon after the infant was admitted to the
intensive care.
PA
Interrupted Aortic Arch
Anatomic Features LA
Interrupted aortic arch (IAA), a discontinuity of the Ao arch,
is an uncommon lesion representing only 1% of all RA
CHD. Affected children have a high incidence of DiGeorge
syndrome (22q11 microdeletion).
This anomaly is defined in terms of the site of interruption
LV
as follows: type A, if distal to the left subclavian artery; type
B, if between the left carotid and left subclavian arteries
(most common variant; Fig. 11.20); and type C, if between
the carotid arteries. The pathology commonly is associated
with a posteriorly malaligned VSD, resulting in the obstruc-
tion of the LVOT. Coexisting anomalies include a right Ao
arch, aberrant origin of a subclavian artery, TA, and aortopul-
monary window.
Pathophysiology RV
Patency of the ductus arteriosus is essential for survival in
this anomaly, as it allows for systemic perfusion. The neo- IVC
nate with IAA presents with congestive heart failure, poor
perfusion, and cardiovascular collapse or shock after con- Fig. 11.20 Graphic representation of type B interrupted aortic arch.
striction of the ductus arteriosus and occasionally with dif- Note the site of interruption between the left carotid and left subclavian
ferential cyanosis. Thus, the physiology resembles that of arteries. The patent ductus arteriosus (PDA) supplies the systemic cir-
culation beyond the level of interruption. Ao aorta, IVC inferior vena
severe CoA. The presence of a VSD can cause pulmonary cava, LA left atrium, LV left ventricle, PA pulmonary artery, RA right
over-circulation and the associated consequences. atrium, RV right ventricle
Management
After the diagnosis is established, stabilization of the infant
is critical; PGE1 therapy is initiated to maintain ductal Anesthetic Considerations
patency [134]. Anticongestive therapy and inotropes are Although echocardiography is diagnostic in most neonates
administered as needed. Surgery is undertaken in the neona- with IAA, additional preoperative studies may be needed to
tal period, typically soon after the diagnosis is made. The further define the details of the arch anatomy. These exami-
aortic arch is reconstructed, the VSD closed, and possible nations in most cases require care at remote locations, add-
subaortic obstruction is resected [135]. Much less coming to the management considerations for the sick infant.
monly, an initial palliative approach is undertaken with Ao Maintenance of the PGE1 infusion is critical before the Ao
arch repair and pulmonary artery banding (PAB) if a VSD is arch is reconstructed. An adequate response generally
also present, followed by delayed complete repair later in implies no significant pressure gradient between proximal
infancy. If the LVOT obstruction is severe (marked subaortic and distal areas of the interruption. In view of the common
narrowing, annular, Ao root, and/or Asc Ao hypoplasia), association between PGE1 therapy and complications such as
alternate approaches including Ao root enlargement, replace- apnea in these neonates, their tracheas are frequently intu-
ment, or other complex interventions may be necessary. A bated and their lungs mechanically ventilated in the critical
single ventricle strategy is required in some cases. care unit.
Specific Issues
• Monitoring. It is important to consider the sites to moni-
tor systemic arterial blood pressure and SpO2 in neo-
nates with IAA [136]. The choice of sites is dictated by
the Ao arch anatomy and the presence of coexistent SVC Ao
anomalies. In the case of a type B interruption with left
Ao arch and aberrant right subclavian artery, for exam-
ple, none of the vessels that supply the limbs are proxi-
PA
mal to the interruption site. Thus, the arterial blood
pressure proximal to the site of interruption cannot be
measured in any extremity. This is a problem during
LA
CPB as the perfusion pressure cannot be recorded from
a vessel supplied by a subclavian artery during recon- RA
struction of Ao arch. Monitoring with cerebral oximetry
can be useful in this setting. Transcranial Doppler may
be used to guide ACP during the reconstruction [137,
138]. SpO2 in the unrepaired neonate may show differ- LV
ential readings in oxygen saturation, with greater values
in the sites supplied proximal to the interruption and
reduced values distally reflecting flow from the ductus
arteriosus (right-to-left shunting) [136].
• DiGeorge syndrome. In view of the potential for develop-
ing hypocalcemia in neonates with DiGeorge syndrome,
calcium levels should be monitored frequently. In such
cases, calcium infusions may be required. The presence
of coexisting noncardiac anomalies in this syndrome must RV
be considered including immune deficiency. Irradiated
blood products should be used to prevent potentially fatal IVC
transfusion-associated graft-versus-host disease.
• Surgical considerations. Interventions for IAA can be Fig. 11.21 Graphic representation of critical pulmonary stenosis. In
quite complex, requiring considerable bypass and myo- this defect, the ductus arteriosus serves as the main source of pulmo-
cardial ischemic times, particularly when concomitant nary blood flow. Ao aorta, IVC inferior vena cava, LA left atrium, LV left
ventricle, PA pulmonary artery, RA right atrium, RV right ventricle, SVC
LVOT obstruction is present. This can be a very challeng- superior vena cava
ing condition to manage.
ventricular septum (Fig. 11.22) are lesions characterized by

ritical Pulmonary Stenosis and Pulmonary
C pulmonary valve/RVOT obstruction. The pulmonary valve in
Atresia with Intact Ventricular Septum the neonate with critical PS, the most severe form of valvar
obstruction in infancy, displays fused raphes with a restric-
Anatomic Features tive, eccentric pin-hole size opening. In the uncomplicated or
Pulmonary stenosis is the most common form of RVOT obstruc- pure form of critical PS, the ventricular septum is intact and
tion among infants, accounting for more than 80% of the cases. an interatrial communication (patent foramen ovale or secun-
This lesion is reported in approximately 10% of patients with dum atrial septal defect) is present. Pulmonary atresia with
CHD. In the classic isolated pathology, leaflet tethering/thicken- intact ventricular septum is a lesion characterized by mem-
ing and commissural fusion lead to the formation of peripheral branous or muscular atresia of the RVOT and wide heteroge-
raphes and narrowing of the valve lumen. Systolic valvar dom- neity in the size of the RV cavity and tricuspid valve,
ing is usually identified on cardiac imaging. infundibular region, and pulmonary arteries.
Critical PS is the third most common cyanotic congenital The tricuspid valve, RV, and pulmonary arteries are fre-
disease in the neonate and accounts for approximately 3% to quently abnormal in both of these defects (abnormal tricus-
4% of all congenital lesions diagnosed in infancy [139]. pid valve leaflets, tricuspid annular hypoplasia, reduced size
Critical PS (Fig. 11.21) and pulmonary atresia with intact of the RV cavity, main and branch pulmonary arteries), but
of both of these pathologies is an increase in the RV systolic

pressure that may exceed systemic values.
In infants with critical PS, the infundibular region (sub-
pulmonary area) hypertrophies, which contributes to the
SVC Ao outflow tract obstruction and reduces the RV cavity size.
Right ventricular hypertrophy serves as a compensatory
mechanism to maintain ventricular output. However, it is
PA associated with diminished RV compliance and diastolic
dysfunction. Subendocardial ischemia that results in myo-
cardial infarction and fibrosis impairs systolic function and
LA leads to dilation of the chamber and congestive heart failure
in some cases.
RA In pulmonary atresia with intact ventricular septum, com-
municating vessels between the coronary arteries and the RV
can be present, as may a number of other abnormalities in the
coronary circulation. In some cases, the myocardium may
LV
rely on coronary perfusion directly from the RV
(RV-dependent coronary circulation) [140]. This is a vulner-
able situation for the myocardium that can predispose to
myocardial ischemia and/or infarction.
In both of these lesions, critical PS and pulmonary atresia
with intact ventricular septum and structural abnormalities
of the tricuspid valve frequently may lead to tricuspid regur-
gitation, particularly in the presence of RV hypertension, and
RA dilation.
RV
Management
IVC The mainstay of therapy in lesions with severe RVOT
obstruction is to stabilize the neonate and institute PGE1
Fig. 11.22 Graphic representation of pulmonary atresia and intact therapy to maintain a reliable source of pulmonary blood
ventricular septum. Note the associated findings in this defect that usu-
ally include a patent ductus arteriosus, hypoplastic right ventricle, atrial
flow via the ductus arteriosus. Options to manage these
septal defect, and, in some cases, some degree of tricuspid regurgita- defects are catheter-based or surgical [141]. Unfavorable
tion. The ductus arteriosus provides the source of pulmonary blood flow anatomy or suboptimal result from a catheter procedure is an
in this lesion. The atrial communication allows for right-to-left shunt- indication for surgery. The most common catheter-based
ing. Ao aorta, IVC inferior vena cava, LA left atrium, LV left ventricle,
PA pulmonary artery, RA right atrium, RV right ventricle, SVC superior
interventions are percutaneous PA balloon valvuloplasty and
vena cava ductal stenting. Surgical options include pulmonary valvot-
omy with splitting of the commissures and/or partial valvec-
tomy. Concomitantly, resecting an infundibular obstruction
they are likely to be of a more severe nature in the neonate or placing a transannular patch may be necessary. In a minor-
with pulmonary atresia and intact ventricular septum. ity of cases, replacing the valve with an RV to PA conduit is
the most suitable option. In rare instances, a systemic-to-PA
Pathophysiology shunt is required.
Cyanosis is a common presentation in both of these congeni- In the neonate with pulmonary atresia and intact ventricu-
tal heart anomalies. The severity of the hypoxemia is deter- lar septum, angiographic data are obtained before any inter-
mined by the degree to which pulmonary blood flow and the vention to determine the presence/absence of communications
extent of interatrial right-to-left shunting are limited. between the RV and coronary arteries [142]. Potential sig-
Affected neonates have ductal-dependent pulmonary blood nificant coronary artery abnormalities (fistulae, stenosis,
flow. The severity of the obstruction in critical PS is deter- interruptions) also need to be characterized for planning
mined by the extent of valvar narrowing. In pulmonary atre- interventional strategies. The concern, once the RV obstruc-
sia with intact ventricular septum, no antegrade flow is tion is relieved, is the potential to develop myocardial isch-
possible across the valve. The main physiologic consequence emia or infarction that is related to reducing the RV pressure
in a patient with RV-dependent coronary circulation [143]. If After surgery that involves relief of the RVOT obstruc-
a patent infundibulum is present and other aspects of the tion, inotropic support should be used judiciously as it can
anatomy are favorable, radiofrequency valve perforation and exacerbate the dynamic RVOT gradient, complicating the
balloon dilation may be undertaken. This procedure has been assessment of the results of the repair. Additional anesthetic
performed successfully in neonates, allowing antegrade flow considerations apply depending on the planned procedure,
into the pulmonary arteries. In some cases, however, the vol- approach, and need for CPB.
ume of pulmonary blood flow is inadequate, as manifested
by significant arterial desaturation upon weaning or discon- Specific Issues
tinuation of PGE1 therapy. This infant requires a surgical • Suicide right ventricle. A potential post-procedure
intervention to augment pulmonary blood flow (i.e., an open problem is that adequate relief of the valvar obstruc-
valvotomy or systemic-to-PA shunt). An approach that com- tion, either by a catheter intervention or surgery, can
bines transventricular valvotomy with a systemic-to-PA result in a p hysiology referred to as suicide right ven-
shunt promotes growth of right-sided structures, increasing tricle. This results as the hypertrophied infundibulum
the likelihood of an eventual biventricular repair [144]. contracts vigorously and creates significant post-pro-
Ductal stenting also has been performed in these neonates. cedural dynamic outflow tract obstruction, in the
Another procedure that may be considered depending on the absence of fixed obstruction. In the case of severe
size of the RV and likelihood of a future biventricular circu- obstruction and associated low cardiac output, therapy
lation is to reconstruct the RVOT. If anatomic factors such as with volume expansion and/or beta-blockade may be
severely hypoplastic pulmonary arteries preclude a definitive required. An important goal is to preserve RV function
intervention, then palliation consisting of a systemic-to-PA by avoiding significant myocardial depression or
shunt is performed to promote vessel growth. Conditions increases in RV afterload.
such as severe coronary obstruction, myocardial ischemia/ • Circular shunt physiology. Another major problem that
infarction, and LV dysfunction warrant consideration for car- can occur after these procedures to relieve PS or pulmo-
diac transplantation because of the likelihood of a poor nary atresia is a circular shunt [143]. This condition is a
outcome. morbid state in which the presence of a large PDA or
systemic to pulmonary shunt after a pulmonary valve
Anesthetic Considerations intervention is associated with pulmonary regurgitation.
An important aspect of the care is to ensure patency of the This leads to retrograde shunt flow into the RV, which
ductus arteriosus by the continuous intravenous infusion of proceeds to the RA due to an incompetent tricuspid
PGE1. Catheter-based therapy can lead to effective relief of valve. Blood then courses across the atrial communica-
the obstruction, but factors such as abnormal ventricular tion into the LA, LV, and Ao, thus re-entering the shunt.
morphology/geometry, relatively small pulmonary/tricuspid This situation is very precarious because it may lead to
annulus, hypoplasia of the pulmonary arteries, and interatrial significant RV volume overload and a pulmonary steal
right-to-left shunting may not improve the systemic SaO2 phenomenon. The unsustainable hemodynamic state
immediately. It is not unusual for the PGE1 infusion to con- requires immediate attention, frequently consisting of
tinue after the procedure is completed. Hemodynamic escalating support and/or immediate surgical interven-
changes that occur during catheter-based interventions aimed tion, for survival.
at relieving the RV obstruction are reasonably well-tolerated,
providing the ductus arteriosus remains patent and the inter-
atrial communication is adequate to maintain LV filling. This Aortopulmonary Window
is particularly important during pulmonary balloon valvulo-
pasty. In some cases, depending on the anatomy, ductal stent- Anatomic Features
ing may be undertaken. It is well-recognized that Aortopulmonary (AP) window, also known as aortopulmo-
catheter-based interventions for these lesions may require nary septal defect, is a rare defect that accounts for only
repeat cardiac catheterizations with serial dilations and at 0.1% of all CHD. This anomaly is characterized by a defect
times even ductal restenting [145]. In infants with pulmonary in the wall between the Asc Ao and the PA, creating a com-
atresia and intact ventricular septum, the potential presence munication between these structures (Fig. 11.23) [147].
of coronary abnormalities that may predispose to myocardial From an anatomic and physiologic standpoint, this anomaly
ischemia warrants monitoring for this problem. As in the resembles TA; however, unlike TA, two distinct semilunar
case of all other neonatal cardiac interventions, adequate valves are present. The size and location of the communica-
preparation for these cases is of utmost importance [146]. tion varies, and thus the defect has been classified into vari-
Management
Currently, the favored approach to this lesion is usually sur-
gical, although successful transcatheter closure of the com-
munication has been reported [149]. In most cases, a patch is
SVC required to obliterate the defect. Associated pathology is also
Ao
addressed at the time of surgery.
PA Anesthetic Considerations
The same anesthetic principles that apply to the management
of the neonate with any large vascular communication (e.g.,
LA
PDA) or any other cardiac defect for which further increases
in pulmonary blood flow are detrimental and for which a bal-
RA ance between pulmonary and systemic blood flow should be
maintained also apply to this lesion.
Specific Issues
LV
• Large left-to-right shunt. The same considerations appli-
cable to other defects associated with a large left-to-right
shunt, including the potential for perioperative pulmonary
hypertension, apply to AP window.
• Associated anomalies. There are a number of surgical
techniques that have been applied to the repair of AP win-
dow successfully. An important consideration is that the
presence of associated anomalies complicates the periop-
erative course and may contribute to greater early mortal-
RV ity [150].
IVC
Ebstein Anomaly
Fig. 11.23 Graphic representation of an aortopulmonary window
demonstrating the defect that allows for left-to-right shunting between
the great arteries. Ao aorta, IVC inferior vena cava, LA left atrium, LV
Anatomic Features
left ventricle, PA pulmonary artery, RA right atrium, RV right ventricle, Ebstein anomaly represents the most common congenital
SVC superior vena cava malformation of the tricuspid valve, but overall, it is a rare
anomaly accounting for 0.3% to 0.7% of CHD. It is charac-
ous types [148]. The lesion can occur in isolation but in most terized by the apical displacement of the septal and posterior
cases is associated with other cardiovascular malformations leaflets of the tricuspid valve towards the RV apex and a
(PDA, intracardiac communications, TOF, double outlet redundant, “sail-like” anterior leaflet (Fig. 11.24). The sever-
right ventricle, IAA). ity of valve displacement and dysplasia varies, accounting for
different degrees of tricuspid regurgitation and the diversity
Pathophysiology of clinical manifestations. The lesion results in an atrialized
The magnitude of the shunt across an AP window depends RV, referring to the region of the RV proximal to the abnor-
on the size of the communication, PA pressure, and relative mal tricuspid valve attachments. The distal portion of the RV
resistances of the pulmonary and systemic vascular beds. represents the functional cavity. An interatrial communica-
Left-to-right shunting across the defect and the increased tion is present in the majority of affected neonates, and some
pulmonary blood flow are associated with increased PA pres- degree of RV dysplasia and/or dysfunction is usually
sures, left-sided volume overload, and congestive symptoms. observed. Other potential associated defects include severe
Furthermore, the large left-to-right shunt at the level of the pulmonary stenosis/valve atresia and a PDA. In some cases,
great arteries can predispose to pulmonary steal, low dia- the RV output is decreased to such an extent that it is difficult
stolic blood pressures, and myocardial ischemia. An uncor- to distinguish between functional and anatomic pulmonary
rected communication can lead to pulmonary vascular stenosis or atresia. Approximately 10% of patients with
disease relatively early in life. Ebstein anomaly have Wolff-Parkinson-White syndrome.
Ebstein anomaly represents a wide clinical spectrum that

ranges from minimal or no symptomatology to intractable
congestive heart failure and even death. In utero, it can result
in fetal hydrops. In fetuses with Ebstein anomaly and tricus-
Ao
SVC pid valve dysplasia, perinatal mortality is high [152]. The
hemodynamic status of the neonate is influenced by factors
such as the severity of tricuspid regurgitation, presence and
PA degree of RVOT obstruction, size and function of the RV, and
associated structural defects (Fig. 11.25). Cyanosis caused
by right-to-left atrial shunting under conditions of increased
pulmonary vascular resistance is the most common presenta-
LA
tion. Severe tricuspid regurgitation almost invariably results
RA in congestive heart failure; if intractable in nature, it can lead
to circulatory collapse. A neonatal presentation implies a
major clinical problem and generally portends a poor
prognosis.
LV
In the neonate with Ebstein anomaly, several additional
cardiac problems can complicate the clinical course. Atrial
arrhythmias related to atrial dilation or abnormal conduction
pathways can occur, and pulmonary stenosis or atresia (either
functional or anatomic) can further compromise pulmonary
blood flow.
Management
Some neonates require only conservative treatment and
RV follow-up. In the symptomatic neonate, the main prob-
lems that require intervention are congestive heart failure
IVC and hypoxemia [153]. Diuretic therapy and inotropic sup-
port are instituted as needed. Initial hypoxemia after birth
Fig. 11.24 Graphic representation of Ebstein anomaly displaying the can improve as pulmonary vascular resistance decreases,
displaced tricuspid valve leaflets, associated tricuspid regurgitation, and
right-to-left atrial level shunting. In the neonate with anatomic or func- allowing for forward pulmonary blood flow. In cases of
tional pulmonary stenosis/atresia, a patent ductus arteriosus is the severe PS or atresia, an intervention is required.
source of pulmonary blood flow. Ao aorta, IVC inferior vena cava, LA Distinguishing hypoxemia related to increased pulmonary
left atrium, LV left ventricle, PA pulmonary artery, RA right atrium, RV vascular resistance from that resulting from anatomic
right ventricle, SVC superior vena cava
RVOT obstruction can be difficult. Hence, PGE1 therapy
is frequently instituted to maintain ductal patency until
the nature of the hypoxemia can be ascertained or the
Pathophysiology expected decrease in pulmonary vascular resistance
Tricuspid regurgitation in this anomaly volume overloads the occurs. Initiating other measures aimed at decreasing pul-
RV and increases the RA pressure [151]. As the RA pressure monary vascular tone and supporting the overall critically
increases, it exceeds LA pressure, stretching an existing ill neonate is warranted.
interatrial communication. This process leads to atrial right- During the neonatal period, a catheter-based interven-
to-left shunting with a decrease in pulmonary blood flow and tion and/or cardiac surgery may be necessary. Catheter
the appearance of clinical cyanosis. The redundant anterior therapy targets the relief of RV outflow obstruction and/or
tricuspid valve leaflet can cause functional obstruction to the to increase pulmonary blood flow (pulmonary valve dila-
RV. Another frequently found feature of the pathology is tion/perforation, ductal stenting). The selection of surgi-
abnormal RV systolic function. These factors can have detri- cal procedure is influenced by factors such as details of
mental effects on the LV because (1) the dilated and/or dys- the anatomy, associated defects, RV size and function,
functional RV can impair LV filling and (2) the abnormal and the clinical status of the neonate. Approaches range
interventricular septum can affect LV geometry and systolic from creation of a systemic-to-PA shunt, tricuspid valve
function related to ventricular interdependence. repair, palliative surgery anticipating a future single ven-
a
b
c d
Fig. 11.25 Panel a, chest radiograph of newborn with Ebstein anom- to severely dilated RV. Panel c, color compare images in equivalent
aly showing severe cardiac enlargement and a stented ductus arteriosus view depicting the wide tricuspid regurgitant jet. Panel d, complemen-
(arrow). Panel b, transesophageal four-chamber view showing dis- tary RV inflow and outflow view confirming the severe tricuspid regur-
placed tricuspid valve leaflets into the right ventricular (RV) apex gitation (arrow). PA pulmonary artery, RA right atrium
(arrow) relative to the level of the valve annulus (line), and a moderate
tricle strategy, and cardiac transplantation. The overall Specific Issues

success of the various surgical interventions in the neona- • Respiratory status. Pulmonary mechanics can be compro-
tal period has generally been poor in the presence of mised by factors such as prematurity, interstitial lung
severe disease [152, 154]. edema, and lung hypoplasia. Mechanical ventilation
The perinatal mortality rate in neonates with Ebstein should be carefully considered while balancing the need
anomaly is the greatest within the CHD group, ~45%. The to enhance antegrade pulmonary blood flow.
presence of pulmonary regurgitation (e.g., circular shunt • Pulmonary vascular resistance. Increases in RV afterload
physiology), prematurity (<32-week gestational age), larger lead to right heart distention and compromise LV perfor-
TV annulus diameter Z-score, and pericardial effusion are mance. Thus, it is important to optimize not only RV con-
strong predictors for mortality. tractility but also to aggressively avoid increases in
pulmonary vascular tone that will depress the function of
Anesthetic Considerations both ventricles.
Anesthetic care, when required, is usually for cardioversion, • Rhythm disturbances. Numerous rhythm abnormalities
cardiac catheterization, or surgery. The neonate with Ebstein have been reported in these children. Although supraven-
anomaly presents a challenge to the provider of anesthetic tricular arrhythmias predominate, other abnormalities
care because the infant’s clinical status is typically poor and include atrioventricular block and ventricular arrhyth-
characterized by severe tricuspid regurgitation, cyanosis, mias. In general, these rhythm disturbances are poorly
congestive heart failure, lactic acidosis, and impending cir- tolerated and require aggressive therapy that may include
culatory collapse. cardioversion, the administration of antiarrhythmic drug
therapy, and/or cardiac pacing. Children with Ebstein The physical examination should note the neonate’s
anomaly and WPW may not tolerate the rapid tachyar- weight and length. General appearance should include the
rhythmia necessitating radiofrequency cardiac ablation of level of distress, if any, presence/degree of cyanosis, and
the accessory pathway depending on the child’s overall clinical status. Vital signs, including blood pressure
condition. measured in the upper and lower limbs and any gradients
• Circular shunt. This physiology can also occur after inter- between the limbs, should be recorded. The measured SpO2
ventions in this lesion, as described in a preceding section. at both pre- and post-ductal levels should be noted. A careful
examination of the airway and the respiratory and cardiovas-
cular systems should be performed. Respiratory evaluation
reoperative Assessment of the Neonate
P should note rate and breathing patterns, quality of the breath
with Congenital Heart Disease sounds noting the presence of rales or rhonchi, and the pres-
ence of intercostal retractions. If the infant is receiving sup-
History and Physical Examination plemental oxygen, the inspired oxygen concentration should
be recorded. If the airway is intubated, the date when the
It is important for the anesthesiologist to perform a compre- current endotracheal tube (ETT) was inserted should be
hensive preoperative evaluation to identify and plan for fac- noted as well as its diameter, depth at the lips/nose, and the
tors that could influence the perioperative management. This presence/absence of a cuff; any difficulties with blockage of
evaluation begins with a review of the prenatal history the ETT should be identified, and a recent chest radiograph
including details of the pregnancy, such as maternal illnesses should also be reviewed. If the lungs are mechanically venti-
(e.g., diabetes, hypertension), medications, and drug use, as lated, mode and settings should be noted. The cardiac exam
well as a family history of adverse anesthetic events. should include assessment of precordial activity, heart
Frequently, the diagnosis of cardiovascular disease is sounds, murmurs, and gallop rhythms. The presence of any
established “in utero.” Prenatal diagnosis positively influ- existing vascular access, patency of the catheter(s), size,
ences the preoperative status, resulting in more widespread number of lumens, and appropriateness of catheter tip posi-
use of fetal ultrasound to detect cardiovascular pathology tion should be recorded. Review of medical records and
[155]. Data regarding fetal studies, if available, should be results of previous studies may assist in the determination of
reviewed. Specific issues of interest beyond details of the vessel patency in the infant with a history of multiple vascu-
anatomy include functional assessment of the cardiovascular lar access or catheterization procedures. The abdomen
system, presence of extracardiac abnormalities, genetic syn- should be examined for the presence of hepatosplenomegaly.
dromes or other disorders of potential impact, as well as an Assessment of the extremities should include examination of
impression of the overall well-being of the fetus. The issue of pulses, capillary refill, skin temperature and color, and over-
associated noncardiac and genetic abnormalities is particu- all perfusion.
larly important given the possible negative effects on clinical Approximately 13% of infants with CHD have chromo-
outcomes [156]. somal abnormalities. Dysmorphic features or any other non-
The child’s gestational age is important at the time of sur- cardiac anomalies that can impact the anesthetic care should
gery as prematurity and low birth weight are also well-known be documented. Medications being administered, including
risk factors for morbidity and mortality. An analysis in the indications, doses, and route, need to be reviewed.
Society of Thoracic Surgeons Congenital Heart Surgery
Database revealed that even birth during the early term
period (37–38 weeks’ gestation) is associated with worse Ancillary Studies and Laboratory Data
outcomes [157]. Relevant information also to be obtained
regarding the delivery includes Apgar scores, events that The preoperative electrocardiogram in the neonate with heart
occurred during neonatal resuscitation, and the need for disease allows for assessment of chamber dilation and/or
other interventions immediately after birth. ventricular hypertrophy, rhythm disturbances, and myocar-
If the diagnosis of heart disease has been made postna- dial ischemia (Fig. 11.26). A recent chest radiograph pro-
tally, details such as clinical presentation, hospital course, vides information regarding cardiac size and shape, chamber
and results of all diagnostic studies, which define the cardio- enlargement, and pulmonary vascularity. In addition, it
vascular abnormalities, interventions performed, and serves to document the position of the ETT tube, stomach
response to these, should be reviewed. It is essential to gather tube, and indwelling vascular catheters (Fig. 11.27). The
information regarding coexistent medical problems or condi- echocardiogram and additional imaging studies obtained
tions that could potentially affect other organ systems and (cardiac magnetic resonance imaging, computed chest
impact on the anesthetic management. tomography, cardiac catheterization and angiography) pro-
Fig. 11.26 Preoperative electrocardiographic recording in a newborn with biventricular hypertrophy, and the diffuse ST-T wave changes sug-
with truncus arteriosus. Note the peaked P waves in lead II indicative of gestive of compromised myocardial blood flow
right atrial enlargement, the prominent precordial voltages consistent
vide important information regarding the structure and func- intervention in a neonate with cardiac disease may imply a
tion of the heart. All of these studies should be reviewed substantive risk of morbidity and even mortality. In addition,
carefully, and the findings documented. the anesthetic care for cardiac surgery also entails greater
The complete blood count, electrolyte levels, blood glu- risks when compared with other neonatal surgeries [95, 158].
cose, renal/hepatic function tests, and coagulation studies Although it may not be possible to specify the contribution of
[prothrombin time, partial thromboplastin times, and inter- anesthesia itself to the overall risks of the procedure, it is rea-
national normalized ratio (INR)] should be reviewed. The sonable to discuss the most likely potential anesthetic prob-
most recent blood gas analysis should be examined to assess lems that may be encountered perioperatively.
oxygenation, ventilation, acid-base status, and lactate values. Over the last several years the subject of potential detri-
The results of any other investigations that may have been mental effects of general anesthesia on the developing brain
performed (e.g., head ultrasound, brain magnetic resonance has received increasing attention [159, 160]. This concern
imaging, renal ultrasound) also should be reviewed. was initiated by observations made in small animal models
and subsequently in nonhuman primates implicating nearly
all anesthetic agents [161–163]. The issue triggered a num-
Informed Consent ber of studies and resulted in heated controversy on the sub-
ject [164–169]. A multidisciplinary effort, SmartTots, was
The preoperative visit allows the anesthesiologist an opportu- launched accordingly to address the issue of anesthetic safety
nity to meet the family, discuss the anesthetic plan, and in young children [170, 171]. Led by this concern and before
address questions in preparation for the procedure. A surgical the availability of clinical trials, the US Food and Drug
countries. Although in recent years these have tended to

become more liberal [181], the gastric emptying times are
prolonged in those with CHD [182]. A significant number of
infants receive maintenance intravenous fluids preopera-
tively. Adequate hydration is particularly important in the
presence of obstructive pathology, cyanotic disease, or single
ventricle physiology, as optimizing the ventricular preload
can limit potential detrimental hemodynamic changes asso-
ciated with anesthesia and surgery.
erioperative Considerations in the Neonate

P
Undergoing Cardiac Surgery
Anesthesia for cardiac surgery in the neonate should be

delivered by highly skilled individuals with expertise in the
various forms of pediatric heart disease. This requires knowl-
edge of the wide spectrum of anatomic and physiologic
abnormalities involved, the natural history of congenital
defects and other conditions that affect the cardiovascular
system, possible management strategies, and overall short-
and long-term outcomes. A comprehensive understanding of
the disease process, hemodynamic perturbations, and how
they are influenced by the anesthetic and surgical procedure
Fig. 11.27 Radiograph in a neonate with congenital heart disease dis-
playing massive cardiomegaly. The position of the tip of the endotra- are of outmost importance. Familiarity with the anticipated
cheal tube (ETT) appears high, prompting readjustment. The nasogastric perioperative course, including potential problems and com-
(NG) tube is the stomach and the tip of the umbilical venous catheter plications, is essential. In addition to these cognitive skills,
(UVC) is in good position at the inferior vena cava to right atrial the care of small infants with critical heart disease requires
junction
consummate technical proficiencies. The ability to commu-
nicate clearly and work effectively with other members of
Administration issued a warning in 2016 on the use of anes- the team is also key to achieving the best possible outcome.
thetic agents in young children [172, 173]. This was followed
by changes in informed consent requirements at several local
levels to include disclosure of this potential risk to parents Transport to the Operating Room
[174]. Although subsequent human studies, including ran-
domized controlled trials, have been less concerning [175– Most infants who require cardiac surgery within the first few
177], the warning is still in place and further research weeks of life are cared for in a critical care setting, either in a
continues to be advocated [178–180]. neonatal or cardiac unit. The collaborative effort of members
Cardiac surgery in the neonate is a major undertaking of the unit’s multidisciplinary team strives to maintain and
regardless of the nature of the procedure, and one must always optimize vital organ function until the planned intervention. At
expect the parents to be apprehensive and concerned. In some the time of transport, excellent communication between the
cases, particularly those with a postnatal cardiac diagnosis or care providers and the operating room team must be assured in
if the infant had been previously discharged from a well-baby order to address any recent changes in the neonate’s clinical
nursery, significant parental stress can be present. The preop- status, current therapy, and any other relevant issues. This
erative consultation provides an opportunity to defuse paren- handoff process is critical so that all relevant information can
tal anxiety, answer questions, and reassure the parents be conveyed between providers. The implementation of the
regarding the unwavering commitment of the entire periop- I-PASS (illness severity, patient summary, action list, situation
erative team towards a good perioperative outcome. awareness and contingency plans, and synthesis by receiver)
for the transfer of patients between units and teams has been
shown to result in improved transfer efficiency, safety, and sat-
Fasting Period isfaction of providers and families [183]. During transport, the
main considerations include temperature homeostasis, ade-
The established preoperative fasting guidelines for surgery quate airway support/ventilation, careful maintenance of nec-
in neonates should be followed, which may vary among essary infusions, and availability of emergency airway
equipment and drugs. Be aware that essential drug infusions because they can limit the speed at which boluses of intrave-
can be compromised by kinking of the lines or alterations in nous fluids, propofol, and blood products are administered,
the height of the delivery systems. In some cases, a self- although they can be useful for clear fluid and drug infusions
inflating bag, air tank, or oxygen/air blender system is needed as well as in the preoperative and postoperative periods.
to deliver room air or a specific inspired oxygen concentration
between room air and 100% oxygen. Monitoring the vital
signs and systemic oxygen saturation is essential during trans- Availability of Emergency Medications
port. For those in whom the levels of oxygenation and ventila-
tion are critical factors, the use of a transport ventilator may be In view of the potential for sudden hemodynamic compro-
preferable to manual ventilation. mise in the neonate with CHD, drugs for emergency situa-
tions should be prepared in anticipation of the procedure and
be immediately available to the anesthesiologist delivering
Premedication the care. It is essential for these drugs to be at hand during
transport to and from the operating room or any other setting
The need for premedication is rarely, if ever, indicated in the where anesthetic care may be provided.
neonate because this age group is not at risk to experience
separation or other forms of anxiety. On rare occasions, pre-
medication can minimize metabolic stresses and facilitate Physiologic Monitoring
the placement of intravenous access in the agitated or strug-
gling infant. Specific concerns, such as the potential for The selection of monitors is guided by the child’s clinical
hypercyanotic spells in tetralogy, also may warrant the judi- status and the nature of the planned procedure. In addition to
cious use of premedication. Close observation including routine monitors, the intricate nature of cardiac surgery man-
SpO2 monitoring and oxygen administration as needed is dates the need for additional monitors as outlined in the sec-
recommended after premedication. tions that follow.
Electrocardiography
Intravenous Access Five-lead electrocardiography during cardiac surgery is used
to assess heart rate, cardiac rhythm, and ST segments. In
Absolutely reliable intravenous access is mandatory to most cases, leads II and V5 are displayed on a monitor, and
administer fluids, blood products, and medications during tracings from other leads can be examined as needed.
surgery. In most neonates with heart disease, a peripheral or Changes in heart rate can be caused by hypoxia, light anes-
indwelling intravenous catheter is already in place when thesia, stimulation, hypovolemia, or the surgical dissection.
they arrive in the operating room, facilitating an intravenous Abnormalities in cardiac rhythm can result from hypoxia,
induction of anesthesia. In the neonate without intravenous electrolyte imbalance, acid-base abnormalities, intravascu-
access, consideration should be given for securing periph- lar/intracardiac catheters, and surgical manipulations within
eral access before induction of anesthesia. The size of the the thorax. Ischemia may be evident on direct examination of
catheter and need for more than a single site of access should the electrocardiographic tracing or ST-segment analysis.
be determined by the infant’s clinical status and nature of
the intervention. When placing an intravenous cannula in a Pulse Oximetry
very small infant, the use of a fine guide wire as the catheter Monitoring the SaO2 is essential during cardiac surgery.
is advanced can ensure a very reliable intravascular route. The need for sampling at various sites is dictated by the
Never rely solely on the integrity of an intravenous access anatomy and pathophysiology. SpO2 monitoring serves as
route that arrives with the child! In many institutions periph- an indicator of intracardiac or great artery level shunting
erally inserted intravenous catheters (PICC lines) are the and of pulmonary blood flow. In addition to providing con-
sole forms of access in sick neonates. While these catheters tinuous assessment of SaO2 and heart rate, the SpO2 wave-
are suitable for the administration of maintenance fluids and form can be used as a surrogate of the adequacy of
other clear fluid infusions, in general they are not appropri- peripheral perfusion and cardiac output [184]. It is wise to
ate for boluses because of the small diameter of the lumen(s) place backup sensors, which can be used if the primary sen-
and length of the catheter. sors fail. Ensure that the sensors are well protected from
In all neonates, the potential for right-to-left shunting extraneous light and direct pressure.
across a patent foramen ovale or the presence of any intracar-
diac communication mandates the meticulous removal of air Capnography
from all injections and the intravenous infusion tubing. Air Capnography confirms proper placement of the ETT, the
filters can be difficult to use in the intraoperative setting adequacy of ventilation, and pulmonary blood flow. It also
facilitates the recognition of acute problems that can Indwelling Arterial Monitoring
influence lung compliance. End-tidal carbon dioxide Because of the involved nature of cardiac surgery in the neo-
(ETCO2) monitoring provides a gross index of pulmonary nate, invasive arterial pressure monitoring is warranted in
blood flow and can be useful during cases in which it may virtually every case. In addition to measuring the blood pres-
be altered. A specific example of its use is during PAB, at sure on a continuous, beat-to-beat basis, it allows for fre-
which time the ETCO2 can be a useful guide of optimal quent blood sampling to determine the hematocrit, acid-base
occlusion. A caveat in interpreting capnography occurs in status, PaO2 and PaCO2, blood glucose, calcium levels, and
cyanotic heart disease, during which ETCO2 measure- electrolyte values.
ments can underestimate PaCO2 values owing to altered
pulmonary blood flow and ventilation-perfusion mismatch Sites for Invasive Monitoring
[185, 186]. ETCO2 may be used to track changes in any of A variety of different sites may be used to invasively monitor
the above variables even in cyanotic heart disease pro- the arterial blood pressure in the neonate, each with specific
vided it is standardized against a blood arterial carbon advantages and disadvantages. Umbilical artery blood pres-
dioxide value at baseline. In neonates, ETCO2 may under- sure monitoring is unique to the neonate. Catheter placement
estimate the true end-tidal carbon dioxide tension because in this vessel is often possible during the first few days of
of the neonate’s small tidal volumes, dilution of end-tidal life. The tip of the umbilical arterial catheter should be posi-
gases with fresh gases, and large end-tidal gas sampling tioned between T6 and T10 (high position) or between L3
rates (see Chap. 7). and L5 (low position). Advantages of umbilical artery access
include relative ease of placement and reliability of access as
Temperature there is a low likelihood for a catheter in the Ao to be “posi-
Temperature is monitored routinely during all cardiac pro- tional” or subject to the problems that can affect peripheral
cedures. In cases requiring CPB, temperature is sampled at arterial catheters (vasospasm upon placement, vasoconstric-
multiple sites. The most common sampling locations tion after CPB). In general, umbilical artery catheters pro-
include the nose, rectum, bladder, esophagus, and skin. The vide optimal tracings of arterial blood pressure and facilitate
objective is to measure core (central), peripheral, and pos- blood sampling. Complications include potential obstruction
sibly, brain temperature, given that hypothermia during of blood flow to specific beds (e.g., renal), distal emboli,
bypass has a major role in organ preservation. Temperature thrombotic complications (e.g., mesenteric, Ao, renal artery),
monitoring is also essential to ensure that the neonate has and infection. Indwelling catheters have also been associated
been cooled for a sufficient period before initiation of cir- with necrotizing enterocolitis and problems during enteral
culatory arrest or related bypass strategy. Similarly, tem- feedings in the neonate [187]. Monitoring the blood pressure
perature must be assessed during the warming period. via an umbilical arterial catheter is not recommended beyond
Although hypothermia is frequently used during neonatal 7–10 days of life.
interventions, failure to re-establish normothermia when The radial artery is the usual site to monitor invasive
coming off bypass increases oxygen consumption and may arterial blood pressure in the neonate. It can be accessed
induce an acidosis, as well as cause detrimental changes in percutaneously with a 24 or 22 gauge catheter depending
hemodynamics and the coagulation status. Be aware that on the size of the neonate, often using a Seldinger tech-
the rectal temperature may be influenced by the cooling nique. This can be facilitated by ultrasound guidance if
blanket temperature in small infants, unless a small pad is necessary [188, 189]. Radial arterial tracings are very occa-
interposed. sionally dampened after CPB, rendering blood pressure
assessment unreliable during this critical period. This situ-
Arterial Blood Pressure ation can be resolved by having the surgeon place a small
recording needle into the Asc Ao. For a more stable setup,
Noninvasive Monitoring a pressure-monitoring catheter can be attached to a stop-
A blood pressure cuff of appropriate size is used in all neo- cock integrated into the arterial pressure transducer tubing.
nates undergoing cardiac surgery to allow automated mea- Vasospasm also can hinder obtaining accurate blood pres-
surements, regardless of the presence of an indwelling sure measurements throughout the case; however, this is
arterial catheter. This offers an alternate option to measure rare. This problem may be solved by infusing lidocaine or
blood pressure in the event the arterial line malfunctions. A papaverine through the arterial catheter.
second site also enables determination of gradients between Before inserting a radial arterial catheter, one should
upper and lower extremities, depending on the pathology or review the anatomy and planned operation. In the case of a
surgical procedure. The selection of suitable monitoring sites CoA, right radial artery catheter placement is preferred, as it
is influenced by the underlying anatomic abnormalities and reflects proximal Ao pressure perfusing the brain and coro-
the history of prior surgical interventions (e.g., mB-T shunt, nary arteries, and the tracing will not be lost if the surgeon
arterial cutdown, subclavian flap aortoplasty). has to clamp the left subclavian artery. Monitoring at this site
also can guide management of regional cerebral perfusion if arterial injury [194], complications were attributable to
this strategy is used (discussed later in the chapter). If an ECMO far more than other reasons for arterial monitoring;
aberrant or retroesophageal right subclavian artery is present only one (4-year-old) child sustained an ischemic injury
and the use of TEE is planned, cannulating the right radial after femoral artery cannulation for monitoring.
artery is discouraged; the tracing will likely be dampened or The foot arteries (dorsalis pedis and posterior tibial ves-
flat after the imaging probe is inserted into the esophagus sels) can be considered as alternate sites for blood pressure
due to compression of the vessel. If the surgical plan involves monitoring. Although they may not be the first option (for
placing a mB-T shunt, an arterial catheter in the ipsilateral arterial cannulation), they can be quite useful during surgery
side of the graft would not be advised because the blood when bypass or hypothermia is not planned, or for monitor-
pressure may not be measurable during portions of the pro- ing in the intensive care unit. Disadvantages of these sites
cedure as the vessel is temporarily occluded. Furthermore, include a high incidence of failure of the catheter to reliably
measurements obtained after opening of the shunt may not display central Ao pressure after hypothermic CPB and a
be accurate. somewhat greater pressure recorded from these sites as com-
The ulnar and the radial arteries constitute the dual blood pared with central pressure due to pulse wave amplification.
supply to the hand. The radial artery usually is preferred over The latter issue can confound the interpretation of blood
the ulnar because avoiding the ulnar artery allows preserva- pressure gradients in some cases.
tion of a larger contributor of blood supply to the hand. The The right temporal artery historically was used for moni-
ulnar artery often is the larger vessel, and it alternatively can toring arterial pressure in neonatal intensive care units. The
be cannulated for monitoring invasive arterial blood pressure. only time it should be considered for arterial access in the
The Allen test to assess the distal adequacy of collateral circu- modern era, if at all and after the risk-benefit ratio has been
lation of the hand as a measured of radial or ulnar patency is carefully assessed, is when all other sites do not allow for
difficult to apply, inconclusive, and not generally performed the arterial blood pressure of interest to be monitored (i.e.,
in neonates. A modification of the test can be performed by CoA or IAA with an aberrant subclavian artery that arises
observing for changes in the hand pulse oximetry signal while distal to the coarctation or interruption). In these situations,
occlusive pressure is applied to one or the other artery. the temporal artery provides the only monitoring site that
Some practitioners find that cannulation of the ulnar reflects the Asc Ao pressure perfusing the brain and coro-
artery is easier than accessing the radial artery, particularly in nary arteries. The very serious concern related to temporal
infants with Down syndrome. This group, known to have a artery catheterization is the fact that emboli can be intro-
high incidence of CHD, can present challenges during percu- duced into the cerebral and ophthalmic circulations by even
taneous radial artery cannulation [190]. Because of the risk minute volumes of flush fluid. Serious neurologic injury and
of ischemia to the hand, placement of a catheter in the ulnar blindness are well-documented complications of the use of
artery is not advisable if the radial artery is thrombosed or this site [195].
after attempts at cannulation have been made. Despite con-
cerns of distal ischemia, a report in the literature indicates a Cutdown for Arterial Cannulation
similar risk for ulnar, radial, and femoral arterial lines [191]. If percutaneous arterial line placement is unsuccessful, arte-
The brachial artery has been considered an end artery rial cannulation via surgical exposure of the vessel can be
without collateral circulation. Because of concerns for distal performed. At some centers, a cutdown is performed primar-
limb ischemia, this site is not usually recommended to estab- ily or very early in the process of gaining arterial access.
lish arterial access. However, it has been used extensively in Advantages of a surgical cutdown include speed of place-
some centers without sequelae. For example, in one institu- ment and direct visualization of the artery/catheter during
tion where the brachial artery was the second choice for arte- cannulation, minimizing trauma to the vessel, creation of a
rial cannulation (after the radial artery) in neonates and false lumen, or formation of a hematoma. Disadvantages
infants, there were no major complications in 386 patients include possible damage to the vessel caused by scarring. If
who underwent brachial artery cannulation [192]. the radial artery is accessed by cutdown, the time for
Femoral artery cannulation is also used in neonates Doppler-detected flow to resume in the vessel after decan-
undergoing CPB as an alternative site (see Chap. 7). nulation is prolonged. It can also be difficult to cannulate the
Catheters 2.5 Fr, 5 cm long, have been used in neonates same vessel during future interventions.
[193]. In one report of 282 infants (median age 10 weeks),
of whom 98 were neonates, pulse discrepancy between the Central Venous Pressure Monitoring
lower limbs and loss of a pulse occurred more frequently Central venous access provides for monitoring of the central
with catheters larger than 2.5 Fr and after prolonged use. venous pressure (CVP) and also for delivery of vasoactive
All of these issues resolved in 100% of instances. The agents safely and expeditiously into the central circulation. It
reported rate of arterial injury after femoral artery cannula- can also be useful for intravascular volume replacement and
tion is 2%. In a retrospective review of 66 children with the administration of blood products. Caution should be exer-
Fig. 11.28 Intraoperative recording in a neonate during junctional waves (“A” waves) are seen in the central venous pressure tracing cor-
rhythm. Note the absence of P waves on the electrocardiographic leads responding to atrial contraction during ventricular systole against a
II and V in the upper panel. The lower panel displays superimposed closed tricuspid valve. The bottom tracing in the lower panel corre-
systemic arterial and central venous pressure tracings. Tall cannon atrial sponds to the pulse oximeter tracing
cised in delivering fluids or blood products rapidly via a cen- Ultrasound Guidance
tral line as this route leads directly to the heart! Complications The success rate and safety of central venous cannulation
may arise if the fluids are inadequately warmed or if the can be markedly improved by the use of imaging techniques
potassium concentration is increased. In addition, the venous (Fig. 11.29) [189, 197]. Various ultrasound modalities that
pressure tracing can facilitate the recognition of an abnormal include audio Doppler and two-dimensional imaging assisted
rhythm (e.g., junctional rhythm, Fig. 11.28), the “fine-tuning” by color flow/spectral Doppler have been applied with good
of pacemaker settings, and the recognition of inadequate success. Real-time ultrasound guidance improves the suc-
venous drainage [e.g., SVC drainage in the case of a catheter cess rate, decreases the procedural time, and reduces the rate
in the internal jugular vein]. Increased CVP pressure may of complications associated with cannulation of the internal
also indicate a problem with the venous cannulae of the CPB jugular vein [198–200].
circuit. Sampling from the SVC also can be obtained to mea-
sure SvO2 and used as a surrogate of cardiac output and oxy- Percutaneous Sites for Central Venous Access
gen delivery. In general, the catheter with the smallest Several sites in the neonate are available for central venous
diameter possible should be used for percutaneous access. access. In addition to the challenges imposed by the small
The length of insertion varies according to the site of place- size of the vessels in the young infant, factors such as venous
ment [196]. In some cases, direct transthoracic placement of anatomy, vessel patency/prior attempts, hydration status, and
catheters may be favored. The position of the tip of the CVP operator skill/experience all influence the success of cannu-
catheter should always be assessed on the postoperative lation. Preferred sites vary according to institutional prefer-
radiograph. It should not extend beyond the junction of either ence; in most cases, the femoral vein and internal jugular
the SVC or IVC with the atrium to avoid the possibility of vein are favored.
cardiac perforation and tamponade (since the junction is the The umbilical vein can be cannulated during the first few
limit of the pericardium). days after birth and can provide useful access to the central
a c
Fig. 11.29 Panel a, short-axis image obtained during ultrasound- confirming wire position (arrow). Panel c, pulsed-wave Doppler inter-
guided right femoral venous (FV) access depicting the location of a rogation showing phasic low-velocity flow (<60 cm/s) in the cannulated
catheter within the vein (arrow). Panel b, corresponding long-axis view vein. The wire is noted by the arrow. FA femoral artery
circulation. As the catheter is advanced, it can be threaded internal jugular vein in infants who weigh less than 4 kg.
either into the hepatic veins or through the ductus venosus Cannulating the femoral vein obviates the need to place a
into the IVC. It is important to document the position of the catheter in the SVC and decreases the likelihood of problems
catheter tip by radiography or ultrasonography. If the cath- such as stenosis and/or thrombosis that can result from can-
eter has entered the IVC, its tip can be seen above the level nulating the internal jugular vein in small infants. Patency of
of the diaphragm on a radiograph. This is the optimal posi- the SVC is crucial in infants with single ventricle physiology
tion as the catheter can be used to monitor CVP and deliver for whom a superior cavopulmonary anastomosis is part of
medications directly to the heart. If the tip of the catheter is the palliation pathway. Infection is a rare complication of
located within the liver, it may not provide an accurate mea- femoral venous cannulation, but the rate of infection is com-
surement of the CVP, and delivery of vasoactive medica- parable to that of other sites in children [201].
tions can cause complications (e.g., liver necrosis and portal The internal jugular vein is a very common site for central
vein thrombosis). In this case, an alternate site should be line placement in children undergoing cardiac surgery and is
considered for the central venous catheter. A clear advan- also commonly used in neonates. The main advantage of the
tage of cannulating the umbilical vein is that other venous internal jugular route is the direct path between the vessel
sites are preserved for future interventions. This is espe- and the RA. However, disadvantages of this site in the neo-
cially important for the neonate with planned staged pallia- natal age group include (1)difficult cannulation due to the
tion and anticipated serial cardiac catheterizations, for small size of the vessels, which are relatively small struc-
which venous cannulation is paramount. Umbilical venous tures in a tiny infant, with little margin for error; (2) increased
catheters generally can be left in place for up to 2 weeks. risk of carotid artery puncture; (3) the possibility of SVC
The femoral vein is another site to site for placement of a complications (thrombus, narrowing); (4) potential for ves-
central venous catheter in the neonate (see Chap. 7). In fact, sel or cardiac puncture and less tolerance for hemodynamic
the femoral vein is favored in many centers as opposed to the compromise as compared with older children; and (5) risk of
lung puncture and development of pneumothorax. The rou- main concerns of these types of lines, however, are bleeding,
tine use of ultrasound to locate the vessel is strongly recom- particularly upon removal, and inability to compress the site.
mended. In some cases, the right internal jugular vein can be Chest drainage tubes are usually maintained well after the
quite small compared with the left internal jugular vein. This catheter has been removed to avoid accumulating blood,
may indicate the presence of a persistent LSVC. which may lead to cardiac tamponade. In rare cases, the
The external jugular vein is sometimes very easy to presence of the catheter against the endocardial surface of
visualize and to puncture. It is often possible to pass a the heart can trigger ectopy or sustained arrhythmias.
catheter centrally through the external jugular vein with a
small diameter “J wire.” This route tends to be overlooked
but is often successful and less likely to result in complica- Urinary Output Measurements
tions than repeated attempts at a difficult internal jugular
puncture [202, 203]. Cardiac surgery involves fluid shifts, blood loss, and altera-
The subclavian vein also can be used for central venous tions in systemic perfusion that can impact renal blood flow/
access in the neonate. Cannulation of the left subclavian vein function. Thus, urine output is routinely measured in most
generally is preferred over the right because the angle taken cases, particularly when the intervention is taking place over
as the vessel continues into the innominate vein and enters a protracted period. Urine output provides a useful index of
the SVC is less acute than on the right, and, therefore, the the adequacy of renal perfusion and cardiac output. For
end of the catheter is less likely to be against the wall of the infants, the use of a miniature-graduated burette makes it
vessel causing potential injury [189]. This site might be pre- possible to record small urinary volumes. Although the pres-
ferred over the internal jugular approach as it may be more ence of urine output is reassuring, no specific value is neces-
stable. Disadvantages of subclavian venous line placement sarily predictive of good renal function postoperatively. In
include a greater potential for pneumothorax, inability to some cases, the neonate receiving chronic diuretic therapy
apply pressure at the vascular entry site, and tendency for may require larger drug doses intraoperatively to augment
malposition (contralateral brachiocephalic vein or the ipsi- the urine output. Factors such as the use of cardioplegic solu-
lateral internal jugular vein) [204]. A catheter in the subcla- tions that may include agents such as mannitol or furosemide
vian vein also is more likely than a catheter in another site to can also influence urine output.
kink or malfunction with placement of a sternal retractor.
The use of the brachiocephalic vein for central venous
cannulation has been reported to be highly successful (see Transesophageal Echocardiography
Chap. 7), even in preterm infants, when guided by supracla-
vicular ultrasound [205]. Intraoperative TEE provides real-time information about
cardiac anatomy and function during surgery (Fig. 11.30)
Direct Transthoracic Pressure Monitoring [206]. It is particularly valuable to confirm the adequacy of
In some cases, transthoracic pressure-monitoring catheters surgical repair, detect residual shunts, evaluate valvar com-
(e.g., in the RA, LA, PA), as well as those with oximetric petence, determine outflow patency, and examine ventricular
capabilities, are placed by the surgeon under direct vision function [207]. If significant hemodynamic abnormalities
while the sternum is open, usually near or after separation
from CPB. This route offers the only approach in some cases
to monitor pressure in a structure of interest (e.g., LA, PA).
LA pressure measurements can assist if poor LV function is
anticipated and in the presence of decreased ventricular com-
pliance or mitral regurgitation. The use of transthoracic PA
pressure monitoring has decreased over the years, but certain
cardiac pathologies in the neonate continue to have a signifi-
cant potential for acute pressure increases after repair (e.g.,
obstructed TAPVR, TA). In these (types of) settings, the
presence of a PA pressure catheter can be useful for postop-
erative management. In addition to monitoring pressure
depending on the location of the catheter, the PA catheter can
be used to infuse drugs and volume, as well as monitor SvO2
saturation. Extreme care must be taken to ensure that emboli
(e.g., air) are not introduced to LA catheters.
A benefit of transthoracic-placed catheters is that they Fig. 11.30 Preoperative deep-transgastric transesophageal echocar-
diogram in a neonate with d-transposition of the great arteries (d-TGA)
preserve other sites for future percutaneous vascular access
and a ventricular septal defect (VSD) undergoing complete repair. Ao
and reduce complications associated with placement. The aorta, LV left ventricle, PA pulmonary artery, RV right ventricle
are identified in the immediate bypass period, revision of the In contrast to embolic episodes, which affect adults undergo-
repair can then be undertaken [208]. ing cardiac surgery, global cerebral hypoxia and/or ischemia
At the time of this writing, two multiplane TEE imaging is the primary etiology of neurologic dysfunction in infants
probes of differing transducer tip size are available for use in and children, thus the value of multimodal brain monitoring
the neonate, one referred to as a micro or neonatal probe and in the form of near-infrared spectroscopy (NIRS), transcra-
the other as the mini or pediatric probe. Both devices incor- nial Doppler ultrasound, electroencephalography, and
porate full capabilities for two-dimensional imaging, spec- bispectral index electroencephalography (BIS). These may
tral and color Doppler, and M-mode echocardiography. Data minimize the potential for neurologic morbidity and opti-
regarding the safety of TEE in the pediatric age group dem- mize outcome [215–222]. Specific applications of neuro-
onstrate a large margin of safety and a small incidence of logic monitors include determining the maximum acceptable
complications, in the range of 1% to 3% [209]. However, the duration of circulatory arrest and minimum acceptable
small infant should be very carefully monitored for evidence bypass flow rates.
of cardiorespiratory decompensation during passage and
manipulation of the TEE probe [210, 211]. Near-Infrared Spectroscopy
Near-infrared spectroscopy is a noninvasive technology
used to monitor regional cerebral tissue oxygenation (rSO2;
Neurologic Monitoring Fig. 11.31) [223]. When the NIRS probe is placed on the
forehead, it directs a light source through the skull and brain
Infants and children undergoing congenital heart surgery are tissue that is then sensed by different detectors (shallow and
at risk for neurologic and behavioral impairment [212–214]. deep). The optical principle relies on the distinct absorption
Fig. 11.31 Near-infrared monitor tracings displaying right (R) and left bypass pump flows are re-established (green arrow), the rSO2 increases.
(L) cerebral oxygen saturation (rSO2) during neonatal cardiac surgery. A very brief period of low pump flows results in a transient drop in the
The red arrow marks the initiation of deep hypothermic circulatory rSO2
arrest and the associated decrease in rSO2 in both hemispheres. As
spectra of hemoglobin species. The wavelengths of infrared ranscranial Doppler Ultrasound

T
light that are used measure the concentrations of oxygen- Transcranial Doppler ultrasonography (TCD) has been used
ated and deoxygenated hemoglobin in order to determine as a monitor of cerebral blood flow velocity and microem-
rSO2. Online trend monitoring of this parameter then pro- boli during cardiac surgery [233, 234]. The technique for
vides indirect information on the adequacy of cerebral oxy- flow assessment uses pulsed-wave ultrasound at 2 MHz and
genation, a surrogate of cerebral perfusion, allowing provides peak systolic and mean flow velocities (expressed
opportunities for intervention if critical values are detected. in cm/s) (Fig. 11.32). Cerebral blood flow velocity in the
In contrast to SpO2 values which reflect saturation in the neonate is monitored using a temporal window or open
arterial component of the circulation, the measured rSO2 anterior fontanelle with insonation of the middle cerebral
combines the saturations in both the arterial and venous artery.
blood, an issue considered a limitation of the technologyor In neonates, TCD has been used to determine the thresh-
aortic clamp in non bypass cases. old for detectable cerebral blood flow during low-flow
This type of cerebral oxygenation monitoring has been bypass. During the arterial switch operation using alpha-
advocated for most neonatal cardiac cases but is particularly stat arterial blood gas management, 30 mL/kg/min was the
effective during Ao arch reconstruction using bypass tech- threshold for detectable cerebral perfusion in this popula-
niques that involve regional cerebral perfusion [138, 224, 225]. tion [235]. In neonatal Ao arch reconstruction during the
It is also known to aid in recognizing problems such as the Norwood operation, a mean bypass flow of 63 mL/kg/min
malposition of bypass cannula or aortic clamp in non bypass maintained both rSO2 (using cerebral oxygenation) and
cases that can result in neurologic injury if not detected [226]. blood flow velocities (using TCD) within 10% on the base-
Treatment algorithms for low NIRS have been developed for line [236]. This represented sufficient but not excessive
use during congenital heart surgery [227]. Ongoing experience cerebral perfusion.
continues to accumulate with respect to the contributions of TCD can detect and quantify cerebral emboli, the latter
this technology to perioperative care [215, 218, 219, 228]. identified as high-intensity signals (HITS) on a display.
Although NIRS monitoring is increasingly being used, it Data regarding the use of TCD to detect cerebral emboli
may not yet be part of the standard of care in all centers that during cardiac surgery in infants and children is somewhat
specialize in the management of infants and children with limited, although one study demonstrated that microemboli
heart disease [222, 229, 230]. To this date no randomized could be detected in the carotid arteries of children during
controlled trials have evaluated the clinical benefits of NIRS congenital heart surgery, particularly immediately after Ao
monitoring in the neonate with CHD and to definitively unclamping [237]. However, interpretation of the Doppler
prove a benefit in outcome. Cerebral oximetry also has been signals was confounded by a variety of artifacts. No corre-
recommended for routine use in the postoperative period lation was identified between the number of emboli detected
after cardiac surgery in view of the observation that infants and acute postoperative neurologic injuries. Currently,
with prolonged, low rSO2 demonstrate a greater incidence of TCD monitoring is reserved for special indications by some
periventricular leukomalacia [220, 227, 231]. This condition centers and is not considered a standard monitor for routine
can contribute to impaired neurodevelopment [220, 232]. use.
Fig. 11.32 Transcranial
Doppler ultrasonography
directed to sample flow across
the right middle cerebral
artery. The signals were
obtained with probe
placement over the anterior
fontanelle in a neonate
undergoing cardiac surgery.
The upper panel displays the
tracing during the pre-bypass
period and the lower panel
during cardiopulmonary
bypass. Note the different
characteristics of the
corresponding flow patterns
I ntraoperative Management of the Neonate impact the kinetics of intravenous agents; a large left-to-right
Undergoing Cardiac Surgery shunt can prolong induction of anesthesia because the drugs are
recirculated through the lungs. Hence, a less concentrated
Induction of Anesthesia amount of anesthetic agent reaches the brain, delaying the
onset of anesthesia. In contrast, a large right-to-left shunt
Induction of anesthesia in the neonate usually is accomplished speeds an intravenous induction because a significant portion
via the intravenous route, which is preferred over the inhala- of the drug bypasses the pulmonary circulation and directly
tional route because the former enables the airway to be rapidly enters the systemic circulation, rapidly reaching the brain.
secured without the use of cardiac depressant drugs and, hence, In the neonate, intravenous access usually is present preop-
provides a greater margin of safety. The presence of shunts can eratively. If this is not the case, access can be established before
induction, or if this is not possible a carefully titrated inhalation in humans [242]. As mentioned, the use of nearly all anesthet-
induction and early placement of an intravenous catheter can ics and sedatives with the exception of opioids and dexme-
be performed. Inhalational anesthetics dilate vascular beds and detomidine has been associated with neuroapoptosis and
reduce sympathetic tone. Although these are desirable goals in neurodegenerative changes in animal studies.
general, the effects can be detrimental in the neonate with During the last several years the use of dexmedetomidine
decreased myocardial performance who requires an increased has significantly increased in pediatric cardiac surgery [243,
resting sympathetic tone to maintain systemic output. 244]. Initially, the use of the drug was reserved for infants
In general only carefully titrated concentrations of inhala- beyond the neonatal age group, although the use of dexme-
tional anesthetic agents are used during neonatal cardiac sur- detomidine in neonates has been increasing over the last sev-
gery. Be especially aware of the danger of controlling eral years. The clearance of dexmedetomidine in term
ventilation during induction with anything but a minimal con- neonates is significantly diminished and increases rapidly in
centration of a inhalational agent. Three factors independently the first few weeks of life, reflecting the relative immaturity of
and substantively affect the uptake and distribution of inhala- the metabolic processes in the neonatal period (see Chap. 3)
tional anesthetics in neonates: the presence of a shunt (right- [245]. This issue warrants consideration when infusions are
to-left or left-to-right), the solubility of the inhalational used. A dosing strategy of dexmedetomidine in infants under-
anesthetic, and a decrease in cardiac output. See Chap. 3 for a going cardiac surgery with CPB suggested that its clearance
full discussion of the pharmacokinetics and pharmacodynam- was reduced after CPB for >1 h, leading the authors to recom-
ics of inhalational anesthetics in neonates with CHD. mend that the infusion rate be reduced in neonates after
An important goal of the anesthetic management in the bypass [246]. In the same study, the incidence and severity of
neonate with heart disease undergoing surgery is the selection arrhythmias, hypotension, and excess sedation were similar
of drugs that have the least impact on the cardiovascular sys- to those published previously. In addition to decreasing the
tem in order to maintain adequate cardiac function and ensure opioid and benzodiazepine requirements, dexmedetomidine
systemic oxygen delivery. A technique that combines several offers several benefits including prophylactic and therapeutic
agents (balanced technique) with minimal myocardial depres- effects for reentrant supraventricular tachycardia, attenuation
sant effects traditionally has been used for induction of anes- of renal injury, and neurologic protection [83, 247–251].
thesia in order to limit the extent of cardiac depression. It should be emphasized that no regimen or combination of
Titrated doses of an opioid and non-depolarizing muscle anesthetic agents has proven to be superior for all neonates
relaxant are commonly used. A benzodiazepine also can be with CHD. The most appropriate technique for each infant
added. It is important to emphasize that even the smallest and each cardiac lesion must be considered individually. The
dose of an opioid can depress cardiac function in the critically main goals of the anesthetic management are to optimize sys-
ill neonate because opioids can reduce the release of endog- temic oxygen delivery, protect and maintain ventricular func-
enous catecholamines. Therefore, it is imperative to monitor tion, and ensure the adequacy of cardiac output.
carefully and intervene promptly if decompensation occurs.
Cardiopulmonary Bypass in the Neonate

Maintenance of Anesthesia
Pre-bypass Period
After induction, anesthesia can be maintained with an inhala-
tion anesthetic, an intravenous technique, or a combination. After monitors have been applied and anesthesia induced,
For many years, a large-dose, synthetic opioid-muscle relax- the neonate is positioned for the procedure. In most cases,
ant technique was used because it minimally decreases cardio- after arterial access is established, baseline measurements of
vascular function and offered significant benefits by blunting blood gases, acid-base status, hematocrit, glucose, and cal-
the physiologic stress response [238, 239]. However more cium levels, and the activated clotting time (ACT) are docu-
recently clinical practice has changed; many centers now favor mented. This is the optimal time for transesophageal imaging
inhalational anesthetics as the primary agents and a limited in order to avoid interference from electrocautery once the
opioid dose. Contemporary data support this approach. The operation commences. Vigilance is of utmost importance
use of large-dose opioids with the goal of providing “stress during this phase of surgery because of the potential for
free” anesthesia is not an important determinant of early post- blood loss, rhythm abnormalities, compression of cardiac
operative outcome [240]. At the same time, when inhalational and vascular structures, and several other factors that can
anesthetics are properly used (e.g., isoflurane or sevoflurane), impact hemodynamic stability.
they do not significantly reduce the cardiac index in children The neonate should be very carefully monitored during
with CHD [241]. The potential benefit of anesthetic precondi- dissection around the heart. Sometimes it is necessary to
tioning of the heart continues to be investigated, with no par- alert the surgeon to pause activity and allow time for the
ticular anesthetic agent as yet proven to be superior in this role heart to recover if function appears compromised. Alternately,
minor changes in cardiac function have to be accepted if the tial bypass, only a portion of the systemic venous return is
procedure is to be performed! The anesthesiologist should captured in the venous reservoir and the remainder reaches
constantly watch the progress of surgery to integrate the the beating heart. Ventilation is required during partial
physiological changes observed on the monitors with the bypass for gas exchange of the blood that enters the pulmo-
actions of the surgeon. nary circulation. Full bypass is almost always required in
neonates and small infants.
Over the years, the sophisticated CPB system has been
erfusion Equipment, Tubing, Circuits,
P modified and miniaturized to make it suitable for use in
and Bypass Prime the smallest of infants and to minimize morbidity [253,
254]. Many elements are common to all perfusion cir-
Neonatal cardiac surgery frequently requires the use of CPB cuits used for bypass in the neonate (Fig. 11.33). The fol-
[252]. During full bypass, all the systemic venous blood is lowing sections describe the various components of a
directed to the extracorporeal circuit; in contrast, during par- CPB circuit:
Pressure P T Temperature
Systemic Flow Line
Cardioplegia Delivery Line
Cross Clamp
Aortic Root Suction
Blood
High Low Cardioplegia
K+ K+ Heat Exchanger/
Bubble Trap
Cardiotomy Suction
Cardioplegic
Left Ventricular Vent Solution
One-Way
Valve
Venous Cardiotomy
Blood Reservour
Sensor
Filter
Blood Gas
Venous
Monitor
Inflow
Air Bubble Regulating
Detector Clamp Membrane
Sensor T Recirculation
(Optional Position) Arterial Line
Blood Gas Sensor Vent Suction Suction Blood
Cardioplegia
One-Way Sampling
Anti-Retrograde Pump
Value Manifold
Flow Value
(with Centrifugal Level Sensor Venous
Pump) Reservoir
Gas Filter
Flowmeter
(with Centrifugal Pump)
Arterial Gas In
Filter and Gas Out Air Bubble Systernic
Bubble (Io Scavenge) Detector Blood
T Sensor Pump
Trap
Cooler
Oxygen Heater
Analyzer Water Source
P
Pressure Air
Gas O2
Anesthetic Flow Blender
Vaporizer Meter
Fig. 11.33 Schematic diagram of a cardiopulmonary bypass circuit. Arrows indicate direction of flow, P pressure sensor, T temperature sen-
Note the venous reservoir with integrated membrane oxygenator. Other sors, and X placement of tubing clamps. From Hessel EA II and Shann
components of the circuit include the cardioplegia solution and pump, KG. Blood pumps, circuitry, and cannulation techniques in cardiopul-
water heater/cooler, safety devices, and monitors. The flow is driven by monary bypass In: Gravlee GP, Davis RF, Hammon JW, and Kussman
either a roller head or centrifugal pump. Bicaval cannulation may be BD editors. Cardiopulmonary Bypass and Mechanical Support:
required during pediatric cardiac surgery for venous drainage, in con- Principles and Practice. 3rd Ed. Philadelphia: Lippincott Williams &
trast to a single cannula as depicted here. Carbon dioxide can be added Wilkins; 2016; with permission
to the inspired gas mixture to facilitate pH-stat blood gas management.
Heart-Lung Machine [(Pump] ervoir; however, this procedure can traumatize blood
Most are non-pulsatile. Occlusive roller pumps are favored elements.
because of their accuracy at very low-flow rates as well as
their smooth revolutions at very low speed (revolutions per Air/Oxygen Blender, Carbon Dioxide Tank,
minute). Most machines incorporate a servo regulating reser- High−/Low-Flow Meter
voir level sensor, high-pressure alarm, and a bubble detector. These instruments provide capabilities for controlling pO2
and pCO2 precisely at all temperatures, facilitating blood gas
Heat Exchanger Unit management on bypass.
These devices cool and warm the blood. In the neonate, an
important feature of these units is their ability to change tem- Cardioplegia Circuit
peratures very slowly and precisely, thereby providing for This circuit is designed to deliver cardioplegic solution and
adequate equilibration of temperature between blood and tis- frequently incorporates the ability for cooling.
sues, during both cooling and warming.
Blood Hemoconcentrator
Membrane Oxygenator This unit allows for ultrafiltration to be performed during
This unit enables gas exchange. The optimal device should CPB aimed at removing free water and inflammatory
be efficient, require a small priming volume, provide appro- mediators.
priate flow capabilities, and be dependable. In addition to
heparizing the neonate before CPB to prevent clot formation Venous Saturation and Hematocrit Monitor
[255], some manufacturers coat the surface of the CPB cir- These monitors, once appropriately calibrated, serve to
cuitry including the oxygenator, to further reduce the pro- enhance the overall safety of the CPB process and allow for
thrombotic risk [256]. less frequent blood sampling.
Arterial Filter Activated Clotting Time Machine

Various arterial filters are available to preclude particulate This machine is able to provide point-of-care testing of the
matter from entering the arterial return line. Desirable fea- heparin activity that is monitored by measuring the activated
tures include a low priming volume, suitable flow capabili- clotting time (ACT) and facilitates anticoagulation manage-
ties, and ease of debubbling. A coating, as described for the ment. Various agents can be used as activators of the coagu-
membrane oxygenator, provides similar benefits. lation system. Kaolin is favored because it is much less
influenced by antifibrinolytic agents.
Cannulas and Tubing
The selection of cannulas and tubing is based primarily on Arterial Blood Gas Machine
the flow requirements. Selecting cannulas of appropriate size Sampling of gas exchange, acid-base status, hematocrit, and
is extremely important for proper arterial flow and venous other chemistries is mandatory during CPB. Having immedi-
drainage in pediatric patients. The size of the neonate/ana- ate accessibility to equipment with those capabilities is
tomic structures (systemic veins, RA, Ao) influences the essential during cases that require bypass.
selection of bypass cannulas. Drainage of venous return can
be accomplished in some cases by a single RA cannula, Cell Saver
although frequently the need for intracardiac surgery requires This system is used to process the sequestered blood aspi-
bicaval cannulation as an alternative to circulatory arrest. rated from the operative field, allowing it to be reinfused
Abnormal venous anatomy may require the use of additional with the goal of decreasing exposure to homologous blood
cannulas. The arterial cannula, which returns blood to the products (in some cases).
neonate, typically is placed in the Asc Ao. However, depend-
ing on the bypass strategy, this site might be altered to a more Miniaturization of Bypass Circuit
distal location. Also based on the nature of the intervention, The miniaturized bypass apparatus provides a simple and
additional arterial cannula sites may be considered to ensure safe method to reduce autologous blood transfusions in the
ACP (graft in innominate artery) or to maintain distal sys- neonate. The small components can significantly decrease
temic blood flow (e.g., ductal cannulation). priming volumes, thus reducing the enormous disproportion
between the extracorporeal volume and small blood volume
Venous Reservoir of the neonate. A small prime volume circuit consisting of
The reservoir functions as the temporary storage site for only a rotary blood pump head and a membrane oxygenator
venous blood during extracorporeal circulatory support. is used. The venous blood returns to the pump through active
Venous drainage generally is passive, relying on gravity. drainage. No venous reservoir or cardiotomy suction device
Vacuum-assisted venous drainage can be an option to facili- is used, minimizing hemodilution and mechanical blood
tate the egress of blood from the patient into the venous res- trauma but at the expense of safety features. Recent studies
demonstrate that a miniaturized circuit significantly reduced Before CPB, satisfactory position of the arterial cannula can
blood transfusions although the short-term outcomes were be assessed by comparing the mean arterial pressures from
similar [257]. the arterial line with that of the arterial inflow cannula of the
bypass circuit to the patient.
Pump Prime Once CPB is established, the adequacy of venous drainage
During the pre-bypass period, the pump prime is adjusted to should be confirmed. This can be achieved among several ways
a physiologically balanced solution, with a desirable hema- by direct inspection of the heart, confirmation of a low CVP
tocrit, procoagulant levels, and oncotic pressure. Other addi- measurement, and assessment of NIRS values. In addition,
tives may include antibiotics, antifibrinolytic agents, and venous distension of head structures (e.g., bulging fontanelles,
corticosteroids. facial congestion), which could suggest SVC obstruction,
should be excluded. Be aware that even modest increases in
SVC pressure can compromise cerebral blood flow during
Stages of Cardiopulmonary Bypass CPB. Despite priming the bypass circuit with banked blood in
the neonate, low arterial pressures related to hemodilution are
Before CPB, the patient’s blood is anticoagulated, purse-string sometimes seen upon initiation of CPB, especially in infants
sutures are placed, and arterial and venous sites are cannulated. with cyanotic lesions. In most cases, this situation is associated
After CPB initiation the following occurs in sequence: core with a transient decrease in rSO2 as documented by NIRS moni-
cooling, Ao clamping and myocardial protection, the surgical toring. Increasing pump flows for a brief period of time or early
intervention, followed by warming, release of the Ao clamp, surgical control of runoff connections (i.e., ductus arteriosus,
reperfusion of the heart, separation from support, reversal of aortopulmonary collaterals, shunts) frequently restores perfu-
anticoagulation, and removal of the cannulas. The following sion pressures to acceptable levels. The use of vasoconstricting
sections highlight selected aspects of the bypass period. agents is undesirable as an important goal at this stage is the
homogeneous cooling of systemic vascular beds.
Anticoagulation The adequacy of perfusion should be assessed carefully
Before placing the cannulas for CPB, heparin is administered, throughout the entire period of extracorporeal support. This
and appropriate anticoagulation should be confirmed. assessment is based on the pump flow rate, mean arterial
Neonates have greater water content and volume of distribu- pressure on bypass, and measurements of mixed venous sat-
tion for hydrophilic drugs such as heparin compared with uration. Additional indirect indices include arterial blood gas
older children. The hemostatic system is immature at birth analysis (pH, lactate, base deficit), regional oxygenation
with reduced levels of thrombin, prothrombin, and antithrom- measurements by NIRS, and urine output.
bin. Most neonates require relatively large doses of heparin Maintaining adequate anesthesia during CPB is impor-
[~400 units/kg] due to a relative heparin “resistance” to tant; light anesthesia, particularly during the cooling or
achieve a target ACT as compared with older children [258]. warming phases of the procedure, can lead to a significant
The optimal ACT for CPB is controversial, but most centers increase in metabolic rate and oxygen consumption, with
consider a value in excess of 400 s to be the minimum value to an increase in systemic vascular tone, compromising
proceed to CPB (480 s at some institutions). A subtherapeutic organ perfusion.
ACT can result from inadequate dosing, low concentrations of
antithrombin III, or relative heparin “resistance.” One alterna- ooling and Temperature Management
C
tive to ACT testing is to measure the heparin concentration Active cooling using the CPB circuit is initiated once it is
[259, 260]. Heparin is also added to the bypass circuit prior to confirmed that bypass is satisfactorily established. The goal
initiation of CPB and at regular intervals thereafter, with serial of hypothermia during CPB is to decrease the metabolic
monitoring of the ACT. Conditions such as hypothermia and rate, thereby preserving vital organ function [261]. Three
renal dysfunction delay the elimination of heparin. levels of hypothermia are used based on the nature of the
intervention: mild (30–36 °C), moderate (22–30 °C), and
annulation and Initiation of Cardiopulmonary
C deep hypothermia (18–22 °C). Extensive or complex sur-
Bypass gery that requires low-flow perfusion or circulatory arrest is
Transient decreases in blood pressure, mild arterial desatura- more likely performed under moderate or deep hypother-
tion, and transient arrhythmias frequently occur when purse mia. Surface cooling of the brain by applying ice bags to the
strings and cannulae are placed in the neonate. These changes neonatal head is still used in clinical practice, particularly
are expected, and usually no treatment or only a minor inter- during conditions of low-flow or circulatory arrest. A key
vention, such as volume replacement, is required. Any blood objective of cooling is to uniformly reduce the temperature
lost into venous cannulas during their insertion and priming of all body tissues homogenously, that is, without local tem-
the circuit should be immediately replaced via the arterial perature gradients. Vasodilators (phentolamine, phenoxy-
cannula. The goal is to avoid any immediate pre-bypass sig- benzamine, nitroprusside) are used during the initial phase
nificant hemodynamic instability or cardiac compromise. of cooling to accomplish this goal, particularly when deep
hypothermia is planned [262–264]. Slow cooling is favored varies among institutions [273]. Some centers favor dopa-
over rapid cooling, as the latter has been linked to neuro- mine as the first-line inotrope, whereas others favor epi-
logic impairment [265]. Although most neonatal surgeries nephrine and yet others favor dobutamine [274].
are performed under hypothermic conditions, some centers Importantly all these drugs increase heart rate, have
advocate for normothermia [266, 267]. Ongoing debate on arrhythmogenic potential, and increase oxygen consump-
this topic continues [268, 269]. tion [275]. Vasopressin has been increasingly reported as
an agent to enhance systemic vascular tone [276–279]. A
ortic Cross-Clamping and Myocardial
A study in neonates after the Norwood procedure or arterial
Protection switch operation demonstrated that low-dose vasopressin
If myocardial arrest is planned, Ao clamping is performed in decreased the need for fluid resuscitation and catechol-
order to deliver a cardioplegic solution into the Ao root or, in amines during the first postoperative day [280]. Milrinone,
some cases, directly into the coronary arteries. The goal of with inotropic properties as well as pulmonary and sys-
cardioplegia is to preserve the myocardium while the heart is temic vasodilatory effects, is of benefit after neonatal car-
ischemic. The Ao clamp usually is placed between the arte- diac surgery [281]. The drug is useful in reducing the risk
rial cannula and Ao root. The catheter used to deliver car- of a postoperative low cardiac output state and thus is
dioplegia into the root in antegrade fashion typically is used frequently. During the rewarming phase, supplemen-
placed just below the Ao clamp. A number of cardioplegic tal doses of muscle relaxants and sedatives should be con-
solutions are used in clinical practice. The optimal combina- sidered. Blood components can be added to the circuit
tion of ingredients in these solutions is the subject of ongo- during this time in order to optimize hematocrit and coag-
ing debate. The advantages of blood cardioplegic solutions ulation factors. Once the neonate’s target temperature has
have led to its increasing use in neonatal patients. After the been reached and ventilation established, weaning from
initial infusion of cardioplegia, additional doses can be given CPB may be commenced. This is a critical intraoperative
at regular intervals, as needed, depending on the duration of time period. As the myocardium has suffered a major
the ischemic time. A good general guide for the perfusionist stress, this process takes place slowly over several min-
is to deliver cardioplegic solution at a pressure near the dia- utes guided by factors such as the appearance of the heart
stolic blood pressure of each individual patient before on direct inspection, TEE monitoring, and hemodynamic
bypass. This delivery usually is coupled with surface cooling parameters (filling pressures, arterial blood pressure). The
of the heart for added myocardial protection. A venting cath- administration of calcium as an infusion and/or as inter-
eter (vent) is placed in the LV to decompress it. The distribu- mittent boluses is often necessary during separation from
tion of cardioplegic solutions throughout the infant CPB in the neonate to address the dependence of the neo-
myocardium may be compromised by hypertrophy and natal myocardium on free cytosolic ionized calcium for
abnormal coronary artery distribution or other pathology. contractility and in order to offset the effects of citrated
blood products on serum ionized calcium levels. If any
elease of Aortic Clamp and Myocardial
R rhythm other than sinus rhythm is present, pacing wires
Reperfusion should be placed and sequential pacing initiated. Once
Once all extraneous air has been removed from the heart, the circulatory support has been discontinued and hemody-
Ao clamp is released, allowing for reperfusion of the myocar- namics optimized, results of the intervention are evalu-
dium, initiation of electrical activity, and spontaneous cardiac ated. TEE is of significant benefit in this regard. If the
beating soon thereafter. TEE can be useful to assist in remov- results of the intervention are deemed satisfactory, antico-
ing any remaining intracardiac air at this stage. In some cases, agulation is antagonized with protamine, cannulas are
cardioversion/defibrillation and/or pacing is required during removed, and efforts towards establishing hemostasis are
this phase of CPB. Warming is initiated around this time as a initiated. If significant hemodynamic residua are identi-
gradual, slow process. Several temperature targets have been fied, a return to bypass may be necessary. In most infants
proposed and vary according to monitoring site (nasopharyn- undergoing open-heart interventions, temporary epicar-
geal end point > 35 °C, skin > 30 °C, bladder > 35 °C, rec- dial pacing wires are placed. In addition to being used for
tal > 35.5 °C) [270, 271]. The temperature of the perfusate pacing as needed, atrial wires facilitate the identification
should not exceed 37 °C, as cerebral hyperthermia at this stage of rhythm disturbances as they allow for an atrial electro-
can be very detrimental to the neonatal brain [272]. In fact, a gram to be obtained. At the conclusion of the surgical pro-
mild degree of hypothermia is more desirable. cedure and after the mediastinal drainage tubes are placed,
chest is closed. Sternal closure may be delayed if severe
eparation from CPB, Reversal
S cardiac dysfunction requiring significant inotropic sup-
of Anticoagulation, and Removal of Cannulas port, myocardial edema resulting from extensive/complex
After the Ao clamp has been removed, active rewarming surgery, pulmonary impairment, bleeding, sustained
begins and vasoactive/inotropic infusions are initiated as arrhythmias, or any other concerns regarding the neo-
needed. The preference for vasoactive/inotropic agents nate’s clinical status were present.
Transport to the Intensive Care Unit and in some cases repair of total anomalous pulmonary
venous connection. DHCA involves lower levels of hypo-
Although early tracheal extubation has been performed suc- thermia (<20 °C) and cessation of bypass flow while the pro-
cessfully in neonates after major cardiac surgery [132, 282, cedure is undertaken. This technique allows for a surgical
283], it remains a rare practice, particularly in view of the field free of cannulae and blood, thus facilitating the surgery.
underlying pathology, nature of the intervention, and con- Not surprisingly, prolonged duration of DHCA has been
cerns for an untoward event. Therefore, with few exceptions, associated with increased neurologic morbidity [284].
the trachea in most neonates remains intubated postopera- Hence, alternate modalities such as SACP have been devel-
tively, even if only for a few hours. Preparing the neonate for oped to maintain continuous cerebral circulation and to min-
transport from the operating room to the intensive care unit imize or avoid the need for circulatory arrest and potentially
is an important time period. Although it can be a distracting to prevent hypoxic ischemic injury [285–288]. However, the
time, continuing surveillance of vital signs and hemodynam- specific technique for SACP varies among centers. In some
ics during this process is essential as terminating the surgical cases, a cannula is advanced into the Asc Ao to provide flow
stimulation may be associated with undesirable changes in to the brain, whereas in others, a graft is sewn into the base
blood pressure. Extreme care must be taken to ensure that of the innominate or subclavian artery to position the arterial
monitoring and infusion lines are safeguarded during trans- cannula away from the surgical field (Fig. 11.34) [138]. At
fer from the operating room table. Note that vertical dis- the time of SACP and after the nasopharyngeal temperature
placement of some infusion pumps may disturb the flow has reached a target value of ~ 18 to 20 °C or the rectal tem-
rates. Adequate oxygenation and ventilation, as well as perature has reached 20 to 22 °C (these temperatures vary
ongoing hemodynamic monitoring, must be ensured during among institutions), snares are placed around the aortic arch/
transport. Hypoventilation during this time can negatively arch vessels and pump flow is reduced to approximately 30%
affect pulmonary vascular tone and overall clinical status in of the predicted full flow. This approach allows for selective
the fragile neonate. Adequate analgesia and, in most cases,
sedation are important postoperative requirements.
A comprehensive report of the intraoperative course
should be given to the team involved in the postoperative care
(anesthesia handoff). This report should include airway man-
Arterial
agement (ETT size, ease, and depth of tracheal intubation), cannula
location of vascular access and invasive monitors, presence/
numbers of chest draining tubes, pacing wires, pacemaker
settings as appropriate, implanted surgical hardware, duration
of bypass, ischemic time, and doses of active infusions of
drugs. Highlights of the procedure and problems should be
Atrial blood
discussed, as should TEE findings and plan, in addition to any
scavenger
specific concerns. Upon arrival in the intensive care unit, a
chest radiograph and blood samples are usually obtained, and
ideally the anesthesia provider should review these results.
The hemodynamic management of the neonate with CHD in
the postoperative setting assumes many of the same physio-
logic principles applicable to intraoperative care.
pecial Cardiopulmonary Bypass

S
Techniques: Deep Hypothermic Circulatory
Arrest, Selective Antegrade Cerebral
Perfusion, and Others
Deep hypothermic circulatory arrest and selective antegrade

cerebral perfusion (SACP; also referred to as antegrade cere- Fig. 11.34 The figure depicts the technique for selective (antegrade)
cerebral perfusion. Note the polytetrafluoroethylene graft that has been
bral perfusion (ACP), regional low-flow cerebral perfusion sewn into the base of the right innominate artery and attached to the
(RLFP), or regional cerebral perfusion) are techniques used arterial inflow cannula of the cardiopulmonary bypass circuit. This
in association with CPB during neonatal cardiac surgery. allows for flow to the brain and a bloodless operative field while aortic
Circulatory arrest is commonly used for cardiac interven- arch reconstruction is undertaken. From Gertler R, Gottlieb EA,
Andropoulos DB. Cardiopulmonary Bypass and Management. In: Cote
tions involving the atria or aortic arch. These include Ao arch CJ, Lerman J, Anderson B, editors. A Practice of Anesthesia for Infants
reconstructive procedures such as the Norwood operation and Children. 6th Ed. Philadelphia: Elsevier; 2019; with permission
blood flow to the brain. The adequacy of brain perfusion dur- usually lower in the neonate (~35–40 mmHg), because of the
ing this period is guided by neuromonitoring [137, 236]. reduced impedance in the systemic circulation.
After the Ao arch reconstruction is completed, full bypass Blood gas management during hypothermic bypass in the
flow is re-established. A study using magnetic resonance neonate has been controversial in the past. The pH-stat acid-
imaging examined the 12-month neurodevelopmental out- based strategy is used more frequently in the neonate/child, in
comes in neonates undergoing Ao arch reconstruction [289]. contrast to the alpha-stat strategy in the adult. The pH-stat acid-
They determined that the technique was effective and safe in base approach maintains a constant blood pH at all tempera-
supporting the brain. Alternate techniques of beating-heart tures; in other words, pH management is temperature-corrected
surgery for aortic arch surgery in neonates have also been and targets a PaCO2 of 40 and pH of 7.40 at the patient’s actual
reported [290, 291]. temperature. Oftentimes, carbon dioxide is introduced into the
oxygenator in order to maintain these parameters within a
desirable range during hypothermic CPB. The proposed bene-
nique Aspects of Neonatal
U fits of the temperature-corrected pH-stat approach in pediatric
Cardiopulmonary Bypass and Differences patients favor tissue oxygenation and cerebral vasodilation,
From the Adult thereby allowing for more uniform cooling and better brain
protection [292]. The pH-stat approach yields better outcomes
Notable differences exist between CPB in the neonate and in with shorter ventilation times and intensive care unit stays
the adult (Table 11.6). Different techniques are used and the [293]. In contrast, the alpha-stat approach corrects the blood
effects of these techniques on the infant’s physiology also gas results to 37 °C irrespective of the child’s actual body tem-
differ, whereas in all age groups in which hypothermia is perature. In other words, alpha-stat maintains the uncorrected
used during cardiac surgery, the neonate is more likely to PaCO2 and pH values at normal levels.
undergo lower levels of hypothermia. Strategies such as total Cannulation for CPB in the pediatric age group fre-
circulatory arrest, low-flow bypass, and SACP are used frequently differs from that in the adult. In the young, placing
quently during complex neonatal surgery. Vasodilating cannulas in both caval veins (bicaval cannulation) seques-
agents such as alpha-blocking drugs are more likely associ- ters all the venous return and facilitates intracardiac inter-
ated with these strategies in the neonate. Flow requirements ventions. In contrast, this procedure is rarely necessary in
and perfusion pressures also differ among patients according the adult. In some cases, even additional venous cannulas
to age, weight, and body surface area. Recommended flow are required in congenital surgery due to abnormal systemic
rates in the neonate (2.6–3.2 L/min/m2) are greater than in venous anatomy. The site of arterial cannulation also may
the infant (2.4–2.6 L/min/m2). During neonatal surgery, a vary in pediatric versus adult patients. In fact, during neona-
wide range of bypass flow rates are used from no flow during tal cardiac surgery, multiple sites of arterial cannulation
DHCA to large flow rates of 200 mL/kg/min, depending on (e.g., Asc Ao and ductus arteriosus during repair of IAA)
the particular strategy. The need for variable flow rates is less may be required. The use of ultrafiltration is standard in the
likely in older children or adults. Perfusion pressures are neonate but is rarely used in adults [294]. Conventional
Table 11.6 Differences between pediatric and adult cardiopulmonary bypass

Parameter Pediatric Adult
Temperature Commonly 18–20 °C Rarely below 32 °C
Use of deep hypothermic Common Rare
circulatory arrest
Pump prime components Blood products and albumin Crystalloid solutions
Dilution effect of pump prime Up to 200% 25–33%
Perfusion pressure 30–50 mmHg 50–80 mmHg
Cannulation sites Variable (arterial may include ductus arteriosus and main Standardized, mostly ascending aorta and
pulmonary artery; venous, mostly bicaval, may require single venous cannula
additional cannulas)
Flow rates 0–250 mL/kg/min 2.5 L/min/m2 or 50–65 mL/kg/min
Blood gas management pH-stat favored Alpha-stat preferred
Hypoglycemia Common, due to low hepatic glycogen stores Rare, seen with severe hepatic dysfunction
Hyperglycemia Less common Frequent, increases mortality
Cannulation techniques Variable, including ductus, aorta, main pulmonary artery, Standardized, mostly ascending and
mostly bicaval venous cannulation single-stage venous cannula
Ultrafiltration Standard modified ultrafiltration or conventional Rare
ultrafiltration
Modified from Gertler R, Andropoulos DB, and Resheidat A. Cardiopulmonary bypass. In Andropoulos DB, Mossad EB, and Gottlieb EA editors.
Anesthesia for Congenital Heart Disease, fourth Ed, Hoboken: Wiley-Blackwell; 2023; with permission
ultrafiltration (CUF) during bypass or modified ultrafiltra- factors associated with increased morbidity and mortality
tion (MUF) at the completion of bypass removes body after cardiac surgery in the infant [306].
water, increases hematocrit, and reduces the plasma concen-
tration of circulating cytokines and vasoactive substances
[295]. This decreases blood transfusion requirements, ffects of Cardiopulmonary Bypass
E
improves coagulation status, and confers additional signifi- and Related Strategies
cant benefits involving major organ function [296]. A meta-
analysis demonstrated that MUF after pediatric cardiac Cardiopulmonary bypass, though essential for the correction
surgery significantly increased the hematocrit and mean of many lesions in the neonate, introduces several significant
arterial pressure after CPB as compared with CUF. However, adverse physiological effects. These effects pose major chal-
postoperative outcome parameters including chest tube lenges in the postoperative period.
drainage, ventilator time, and duration of intensive care unit
stay remained unchanged [297].
Many physiologic effects of CPB differ between children Systemic Inflammatory Response Syndrome
and adults. In neonates there is a larger disproportion of the
pump prime volume relative to the patient’s blood volume. The systemic inflammatory response syndrome (SIRS) is
Thus, there is the need for whole blood or packed red cells characterized by a capillary leak state, body edema, hemody-
and plasma in the prime to achieve a target hematocrit and namic instability, and multisystem organ dysfunction [307].
thus ensure adequate oxygen carrying capacity. In the past, Although the mechanisms responsible for the development of
the target during hypothermic CPB was a low hematocrit, but this syndrome are not fully understood, it is thought that acti-
over time, the target has increased from 20% to 30% as evi- vation of humoral cascades due to contact of blood compo-
dence has demonstrated better short-term outcomes and nents and endothelial cells with the plastic circuit surfaces
1-year neurodevelopmental scores with a higher hematocrit plays a major role [308, 309]. Other systems activated during
[298]. However, a follow-up study that compared hematocrit CPB include the complement system, coagulation, and fibri-
levels of 25% and 35% showed no major benefits or risks of nolytic cascades. SIRS has been linked to major morbidity and
the greater hematocrit among infants undergoing two- mortality rates in the pediatric age group [310, 311]. Several
ventricle surgery [299]. bypass strategies have been devised to ameliorate the inflam-
Glucose homeostasis is important in neonates undergoing matory response and its associated morbidity including hepa-
cardiac surgery. Although the neonate is prone to hypoglyce- rin coating of circuits, ultrafiltration, the administration of
mia, there is a tendency towards hyperglycemia during peri- corticosteroids, the use of protease inhibitors (such as apro-
ods of stress. Both of these glucose perturbations have been tinin), and other pharmacologic approaches (complement
associated with adverse clinical outcomes. The reduced inhibitors, thromboxane antagonists, anticytokine therapy)
hepatic glycogen stores, particularly during physiologic [312–315]. Regarding the use of corticosteroids, a recent ran-
stress, increase the risk for hypoglycemia in the neonate, domized controlled trial examined the impact of intraoperative
which supports the routine use of glucose-containing intra- methylprednisolone in the postoperative recovery in neonates
venous solutions to prevent related morbidity in this popula- undergoing cardiac surgery and failed to demonstrate an over-
tion. However, CPB can lead to hyperglycemia by activating all significant benefit [316]. A recently published prospective,
the stress response, through the use of components that randomized, placebo controlled trial involving infants under-
contain large amounts of glucose (e.g., blood products and going cardiac surgery with CPB reported that methylpredniso-
cardioplegic solution) and the administration of steroids. lone did not significantly influence the likelihood of a poor
The perioperative management of glucose during pediat- clinical outcome and it was associate with postoperative
ric cardiac surgery remains a controversial issue, largely the hyperglycemia requiring appropriate therapy [471].
result of limited and conflicting data [300, 301]. Some stud-
ies reported a link between hyperglycemia and poor out-
comes after cardiac surgery in children [302, 303]. Effects on Bleeding and Coagulation
Postoperative hyperglycemia upon arrival at the intensive
care unit has been associated with a younger patient age, Bleeding is a major clinical problem after cardiac surgery in
reduced body weight, and decreased bypass temperature the neonate. Risk factors include low birth weight, use of
[304]. Conversely, an investigation using tight glycemic con- profound hypothermia, an increased preoperative hemato-
trol with the use of insulin in children (similar to that shown crit, cyanosis, and complex surgery [317]. The increased risk
to be beneficial during adult cardiac surgery) failed to sig- of bleeding in the neonate is due to immaturity of the coagu-
nificantly affect the infection rate, mortality, duration of stay, lation system, characterized by reduced plasma concentra-
or measures of organ failure after pediatric cardiac surgery, tions of both procoagulant and anticoagulant proteins
questioning the utility of this strategy [305]. This latter find- (30–70% of adult values) [318]. The levels of factors II (pro-
ing is consistent with previous data that suggested that post- thrombin), V, VII, X, XI, XII, and XIII are decreased in the
bypass and postoperative hyperglycemia were not risk neonate and infant until approximately 6 months of age. The
levels of fibrinogen or dysfunctional fibrinogen are also infusion of vasoactive agents, prolonged duration of mechan-
reduced in neonates [319]. All of these factors are com- ical ventilation, and extended duration of intensive care stay
pounded by the relatively large volume of the pump prime and hospitalization [320–323]. Therefore, early detection
relative to the blood volume and the resultant dilutional and treatment of bypass-related coagulopathy, as well as
effect on the coagulation factors. The fact that the liver is not sound transfusion strategies, are essential [324].
completely functional at birth, given that hepatic maturation An individualized strategy that includes patient-specific
continues throughout the first few weeks of life, also com- heparin and protamine management to optimize anticoagula-
pounds the problem. Hypoperfusion states can delay the tim- tion and minimize bleeding problems in infants has been
ing of hepatic maturation, adding further to the bleeding risk. advocated [325]. For many years, the approach to bleeding
Many neonatal surgical procedures are complex, requir- during neonatal cardiac surgery was to administer blood
ing extensive surgical dissection, extracardiac suture lines, components early and prophylactically. Today, several tech-
prolonged periods of CPB, and low levels of hypothermia. nologies are available to objectively manage coagulation/
Cyanotic CHD is associated with hemostatic abnormalities bleeding metrics. These point-of-care testing devices pro-
that include polycythemia, thrombocytopenia, platelet func- vide immediate or rapid results for partial thromboplastin
tional abnormalities, disseminated intravascular coagulation, time and prothrombin time, thromboelastography (TEG),
decreased production of coagulation factors (due to impaired rotating thromboelastometry (ROTEM, Fig. 11.35), and spe-
liver function and vitamin K deficiency), and fibrinolysis cific assays of platelet function (Sonoclot analyzer, PFA-
[319]. When these factors are combined with dilutional 100, and multiplate platelet aggregometer) [326–329]. TEG
coagulopathy and platelet dysfunction related to CPB, the is a widely available technology that allows for a live graphic
risk of bleeding increases. display of the coagulation process. This can detect residual
The need for large volumes of blood and blood compo- anticoagulant or deficiency of clotting factors, poor clot
nents has been associated with poor outcomes. The detri- strength, or fibrinolysis. This technology is used now to
mental effects of blood transfusion include activation of the assess post-bypass coagulopathies and to guide blood com-
inflammatory cascade, hemodynamic alterations requiring ponent therapy [330–332].
a
mm
FIBTEM
60
40
20 CT : 70 S
20 CFT : S
40 α : °
60
A10 : 8 mm
A20 : 10 mm
10 20 30 40 50 min
MCF : * 11 mm
ML : * 0 %
b
mm HEPTEM
60
40 CT : 189 S
20
CFT : 268 S
20 α : 59 °
40
60 A10 : 30 mm
A20 : 37 mm
10 20 30 40 50 min MCF : * 40 mm
ML : * 0 %
Fig. 11.35 Rotational thromboelastometry (ROTEM) tracing upon tion issue, suggesting the need for clotting factors (plasma or prothrom-
rewarming during cardiopulmonary bypass in a neonate undergoing bin complex concentrate) to correct the delay in clot formation
cardiac surgery. Panel a, FIBTEM channel showing a borderline MCF (prolonged CT and CFT) and platelets to improve the clot strength
value, suggesting inadequate fibrin contribution to clot firmness consis- (decreased MCF). CT coagulation time (seconds), CFT clot formation
tent with a requirement for fibrinogen replacement. Panel b, HEPTEM time (seconds), A10 and A20 amplitude at 10 and 20 min after CT
channel displaying prolonged CT and CFT, as well as decreased α angle respectively (mm), ML maximum lysis (percentage of lysis at any
(<70°) and MCF (<50 mm). This pattern indicates a complex coagula- time), MCF maximum clot firmness (mm)
Antifibrinolytic agents have been used to minimize Neurologic Effects

bleeding in the perioperative period [333–337]. Agents
such as ε-aminocaproic acid (EACA) and tranexamic acid Neurologic (CNS) morbidity has received increasing atten-
are analogs of the amino acid lysine and exert their antifi- tion as survival after neonatal cardiac surgery continues to
brinolytic effects by interfering with the binding of plas- improve [212, 286, 353–355]. Injury (to the central nervous
minogen to fibrin, which is necessary for activation to system during surgery for CHD) can be manifested acutely
plasmin. Recent allometric studies of EACA showed that in the postoperative period as seizures, stroke, and/or coma
clearance is reduced in neonates undergoing elective car- [286, 356]. The incidence of seizures, as documented by
diac surgery compared with older children and adults. electroencephalographic monitoring, is 14–20% when
Dosing should be approximately half that used in children DHCA or low flow is used but is noted to be infrequent when
and adults. The current recommendation is a 40 mg/kg normal flow rates are used [286, 357]. Seizures are more
loading dose and a 30 mg/kg/h infusion and a loading dose likely to occur after prolonged duration of DHCA. However,
in the bypass prime is of 0.1 mg EACA per 1 mL of blood seizures after surgery did not predict worse developmental
prime to maintain a target concentration [337]. A pharma- outcome on short-term follow-up (e.g., after 1 year) of 178
cokinetic study of tranexamic acid in neonates and young neonates and infants with complex congenital heart defects
infants undergoing cardiac surgery proposed dosing recom- [358]. With regard to stroke, a study of 122 infants undergo-
mendations based on selected plasma concentrations [338]. ing cardiac surgery reported a prevalence of 10%, half of
For neonates and infants up to 2 months of age, these which was found to exist preoperatively [359]. Most strokes
ranged between loading doses of 15–120 mg/kg, infusion were clinically silent and undetected without neuroimaging.
rates of 2.5–17 mg/kg/h, and CPB prime doses of 20–150 Significant factors associated with stroke identified in multi-
mcg per mL of volume, to maintain target plasma concen- variate analysis were reduced birth weight, preoperative
trations between 20 μg/mL at the low end and 150 μg/mL at intubation, reduced intraoperative hematocrit, and greater
the high end throughout the surgery. blood pressure postoperatively at admission to the intensive
Aprotinin causes inhibition of kallikrein and plasmin. In care unit.
addition to having hemostatic properties (decreased hemo- A significant concern is the substantial incidence [>50%]
static activation, antifibrinolysis, and preservation of plate- of periventricular leukomalacia reported in neonates after
let adhesiveness), the drug also has favorable effects on cardiac surgery [360, 361]. This finding of cerebral white
inflammation [339]. Based on the published evidence, all matter necrosis that results from injury to immature neurons
three antifibrinolytic agents decrease bleeding to a similar has been linked to an increased incidence of developmental
degree [340–343]. However, there are studies that suggest delay and attention-deficit/hyperactivity disorder [362].
aprotinin is ineffective in neonates undergoing open-heart Neurodevelopmental deficiencies after cardiac surgery
surgery [344]. Aprotinin was withdrawn from the USA mar- include problems such as cognitive impairment, speech and
ket in 2008 due to the risk of renal dysfunction and death in language abnormalities, impaired visual and spatial motor
adult cardiac surgery [345]. These detrimental effects have skills, impaired attention and executive function, and learn-
not been reported in children. Retrospective studies in neo- ing disabilities [363]. There has been intense interest in and
nates with renal dysfunction who received aprotinin when investigation of this complication, given the relatively high
the drug was available in the USA indicated that either the incidence of neurodevelopmental sequelae among children
duration of CPB or the transfusion of blood products was with CHD [212, 364, 365] . Thus far, patient-specific factors
more likely the etiology for the kidney injury than the drug play a significant role on neurologic outcomes [366] as well
itself [336, 346, 347]. as potentially modifiable perioperative interventions [289,
Despite advances, empiric treatment of excessive bleed- 367, 368].
ing after reversal of heparin may sometimes be needed in Techniques such as DHCA and low-flow bypass have
the absence of point-of-care testing devices; waiting for been considered major contributors to these sequelae [286,
the results of coagulation studies can only delay in treat- 369]. In addition, other factors associated with CPB, such as
ment and additional bleeding. In many cases, components the rate of cooling and rewarming, arterial blood gas man-
such as platelets, plasma, and cryoprecipitate or human agement strategy (alpha- versus pH-stat), and hematocrit lev-
fibrinogen concentrate are still used based on clinical judg- els during this period, also impact neurologic outcome [292,
ment. Products such as activated factor VII (factor VIIa) 298, 299, 370–372]. The neonate with CHD may have an
and prothrombin complex concentrates can be adminis- abnormal and, in many cases, immature central nervous sys-
tered in selected cases to manage perioperative surgical tem, potentially also increasing the risk of neurologic injury
coagulopathic bleeding [348, 349]. The use of these prod- [328, 373–376]. A younger gestational age has been associ-
ucts however has raised concerns of their potential pro- ated with worse neurodevelopmental outcomes after cardiac
thrombotic risk [350–352]. surgery during infancy [377]. Preoperative structural brain
abnormalities and abnormal cerebral blood flow are present Myocardial Effects
in neonates with severe CHD [378]. These neurologic abnor-
malities can be exacerbated by a concomitant genetic syn- An element of myocardial dysfunction after cardiac surgery
drome or chromosomal abnormality unrelated to the that requires CPB is present in most, if not all, neonates. The
cardiovascular pathology [379]. mechanisms appear to be related to ischemia-reperfusion
Fetuses with left-sided obstructive cardiac lesions have and the inflammatory response [394]. These alterations
abnormal cerebrovascular physiology, the brain being perfused affect the ability of the myocardium not only to contract
via retrograde flow through the ductus arteriosus with blood (systolic function) but also to relax (ventricular compliance
that has a less-than-usual oxygen content. This can affect brain or diastolic function). Thus, inotropes and vasoactive drugs
development. For example, microcephaly has been associated are commonly required. The requirement for these may
with a small Asc Ao [380, 381]. In infants with d-TGA, preop- increase in the first few hours postoperatively.
erative brain injury has been linked to preoperative balloon
atrial septostomy [382], although others dispute this associa-
tion [383, 384]. To confound matters further, there is the Renal and Gastrointestinal Effects
debated issue of the effects of anesthesia in the developing
brain as previously noted. The issue of neurologic morbidity in Several studies reported an 11% to 17% incidence of varying
this and other lesions is a complex one, with the evidence sug- degrees of acute kidney injury (AKI) in children undergoing
gesting that the etiology is likely multifactorial [385]. Recent CPB [395–397]. Major degrees of AKI portend a poor clinical
data that report a declining incidence of postoperative neonatal outcome [398]. The vulnerability of the neonate to AKI is well
brain injury in CHD within the context of higher postoperative known and is due to loss of autoregulation and ischemia [395,
blood pressures is reassuring as it suggests that modifiable 399]. Over the years, there has been a growing interest to eluci-
clinical targets may limit perioperative neurologic morbidity in date the risk factors for AKI in infants undergoing CPB. Five
neonates with complex CHD [386]. factors predict AKI including younger age, weight < 10 kg,
In addition to the previously discussed neuroprotective myocardial dysfunction, sepsis, and duration of CPB >90 min
strategies, other approaches have been explored in an effort [396]. Other studies have reported multiple perioperative risk
to limit neurologic morbidity after cardiac surgery [387]. factors (for acute kidney risk or injury, failure, and mortality in
These strategies include specific anesthetic regimens (e.g., children undergoing CPB) [400–402]. The perioperative use of
ketamine, dexmedetomidine), administration of drugs (e.g., milrinone, particularly in young infants, and furosemide inde-
erythropoietin, anti-inflammatory agents, free radical scav- pendently predicted poor renal outcomes. In recognition of the
engers, and neurotrophic factors), preconditioning (hypoxia- risk of AKI, peritoneal dialysis catheters are routinely placed at
ischemia and remote ischemia), and stem cell treatment some centers after separation from CPB. These catheters can
[388]. This field continues to evolve, with, as yet, no defini- be connected in a sterile manner to a bag and passively allowed
tive results that would merit a change in clinical practice. to drain or can be used for dialysis as needed for removal of
fluid or in the event of reduced renal function in the postopera-
tive period [403]. A randomized clinical trial that compared the
Pulmonary Effects use of furosemide and peritoneal dialysis concluded that PD
should be strongly considered among infants at high risk for
Lung injury in the neonate after CPB is manifested by postoperative acute kidney injury and fluid overload [404].
impaired pulmonary function characterized by arterial Postoperative gastrointestinal complications associated
hypoxemia, carbon dioxide retention, and inability to wean with CPB are relatively rare. They have been mostly attrib-
from ventilatory support. The insult likely is the result of uted to alterations in splanchnic blood flow and have been
ischemic-reperfusion injury and the inflammatory process. linked to high mortality rates in adults [405, 406]. Factors
Preexisting causes or other issues also contribute to postop- such as hemodynamic instability and the use of vasoactive
erative pulmonary dysfunction. Phrenic nerve injury lead- agents are believed to contribute, although the data are lim-
ing to diaphragmatic paralysis should be excluded by ited. In view of ductal dependency in many congenital
ultrasound or other types of screening. Additional factors lesions and the potential for pulmonary steal, it is not unrea-
possibly involved include atelectasis, pulmonary edema, sonable to consider the presence of this physiology as a
decreased functional residual capacity, altered total lung potential perioperative risk. CHD is a risk factor for necrotiz-
capacity, ventilation-perfusion mismatch, and increased ing enterocolitis in term infants [405, 407].
dead space [389, 390]. Given that pulmonary complications A study that quantified the serum transaminase levels as a
are one of the most frequent contributors of adverse periop- prognostic factor in children after cardiac surgery deter-
erative outcomes, several approaches that may moderate mined that increases in transaminases occur more frequently
pulmonary dysfunction (e.g., leukocyte-depleted lung than previously reported, more commonly in the setting of
reperfusion) have been explored with variable results right heart failure [408]. Significant increases in transami-
[391–393]. nases (alanine aminotransferase [ALT] and aspartate amino-
transferase [AST]) and lactate dehydrogenase (LDH) restrict pulmonary blood flow is to alleviate congestive symp-
correlated with decreased postoperative survival. toms and prevent the development of pulmonary hypertension
and eventual changes to the pulmonary vasculature.
Sometimes, the procedure is performed via a median sternot-
Cardiothoracic Surgery Without omy approach. The adequacy of the PAB can be assessed by
Cardiopulmonary Bypass in the Neonate direct measurement of the distal PA pressure or by estimation
of the band gradient by intraoperative echocardiography. A PA
In some cases, cardiac surgery can be undertaken without pressure between 25% and 30% of systemic values or peak
CPB. These interventions can be performed through a lateral PAB flow velocity near 3.5 m/s (estimated band gradient of
thoracotomy or median sternotomy incision. The most com- ~ 50 mmHg) is considered satisfactory. The systemic SaO2,
mon palliative operations are PAB and systemic to pulmonary PaO2, and ETCO2 are very helpful in guiding band adjust-
shunt placement. Corrective procedures that are performed ments. Tightening the band until ETCO2 just begins to decrease
through a thoracotomy include PDA ligation (discussed earlier and then loosening it slightly may reliably indicate an optimal
in this chapter), CoA repair, and vascular ring division. More band. It is advisable during banding to mimic conditions of
complex operations, either palliative or corrective, may also be room air or minimal inspired oxygen supplementation and
undertaken (e.g., unifocalization of aortopulmonary artery normocarbia. In most cases, a PAB improves the symptoms
collaterals). From an anesthetic standpoint, these cases require and allows for later staged palliation or corrective repair.
many of the same considerations as outlined above for proce-
dures requiring CPB, reliable vascular access and intraopera-
tive monitoring, as well as planning for postoperative care. ystemic to Pulmonary Artery Shunt
S
Placement
Pulmonary Artery Banding When pulmonary blood flow is inadequate or ductal depen-
dent, a procedure to increase pulmonary blood flow is indi-
A palliative approach to mechanically limit excess pulmonary cated. Creation of a systemic-to-PA shunt is usually performed
blood flow is to apply a PAB (Fig. 11.36). This intervention by placement of a graft between the innominate or subclavian
may be indicated for pulmonary over-circulation in the neo- artery and a branch PA (mB-T shunt; Fig. 11.37). In many
nate with single ventricle physiology, for lesions where the
anatomy precludes a definitive repair, or when delaying a cor-
rective procedure is beneficial. The goal of the surgery to
Fig. 11.36 Graphic representation of a pulmonary artery band Fig. 11.37 Graphic representation of modified Blalock-Taussig shunt
cases, a central shunt to the MPA may be preferred as this impact rSO2 as assessed by NIRS; thus, NIRS monitoring
encourages more uniform growth of the branch pulmonary has been recommended as a good clinical practice [410]. The
arteries. The surgical approach is by either a median sternot- need for inotropic support usually is established preopera-
omy or lateral thoracotomy, whereas other extracardiac tively based on the clinical status and echocardiographic
shunts in most cases require a sternotomy. Specific consider- assessment of LV systolic function. Continuing the infusion
ations include the selection of appropriate site(s) for monitor- of these drugs perioperatively is appropriate in most cases.
ing blood pressure and SpO2, as this is influenced by the site Ventilatory adjustments may be required during the dissec-
of the shunt placement, the need to continue PGE1 infusion tion phase, as the non-dependent lung is retracted by the sur-
intraoperatively, and the administration of low-dose heparin geon. Significant blood loss is possible [411]. The
during the intervention. The problems with this procedure are administration of low-dose heparin (100 units/kg) to obtain a
that the partially occluding clamp on the PA will further target ACT value near 200 s may be part of the center-specific
restrict pulmonary blood flow and that once the anastomosis protocol before applying the Ao cross-clamp. Mild hypother-
is commenced, the clamp cannot be removed until the anasto- mia [~34–35 °C] is a standard strategy at some centers for
mosis is completed. On rare occasions, it may be necessary to spinal cord protection due to the risk of ischemia; however,
administer inotropic agents to support the patient until the as previously stated, overt evidence of spinal cord injury in
clamps can be removed. It is important to ensure adequate this setting is extremely rare. Transient changes in blood
oxygenation well before clamp placement. In many instances pressure associated with application and removal of the Ao
there may be a need to increase the FiO2 during shunt place- clamp usually are managed by altering the anesthetic depth
ment. Occasionally the position of the clamps needs to be and augmenting intravascular volume and/or administering
modified to correct significant reductions in pulmonary blood calcium. Controlling the blood pressure is a key aspect of
flow. Before and after shunt placement, fluctuations in the postoperative management. Agents such as esmolol, nitro-
level of systemic SaO2 parallel changes in systemic arterial prusside, nicardipine, and others have all been utilized to
pressure as it represents the driving force at the Ao end of the control post-repair rebound hypertension. Adequate pain
ductus arteriosus (preoperatively) or shunt (postoperatively). control is an important aspect of the perioperative care in
It is important to confirm the expected changes at the time of these infants. Given the need for perioperative opioid-based
shunt unclamping, namely, an increase in SpO2 and a decrease analgesia and concomitant risks in the neonate, regional
in diastolic and, possibly, systolic blood pressures, in addition anesthesia techniques have been applied. For thoracotomy
to a widening of the pulse pressure. In rare cases, the decreased options include epidural, intercostal, paravertebral, and
diastolic pressure may adversely affect myocardial perfusion newer techniques such as erector spinae blocks [412].
leading to ventricular failure; this may require inotrope ther-
apy. After the intervention, if the shunt is too large, an impor-
tant concern may be successfully balancing the systemic and Vascular Ring Division
pulmonary circulations [409]. In some cases the shunt may
require banding. Vascular rings are anomalies of the great arteries/their
branches that can cause extrinsic compression of the tracheo-
bronchial tree and/or esophagus. The presentation usually is
Coarctation of the Aorta Repair that of airway or feeding difficulties. The most common ana-
tomic causes of a vascular ring are a double Ao arch (50–
CoA represents one of the most common congenital defects 60%) (Fig. 11.39) and a right Ao arch with retroesophageal
requiring intervention within the first few weeks of life left subclavian artery and left ligamentum arteriosum (12–
(Fig. 11.38a and b). The surgical approach to this lesion 25%, Fig. 11.40) [413, 414]. The evaluation of these anoma-
depends on the status of the Ao arch and associated pathol- lies frequently requires multimodality imaging [415]. A
ogy. These factors determine whether the repair is under- double Ao usually is an isolated anomaly not associated with
taken via a thoracotomy approach, usually as resection of the CHD. A report indicated that a right-sided Ao arch was domi-
diseased segment and end-to-end anastomosis (Fig. 11.38c– nant in 75% of cases and a left-sided Ao arch in 18%, and
f) or as a more complex procedure through a median ster- arches were of equal size in 7% [416]. Surgical treatment
notomy incision using CPB. The main considerations for consists of division of the non-dominant arch via thoracot-
providing care for the neonate during thoracotomy repair omy. The ligamentum arteriosum or any other constricting
include continuation of the PGE1 infusion (if ongoing), ade- bands are also released. Right Ao arch with retroesophageal
quate vascular access (may include central venous access left subclavian artery and intact ligamentum arteriosum is
depending on clinical status and institutional preference), more likely to be associated with CHD. The approach to this
and ready availability of blood products. A right radial arte- lesion varies, but division of the ligamentum arteriosum is the
rial line is preferred for arterial pressure monitoring. The Ao primary intervention. Passage of an esophageal stethoscope
clamp placement may compromise cerebral blood flow and or TEE probe can cause airway obstruction in these patients.
a b
c d
e f
Fig. 11.38 Panel a, chest computed tomography showing a discrete tation of coarctation of the aorta. Panels d–f, illustrations of the surgical
aortic coarctation (arrow). Panel b, three-dimensional reconstruction in technique for coarctation repair including clamp position (panel d),
the same neonate showing the region of stenosis immediately beyond the resection of diseased segment (panel e), and the end-to-end anastomosis
takeoff of an aberrant right subclavian artery. Panel c, graphic represen- (panel f). Reproduced with permission from Texas Children’s Hospital
RSA T LSA
RSA T LSA
RCA
LCA
RCA LCA
Lig Art
Lig Art
RPA
LPA RPA
LPA
AscAo AscAo
MPA MPA
DesAo
E E
Fig. 11.40 Graphic representation of a right aortic arch and aberrant sub-
Fig. 11.39 Graphic representation of a double aortic arch. Note the clavian artery creating a vascular ring. In this anomaly, a left ductus arte-
relationship of the right and left aortic arches around the trachea and riosus arises from a bulbous region at the base of the left subclavian artery
esophagus. Asc Ao ascending aorta, E esophagus, LCA left carotid (Kommerell diverticulum) and attaches to the left pulmonary artery. Asc
artery, LPA left pulmonary artery, LSA left subclavian artery, Lig Art Ao ascending aorta, Des Ao descending aorta, E esophagus, LCA left
ligamentum arteriosus, MPA main pulmonary artery, RCA right carotid carotid artery, LPA left pulmonary artery, LSA left subclavian artery, Lig
artery, RPA right pulmonary artery, RSA right subclavian artery, T Art ligamentum arteriosus, MPA main pulmonary artery, RCA right carotid
trachea artery, RPA right pulmonary artery, RSA right subclavian artery, T trachea
Vascular rings frequently are associated with tracheobron- untreatable/end stage for which the patient awaits heart
chomalacia and other abnormalities of the airway. Anesthetic transplantation. In most cases, there is acute or impending
care may be required for diagnostic evaluation as well as sur- total hemodynamic decompensation. When mechanical sup-
gical treatment. In some cases, a formal bronchoscopic exam- port is instituted before circulatory collapse occurs, the goal
ination is performed as part of the overall evaluation. The is to prevent irreversible end-organ damage. Indications for
airway should be assessed during spontaneous ventilation, mechanical circulatory support associated with cardiac sur-
examining the trachea for pulsatile compression(s). gery in the neonate are listed in Table 11.7. This therapy can
Recognizing that preexisting tracheobronchomalacia persists be applied in the preoperative, intraoperative, or postopera-
postoperatively, when it may influence patient management, tive period. Preoperatively, the indication for support usually
is also important. Regional anesthesia techniques may be is related to either the need for stabilization or due to circula-
beneficial for postoperative analgesia in these cases. tory compromise. In the intraoperative setting, the use of
mechanical support is more likely related to failure to wean
from CPB, which may be due to the effects of surgery,
echanical Circulatory Support in the Neonate
M bypass, and/or preoperative impairment of myocardial func-
with Congenital Heart Disease tion. This clinical problem is referred to as postcardiotomy
failure. More unusual in the intraoperative setting is the
Circulatory support may be required for cardiac or cardio- unanticipated need for acute circulatory support during pro-
pulmonary failure [417–420]. The history typically is that of cedures that do not require bypass. In the postoperative
a reversible cause of circulatory failure or a condition that is period, the indication usually is related to a low cardiac out-
Table 11.7 Indications for mechanical circulatory support in the neo- lem, the clinical situation, details of the anatomy (e.g., pres-
nate with congenital heart disease
ence of intracardiac shunts), and pulmonary function. Other
Stabilization prior to cardiac surgery or catheter-based intervention issues such as availability of equipment, training of person-
Inability to wean from cardiopulmonary bypass nel, familiarity among practitioners, and institutional prefer-
Postoperative low cardiac output state
ence also influence the selection of technology. Each support
Acute cardiopulmonary decompensation resulting from cardiac
surgery strategy has definitive benefits and limitations, which also
have an important impact on decision-making.
VAD is placed via a sternotomy; a temporary centrifugal
LVAD, for example, requires an inflow cannula in the LA
put state or cardiopulmonary arrest. Contraindications to and an outflow cannula in the Ao. The use of a long-term
supporting the circulation mechanically include multisystem LVAD in the neonate involves placing an inflow cannula in
organ dysfunction, sepsis, severe coagulopathy, neurologic the LV apex and an outflow cannula in the Asc Ao. At the
impairment, or intracranial hemorrhage. time of this writing, paracorporeal pulsatile devices, refer-
Mechanical support in the neonate can be performed ring to those placed outside the body, are the only option
using venoarterial ECMO or a ventricular assist device for long-term VAD support in the neonate, in contrast to
(VAD). These strategies vary somewhat in their abilities to intracorporeal or implantable devices available in older age
support body functions. ECMO provides isolated support of groups [426]. The Berlin Heart Excor Pediatric VAD®
the respiratory system or full cardiopulmonary support; in (Fig. 11.41) was the first device to become commercially
contrast, VAD only supports the circulation. The components available specifically for use in children [427]. This air-
of an ECMO circuit include a centrifugal or roller pump, hol- driven device is available in a variety of pump sizes includ-
low fiber membrane oxygenator, oxygen blender, pump con- ing one suitable for the newborn. Already in use in
sole, and heat exchanger. ECMO is the form of mechanical numerous countries for several years, this device was
circulatory support used most frequently in the neonate. This granted regulatory approval in the USA by the Food and
choice is due to the extensive clinical experience with the use Drug Administration for pediatric use as bridge to cardiac
of ECMO in patients with respiratory failure secondary to transplantation in the USA in 2011 [424, 428]. The device
meconium aspiration, persistent pulmonary hypertension, is beneficial to many neonates, infants, and small children
and congenital diaphragmatic hernia. ECMO also has been [429–431]. The MEDOS HIA® device is also a pneumatic
shown to be extremely valuable in the neonate suffering from paracorporeal VAD available in Europe for infants and chil-
a cardiopulmonary arrest, serving as rescue therapy [86, dren [432, 433]. It should be emphasized that while all
421]. This form of therapy, also referred to as extracorporeal these forms of support are lifesaving and offer the only
support during cardiopulmonary resuscitation (ECPR) or option for survival in many infants, they are associated with
ECMO during cardiac arrest or rapid response, led to an significant morbidity and mortality. Major complications
overall survival of 40% in almost 600 patients who received are hemorrhage, thromboembolism, and/or infection [434].
this therapy [421]. These can result in devastating consequences to the central
In the less likely case of the neonate with isolated ventricu- nervous system. Although good neurological outcomes
lar impairment and good pulmonary function, a VAD may be have been documented after mechanical circulatory sup-
a better option. In postcardiotomy heart failure, however, port, a number of questions, including long-term neurocog-
numerous considerations come into play. The presence of nitive outcomes and other important issues that impact
biventricular dysfunction, hypoxemia, and pulmonary hyper- quality of life, remain unanswered [435]. Therefore, the
tension, common findings in the neonate with CHD, favors deployment of these sophisticated circulatory support
the use of ECMO in this patient group. The mortality in pedi-
atric cardiac patients on ECMO remains substantial [422].
When ECMO is required, cannulation is performed either
peripherally, using the neck, or centrally, via a sternotomy.
Neck access to the central circulation is via the jugular vein
and carotid artery. When the sternum is open, cannulas are
placed in the RA and Ao, and left-sided ventricular decom-
pression is performed if needed. This is referred to as central
cannulation.
There are several different types of VADs that can support
the left, right, or both ventricles [423–425]. A biventricular
assist device (BIVAD), when necessary, is more likely to be
used in the older child. The selection of the form of support Fig. 11.41 Photograph depicts a Berlin Heart Excor Pediatric VAD®
depends on many factors, including the nature of the prob- left ventricular assist device in a neonate
modalities requires a careful risk-benefit assessment in rec- knowledge than just the technology (e.g., hardware, settings)
ognition of the associated significant potential complica- but also the physiologic aspects of the various circulatory
tions associated with these treatments. support modalities and anticoagulation algorithms that may
The choice of mechanical support depends on the antici- be in use [441]. This knowledge implies an understanding of
pated duration of therapy (short versus long term). Both how device parameters can be affected and what types of
ECMO and VAD are suitable support strategies in the short interventions may be indicated to address any unfavorable
term. This is the case when the goal is used as a bridge to hemodynamic effects. For example, an important issue in
immediate survival, to recovery, to decision-making, or to a these patients relates to factors that can influence LV preload
prolonged type of support (bridge to bridge). A greater and, consequently, filling of the device and stroke volume.
period of circulatory support as a bridge to transplantation Increases in pulmonary vascular tone or acute alterations in
requires a different hardware that allows for more patient RV function can be detrimental. Therefore, strategies that
mobility. Technological innovations over the years have maintain low pulmonary vascular resistance and promote RV
resulted in miniaturization of pumps and cannulas, render- performance are essential for successful management of
ing the use of specialized long-term VAD feasible in the these infants [442].
neonate [423, 436, 437].
Anesthetic care of the neonate who requires mechanical
support is greatly influenced by factors such as the neonate’s erioperative Issues and Some Special
P
clinical condition, situation, and the type of therapy being Considerations in the Neonate Undergoing
instituted. During an acute event when ECMO is being Cardiac Surgery
applied for immediate survival, management is similar to
that involving any cardiopulmonary resuscitation effort in There are special considerations related to individual cardiac
the neonate. Additional considerations include the underly- defects and the pathophysiology of the disease process,
ing structural cardiovascular abnormalities, need for antico- which present challenges in the care of the neonate with
agulation, and administration of volume/blood components heart disease. Some of these potential problems and their
as needed [438]. Vasodilators are required on occasion upon intraoperative considerations are addressed briefly below.
initiation of support in order to be able to deliver full flows,
particularly after vasoconstrictive agents have been adminis-
tered as part of the resuscitation effort. Although ECMO has Pulmonary Hypertension
been applied on a routine basis in neonates with HLHS after
the Norwood procedure to facilitate postoperative manage- Pulmonary hypertension in the neonatal period has different
ment in the past, it is not current practice [439]. etiologies including persistent pulmonary hypertension of
The use of short-term circulatory support for postcardi- the newborn (PPHN), lung disease such as bronchopulmo-
otomy failure usually follows a long operative procedure nary dysplasia, congenital anomalies including congenital
and several failed attempts at weaning from CPB. An diaphragmatic hernia, and CHD. Increased PA pressure is a
extended bypass period is invariably associated with prob- common feature in congenital cardiovascular diseases.
lems of bleeding, a heightened inflammatory response, Usually, it results from increased pulmonary blood flow that
potential pulmonary dysfunction, and many other distur- is caused by an unrestrictive direct communication between
bances that complicate management. The need for operative the atria, ventricles, and great arteries or an obstruction to
procedures such as mediastinal exploration for bleeding, pulmonary venous flow [443, 444]. Pulmonary arterial
adjustments of cannula position, or weaning of support hypertension develops over a variable period depending on
requires adequate planning, preparation, and communica- the extent to which pulmonary blood flow is increased and
tion among all team members. the level of the shunt. Lesions associated with excess pul-
Data regarding anesthetic care in children with long-term monary blood flow in the neonatal period or early infancy
devices are extremely limited. A study in children with a include a large PDA, VSD, complete atrioventricular septal
Berlin Heart, including infants undergoing anesthesia for defect, and over-circulated HLHS. Over time, high-flow
noncardiac procedures, demonstrated poor tolerance for lesions can remodel the pulmonary arterial smooth muscle
reductions in systemic vascular resistance due to the rela- and induce vascular changes. Defects such as TA and AP
tively fixed cardiac output of the device [440]. Preoperative window predispose to accelerated pulmonary vascular dis-
stability was not predictive of the intraoperative hemody- ease. Down syndrome is considered an independent risk fac-
namic course. The study recommended that volume and tor to develop pulmonary vascular disease [445].
alpha-agonists should be used to treat hypotension in this Perioperative management of infants with lesions that pre-
patient group. Lastly, caring for these infants involves greater dispose to excess pulmonary blood flow includes avoiding
maneuvers that decrease pulmonary vascular resistance so Systemic Hypotension

that left-to-right shunting does not increase and exacerbate
the increase in pulmonary blood flow. Pulmonary venous Intraoperative hypotension can be secondary to factors such
hypertension associated with pulmonary venous obstruc- as hypovolemia (due to fluid restriction, diuretic therapy, or
tion, LV failure, or left heart lesions that impede blood flow blood loss), the effects of sedatives/anesthetic agents, rhythm
results in reflex pulmonary arterial hypertension. It can be abnormalities, ventricular dysfunction, or mechanical influ-
secondary to defects such as TAPVR, mitral stenosis, cor ences of the surgical intervention. A helpful management
triatriatum, congenital pulmonary vein stenosis, and HLHS algorithm to determine the cause and initiate appropriate
with a restrictive atrial septum. Over time and depending on therapy is to consider the contributions of ventricular preload,
the degree of obstruction, the lungs become congested and contractility, afterload, and factors related to the physiology
pulmonary arterial hypertension develops. The benefits of of the defect, to the hemodynamic problem. In addition, the
early interventions in CHD are limitation of pulmonary electrocardiogram should be evaluated for evidence of rhythm
blood flow and repair of obstruction to pulmonary venous disturbances or myocardial ischemia. Treatment should focus
blood flow. The end result is a reduction in PA pressures and on the cause and consider whether it represents an unavoid-
in the likelihood of pulmonary vascular reactivity [446]. able transient occurrence related to the procedure itself or an
Reduced PA pressures and a low vascular resistance are event of more concern. If an acute intervention is necessary to
critically relevant in the infant with a single ventricle, as increase blood pressure, it can be accomplished by the admin-
they are prerequisites for future palliative strategies that rely istration of volume, calcium, a vasoconstrictor, or other phar-
on passive pulmonary blood flow. macologic agents while definitive therapy is instituted.
In the neonate, predisposing factors for a reactive pulmo-
nary vascular bed during the perioperative period include the
underlying increased pulmonary vascular tone, effects of Congestive Heart Failure
CPB, and physiologic consequences of the cardiac pathol-
ogy. In neonates with increased pulmonary blood flow or In the neonate, congestive heart failure is always biventricu-
obstruction to pulmonary venous return, the potential for lar, and failure of one ventricle compromises the action of the
pulmonary hypertension immediately after bypass and in the other. It can be caused by volume overload resulting from a
postoperatively setting should be recognized. Pulmonary physiologic left-to-right shunt, severe valvar regurgitation,
hypertensive crises result from acute increases in pulmonary obstructive pathology, and imbalance between the pulmonary
vascular tone, triggered by a variety of factors (Table 11.8). and systemic circulations favoring pulmonary blood flow.
Hemodynamic decompensation during these events is due to Heart failure is also present in conditions associated with
acute right heart failure, decreased LV preload related to poor myocardial contractility. Severe heart failure is a known
resistance to the egress of blood across the pulmonary bed, risk factor for perioperative complications in children [451].
and unfavorable leftward shift of the interventricular septum,
compromising LV filling and decreasing cardiac output.
Prevention and management of these crises include minimal Cyanosis
handling, sedation, and measures that favor a low pulmonary
vascular resistance [e.g., hyperventilation, hyperoxygen- Cyanosis related to CHD is the result of limited pulmonary
ation, and alkalosis] [447]. Treatment focuses on optimizing blood flow and/or intracardiac mixing. Delayed surgery, pal-
RV function using inotropic support as necessary [448]. liation, or staged correction of CHD is often associated with
Milrinone also can be quite helpful to decrease pulmonary some degree of cyanosis. In the neonate, the effects of cyano-
vascular tone and enhance RV function [449]. The use of sis may not be as pronounced as in older infants and children
selective pulmonary vasodilators such as inhaled nitric oxide with long-standing hypoxemia. Chronic hypoxemia affects
may also be indicated [449, 450]. all major organ systems and invokes compensatory mecha-
nisms to enhance systemic oxygen delivery. Despite the
Table 11.8 Factors that can increase pulmonary vascular tone favorable effects of these adaptive responses, they can also
Hypoxemia be detrimental due to increased blood viscosity, red cell
Hypercarbia sludging, and alterations in the coagulation system. Important
Acidemia perioperative considerations in cyanotic infants include the
Hypothermia need for adequate preoperative hydration (refer to the section
Atelectasis on fasting period) and meticulous care of venous lines in
Transmitted positive airway pressure order to avoid the potential risk of paradoxical embolization
Agitation, pain, stimulation, light anesthesia, stress response (discussion to follow).
Ventricular Pressure Overload leading to interstitial pulmonary edema and compressing

small airways. These alterations in lung mechanics increase
Outflow tract obstruction or increased PA pressure/vascular airway resistance and decrease lung compliance [452]. In
resistance imposes a pressure load on the ventricle, thereby addition to inadequate palliation or residual shunts and the
increasing the wall tension. Compensatory hypertrophy leads to effects of surgery, such alterations may further exacerbate
reduced ventricular compliance. This condition results in a vul- the already vulnerable respiratory status of the neonate [453].
nerability of the myocardial supply-and-demand relationship,
reduced tolerance for factors that can alter this fine balance, and
the potential increased risk of ischemia. Be aware that in some Systemic Air Embolization
defects, RV pressure can exceed the systemic values and nega-
tively impact LV function. The negative effect of the RV on the It is essential to appreciate that the presence of shunts or sim-
LV is explained by the direct mechanical interaction between ply a patent foramen ovale introduces the risk of a right-to-
the ventricles referred to as ventricular interdependence. left shunt and a paradoxical systemic air embolus in the
neonate. The risk is magnified by the increased right-sided
pressures or pulmonary vascular resistance associated with
Ventricular Volume Overload CHD. This risk mandates meticulous de-airing of all vascu-
lar lines and the use of in-line air filters where possible.
A volume load to the LV is characterized by increased LA
pressure, LV end-diastolic volume, and stroke volume. This
physiology is associated with LA and LV dilation and car- Conduction Disturbances and Arrhythmias
diomegaly. The dilated ventricle must generate a greater wall
tension to achieve the same intra-cavity pressure [Laplace Infants, particularly those with Down syndrome, can develop
Law]. This may precipitate ventricular failure. In the postop- bradycardia during induction of anesthesia in association
erative neonate, residual valvar regurgitation can be associ- with the administration of drugs (e.g., opioids) and at the
ated with altered loading conditions that, if significant, can time of laryngoscopy tracheal intubation or placement of a
cause congestive symptoms and ventricular dysfunction. TEE probe. Usually, bradycardia is self-limited and requires
Neonates with palliated single ventricles can be particularly no treatment; however, if it persists, the administration of
vulnerable to conditions associated with ventricular volume drugs such as atropine or glycopyrrolate or, less likely, a
overload (e.g., systemic-to-PA shunts). small dose of epinephrine if the slow heart rate results in
hemodynamic instability should be considered. Cardiac
arrhythmias are known to occur during placement of central
Myocardial Ischemia venous catheters. Usually, arrhythmias are transient and
require no intervention unless they persist, in which case
Anomalies associated with increased systolic and diastolic wall either pharmacologic treatment or cardioversion/defibrilla-
stress and those with decreased coronary perfusion secondary tion is indicated. Because arrhythmias may not be tolerated
to low diastolic pressures (e.g., PDA) may cause myocardial in the critically ill neonate, caution must be exercised to
ischemia in the neonate. Lesions such as anomalous origin of minimize stimulation of the heart during central catheter
the left coronary artery from the pulmonary artery (ALCAPA) placement by limiting the depth the catheter is inserted to the
and large coronary fistula(s) also have a propensity to develop SVC/IVC-RA junction.
myocardial ischemia. Although the clinical manifestations of
these anomalies usually become evident beyond the neonatal
period as pulmonary vascular resistance (ALCAPA) or RV Perioperative Stress Response
pressure (coronary fistula[s] to the RV) decrease, an element of
ischemia can be present in the neonate. For the neonate under- The typical physiologic response to painful stimuli in normal
going a surgical intervention for any type of CHD, the negative children consists of an increase in heart rate and blood pres-
effects of CPB, Ao cross-clamp, coronary manipulations, and sure and a transient decrease in PaO2. These normal responses
the procedure itself should also be considered as potential eti- however can be detrimental to infants with CHD. Tachycardia
ologies for myocardial ischemia. abbreviates the diastolic filling time, and hypertension
increases ventricular afterload, thereby decreasing stroke
volume. These responses reduce the ability of the neonate
Altered Respiratory Mechanics with CHD to offset the effect of perioperative stresses with
an increase in cardiac output.
Many congenital defects associated with increased pulmo- Several studies have highlighted adrenal insufficiency in
nary blood flow and vascular pressures increase LA pressure, neonates after CPB, as well as the role of corticosteroids in
treating it and reducing the prevalence of postsurgical low immediately available, (2) use agents with a direct action on
cardiac output [454, 455]. At the same time, data have shown the myocardium and vasculature, and (3) prepare for emer-
that reduced levels of cortisol in the immediate postoperative gent cardiac pacing. Several additional considerations are
period are not associated with worse outcomes, nor predic- important in the anesthetic care of the transplanted patient
tive of steroid responsiveness [456]. [468]. Immunosuppressant agents, which may need to be
Although the use of regional anesthesia in the neonate given during the perioperative period, may have secondary
undergoing major surgery is well documented as previously effects on various organ systems (particularly the heart, liver,
noted, with benefits that include blunting of the stress and kidney) and can interact with muscle relaxants. Other
response and pain control, the application of these tech- considerations include the potential need for “stress”-dose
niques during cardiac surgery remains the subject of debate corticosteroids (a controversial subject), the requirement for
[457–459]. In many cases, the need for postoperative seda- strict aseptic techniques, and the adequate preparation of
tion and mechanical ventilation that frequently includes the blood products (irradiated, leukocyte reduced, and cytomeg-
use of opioids has limited an interest in perioperative regional alovirus negative/safe).
techniques [460]. A meta-analysis that compared regional
and general anesthesia with general anesthesia plus systemic
analgesia for children undergoing cardiac surgery concluded Summary
that compared with systemic analgesia, regional techniques
decreased postoperative pain for up to 24 h postoperatively The last few decades have witnessed remarkable improve-
[461]. However, it was also noted that “currently there is no ments in outcomes of CHD in the neonate. However, despite
evidence that regional anesthesia for pediatric cardiac sur- advancements in many aspects of clinical care, neonates with
gery has any impact on major morbidity and mortality.” congenital cardiac malformations present ongoing challenges.
Given the paucity of data regarding increased benefits of The ability of the anesthesiologist to provide optimal care
regional anesthesia over standard management, and concerns depends heavily on an understanding of the structural abnor-
of complications after neuroaxial anesthesia, there continues malities, hemodynamic consequences of the defects, available
to be ongoing reluctance to adopt this approach. This percep- management strategies, and the impact of anesthetic/surgical
tion has persisted despite the lack of reported adverse events interventions on the physiology. Optimal management of the
or serious complications after regional analgesia, in children neonate with CHD is most likely to be achieved in specialized
with CHD. The use of regional techniques is more common centers that have a dedicated comprehensive multidisciplinary
during thoracic surgery [462]. team and a large volume of surgical cases [469]. The reader is
referred to a recent comprehensive publication by the Neonatal
Cardiac Care Collaborative in the form of a journal supple-
Post-cardiac Transplant Recipients ment addressing contemporary topics related to neonatal car-
diac care. This work represents a multisocietal effort to outline
Heart transplantation may be the only option for survival for clinical guidelines for the care of neonates requiring congeni-
some neonates with CHD that is not amenable to palliation tal heart surgery and further expands on many of the topics
or correction [463, 464]. In neonates, this is more likely to highlighted in this chapter [470].
occur in the case of severe cardiac dysfunction, high-risk
anatomy, or failed surgical intervention [465]. The use of
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ECMO for the Neonate
12
Omar Alibrahim and Christopher M. B. Heard
Introduction cerning including bleeding and thrombosis, which carries a

greater morbidity and mortality [7].
Extracorporeal membrane oxygenation (ECMO) or extracor- It is important to recognize that ECMO is a support
poreal life support (ECLS) has been utilized to support criti- modality and not a treatment. It provides caregivers the time
cally ill neonates, children, and adults for more than 45 years to perform diagnostic and therapeutic interventions to facili-
[1]. ECLS, which better describes this technology, is a modi- tate organ recovery while providing gas exchange and opti-
fied prolonged form of cardiopulmonary bypass (CBP) that mal tissue perfusion. ECMO is a complex, invasive, high-risk,
can be used in the intensive care unit to support patients with and costly technology; it is restricted to centers where suffi-
severe, but reversible, cardiopulmonary failure who are unre- cient experience, up-to-date knowledge, trained personnel,
sponsive to conventional treatment. ECMO removes carbon and advanced technology for the use of ECMO in neonates
dioxide (CO2) and adds oxygen (O2) from blood using an are available.
artificial lung (the oxygenator) by draining blood from the
venous system and returning it using a pump via an artery
(venoarterial [VA] ECMO) or a vein (venovenous [VV] Patient Selection
ECMO). The first successful neonatal ECMO was performed
by Dr. Robert Bartlett in 1975 in which he supported a 1-day- ECMO is used for term and near-term neonates with severe
old baby with severe hypoxic respiratory failure secondary respiratory and/or cardiac failure secondary to potentially
to meconium aspiration pneumonitis [2]. Earlier trials with reversible pathology that has failed conventional therapies.
ECMO support demonstrated improved survival in infants Centers differ in their criteria for eligibility for ECMO, but
with severe, but potentially reversible, respiratory failure many follow the ELSO guidelines [8]. Table 12.1 lists the
[3–6]. According to the July 2020 report of the extracorpo- indications and contraindications for neonatal ECMO. These
real life support organization (ELSO) registry, more than neonates present with inadequate tissue oxygen delivery
133,000 patients had been supported by ECMO, of which manifested by hemodynamic instability, lactic acidosis, and
more than 43,000 were neonates, with survival rates of 73% multiorgan dysfunction.
in the neonatal respiratory group. Many have severe hypoxic respiratory failure manifested
Despite significant improvements in ECMO equipment, by a PaO2 < 40 mmHg and an oxygenation index (OI)
monitoring, understanding of pathophysiology, and wide- exceeding 40 for >4 h, with or without hypercapnia. The
spread clinical experience, complication rates remain con- most common underlying etiologies are congenital diaphrag-
matic hernia (CDH), meconium aspiration syndrome (MAS),
sepsis, and primary pulmonary hypertension. Persistent pul-
monary hypertension whether primary or secondary increases
O. Alibrahim (*) the right ventricular (RV) afterload. resulting in RV systolic
Division of Pediatric Critical Care Medicine, Duke University and diastolic dysfunction with RV dilation, which in turn
Medical Center, Durham, NC, USA leads to RV failure, a leftward shift of the interventricular
septum resulting in left ventricular failure, poor cardiac out-
C. M. B. Heard put, and, if prolonged, biventricular heart failure [8–12].
Division of Pediatric Critical Care Medicine, Department of
As soon as a decision to institute ECMO has been con-
Pediatric Anesthesiology, Oishei Children’s Hospital, Jacobs
School of Medicine and Biomedical Sciences, University at firmed, a complete blood count, serum electrolytes, renal and
Buffalo, Buffalo, NY, USA liver function tests, coagulation profile, and chest and

440 O. Alibrahim and C. M. B. Heard
Table 12.1 Indications and contraindications of neonatal respiratory considered a relative contraindication for ECMO [17].
and cardiac ECMO Accordingly, we suggest that patients who received more
Inclusion criteria Exclusion criteria than 14 days of mechanical ventilation should be carefully
Severe respiratory failure Severe brain damage screened once ECMO is under consideration. Few condi-
Severe hypoxia with acute Significant intraventricular/ tions such as alveolar capillary dysplasia, severe pulmonary
decompensation intracranial hemorrhage
(PaO2 < 40 mmHg)
hypoplasia, and surfactant protein B deficiency may present
Inadequate DO2a Lethal chromosomal disorder or with severe hypoxic respiratory failure similar to more com-
anomalies mon reversible etiologies for respiratory ECMO. Neonates
Sustained elevation of OIa Irreversible organ damage (unless with these irreversible lung diseases may be placed on
(>40 for >4 h) plan for transplant, e.g., cardiac ECMO inadvertently before the diagnosis can be confirmed.
transplant)
Cardiac ECMO describes the need for VA ECMO for car-
Severe pulmonary Neck vessels are too small to
hypertension with or without cannulate (unless considered for diac and circulatory support. The number of neonatal cardiac
RV failure thoracic cannulation) ECMO cases in the ELSO registry has increased over the last
Congenital heart disease Gestational age less than 20 years [18, 19]. Neonates with congenital heart disease
34 weeks (CHD) may require ECMO support preoperatively to stabi-
Myocarditis/cardiomyopathy Weight less than 2 kg lize cardiac function, immediately postoperatively after fail-
Arrhythmias Uncontrolled bleeding, severe
ing to wean off CBP, or shortly after coming off CBP because
coagulopathy
of a persistent low cardiac output syndrome or arrhythmias
OI: Oxygenation index = FiO2 × mean airway pressure × 100)/PaO2
a
DO2: Tissue oxygen delivery [16]. Hypoplastic left heart syndrome represents the most
common CHD for which ECMO has been salutary.
Neonatal myocarditis is another possible indication for
abdominal radiographs should be obtained. Cranial ultra- ECMO support. However, diagnosing myocarditis in the
sound should be performed to establish a baseline view of neonate can be very difficult, with a prevalence that is not
the brain in the event an intraventricular hemorrhage occurs. well described. Acute fulminant myocarditis may present
An echocardiogram should also be undertaken to assess with cardiogenic shock, left ventricular failure, and arrhyth-
baseline cardiac structure and function to determine whether mias that require ECMO support as a bridge to recovery or
the neonate is eligible for EMCO and the mode of ECMO transplantation [16, 20].
support that is most appropriate.
Given the need for systemic anticoagulation during ECMO,
the risk of an intracranial hemorrhage (ICH), particularly in ECMO Circuit Components
neonates, is substantial in light of the developing coagulation
system and immature germinal matrix, particularly in prema- The major components of any ECMO circuit include the
ture neonates. This risk increases significantly with gestational cannulae, tubing, mechanical blood pump, and gas exchange
age < 34 weeks [8, 9]. An earlier study demonstrated reduced device (membrane oxygenator). ECMO circuit design differs
survival and a greater rate of ICH in neonates <34 weeks’ ges- among institutions to suit their needs and patients’ popula-
tation compared with term neonates (63% vs. 84%, p < 0.001, tions. In the last two decades, the safety and efficacy of
and 37% vs. 14%, P < 0.001, respectively) [13]. Recent stud- ECMO have undergone major advances as described below.
ies, however, reported improved survival and reduced morbid- ECMO pumps consist of two types: roller head (semioc-
ity in neonates <34 gestational age. It is reasonable to consider clusive) pumps and centrifugal pumps. Roller head pumps
ECMO as a possible option for premature neonates on a case- were the standard of care for many years until the middle of
by-case basis, once the risks have been identified and close the 2000s, at which time centrifugal pumps became more
monitoring is followed [14, 15]. popular with improvements and advances.
Neonates who are small for gestational age (< 2 kg) carry Roller head pumps have more limited use in neonates in
a greater risk of intracranial bleeding and mortality. Their some centers, as they present a smaller risk of hemolysis
neck vessels may be too small to fit standard ECMO cannu- compared with centrifugal pumps in neonates [1, 21, 22].
lae, although the neck vessels in neonates <2 kg have been The blood is pressed forward through the tubing, “the race-
cannulated successfully using thin-walled catheters or cen- way,” against a plate in the pump housing at two pressure
trally (transthoracic cannulation) by draining blood directly points while the pump is rotating. This provides continuous
from the right atrium (RA) (atrial appendage) and returning forward motion of the blood toward the oxygenator and then
it to the aortic arch [16]. back to the body. The venous blood that flows into the pump
Prolonged mechanical ventilation before commencing (preload) flows by gravity; hence, the neonate must be posi-
ECMO could suggest irreversible lung disease. In some tioned above (100–150 cmH2O) the pump and the bladder
institutions, mechanical ventilation for more than 14 days is reservoir to assure an efficient operation. Venous drainage
12 ECMO for the Neonate 441
slows in the presence of several factors including hypovole- although the longevity of these devices was limited to a few
mia, tamponade physiology (e.g., large pleural or pericardial hours. Plasma was known to leak into the gas phase causing
effusion/hemorrhage, pneumothorax), or kinked tubing on these devices to fail prematurely and suddenly, requiring
the venous side of the circuit (premembrane). As a result, the their urgent replacement.
pump will slow down or stop until the venous drainage is re- The present oxygenators (e.g., Quadrox-iD, Maquet,
established or the cause of the problem is corrected. Hirrlingen, Germany) have incorporated many of the advan-
Most of the present roller head pumps have servo- tages of earlier membrane oxygenators using polymethylpen-
regulation capabilities that allow the ECMO specialists to set tene (PMP) and polyurethane fibers. The PMP is a microporous
alarms to slow the pump flow when a threshold negative material that is very efficient for gas exchange over an
venous (access, premembrane) pressure is detected. This extended period (weeks and months). These devices are dura-
gives the specialist time to troubleshoot and address the ble and may attenuate the inflammatory response during the
problem without interrupting or stopping the pump flow. onset of ECMO. These devices have a low resistance to blood
In contrast, centrifugal pumps deliver flow using an flow, which makes them easy to prime, reducing the potential
afterload-dependent technique that utilizes rotatory forces for clot formations and early oxygenator failure. Contrary to
generated by a rotating impeller. Centrifugal pumps are non- previous designs, the new models are very efficient and dura-
occlusive. The newer pumps utilize magnetic levitation to ble [25]. Their rated flow (the volume of venous blood whose
suspend and spin the impeller. Their blood-handling quali- oxyhemoglobin saturation can be increased from 75% to 95%
ties have also improved, minimizing heat generation, hemo- in a given period) is substantial, at 7 L/min. In most cases, a
lysis, and air cavitation. Blood enters these pumps at the single oxygenator provides sufficient support for a child of
apex and is expelled at the base toward the membrane oxy- any size or age for the entire ECMO run.
genator. These pumps are easy to set up, have small priming Several types of vascular catheters (cannulae) are available
volumes, can trap air and debris within the vortex, and are for neonatal ECMO support. Single lumen cannulae with dif-
independent of gravity for a steady drainage of blood. These ferent sizes are available for VA ECMO for the right internal
pumps can be placed at any height relative to the patient, jugular vein (RIJV) and carotid artery access. They are avail-
which makes them suitable for transport. Despite these able in sizes from 8 to 14 Fr. These cannulae have wire-rein-
favorable characteristics, several reports showed that neo- forced bodies that are designed to keep patency and prevent
nates and young infants who are supported by centrifugal luminal occlusion. Venous cannulae have 3- to 4-centimeter-
pumps have increased morbidity, ECMO complications long multi-fenestrated flexible tips with side and end holes to
(e.g., hemolysis), and mortality [21–24]. Nonetheless, cen- augment venous drainage. In contrast, arterial-type cannulae
trifugal pumps can be safely used in neonates and infants have a single end hole for blood return via the aortic arch.
who require ECMO support. Arterial cannulae are also used for cephalic venous drainage
During ECMO, gas exchange occurs through the mem- (cephalad drainage) in VV-V ECMO [26].
brane oxygenator or artificial lung. There have been major Double-lumen catheters are used to access the RIJV for
advances and innovations in oxygenators over the last few VV ECMO. Blood is drained from both venae cavae to the
decades. Initially, the only membrane oxygenator was a flat, RA toward the tricuspid valve. Until recently, the OriGen
reinforced silicone membrane envelope that was wound in a (Austin, TX) dual-lumen cannula was the most common can-
spiral coil around a polycarbonate spool. A highly gas- nula used for VV ECMO support in neonates. However, pres-
permeable membrane separated the blood and gas compart- ently, this cannula is unavailable. Avalon Elite Bi-Caval
ments, with no direct blood-gas interface. Gas transfer dual-lumen catheters (Maquet, Hirrlingen, Germany) are not
occurred by molecular diffusion as it does in the human lung. very commonly used in neonatal VV ECMO due to the risk of
The design and quality of the silicone membrane oxygenator RA perforation and rupture [27, 28]. Recently, a newly
made it very effective for gas exchange. However, the com- designed Crescent™* RA jugular dual lumen catheter
pact design created a long blood path with high resistance, (Manufactured by MC3, Inc. Dexter, MI USA and exclu-
which proved difficult for priming and increased the risk of sively distributed by Medtronic) are becoming available in
clot formation. Additionally, a separate blood warmer (heat the market to use for neonatal VV ECMO support.
exchanger) was added to these ECMO circuits to warm up
the blood before it returned to the neonate. Silicone mem-
brane oxygenators are no longer available for clinical use. A Gas Exchange on ECMO
newer generation of devices, the hollow fiber oxygenators,
became available in the 2000s. These oxygenators consisted ECMO removes CO2 and adds O2 through an artificial lung
of microporous material where gas exchange occurs by bulk (the oxygenator) by draining blood from the venous system
gas transfer via a direct gas-to-blood interface. These devices through a cannula in the venae cavae and returning the bloods
proved easy to prime and exhibited efficient gas exchange, in the case of VA ECMO via the aorta through a cannula in
the common carotid artery or in the case of VV ECMO into that can be added to inlet blood, Hb, blood flow, surface area
the RA through a separate cannula or a separate lumen of the and oxygenator membrane permeability, and rated flow.
same cannula used for drainage (dual-lumen cannula) [9]. CO2 removal in the ECMO circuit depends on the oxy-
ECMO provides gas exchange via the oxygenator to per- genator membrane permeability, the membrane surface area,
mit caregivers time to confirm the underlying diagnosis and and mainly the oxygenator ventilation gas flow (the sweep
to institute treatment until the neonate recovers or the gas). The CO2 diffusion coefficient is at least six times
affected organ is replaced (e.g., cardiac transplant). This greater than that of O2, so even with a smaller gradient, CO2
technique minimizes the risk of iatrogenic lung injury from can be removed easily via the ECMO circuit. Increasing the
high-pressure ventilator settings and/or inotropic and vaso- sweep gas flow (analogous to adjusting the minute ventila-
pressors’ use. tion on a ventilator) and the total surface area of the oxygen-
The entirety of the gas exchange occurs in the oxygenator. ator in the ECMO circuit can selectively transfer more CO2,
The patient’s arterial oxygenation is an admixture of ECMO with less effect on O2 delivery [29].
blood and native venous blood. Gas exchange should not be The output of the ECMO circuit is determined by the
managed by adjusting the mechanical ventilator, as the lungs amount of venous blood that is withdrawn from the venous
are placed on rest settings oaor the trachea is extubated while reservoir. In roller head pumps, venous drainage is gravity-
on ECMO support. dependent, with the driving force being the difference in the
To understand ECMO and to manage patients on ECMO, height of the column of blood in the venous cannula and the
we must understand the kinetics of O2, its delivery, and O2 bladder. Several factors can affect venous drainage including
consumption. hypovolemia, kinking or constriction of the circuit lumen,
Oxygen delivery (DO2) is the amount of O2 delivered to clotting of the venous cannula, and patient’s tamponade
peripheral tissues each minute, which depends on the lungs, physiology (e.g., pneumothorax and pneumopericardium).
blood, and circulation. DO2 equals the O2 content (CaO2) In VA ECMO, DO2 is controlled by the combination of
times the cardiac output/index (DO2 = CaO2 × CI = 600 mL blood oxygenation in the oxygenator, the flow through the
O2/min/m2). CaO2, the amount of O2 carried by the hemoglo- circuit, O2 uptake through the native lung, and the cardiac
bin (Hb), is best represented by this equation: CaO2 = (1.36 output through the native heart (total DO2 = DO2 via ECMO
cc/gm × SaO2 × Hb g/dL) + (PaO2 × 0.003 ccO2/mmHg/dL), + DO2 via the native heart). When choosing the size of the
where SaO2 is the patient’s arterial saturation and PaO2 is the circuit and the extracorporeal flow, it is important to assume
arterial partial pressure of O2. O2 consumption (VO2) repre- that there will be a complete bypass of the native heart (i.e.,
sents the amount of O2 demand of the body and is deter- no gas exchange across the lungs and the native heart).
mined by tissue metabolism. O2 demand decreases with rest, During VA ECMO, some venous return enters the
sedation, muscle relaxation, and hypothermia and increases patient’s pulmonary circuit. In the diseased lung, this blood
with infection, fever, catecholamines, and muscle activity. will remain poorly oxygenated. As it admixes with the well-
The normal VO2 in neonates is 5–8 mL O2/kg/min, in chil- oxygenated blood from the ECMO circuit in the aortic arch,
dren 4–6 mL O2/kg/min, and in adults 3–5 mL O2/kg/min. arterial desaturation may occur. The blood that is in the LV
DO2 is three to five times greater than the VO2 with a large is identical to the blood in the RA, typically with a satura-
reserve in supply. Using the Fick principle, the amount of O2 tion of 75% and a PaO2 of 35 mmHg. The blood that emerges
absorbed during gas exchange is equal to the amount of O2 from the ECMO circuit is 100% saturated with a PaO2 of
consumed by peripheral tissues during metabolism regard- about 400–500 mmHg. So, the resulting PaO2 and CaO2 will
less of the status of pulmonary function. The VO2 reflects the reflect the relative amounts of the circuit and the native
metabolic demand, a variable that is independent of the O2 lung/heart flow.
supply. So, mild to moderate reduction in DO2 is well toler- In VA ECMO, an increase in systemic PaO2 may indicate
ated and does not compromise VO2. As DO2 decreases fur- improving lung function or decrease in native cardiac output
ther, the O2 extraction increases until it can no longer given the ECMO flow is constant. It may also reflect an
maintain the VO2. At this point, tissue hypoxia occurs lead- increase in ECMO flow with no change in lung and cardiac
ing to multiorgan failure and death. In VA ECMO, mixed function.
venous O2 saturation (SvO2) is an excellent indicator of ade- Increasing the FiO2 in the ECMO circuit may increase the
quate DO2, with a goal of achieving 65–80%. SvO2 is inter- saturation but only to a limited extent.
preted differently in VV ECMO as it indicates premembrane The VA ECMO pump creates a nonpulsatile flow. As
saturation as a monitor of recirculation, i.e., that portion of more blood is routed through the ECMO circuit, the sys-
oxygenated blood draining from the patient to the ECMO temic arterial pulse contour becomes flatter, and the pulse
circuit that was just delivered to the patient’s RA. pressure becomes narrower. If complete bypass is achieved,
The efficiency of oxygenating blood in the membrane the arterial contour will be flat, and the pulse pressure will be
lung depends on several factors including the amount of O2 <5 mmHg.
VA ECMO places the oxygenator in parallel with the cal technique is the most used method of cannulation.
native lungs and provides both cardiac and pulmonary sup- Initially, the infant is properly positioned by placing a small
port. In contrast, VV access places the oxygenator in series roll under the shoulders to extend the neck slightly with the
with the native lung and provides only pulmonary support. face turned to the left. An X-ray plate is placed under the
For full support, ECMO blood flow is about 80–100 mL/kg/ neck and chest if possible. After establishing intravenous
min. With that target flow in mind, cannula size selection is access, securing an endotracheal tube, and prepping the skin,
imperative to ensure successful ECMO support [10]. a sterile field is created. A transverse incision is made 1 cm
superior to the right clavicle, and the tissue plane between
the heads of the sternocleidomastoid muscle is dissected,
Modes of ECMO exposing the carotid sheath that contains that common
carotid artery and the vagus nerve. Care must be taken to
The primary modes of ECMO used in neonates are VA and avoid any irritation or damage to the vagus nerve while dis-
VV ECMO. In VA ECMO, blood is drained from the venous secting the artery. Intensivists should be aware that bradycar-
system, mainly the RA, to the ECMO circuit and returned to dia with hemodynamic instability can occur during
the arterial circulation via the aorta. In VV ECMO, blood is dissection, which can be prevented by infiltration with local
drained from the venous system, usually the venae cavae, anesthesia or by administering atropine. The RIJV is also
and returned to the venous system, via the RA [1, 29, 30]. identified at this time. The vessels are usually tied cranially
This commonly occurs with double-lumen 13 Fr and 16 Fr (distally), and a vascular clamp is applied proximally.
cannulae. Additional venous drainage can be obtained in VA Unfractionated heparin (UFH) (50–100 unit/kg) is given as a
and more commonly in VV ECMO using a cephalic drainage bolus a few minutes before creating the venotomy and arteri-
catheter [26]. otomy incisions. Each catheter is then advanced one at a
VA ECMO provides cardiac and pulmonary support, so it time. Care must be taken while advancing the catheters to
is suitable for cardiac failure, myocarditis, and postoperative avoid damaging or dissecting the vessels. The venous can-
congenital heart surgery. It is commonly used in neonates nula is advanced until the tip rests in the middle of the RA,
with CDH who require ECMO for severe pulmonary hyper- whereas the arterial cannula is advanced until the aortic arch
tension and/or RV failure. is reached. The arterial cannula can point toward the ascend-
VA ECMO provides several advantages including rapid ing aorta but must not encroach on the aortic valve. Accurate
stabilization and circulatory and cardiac support; however, it placement of the arterial cannula is critical as the coronary
requires ligation of the carotid artery, increases in left ven- arteries perfuse the myocardium via retrograde flow from the
tricular afterload, and increases in the risk of systemic emboli tip of the arterial cannula. The neonatal/pediatric VA ECMO
especially cerebral ischemic strokes. Alternately, VV ECMO cannulae are available in four sizes, from 8 to 14 Fr catheters.
maintains pulmonary blood flow with oxygenated blood, Venous cannulae have several side holes in addition to a dis-
which relaxes the pulmonary vasculature and decreases pul- tal drainage site (https://www.medtronic.com/content/dam/
monary vascular resistance, provides oxygenated blood to the medtronic-c om/products/cardiovascular/cannulae/docu-
coronary circulation and myocardium, and minimizes and ments/pediatric-cannula-catalog.pdf). These cannulae are
sometimes eliminates the risk of systemic embolization [1]. wire reinforced throughout, which reduces the risk the can-
nula will collapse or kink [1, 9, 10]. The femoral vessels are
not commonly cannulated in neonates or infants because
ECMO Management they are too small to support adequate gas exchange and cir-
culation, in addition to the risk of limb ischemia.
Cannulation and ECMO Initiation Transthoracic (central) cannulation is used after congeni-
tal heart surgery if the neonate fails to wean off CPB. The
A thoughtful cannulation strategy and optimal placement of ECMO circuit employs the preexisting cannulae used for
the cannulae are critical to ensuring successful ECMO sup- CPB. In general, central cannulation allows the use of larger
port for better patient outcomes and fewer complications. cannulae that are needed to provide larger than usual ECMO
Cannula selection depends on the mode of ECMO used (i.e., flow (e.g., 200 mL/kg/min) for complete cardiac support [16,
VA versus VV), patient size and age, and vessel size and 31–33]. It is not unusual to use a left atrial (LA) cannula on
patency. Cannulation methods vary from open surgical tech- the venous side of the circuit, thereby increasing the venous
nique to percutaneous approach depending on the patients’ drainage from the ECMO circuit. This vents the left side of
characteristics, mode of ECMO, and physician and institu- the heart to allow 100% bypass, giving the myocardium time
tional experience [31]. to recover after CPB or circulatory arrest without the need
In neonatal VA ECMO, direct (peripheral) cannulation of for LV to empty blood from the native pulmonary venous
the right common carotid artery and RIJV via an open surgi- return, bronchial veins, or thebesian venous drainage to the
LA [16]. This venting is important to prevent subendocardial the RA when the OriGen catheter (Austin, TX) or the
ischemia and pulmonary edema. Other techniques used, Crescent™* RA jugular dual lumen catheter (MC3 Dexter,
include septostomy, or inserting a superior pulmonary MI USA) are used or within the IVC when the Avalon Elite
venous cannula, a peripheral cannula through the atrial sep- Bi-Caval dual-lumen catheter (Maquet, Hirrlingen,
tum into the LA, or by placing a vent through the LV apex. Germany) is used. With the lack of availability of the OriGen
Short of septostomy, the other techniques are primarily in catheter and myocardial perforations associated with the use
older children and adults [16, 31]. of the 13 Fr Avalon Elite Bi-Caval dual-lumen catheter [28],
Recently, a few reported the use of central cannulation in many institutions are using VA ECMO support instead of VV
patients with severe refractory septic shock with promising ECMO for acute respiratory failure. Nonetheless, a few
results [34, 35]. ECMO centers continue to use the 13 Fr Avalon Elite
In neonatal VV ECMO, vessels may be cannulated Bi-Caval dual-lumen catheter for neonatal VV ECMO respi-
through a percutaneous Seldinger technique. This is best ratory support [37]. The Crescent™* RA jugular dual lumen
performed using ultrasound guidance to assure the optimal catheter (MC3 Dexter, MI USA) is a promising cannula to
size of the cannula and proper visualization of the vessel use for neonatal VV ECMO support.
before inserting the cannula. This commonly occurs when a
double-lumen 13 Fr and 16 Fr cannula is used. Additional
venous drainage can be obtained in VV ECMO using a nticoagulation and Homeostatic System
A
cephalic drainage catheter placed in a retrograde fashion via in Neonates
the RIJV (Fig. 12.1).
Venous cannulation in VV ECMO can also be achieved The extracorporeal circuit disrupts the normal balance of
through a semi-percutaneous approach using a modified coagulation and fibrinolysis by exposing large amounts of
Seldinger technique. This has been described by initially blood to non-endothelial surfaces. This leads to activation of
making a transverse incision 2 centimeters (cm) superior to coagulation, fibrinolysis, and acute inflammatory responses,
the right clavicle to expose the anterior surface of RIJV [36]. with the coagulation cascade shifting the hemostatic balance
Once the vessel is exposed, an angiocath is placed through to a hypercoagulable state, thus requiring systemic antico-
the skin 2 cm superior to the incision, the needle is intro- agulation [38–40].
duced into the vein using the Seldinger technique, a guide- Despite the improved technology, increasing clinical
wire is advanced, UFH bolus is given, the dilating catheter is practice and experience, and better monitoring, hemorrhagic
advanced, and, lastly, the double-lumen cannula is advanced and thrombotic events remain the most common causes of
over the guidewire into the RIJV with the tip resting within morbidity and mortality in neonates supported with
ECMO. The risk of hemostatic complications in neonates is
greater than that in older children and adults. This is related
to the developing hemostatic system and immature germinal
matrix, especially in premature neonates.
Although all components of the hemostatic system are
present at birth, important differences exist among neonates.
Platelets play a pivotal role in primary hemostasis. The plate-
let count and size do not differ in neonates compared with
adults, although the platelet response to agonists decreases in
neonates and tends to be hypoactive. However, neonates
have greater plasma concentrations of von Willebrand factor
(VWF), a greater hematocrit, and a greater percentage of
large VWF multimers, which adhere more to platelets [41].
All these elements may explain the shorter bleeding time in
neonates compared with older children and adults.
Secondary hemostasis consists of a series of interactions
of coagulation factors that lead to an insoluble fibrin clot.
The liver and endothelial cells of the fetus are responsible for
producing coagulation factors early in gestation with increas-
ing plasma levels by birth. Nonetheless, the plasma levels of
most of the procoagulant and anticoagulant factors are
Fig. 12.1 Double-lumen VV cannula with a cephalad cannula in a decreased at 50% of the levels in older children and adults.
neonate So, with this immature hemostasis system in neonates, ill-
nesses (e.g., sepsis) and other stresses, including exposure to assimilating all of this information, providers should understand
the ECMO circuit, may disrupt the hemostasis system lead- how to address any abnormal result and titrate the anticoagula-
ing to severe consumptive coagulopathy that triggers bleed- tion therapy to meet the desired targets [43–45].
ing and thrombosis [11]. Direct thrombin inhibitors (DTIs) have been increasingly
Intravenous continuous infusion of UFH is the present stan- used to anticoagulate on ECMO, especially adults and older
dard of care for anticoagulation in neonatal ECMO. Maintaining children. Their use in neonates is limited to rare occasions of
the patency of the ECMO circuit is critical to preventing both UFH resistance, allergy, or heparin-induced thrombocytope-
circuit and patient vascular thromboses [42]. nia (HIT). DTIs such as bivalirudin and argatroban bind both
UFH is a complex glycosaminoglycan that blocks clot the free circulating and fibrin-bound thrombin. They bind
formation by binding to antithrombin (AT), an endogenous directly to either the catalytic site or both the catalytic site and
anticoagulant produced by the liver, to inhibit factors Xa and exosite-1 on thrombin. Additionally, DTIs are independent of
IIa. Binding results in a conformational complex that AT, selectively binding to thrombin and not to other circulat-
increases the inhibitory activity of AT by more than 1000- ing plasma proteins, which make them more effective, with
fold, inactivating the free, unbound thrombin, thereby pre- consistent and predictable effects [39].
venting further clot formation.
At the time of ECMO cannulation, intravenous UFH (50–
100 units/kg) is given just a few minutes before placing the Mechanical Ventilator Management
cannulae in the vessel(s), followed by a continuous IV infusion
starting at 20–25 units/kg/h to continue the anticoagulation. In neonatal respiratory failure, ECMO supports gas exchange
The anticoagulation is closely monitored using the activated and provides the opportunity to minimize the risk of
clotting time (ACT), prothrombin time (PT), activated partial ventilator-induced lung injury. Despite the positive impact of
thromboplastin time (aPTT), fibrinogen levels, platelets, AT a protective and gentle lung ventilation strategy on survival
levels, and anti-factor Xa [39, 40]. The UFH infusion is adjusted in acute respiratory failure in neonates, children, and adults,
to maintain an appropriate level of anticoagulation. there is limited evidence to guide the ideal lung “rest”
ACT is a bedside, point-of-care test that measures the mechanical ventilation strategies in neonates while receiving
time for a sample of whole blood to clot when exposed to an ECMO support. Practice variations in the use of lung rest
activator such as kaolin or celite. The target range for antico- ventilator settings during ECMO for neonatal respiratory
agulation varies with the institution, the laboratory analyzer, failure vary widely [46–49].
activator used, and test indication. These devices need to be Conventional mechanical ventilation (CMV) is used in
calibrated frequently to avoid major discrepancies. The tar- the vast majority of neonatal ECMO with pressure control
get range for the ACT in neonates on ECMO varies from 180 mode being the most common mode [49].
to 200 s for older devices and 150 to 170 s for newer devices. Pressure control mode maintains plateau pressures ≤20
Thromboelastography (TEG) is one of the global assays cmH2O, thereby preventing large swings in PIP that may
of coagulation that measures the viscoelastic properties of occur while using a volume control mode. It also allows
blood and provides information on clot dynamics and fibri- serial monitoring of lung compliance and tidal volume dur-
nolysis. TEG can detect deficiencies in the hemostasis pro- ing lung recovery.
cess throughout the coagulation cascade with more Gentle ventilation or “rest ventilator” settings have been
information about initial clot formation, clot acceleration, widely adopted in many ECMO centers in recent years [47].
maximum clot strength, and fibrinolysis. TEG technology However, there is variability in mechanical ventilator prac-
and expertise are not widely available, and its value in moni- tices while on ECMO. Serial daily monitoring of plateau
toring anticoagulation in neonates on ECMO has neither pressure, compliance, and tidal volume may offer valuable
been studied nor established [38]. information. Generally, the approach consists of low ventila-
Despite a better understanding and more advanced monitor- tor rates, five to ten breaths per minute, moderate positive
ing of anticoagulation management in ECMO, a paucity of end expiratory pressure (PEEP), 4–12 cmH2O, and low peak
high-quality research and evidence on the most effective and inspiratory pressure (PIP) ≤ 20 cmH2O and FiO2 of 0.21–0.4
safest methods of anticoagulation in neonates persists. To man- [49]. Although the only randomized trial reported that a
age anticoagulation well, it is important to understand which PEEP of 12–14 cm H2O was favorable compared with a
aspect of the coagulation cascade each test analyses and the PEEP of only 4–6 cm H2O and decreased the duration of
threshold for abnormal values. This is in addition to understand- ECMO by an average of 34 h [50], neonatal critical care and
ing all details related to the patient clinical status including num- ECMO today differs significantly from 25 years ago when
ber of days on ECMO, presence of bleeding, clots in the ECMO the study was conducted in that VA ECMO was the main
circuit, hemoglobin levels, UFH dose and recent adjustments, mode of ECMO and mechanical ventilation equipment and
recent and upcoming procedures, and recent transfusions. After strategies differed.
High-frequency oscillatory ventilation (HFOV) is also Morphine is not as lipophilic as fentanyl and only 30–40%
used in neonatal ECMO. It is preferred in cases of severe air protein-bound [56]. The Vd of morphine is increased due to
leak syndrome, severe pulmonary edema, and pulmonary drug extraction during ECMO [57]. This may necessitate
hemorrhage. HFOV ventilation settings (amplitude and fre- larger initial doses of morphine after initiation of ECMO to
quency) should be set to minimum values. Similarly, lung achieve the desired level of analgesia and sedation. Morphine
rest strategies should be followed with a mean airway pres- may be preferable to fentanyl for analgesia in ECMO as the
sure ≤ 20 cmH2O and a maximum pressure of 25 cmH2O latter is more highly extracted by the ECMO circuit.
being implemented. It is uncommon to use HFOV during However, unlike fentanyl, morphine has active metabolites
ECMO support; its use could make it difficult to perform with prolonged half-lives, especially in neonates, which may
pulmonary toilet and assess tidal volumes and lung compli- make its use less predictable.
ance, in addition to the need for heavy sedation and neuro- Midazolam is highly lipophilic and highly protein-bound
muscular blockade. (97%). It is highly extracted by the ECMO circuit. Vd and
Continuous positive airway pressure (CPAP) with pres- CL of midazolam are greater during ECMO. Accordingly,
sure support (PS) is a modality that is presently more accept- the dose requirement for midazolam for sedation increases
able especially in awake patients with or without tracheostomy after the start of ECMO [58]. The use of a centrifugal pump,
but less in neonates and infants. In adults, CPAP can facili- circuit priming with albumin, and older used ECMO circuits
tate early extubation after ECMO course. reduce the extraction of midazolam by the ECMO circuit
[51, 59]. The dose of midazolam will have to be adjusted
throughout the ECMO period based on these factors.
Sedation and Analgesia Dexmedetomidine is used increasingly as an adjunct sed-
ative in pediatric and neonatal populations. Despite the lim-
Optimal sedation and analgesia during ECMO in neonates ited evidence, data suggest that dexmedetomidine is
remain unclear. Many studies have demonstrated the need to moderately extracted by the ECMO circuit, requiring larger
escalate sedation requirement during ECMO because of an doses to achieve therapeutic plasma concentrations in
increase in the volume of distribution, increased sequestra- patients supported by ECMO [60, 61].
tion of drugs in the ECMO circuit tubing and oxygenator,
and decreased metabolism. ECMO support can have a sub-
stantial impact on drug disposition, and dosing is likely dif- Fluid Management
ferent in children on ECMO. Dexmedetomidine, midazolam,
fentanyl, hydromorphone, morphine, and ketamine are the Maintaining a strict fluid balance in neonates supported on
most used sedatives in pediatric patients during ECMO. In ECMO is crucial. Fluid overload has been associated with
this section, we will discuss mainly fentanyl, morphine, and increased morbidity and mortality. It is not unusual to require
midazolam as they are the most studied sedatives for neo- a large volume of fluids at the initiation of ECMO because
nates and infants on ECMO. acute inflammation and capillary leak require large amounts
During ECMO, the volume of distribution (Vd) of all of colloid and crystalloid fluid resuscitation for the first
drugs is increased. The disposition of drugs during 24–48 h. Fluids should be infused with great care and aim for
ECMO depends on several factors including their lipo- dry weight once hemodynamic stability is achieved [62]. The
philicity and percentage of protein binding [51, 52]. The use of diuretics, concentrating medication infusions, and the
more lipophilic and the greater protein binding, the more early initiation of ultrafiltration and CRRT are useful maneu-
drug extraction occurs. Additionally, clearance (CL) is vers to remove fluids and reduce the duration of ECMO and
generally decreased, resulting from underlying renal the ICU length of stay [8, 63].
and/or hepatic dysfunction in children who require
ECMO. In aggregate, these factors require a significant Decannulation
increase in the dose of sedatives and analgesics used Decannulation is undertaken to separate the neonate from the
after initiation of ECMO that may require further adjust- ECMO circuit. It should be considered when the neonate’s
ment during ECMO as organs recover and CL of the underlying pathology has improved, lungs have been
medications increases. recruited, and only minimal ECMO flow is required to main-
Fentanyl is significantly extracted during ECMO because tain gas exchange and hemodynamic support. Decannulation
it is very lipophilic, is highly protein-bound (80–85%), and is typically performed in the ICU but can also be performed
has a strong affinity for the membrane oxygenator [53, 54]. in the OR [64]. A “trial off” ECMO is conducted once the
This translates into substantially larger doses with the onset criteria for improvement have been met. This entails separat-
of ECMO, an effect that is compounded by possible toler- ing the neonate functionally from the ECMO circuit by
ance to fentanyl [51, 55]. briefly clamping the draining and return tubing closer to the
patient and monitoring the gas exchange and hemodynamics ECMO, several factors may contribute to bleeding com-
without ECMO support while discontinuing flow from the plications including anticoagulation therapy, surgical
neonate to the circuit. This is typically performed in the case causes, and consumptive coagulopathy that is either
of VA ECMO patients from a few minutes to 30 min while related to the ECMO circuit or the patient’s underlying
sporadically maintaining patency of the cannulae. Once this disease [11].
is deemed to be successful, the ECMO support is resumed at Thrombosis and clots in the ECMO circuit (oxygenator,
minimal flow to maintain the integrity of the ECMO circuit bridge, bladder, hemofilter, or others) are the most common
while providing minimal or no support for the patient. It is mechanical complication for neonatal respiratory and car-
not uncommon to separate the oxygen source from the oxy- diac ECMO support. Thrombotic complications are defined
genator during that period. VV ECMO trialing off does not as those that result in mechanical failure such as thrombosis
require that the cannulae be clamped. This can be achieved in the circuit component (e.g., oxygenator). About 20% of
by reducing the ECMO flows and separating the oxygen patients require a circuit change or change of components
source from the oxygenator for 2–6 h or longer, the sweep due to thrombotic issues.
gas is turned off, and the oxygenator is capped, thereby elim- Other complications include cannula dysfunction, seizure
inating gas exchange across the oxygenator. This “trialing disorders, renal failure, and infection [67].
off” interval is deemed neonates is surgical site bleeding to
be successful if gas exchange is maintained during this
period. Echocardiography might be needed during these tri- Survival and Outcome
als if an assessment of myocardial function or RV pressure is
required to establish the patient’s readiness for Neonates on ECMO are at risk for several complications as
decannulation. mentioned earlier especially neurological injuries including
Communication among the multidisciplinary personnel is ICH, embolic strokes, and seizures. In addition to a greater
important. This includes the ECMO specialist, the intensive mortality in patients with these complications [9, 66, 67],
care physicians, nursing staff, respiratory therapist, the sur- previous studies reported major disabilities, including devel-
geon, and the OR staff [12]. Typically, neck vessels are opmental delay, cerebral palsy, and visual or hearing loss,
ligated distally; however, a few reported carotid artery repair among survivors [68].
safely after decannulation [65]. Based on the ELSO registry data, the overall survival to
hospital discharge is 73% for neonates treated with ECMO
for respiratory disease. However, the overall survival rate to
Complications decannulation from ECMO support is even greater, 83% [8].
The average ECMO run times have increased 33% during
Bleeding and thrombosis remain the most common compli- the last 15 years from 150 h in the 1990s to more than 200 h
cations of ECMO. Bleeding at the ECMO cannulation site, per ECMO run. This can be attributed to offering ECMO
surgical site bleeding, and ICH are the most common com- support to more complex critically ill patients with more
plications. The most common hemorrhagic event in neonates associated comorbidities. This has been born out in a recent
is surgical site bleeding (12.4% respiratory and 29.1% car- report in which neonatal ECMO for respiratory indications
diac), followed by cannula site bleeding (18.2% respiratory was reduced by one-third, whereas ECMO use for patients
and 10.7% cardiac) and lastly gastrointestinal (4.2% respira- with complex diagnoses such as CDH along with prolonged
tory and 1.1% cardiac). ELSO defines bleeding events as ECMO runs was increased, combined with significantly
those resulting in a transfusion of more than 20 mL/kg per decreased survival [69].
day or 3 units per day in either the gastrointestinal, pulmo-
nary, cerebral, peripheral/mediastinal cannulation site, or
surgical sites. nesthesia Considerations for a Surgical
A
ICH is the most devastating complication of ECMO Procedure on ECMO
and is associated with high mortality and morbidity [66].
Severe ICH is the most common cause of death in neona- Several issues should be considered by the anesthesiology
tal ECMO and is associated with poor outcomes in survi- team before commencing anesthesia/sedation for a neonate
vors. Pre-ECMO factors which may increase the risk for on ECMO [70]. The anesthesiologist should be aware of the
ICH include asphyxia, severe hypoxia, hyperventilation, patient’s medical status including the severity of the cardio-
hypoventilation, metabolic acidosis, multiorgan failure, respiratory conditions, the ECMO strategy, and procedure
sepsis, and hypotension [9, 18]. While neonates are on factors as outlined in Table 12.2.
Table 12.2 Anesthesia preparation for ECMO procedure nate’s circulation and anesthesia may be overwhelming.
Patient/ECMO parameters Before commencing a transport, a portable ECMO power
Indication for VA/VV ECMO supply such as a battery pack with hand cranking ability
Present ECMO parameters must be provided. All infusions should be reviewed and con-
Cardiac support/inotropes/vasopressors
solidated; only essential infusions and their pumps should be
Anticoagulation parameters and therapy
Sedatives and their dosing included in the transport. Each infusion line should be
Procedure labeled before banding the multiple lines together to pre-
Operative plan clude them from becoming entangled. Bulky equipment
Intraoperative anticoagulation plan including the ventilator/oxygenator, gas supply, and infusion
Intraoperative ventilation plan
pumps with battery supplies should be consolidated as much
Plan for transfer to operating room if indicated
ECMO, is decannulation with procedure anticipated?
as possible as it may present challenges passing through
Strategy to wean from ECMO doorways and into elevators. A care provider will be required
Parameters to initiate weaning and to abort weaning just to monitor the cannula positions and warn of and prevent
Post-ECMO anticoagulation strategy any potential accidental catheter movement or removal.
Post-ECMO ventilation strategy
onitoring During ECMO and Surgical

M
Intraoperative Conduct of Anesthesia Procedure
In most cases, sedation for ECMO is achieved using systemic Anesthesiology and/or the critical care team usually care for
opioids, in doses that may require adjustment during ECMO these patients during the critical period before commencing
if opioid tolerance develops. Tolerance may also apply to ECMO and during cannulation, surgical procedures, and
other commonly used ICU sedatives such as benzodiazepines decannulation. Invasive blood pressure should be monitored
and dexmedetomidine. Propofol may be used for both seda- during ECMO as well as during all surgical procedures while
tion and general anesthesia, although its high lipid solubility, the neonate is on ECMO.
substantial absorption by the ECMO circuit, and unpredict- Mean arterial pressure (MAP) should be maintained
able blood levels limit its appeal. Furthermore, propofol infu- within normal limits using either noninvasive or invasive
sion syndrome is a potentially fatal threat that is best avoided monitoring. Intraoperative hypotension may be corrected by
in neonates and infants, especially when associated with a increasing the ECMO flow in case of VA ECMO support, by
systemic inflammatory condition and prolonged propofol IV fluid administration, and/or by inotropic and vasopressor
infusions [71]. Inhalational agents such as isoflurane may support especially in cases of severe vasodilation/vasoplegia
also be used with specialized ICU ventilators (Maquet) to and low systemic vascular resistance (SVR) [73]. Even with
confer sedation or general anesthesia [72]. Neonates on high levels of VA ECMO support, there should be a degree of
ECMO are often paralyzed, not to improve ventilator compli- pulsatility if the patient’s myocardium is healthy and the LV
ance, but to avoid movement that could affect the position of is emptying its stroke volume via a normal aortic valve. If
the cannulae, thereby reducing venous return and/or obstruct- pulsatile flow is absent, then the LV may become overdis-
ing arterial outflow. If a procedure will be performed, then tended, leading to myocardial ischemia. Other causes of
paralysis or a deeper level of anesthesia may be required. decreased pulsatility include mechanical obstruction, severe
hypovolemia, right-sided heart failure, or arrhythmias.
Blood gas samples should be analyzed frequently during
ransfer of Neonates to the Operating
T ECMO and “on” pump procedures. In the case of VA ECMO,
Theater oxygen delivery is determined by several factors including
the membrane oxygenator function and ECMO flow rate and
In many circumstances, the operative procedure can be com- to a lesser extent the native lung function and ventilator set-
pleted in the PICU setting with the appropriate lighting, tings which would have a greater role in gas exchange during
operating room staff, and surgical equipment. However, if the lung recovery phase.
the neonate on ECMO must be transferred to the operating With the neck vessels cannulated, 50–80% of the total
room, this can provide some significant challenges in man- cardiac output is diverted to the ECMO circuit, while the
aging these patients. remainder passes through the neonate’s native heart and
The practical considerations for moving such a patient lung. The distribution of the blood flow depends on the
with precarious large-bore cannulae in the neck who amount of ECMO flow, cannula sizes, and native cardiac
depended on ECMO for gas exchange and circulatory stabil- function. ECMO blood that is returned to the neonate mixes
ity and possibly multiple infusion pumps to support the neo- with blood in the aorta.
With VV ECMO, the ECMO blood mixes with the sys- The neonate’s temperature should be monitored continu-
temic venous return in a phenomenon called recirculation. ously throughout the ECMO run. The ECMO circuit usu-
This is determined by the type of cannulation, position of the ally maintains the blood temperature at 37C using a water
cannula(e), cardiac function, and fluid status of the patient. bath heater. However, if the patient is decannulated, this
The percent of blood that is recirculated is acceptable if sys- benefit will be lost, and other strategies to maintain an
temic saturation exceeds 80%. The premembrane saturation acceptable core temperature must be used. This is espe-
is 10–20 percent less than the systemic saturation. As the lung cially important as hypothermia may worsen the coagula-
recovers, the systemic arterial saturation (SaO2) increases. tion status, leading to intraoperative bleeding. Urine output
Oxygen delivery (DO2) and oxygen content (CaO2) are is also a useful monitor of renal perfusion; however, if
more important parameters of oxygenation than simply the diuretics are used, the urine output cannot be used to moni-
SaO2. DO2 is the amount of oxygen delivered to peripheral tor renal function. As a result, urine output may depend
tissues each minute. It depends on the lungs, blood, and cir- more on the dose of the diuretic than on the blood volume/
culation, and it is the product of CaO2 and cardiac index (CI) fluid status. Also, some patients may require dialysis/ultra-
DO2 = CaO2 × CI = 600 mL O2/min/m2. Clinical indicators filtration to remove excess fluid. These patients may have
of adequate DO2 are important to monitor regularly. reduced native urine output during this treatment. Reducing
Appropriate neurological examination, organ recovery, the tissue edema is important to improve the conditions for sur-
absence of lactic acidosis, and an adequate urine output are gery and assist with weaning from the ventilator in the
markers of an adequate DO2 that providers can easily evalu- postoperative period. Serial monitoring of hemoglobin,
ate at the bedside. SvO2 can be very helpful when available blood gas analysis, coagulation status, and electrolytes is
to monitor DO2 and oxygen consumption status in VA important for several reasons. It is important to replace car-
ECMO. When the SvO2 exceeds 70%, it suggests an ade- diac protective electrolytes as needed and correct acid-base
quate DO2 given proper venous cannula placement and disturbances to optimize cardiac function. Also, monitoring
SaO2 > 90%. In VV ECMO, premembrane (venous) satura- the coagulation status is critical to minimize the risk of
tion is helpful to detect recirculation but cannot be used to intraoperative bleeding and to help to guide the need for
assess DO2 as it does in VA ECMO. blood transfusions during the procedure.
Central venous pressure (CVP) is another important mon- Table 12.3 summarizes some of the more common emer-
itor used during both VA and VV ECMO. A sudden increase gencies and clinical scenarios that may arise at the bedside of
in CVP could indicate an urgent process such as tension a child on EMCO, the clinical presentations, and proposed
pneumothorax and pericardial and pleural tamponade. management strategies.
Table 12.3 Troubleshooting common clinical problems and emergencies on VV and VA ECMO
VV ECMO VA ECMO
Problems Presentation Management Presentation Management
Pneumothorax, − Interruption of ECMO − IV fluid boluses − Interruption of ECMO − IV fluid boluses
large pleural venous drainage − Chest tube placement venous drainage − Chest tube placement
effusion, large − Worsening negative − Pericardial tube placement − Worsening negative − Pericardial tube
hemothorax, ECMO venous ECMO venous pressures placement
pericardial pressures
tamponade
Dehydration/ − Hypotension and − IV fluid replacement − Hypotension and − IV fluid replacement
over-diuresis tachycardia − Interruption tachycardia −
of ECMO venous Interruption of ECMO
drainage − Recirculation venous drainage
(small RA) − Narrow pulse pressure
Myocardial − Hypotension and − Inotropes and vasopressors − Narrowing pulse − Inotropes
dysfunction tachycardia − − Change to VA ECMO pressure − Increase ECMO flow
Narrowing pulse − Tachycardia (may be
pressure hypotension)
− Lactic acidosis
− Multiorgan failure
Ventricular − Cardiac arrest − CPR, PALS − Flat arterial line − Increase ECMO flow if
arrhythmias − Circulatory collapse − Change to VA ECMO waveform hypotension
(non-perfusing VT, − Slight decrease in blood − No chest compressions
VF) pressure − Anti-arrhythmic
medications (e.g.,
amiodarone)
(continued)
Table 12.3 (continued)
VV ECMO VA ECMO
Problems Presentation Management Presentation Management
Bleeding at − Hypotension and − Blood transfusion − Hypotension and − Blood transfusion
cannulation site tachycardia − Address surgical tachycardia − Address surgical
− Interruption of ECMO intervention for stopping the − Interruption of ECMO intervention for
venous drainage if bleed venous drainage if stopping the bleed
bleeding is significant − Proper correction of bleeding is significant − Proper correction of
thrombocytopenia and thrombocytopenia
coagulopathy
Thrombosis (clots − Other than visual − On venous side: no action is − Similar to VV ECMO − Immediate attention
in the oxygenator presence of clots in the required if the oxygenator is except for high risk of and plan to replace
and ECMO circuit) tubing and the working systemic embolization ECMO circuit if clots
oxygenator, usually no − On arterial side: may plan to and stroke if clots are on are on the arterial side
symptoms. May cause change the circuit if the arterial side
oxygenator failure (i.e., planning for a longer run on (post-pump) of the
patient hypoxemia) ECMO ECMO circuit
Pump failure Sudden loss of ECMO Manual (hand crank) operation Sudden loss of ECMO flow Manual (hand crank)
flow and support resulting of the ECMO pump until and support resulting in operation of the ECMO
in severe respiratory power restored or pump severe cardiorespiratory pump until power
insufficiency replaced insufficiency restored or pump
replaced
Extubation (loss of No change given ECMO − No action needed, may No change given ECMO − No action needed, may
airway), ventilator support is adequate choose to reintubate (not support is adequate choose to reintubate
failure. urgently) (not urgently)
− May need to increase − May need to increase
ECMO flow ECMO flow
Air trapped in the − Sudden stoppage of − Emergency: need to clamp − Sudden stoppage of − Emergency: need to
ECMO circuit ECMO pump ECMO circuit and plan for ECMO pump clamp ECMO circuit
− Risk of air embolism immediate de-airing of the − Risk of air embolism and plan for immediate
circuit or replace it de-airing of the circuit
or replace it
Circuit tubing − Sudden stoppage of −− Emergency: need to clamp − Sudden stoppage of − Emergency: need to
rupture ECMO pump ECMO circuit and plan for ECMO pump clamp ECMO circuit
− Circulatory collapse immediate reconnection at − Circulatory collapse and plan for immediate
rupture site or replace it reconnection at rupture
site or replace it
Hypoxemia Low SpO2 and PaO2 − I ncrease ECMO flow if Low SpO2 and PaO2 − Increase ECMO flow
needed. May consider adding − Check oxygenator
another venous cannula to function by checking
augment venous return post-oxygenator gasa
− Need to rule out recirculation:
if present, lower ECMO flow,
assure cannula position
(CXR, echocardiography),
and give IV fluid to increase
RA size and CVP
− Check oxygenator function
by checking post-oxygenator
gasa
Agitation − Tachycardia − Provide further sedation − Tachycardia − Provide further
− May interrupt ECMO − May interrupt ECMO sedation
flows and venous return flows and venous return
by creating significant by creating significant
intrathoracic negative intrathoracic negative
pressures when agitated pressures when agitated
Seizures − Tachycardia, altered − Long-term EEG − Tachycardia, altered − Long-term EEG
mental status − Anti-epileptic therapy mental status − Anti-epileptic therapy
− Convulsive movements − Convulsive movements
− Decrease in SvO2
saturation
a
Post-oxygenator gas: increasing the FiO2 in the ECMO circuit flowmeter to 100%; then, 15 min later, obtain a blood gas sample from the port
right after the oxygenator. A PaO2 in the range of 300–500 mmHg indicates a properly functioning oxygenator
CDH and ECMO Anticoagulation during ECMO for CDH is an important

aspect of the care especially if CDH repair is performed dur-
CDH, which occurs in about 1:2500 live births (see Chap. 9), ing the ECMO run. The inflammatory response triggered by
presents with pulmonary hypoplasia and a varying degree of ECMO also causes significant changes in the coagulation
pulmonary hypertension. After birth, severely affected neo- cascades resulting in the significant consumption of blood
nates are hypoxic and hypercarbic and have pulmonary products. Optimization of the AT activity is important for
hypertension that requires targeted ventilation strategies to effective heparin anticoagulation in ECMO patients. A
correct the hypoxia and hypercapnia using nitric oxide and review of AT use (target activity >65%) in CDH ECMO
pulmonary vasodilators to attenuate the pulmonary hyper- patients when compared with the institutions’ historical con-
tension. ECMO may be required to correct or attenuate trol demonstrated that when AT was maintained, the use of
hypoxia, acidosis, and complications related to barotrauma FFP, packed red cells, and platelets were significantly
and the inability to control the pulmonary vascular tone. reduced in the first 3 days of ECMO [78]. The use of large
ECMO corrects the inadequacy of ventilation while offering volumes of blood products may adversely affect lung
a period to rest the lung and offering further protection from mechanics and delay recovery.
barotrauma and a chance for the pulmonary hypertension to Pulmonary hypoplasia is the underlying cause of hypoxia
abate. Both VA and VV ECMO have been used to manage and hypercapnia that results in the need for ECMO support.
neonates effectively; cardiovascular support from VA Perfluorocarbons (PFC) have been used to support alveolar
ECMO may be needed especially if there are any questions maturation. In a prospective randomized study of CDH
regarding cardiac anomalies and function. patients on ECMO, the use of PFC was evaluated for lung
One of the most contentious issues is the timing of correc- growth using L1 vertebral body size for comparison [79].
tive surgery for CDH in neonates managed with ECMO: (1) After the PFC was instilled into the tracheal tube until a
after the ECMO run was complete or (2) during the ECMO meniscus could be seen and CPAP was maintained at 8 cm
run itself. Surgery performed during ECMO can be either H2O, the PFC was “topped off” as needed during the ECMO
early on after stabilization on ECMO or when the patient is run to maintain a visible meniscus in the tracheal tube. The
deemed ready for ECMO decannulation. A CDH repair on size of the left (affected) lung increased 130% during the use
ECMO ensures better management of the most common intra- of PFC, without side effects or other complications. However,
operative concerns, which are intraoperative oxygenation and the lung growth in the non-PFC group was not reported, and
ventilation, especially during thoracoscopic procedures [74]. the mortality was similar in both groups.
Reports are conflicting regarding which repair modality In severe CDH, every ventilator strategy is capable of caus-
offers a better outcome. Each of these approaches holds ben- ing barotrauma before ECMO support can be initiated, result-
efits and risks. In a review of over 600 cases from the CDHSG ing in pneumothoraces and further damage of the lung
registry [75] that were accumulated over 10 years, the out- parenchyma. The ex utero intrapartum treatment (EXIT) pro-
comes from surgery either during or after ECMO were more cedure has been used for specific neonatal conditions. For neo-
favorable if the repair had occurred post-ECMO. The better nates in whom ECMO is considered 100% likely, then an EXIT
outcomes were attributed to a reduced risk of bleeding as to ECMO management strategy provides maximal protection
well as a bias toward patients who have improved more rap- for the hypoplastic lung. In a small study that reported the
idly allowing for ECMO decannulation. However, their data EXIT to ECMO strategy for CDH patients with prenatal lung
failed to demonstrate whether the early/late timing of sur- volumes <15% predicted [80], there were no demonstrable
gery during ECMO was superior. benefits to using the EXIT procedure in terms of the mortality,
The ability to wean off ECMO within 2 weeks may con- complications, or duration of ECMO. The EXIT procedure is
tribute significantly to the outcome vis-a-vis the timing of no longer offered as an option now at that institution.
surgery [76]. If the patient was weaned off ECMO within
2 weeks, surgical correction post-ECMO was associated with
a significantly better outcome and a significantly reduced risk Trends in Neonatal ECMO: The Future
of bleeding when compared with patients at that institution
who were repaired on ECMO who were not able to be weaned ECMO continues to be an important supportive therapy for
off ECMO and had a “late” on ECMO CDH repair. neonates with severe cardiorespiratory failure that is unre-
Early repair on ECMO offers the benefit of surgery before sponsive to conventional therapies. Over the last 3 decades,
the anasarca becomes extensive and allows recovery from the use of neonatal respiratory ECMO has decreased
the physiologic insult while on ECMO, without prolonging because of advances in neonatal medicine including surfac-
the duration of ECMO. Early repair on ECMO demonstrated tant use, HFOV, and inhaled nitric oxide. At the same time,
that the risk of bleeding was <10%, and the operative repair the use of ECMO has increased for patients with more
took less than 2 h with a 70% survival rate [77]. complex diagnoses, and the duration of ECMO support has
also increased. A standardized evidence-based approach to 11. Van Ommen CH, Neunert CE, Chitlur MB. Neonatal ECMO. Front
managing anticoagulation in neonatal ECMO has not been Med. 2018;5:289.
12. Fletcher K, Chapman R, Keene S. An overview of medical ECMO
forthcoming. Nonetheless, the use of DTIs is an emerging for neonates. Semin Perinatol. 2018;42(2):68–79.
alternative to UFH, but more evidence and experience are 13. Hirschl RB, et al. The efficacy of extracorporeal life support
needed before these strategies become widely adopted. in premature and low birth weight newborns. J Pediatr Surg.
Pulmonary diseases continue to be the principal diagno- 1993;28(10):1336–41.
14. Wild KT, Hedrick HL, Rintoul NE. Reconsidering ECMO in pre-
ses for the use of neonatal ECMO support, with an overall mature neonates. Fetal Diagn Ther. 2020;47(12):927–32.
73% survival rate and up to one-third of cases due to CDH. 15. Delaplain PT, et al. Cannulating the contraindicated: effect of low
The future is full of potential advances in knowledge, tech- birth weight on mortality in neonates with congenital diaphrag-
nology, and expertise that will push neonatal ECMO bound- matic hernia on extracorporeal membrane oxygenation. J Pediatr
Surg. 2017;52(12):2018–25.
aries toward younger and younger neonates and increasingly 16. Roeleveld PP, Mendonca M. Neonatal cardiac ECMO in 2019 and
complex patients, with less ECMO-related complications and beyond. Front Pediatr. 2019;7:327.
improved overall survival and quality of life. 17. Domico MB, et al. The impact of mechanical ventilation time
before initiation of extracorporeal life support on survival in pediat-
ric respiratory failure: a review of the Extracorporeal Life Support
Registry. Pediatr Crit Care Med. 2012;13(1):16–21.
Conclusion 18. Mahmood B, Newton D, Pallotto EK. Current trends in neonatal
ECMO. Semin Perinatol. 2018;42(2):80–8.
ECMO is a life-saving support strategy that is offered to 19. Thiagarajan RR, et al. Extracorporeal life support organization reg-
istry international report 2016. ASAIO J. 2017;63(1):60–7.
increasingly complex neonatal patients with cardiorespira- 20. Xiong H, et al. Clinical outcomes in pediatric patients hospitalized
tory failure that is unresponsive to conventional therapies. with fulminant myocarditis requiring extracorporeal membrane
Bleeding and thrombosis are the most common complica- oxygenation: a meta-analysis. Pediatr Cardiol. 2017;38(2):209–14.
tions. Major advances in ECMO care have resulted in a safer 21. Barrett CS, et al. Outcomes of neonates undergoing extracorpo-
real membrane oxygenation support using centrifugal versus roller
practice with decreasing trends of mechanical complications. blood pumps. Ann Thorac Surg. 2012;94(5):1635–41.
CDH remains a major challenge in neonatal ECMO with 22. Lequier L, et al. Extracorporeal membrane oxygenation circuitry.
relatively high mortality throughout the years. Initiating Pediatr Crit Care Med. 2013;14(5 0 1):S7.
ECMO before the onset of severe hypoxemia, hypotension, 23. O’Halloran CP, Thiagarajan RR, Yarlagadda VV, et al. Outcomes of
infants supported with extracorporeal membrane oxygenation using
and acidosis may improve outcomes and reduce mortality centrifugal versus roller pumps: an analysis from the ELSO regis-
and long-term morbidity. try. Pediatr Crit Care Med. 2019;20(12):1177–84.
24. Dalton HJ, Hoskote A. There and back again: roller pumps versus
centrifugal technology in infants on extracorporeal membrane oxy-
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Anesthesia Outside the Operating
Room 13
Christopher M. B. Heard, Satyan Lakshminrusimha,
and Jerrold Lerman
Neonates Are Not Small Children preoxygenated for several minutes to prevent desatura-
tion while the airway is secured, although most neonates
In the same way children are not just small adults, neonates do not tolerate a face mask without objection. This prac-
(especially premature neonates) are not small children. There tice continues today. A 2008 survey of 247 anesthetists
are a number of unique physiological features in term and in the United Kingdom reported that 52% of respondents
premature neonates that hold great importance to the anes- delivered <40% oxygen during neonatal anesthesia
thesiologist. Some of these features are shown in Fig. 13.1 and < 16% delivered >40% oxygen [11]. Few anesthesi-
and described below: ologists administered 100% oxygen to neonates and pre-
mature infants [11]. However, 10% of the respondents
1. Oxygen toxicity: Human fetuses are hypoxemic with PO2 suggested that they do not make a conscious effort to
values ranging between 20 and 32 mmHg. The antioxi- avoid 100% oxygen during neonatal anesthesia even
dant mechanisms are not well developed in neonates [1], though this concentration is associated with pulmonary
and premature infants are even more susceptible to oxy- atelectasis. The potential risks of desaturation during
gen toxicity after exposure to excessive levels of oxygen anesthesia and concern over the need for a margin of
[2]. The associations between oxygen exposure and reti- safety in light of the evidence that the incidence of desat-
nopathy of prematurity (ROP) and bronchopulmonary uration including severe desaturation (<80%) increases
dysplasia (BPD) are well established [3–7]. Several ani- with decreasing age [12] have led to the use of 30–40%
mal and human studies have also reported increased pul- oxygen during neonatal anesthesia (in the absence of
monary arterial contractility [8], biochemical oxidative significant lung disease) to maintain a target preductal
stress [9], and increased risk of cancer [10] after even oxygen saturation (SaO2) of ~90% (see Chaps. 2 and
brief exposure to 100% oxygen in the delivery room at 17). The pulse oximeter should be sited on the right hand
birth. In the past, anesthesiologists routinely used 100% (preductal) to display the SaO2. SaO2 of 99–100% are
oxygen to ventilate the lungs of neonates with during often associated with supraphysiological PaO2 and
surgery to avoid hypoxia or due to a lack of the avail- potential toxicity to the retina and lungs in neonates and,
ability of air in the OR. Increased awareness of oxygen in particular, in very low birth weight (VLBW) infants.
toxicity has led to changes in this practice. In the OR, all SaO2 of 85–89% have been associated with an increased
neonates undergoing emergent surgery with a rapid mortality when compared with 91–95% in infants
sequence induction (RSI) to secure the airway are still <28 weeks’ gestation at birth, although this notion
remains contentious and unresolved (see Chaps. 2 and
17). SaO2 should be closely monitored during mechani-
C. M. B. Heard (*) cal ventilation of both premature and full-term neonates
Division of Pediatrics, Department of Anesthesiology, John under anesthesia with a target SaO2 range set to 90–93%,
R. Oishei Children’s Hospital, Buffalo, NY, USA to limit ROP and lung disease while avoiding a possible
S. Lakshminrusimha increase in mortality [5–7].
Division of Neonatology, Department of Pediatrics, UC Davis 2. Similarly, the use of 100% oxygen for transport from the
Children’s Hospital, Sacramento, CA, USA
NICU to the OR is also contentious. The use of 100%
oxygen delays the time to serious desaturation in both
J. Lerman
infants [13] and critically ill patients during transport
Department of Anesthesiology, John R. Oishei Children’s Hospital,
Buffalo, NY, USA [14]. This allows more time for corrective action before

456 C. M. B. Heard et al.
Fig. 13.1 Physiologic factors

2. Risk of IVH
in the full-term and premature
infants that can influence their
management during 3. Obligate
anesthesia and surgery. See nose
text for details breathing
1. Oxygen toxicity (ROP)
5. Uncuffed
endotracheal
tubes (risk of
4. Risk of fractures
leak around the
(osteopenia of
tube)
prematurity)
6. Tendency to 7. High PVR and

Collapse alveoli shunts at PDA and
(lung immaturity, PFO levels
surfactant deficency, 8. Hepatic enzyme
compliant chest wall) immaturity
10. Vascular access 9. Renal immaturity

(umbilical vessels)
12. Thin skin
(premature
infants)
HbF
Hemoglobin Saturation %
HbA
13. Hypothermia
11. Presence
of fetal hemo-
globin
PO2
cardiac and neurologic sequelae from hypoxia may risk of air trapping. The use of appropriate PEEP, low
occur. The practice of using 100% oxygen for high-risk rates, and prolonged expiratory times may be necessary
procedures balances the potential of a possible long- to optimize ventilation (see Chap. 6).
term risk of ROP and lung disease against the immediate 4. Respiratory control is immature in premature infants
potentially lifesaving benefits of delayed desaturation resulting in episodes of apnea and bradycardia. The risk
and cardiac arrest. of postoperative apnea (of prematurity) increases with
3. Lung development continues during fetal life with lim- infants of younger gestational and/or postconceptional
ited surfactant production until almost 34 weeks’ gesta- age and anemia [16].
tion [15]. The combination of a lack of surfactant and a 5. Premature and full-term neonates are considered obli-
compliant chest wall increases the risk that the small gate nose breathers, although they are capable of mouth
bronchioles will collapse during expiration. Positive breathing during nasal occlusion [17]. The shift to mouth
end-expiratory pressure (PEEP) is crucial during venti- breathing in response to nasal occlusion becomes more
lation in premature infants. Furthermore, if BPD is pres- automatic with advancing postconceptional age [18].
ent, airway resistance is increased leading to an increased Nonetheless, infants with choanal stenosis and atresia
13 Anesthesia Outside the Operating Room 457
and some craniofacial anomalies (e.g., Pierre Robin the lateral ventricles is prominent during early gestation
sequence, Crouzon syndrome) remain at risk for apnea. and involutes with advancing gestational age. Several
It is important to suction the nares and ensure the patency risk factors increase the risk of IVH including wide fluc-
of the nasal passages before extubating the trachea in tuations in PaCO2 or hypercapnia, rapid infusion of flu-
these infants. ids and sodium bicarbonate, and increases in intrathoracic
6. Uncuffed tracheal tubes (TTs) have been the standard pressure (e.g., as a result of pneumothorax) [30]. Studies
for premature and term neonates until recently. Issues in ELBW infants (<1000 g at birth) suggest that wide
associated with the use of uncuffed TTs during anesthe- fluctuation in PaCO2 (i.e., difference between maximum
sia include difficulties in maintaining targeted tidal vol- and minimum pCO2 > 42 mmHg) during the first 4 days
umes during mechanical ventilation (particularly in of life is an important risk factor for IVH [31]. Wide
infants with poorly compliant lungs), multiple tracheal swings in monitored variables should be avoided during
intubations to achieve a properly sized tube, and expira- anesthesia as well [32], although this presents a great
tory gas leak and OR pollution [19, 20]. Two manufac- challenge in infants with BPD.
turers presently supply small-diameter cuffed TTs: the 9. Immaturity of the hepatic enzyme systems increases the
Lo-Pro/Lo-Contour 3.0 mm internal diameter TT neonate’s risk for toxicity from medications [33].
(Mallinckrodt© USA) and the 3.0 mm Microcuff® TT Neonates receiving parenteral alimentation for pro-
(Kimberly Clark, USA). These TTs have similar outer longed periods are at risk for cholestatic liver disease
diameters as the comparable uncuffed TTs, although the [34] resulting in further compromise to hepatic
latter tubes are uniquely designed to include an elliptical- function.
shaped, more caudally placed, thin-walled cuff without a 10. Fetal accretion rates for calcium and phosphorus are
Murphy eye. Few studies have documented the safety large. Many growing premature infants cannot maintain
and long-term use of these TTs in premature and full- similar bone mineralization after birth because of low
term neonates [21]. A recent report cited three cases of calcium and phosphorus absorption from parenteral and
stridor in young infants whose weights were less than enteral nutrition [35]. In addition, many extremely pre-
those recommended for the 3.0 mm Microcuff® TT, mature infants receive medications such as diuretics,
3 kg, suggesting that even high-compliance cuffed TTs methylxanthines, and steroids that interfere with cal-
may cause stridor and possible airway trauma in prema- cium metabolism. These infants may develop osteopenia
ture neonates [22]. Conflicting retrospective data have of prematurity [36] and are susceptible to pathological
been reported: in one study of 324 neonates, post- fractures. The risk of osteopenia and fractures increases
extubation stridor occurred in 17.2% of those who had as gestational age decreases. These fractures can occur
the Microcuff® tube (compared with 7.5% with uncuffed during routine limb manipulations such as placement of
tubes) which logistic regression concluded that stridor an intravenous catheter. Anesthesiologists should be
after the cuffed tubes occurred with an adjusted odds aware of the existence of previous pathological fractures
ratio of 9.27 [23], whereas in a second retrospective and the present serum alkaline phosphatase levels [35,
study of 46 neonates with Microcuff® or uncuffed tubes, 37]. Alkaline phosphatase levels >750 IU/L may be
complications including stridor after extubation were associated with radiological features of osteopenia in
similar [24]. The use of cuffed TTs in premature and some premature infants. In the 1980s, the incidence of
full-term neonates <3 kg should only be undertaken with osteopenia was 50% in premature infants (<1000 g birth
great caution, pending further large-scale studies [25] weight). Fractures were detected in as many as 24% of
(see Chap. 5). these infants. With better nutrition, the incidence of
7. Premature and term infants may have increased osteopenia and fractures has decreased in recent years
PVR. When PVR increases as in the presence of hypoxia [35], although this problem persists.
or acidosis, right-to-left shunting of blood at the patent 11. Glomerular filtration rate (GFR) is reduced in premature
foramen ovale (PFO) or patent ductus arteriosus (PDA) and term neonates but improves postnatally reaching
may occur, resulting in cyanosis [26, 27]. Since the adult rates by 1–2 years of age [38]. The use of nephro-
pCO2 may directly increase the PVR, one strategy to toxic medications such as indomethacin and vancomy-
reduce the PVR is to reduce the pCO2. However, hypo- cin may compromise renal function in some cases
carbia from overventilation decreases cerebral perfusion requiring blood sampling to determine concentrations at
and may lead to periventricular leukomalacia (PVL) in increased intervals between doses.
premature infants [28]. 12. During the first few postnatal days, umbilical vessels
8. Intraventricular hemorrhage (IVH) is common in provide arterial and venous access to sick neonates.
extremely low birth weight (ELBW) premature infants Anesthesiologists should be familiar with the location of
[29]. Friable vasculature in the subependymal region of these lines (see below).
13. Term infants at birth have approximately 70% fetal

Table 13.1 Risks of transporting neonate
hemoglobin (HbF). HbF has increased affinity for oxy- Disrupting of stable ventilation parameters
gen resulting in a greater SaO2 compared with adult Loss of the airway or movement of the endotracheal tube
hemoglobin (HbA). For example, a pulse oximeter read- Loss of IV or central line access and interruption of infusions
ing of 90% is associated with a PaO2 close to 60 mmHg Hypothermia
with HbA but maybe as low as 50 mmHg in premature Requirement for four transfer episodes
infants with increased levels of HbF. Some infants Distance to operating room
Cardiovascular instability
receive multiple packed RBC transfusions, thereby
The postoperative patient is usually more fragile
increasing the HbA content. The oxygen dissociation
Difficulty in examining the neonate during transport
curve in such infants with multiple blood transfusions Incompatibility of monitoring systems between the NICU and the OR
resembles that of adults resulting in a reduced SaO2
(e.g., PaO2 of 50 mmHg will result in an SaO2 of 85% in
a baby that has received multiple transfusions). ture [42]. The neonate requires four transfers [43] during the
14. Premature infants have thin permeable skin and are
trip to the OR (NICU bed to the transport incubator, incuba-
prone to increased heat and water loss by evaporation tor to the OR table, OR table back to the transport incubator,
during the first few days of life (see Chap. 8). This thin and lastly from the incubator back to the NICU bed). The
fragile skin is vulnerable to accidental loss from peeling risks are increased with the distance to be traveled and the
adhesive tape. need to use an elevator [42]. In a report of neonatal surgical
15. The ratio of surface area to body weight in neonates practices from the United Kingdom in 2005 [44], more than
exceeds that in adults. As a consequence, the neonate is one-third of the transports to the OR involve transfer to a
at increased risk for heat loss by radiation (39%), con- separate building from the NICU, whereas only 3% of the
vection (34%), evaporation (24%), and conduction (3%) responders provide anesthesia for surgical procedures in the
[39] (see Fig. 8.6). NICU. Furthermore, the neonate is difficult to observe dur-
ing the transport. Monitors during the transport often suffer
During surgery, appropriate measures to maintain thermal from interference or movement artifact rendering the mea-
homeostasis must be used including a servo-controlled or surements unreliable, and the frequency of false alarms may
thermal-neutral incubator during transport to the suite in mask true critical events. This, along with the fact that it is
which the procedure/investigation takes place, increasing the more difficult to clinically assess the neonate in the closed
OR temperature before the neonate arrives, using an over- incubator, may cause a delay in the diagnosis and manage-
head heat lamp, a thermal mattress, and a forced-air warmer. ment of complications such as hypoxia, bleeding, pneumo-
Some or all of these devices may not be MRI compatible and thorax, and cardiac arrest.
cannot be used in that environment. The skin should remain When transporting the neonate, ventilation is usually
dry, and contact with wet linens should be avoided to prevent manually performed. If a self-inflating resuscitation bag sys-
heat loss. Direct contact with the heating sources must also tem or T-piece (Mapleson C or F) resuscitator is used, acci-
be avoided to minimize the risk of skin injury. dental extubation may not be detected as the change in
compliance may be difficult to detect [45] and the resuscita-
tion bag automatically reinflates even with a large leak. A
Benefits of Performing Surgery in the NICU Mapleson type C anesthesia circuit will not reinflate fully
without adjustment of the expiratory valve, and the change in
The most common reason for performing surgery in the compliance due to esophageal, pharyngeal TT placement
NICU is to avoid comorbidities that may occur during trans- will be more easily felt. Capnography may facilitate early
port of the critically ill neonate to another unit, such as the detection of extubation, but it is infrequently included in the
OR. There are several potential risks associated with trans- transport monitors.
porting these infants (Table 13.1) [40]. The transport may Hypothermia is more common after a procedure in the OR
require a change in the mode of ventilation [41]. Transporting than in the NICU [46, 47]. In a comparison of 80 infants
a neonate whose lungs are ventilated with a high-frequency undergoing laparotomy or diaphragmatic hernia repair, the
oscillatory ventilator (HFOV) or high-frequency jet ventila- core temperature decreased by 2.2 °C in those who underwent
tor (HFJV) is difficult and very challenging. Often, the lungs surgery in the OR compared with 0.6 °C in those who under-
must be ventilated manually during transport and HFOV went surgery in the NICU [48]. Extreme hypothermia (30 °C)
reinstituted only upon arrival in the OR. The transport incu- has also been reported in neonates after surgery in the OR
bator should be designed to maintain the neonate’s tempera- [41]. The risk of extreme hypothermia (<33 °C) is more com-
mon in VLBW neonates <1500 g. Strategies to reduce periop- Logistics of Performing Surgery in the NICU
erative hypothermia during transport to and from the OR and
during surgery have been the focus of quality improvement In order to provide anesthesia and perform operative proce-
projects in many institutions with salutary results [49]. dures in the NICU, several logistic considerations need to
Interestingly, there are also reports of hyperthermia be appreciated (Table 13.3). Consent must be obtained for
(>37.5 °C) in neonates who underwent surgery in the OR the anesthetic and surgery from the parents or guardians. A
[26, 49]. Hyperthermia in the perioperative period should be thorough discussion of risks and benefits of anesthesia and
eschewed. Hyperthermia in the immediate postnatal period surgery in very unstable infants must be completed in
in infants with hypoxic–ischemic encephalopathy has been advance, in order to prepare for all possible options that
associated with worse outcomes [50]. Perioperative hyper- may ensue including the need for changes in ventilation,
thermia and transfusions in healthy neonates and infants blood transfusion, and cardiopulmonary resuscitation.
<6 months are associated with similar increases in the odds Although parents may be present at the infant’s bedside
ratios for surgical site infections (~3.7) in the first 30 postop-
during routine care, we do not allow parents to be present
erative days [51]. during surgery in the NICU.
The surgeon and surgical team require a complete sterile
surgical equipment tray, gowns, gloves, and masks.
Patient Indications for Surgery in the NICU Appropriate surgical lighting must also be available, includ-
ing portable overhead lights as well as surgical optical head-
There are several patient indications for performing surgery lights and light sources [53]. Appropriate suction and
in the NICU (Table 13.2). Neonates who are too unstable to cautery equipment must also be available. A full array of
transfer either within the hospital or between hospitals and surgical instruments must be immediately available in the
those in whom the risk of mortality is very high with or with- NICU in the event additional instruments are unexpectedly
out the operative procedure (ASA class 5) are good candi- required urgently.
dates to undergo surgery in the NICU. Performing surgery in The anesthesiologist requires access to pharmacological,
VLBW neonates <1500 g in the NICU has resulted in more airway, and fluid supplies. An anesthetic workstation is usu-
stable clinical situation with less disruption of physiologic ally neither available in the NICU nor required as inhala-
parameters [41]. Transporting neonates who require high- tional anesthetics are infrequently used for several reasons
frequency (HFJV or HFOV) ventilation is difficult, requiring including the absence of waste gas scavenging in the
the presence of a respiratory therapist and neonatologist in NICU. As a result, anesthesia in the NICU is usually a total
the OR for the duration of the surgery to assist with the ven- intravenous technique that consists of intermittent boluses of
tilation management as well as the transport back to the opioids and muscle relaxants. Infusion pumps are generally
NICU. However, there is insufficient evidence to suggest that not used unless inotropes are required. Most monitors that
specialized neonatal transport teams impact perioperative are required are present in the NICU, although they may be
morbidity and mortality [52]. Furthermore, the anesthesia difficult to access. One monitor that historically has been
workstation ventilator may be incapable of ventilating the absent in the NICU is a capnogram. Many NICUs are now
neonate’s lungs with the same mode and parameters as were routinely using end-tidal CO2 monitors, especially in VLBW
used with the NICU ventilator. In the latter instances, respi- infants, although modern transcutaneous CO2 (TCCO2) mon-
ratory therapy could provide an appropriate ventilator for the itoring responds more rapidly and is more reliable than was
neonate in the OR. Additionally, when emergent surgery is reported previously (see below). If a capnogram is not pres-
required and the OR is fully occupied, the surgery can be ent, a portable capnogram may be brought from the OR,
performed in the NICU without delay, assuming OR person- unless the neonate is ventilated with HFO, in which case the
nel is available. capnogram will be of limited value. A fluid warming device
Table 13.2 Indications for neonatal surgery in the NICU

Too unstable for transfer Table 13.3 Logistics of performing operative procedure in the NICU
Weight <1000 g or <1500 g Availability of surgical equipment and lighting
High-frequency oscillatory ventilation Availability of anesthesia equipment
Jet ventilation Location for operative procedure
Inhaled nitric oxide Consideration for other NICU patients
Complex conventional ventilatory requirements Infection control
Surgical team willing to do “out-of-OR surgery” Communication
Emergency procedure and delay in the OR Team concept
is recommended if large volumes of fluids or blood are for ventilation management in both locations. The incidence
required. Emergency equipment should also be available in of hypothermia was reduced fivefold. Also, routine NICU
the NICU including a resuscitation cart. care for other patients as well as family access to the patient’s
TCCO2 is a commonly used monitor in the NICU, whereas room was unaffected. After the operative procedure, the neo-
in the OR end-tidal CO2 monitoring (ETCO2) is the standard nates remained in the NICU procedure room until they were
monitor to assess the adequacy of ventilation. In neonates, stable, managed by their regular bedside nurse and physician
ETCO2 may not be accurate due to the large sampling flow team, before being transferred back to the regular bed loca-
rates, rapid respiratory rates, and circuit dead space. tion. This arrangement may offer the best of both worlds but
Moreover, when HFOV or jet ventilation is used in the does require significant capital and operational investment.
NICU, ETCO2 is simply impossible. In a comparison of Good communication among the NICU and the OR staff, the
ETCO2 and TCCO2 in neonates and infants <10 kg to the surgical team, and the anesthesiologist is very important.
venous CO2 as the gold standard, a Bland–Altman analysis Moreover, establishing a close liaison with the NICU bedside
demonstrated that ETCO2 underestimated PvCO2 [54, 55]. nurse before anesthesia and surgery commence is very helpful
This underestimation was much more apparent in NICU neo- to ensure that the latest laboratory values are available and
nates (ETCO2 about −30 mmHg PvCO2) than in healthy OR within acceptable limits, that intravenous and intra- arterial
neonates (ETCO2 about −10 mmHg PvCO2). This significant accesses are available at a distance from the neonate, and that
bias in the NICU may be due to the increased ventilation set- blood products are available if deemed necessary. Since anes-
tings required in these critically ill patients. These studies thesiologists have a limited knowledge of the layout of the
suggested that the TCCO2 may be a more accurate assess- NICU, it is imperative that the bedside nurse is available to pro-
ment of the respiratory status of critically ill neonates and it vide syringes, needles, and other supplies during the surgery.
may be helpful even during surgery involving conventional For sites where anesthesia does not customarily provide
ventilation modes. However, if the ETCO2 is available, it general anesthesia, we always include a portable anesthesia
should be used as it will detect events such as accidental equipment cart that is stocked with a full complement of air-
extubation or tube occlusion episodes more rapidly than way supplies, noncontrolled medications, and IV equipment
TCCO2 [56]. If TCCO2 monitoring is used, attention should that may be needed during the procedure. Securing the air-
be paid to frequently calibrate the sensors and to carefully way with a TT before the surgery whether in the NICU or
monitor the skin site for burns. The sensors should be repo- OR is mandatory. In most instances, direct laryngoscopy
sitioned in extremely preterm infants as their fragile skin is with the Miller 0 or 1 blade is effective [58, 59], although
more likely to break down than that of older neonates. backup equipment in the form of a videolaryngoscope is
When surgery is performed in the NICU, it occurs at the essential should a difficult airway be encountered. Both the
neonate’s bedside location. Before surgery, all visitors and C-MAC Miller and the Glidescope video laryngoscopes
nonessential staff are cleared from the procedure area before have been used successfully in neonates [60–62]. The
the OR staff arrive. This should limit the risk of airborne C-MAC video laryngoscope with a Miller 0 blade has
contamination and microbial shedding resulting in infec- recently been shown to be safe and effective for tracheal
tions. The use of barriers will also discourage inadvertent intubation in both premature and ex-premature infants in a
access to the operative procedure by unauthorized persons. small sample [63]. Apart from its use to improve proctoring
Many new neonatal units have single-patient room design to and teaching, there is no evidence that videolaryngoscopy is
address these concerns. Space constraint may necessitate superior to direct laryngoscopy in trainees performing tra-
transfer to a larger room. Some NICUs have a fully equipped cheal intubation in neonates [64]. Access to such equipment
procedure room with a high airflow exchange or a “twin should be readily available for both anticipated and unantici-
room” with a larger area that may be used in the NICU unit. pated airway situations [65, 66].
In this case, the infant is transferred to the procedure room, Similarly, the presence of the neonatologist at the bedside
which is usually a short distance away, while being accom- is extremely important in order to ensure that changes in
panied by the NICU support staff. management strategies of the neonate, such as ventilation
A study compared outcomes for both PDA and congenital changes, are undertaken with a thorough understanding of
diaphragmatic hernia (CDH) patients operated in a dedicated the child’s preexisting conditions. A cooperative environ-
surgical procedure room within the NICU and the OR [47, ment will increase the efficiency and safety of the anesthetic
57]. The main benefits for performing surgery in the NICU and surgery. An efficient and organized surgical service for
were a reduction in waiting time for procedure start, a the NICU minimizes disruption of the care the nurses must
reduced postoperative FiO2, and a reduction in the frequency provide to the other infants in the room and minimizes the
of hypothermia. Surgical-related complications were similar. time that family members of other neonates in the room are
Start time efficiency was improved aided by not having to barred from visiting their infants.
transfer the neonate to the OR. The ventilation status was The recent COVID-19 pandemic demonstrated additional
improved despite the fact the neonatologist was responsible concerns with operating and providing anesthesia outside the
OR. Aerosol-generating procedures with intubation and vena cava, foramen ovale, left atrium, pulmonary veins
other respiratory support modalities (high-flow nasal oxy- (Fig. 13.3), right ventricle, or pulmonary artery. These
gen) increase the risk of transmission. Prior testing of the locations may be associated with complications such as
neonate for SARS CoV-2, minimizing personnel in the pericardial effusion, pleural effusion, and cardiac arrhyth-
NICU room, wearing appropriate PPE, and having adequate mias. Umbilical venous catheters are usually 5 Fr in diam-
airflow are key to reducing risk of SARS CoV-2 transmission eter (occasionally 8 Fr in large term infants), consisting of
to healthcare workers [67]. either single-lumen or double-lumen catheters. These cath-
Vascular Access Superior

vena Pulmonary
Establishing adequate vascular access in neonates may be cava veins
challenging. This is particularly challenging in ELBW Right
infants (<1000 g birth weight). In addition to peripheral atrium Left
venous access, some neonates may have umbilical lines and atrium
percutaneous peripherally inserted central catheter (PICC)
lines. Anesthesiologists should be comfortable using these Inferior
vena Foramen
access lines and should be capable of inserting lines in emer- ovale
cava
gency situations. A brief review of umbilical venous and
arterial lines and PICC lines is given below:
Ductus
1. Umbilical venous catheter: The umbilical vein is large and venosus
easily accessible in neonates. Many infants in the NICU
have an indwelling umbilical venous line for the first Umbilical
5–7 days of life. It is important to document the exact loca- stump
Liver
tion of the tip of the umbilical venous catheter on a recent
X-ray before using it during anesthesia. The optimal loca- Umbilical
tion of the catheter tip should be in the inferior vena cava at venous
or just above the level of the diaphragm (Fig. 13.2). If the catheter
catheter tip is caudal (in hepatic veins), hepatic necrosis
can occur in response to the infusion of hypertonic or vaso-
Fig. 13.2 Optimal position of the umbilical venous line. The tip of the
spastic solution into the liver tissue [68]. If the catheter tip umbilical venous catheter should be located in the inferior vena cava
is too rostral, it may be located in the right atrium, superior just above the level of the diaphragm
Fig. 13.3 Umbilical venous

catheter advanced into the Superior vena cava
right atrium, PFO, left atrium,
and pulmonary veins (shown Pulmonary veins
by dashed blue lines). This is
an inappropriate location for
Left atrium
an umbilical venous catheter.
The umbilical arterial catheter
is shown in red dashed lines Patent foramen
ovale
Right atrium Descending

aorta
Inferior vena cava
Umbilical arterial
Hepatic veins line
Ductus venosus Umbilical venous

line
Umbilical vein
Common iliac artery
Umbilical stump
eters should not be left open to atmosphere (because of the sure and to sample blood (especially arterial blood gas
risk of an air embolus) [68]. For emergency vascular samples). The catheter is usually a 3.5 Fr or a 5 Fr single-
access, vital infusions (not hypertonic solutions) may be lumen catheter placed in the umbilical artery and
administered slowly through an umbilical venous catheter advanced into the aorta. The catheter tip is usually located
placed in the umbilical vein (usually 2–4 cm below the either high (at the level of thoracic vertebrae 6–9) or low
skin) [68] and checking for blood return, prior to use. The (at the level of lumbar vertebrae 3–4). Locating the cath-
umbilical venous catheters traverse the falciparum liga- eter tip between thoracic vertebra 10 and lumbar vertebra
ment and are usually removed before laparotomy. 2 is best avoided because this region includes the origins
2. Umbilical arterial catheter: An umbilical arterial catheter of the celiac, mesenteric, and renal arteries (Fig. 13.4). If
is often placed in a sick neonate to monitor blood pres- the catheter tip is located above thoracic vertebra 6, there
Fig. 13.4 Appropriate
locations of the umbilical
venous and arterial catheters
from a lateral view. The
umbilical venous catheter
traverses the umbilical and
portal veins and enters the
inferior vena cava through the
ductus venosus. The optimal
location of the tip is in the
inferior vena cava just below
the right atrium. The
umbilical arterial catheter is
advanced through the
umbilical, internal iliac, and
common iliac arteries and
advanced into the aorta. The
celiac axis, superior and Aortic arch
inferior mesenteric arteries, UVC position
and renal arteries arise from High UAC position
the abdominal aorta at the T6 - T9 inferior vena cava
level of thoracic vertebra T12 just below the right
to lumbar vertebra L3. The Thoracic atrium (T9 - T10)
umbilical arterial catheter can Vertebrae
be positioned below this Inferior vens cava
region (low line L3–L4) or
above this region (T6–9, as Renal artery Ductus venosus
shown in this figure)
Low UAC position Umbilical vein
L3-L4 Portal vein
Lumber
Vertebrae
Umbilical artery
Internal
Sacrum iliac
Sa artery
ty
an
is a risk of embolization to the carotid and subclavian first-pass cannulation of the radial artery increased with
arteries. Umbilical arterial catheters can also be used to the use of the ultrasound compared with direct palpation
deliver parenteral fluids, although vasospastic agents [75]. Most recently, cannulation of the radial artery in neo-
such as dopamine are best avoided. If there is evidence of nates using ultrasound in the short-axis view was com-
vascular compromise (pallor in the lower limbs and but- pared with direct palpation [76]. Ultrasound resulted in a
tocks), the umbilical line should be removed immedi- first attempt greater success rate as well as faster insertion
ately. In neonates in whom abdominal emergencies such time and fewer complications than the direct palpation
as spontaneous intestinal perforation (SIP) are develop- approach. The introduction of new techniques for vascular
ing, the umbilical arterial catheter should be removed cannulation in neonates including the use of a guidewire
before surgery. To remove an umbilical arterial catheter, and ultrasound has increased the success rate for radial
the catheter should be withdrawn slowly until approxi- artery cannulation and reduced the complication rates.
mately 5 cm remains in the vessel and then tightened The site of insertion should be covered with a trans-
using an umbilical tie around the base of the umbilical parent semipermeable dressing to facilitate early detec-
cord (and not on the skin). The remainder of the catheter tion of bleeding at the site. All fingers/toes should be
should be pulled out of the vessel at a slow rate of 1 cm/ clearly visible to monitor for signs of vascular insuffi-
min (to allow vasospasm of umbilical artery). If bleeding ciency. Complications of peripheral arterial cannulation
occurs once the catheter has been removed, lateral pres- in neonates include thrombosis, vasospasm, infection,
sure should be applied to the cord by compressing it hematoma, damage to peripheral nerves, and air embo-
between the thumb and first finger [69]. lism [71, 77–79].
3. Peripheral arterial cannulation: The most peripheral 4. Central venous catheterization: Placing a PICC is a com-
artery with good collateral flow, with low infectious risk, mon procedure in the NICU to establish long-term central
and that is large enough to measure systemic blood pres- venous access in neonates. PICC lines are 1.1–5 Fr cath-
sure should be selected for cannulation [70]. Ongoing bac- eters of varying lengths, with the smallest single-lumen
teremia and fungal infections are relative c ontraindications size being 1.1 Fr and the smallest double lumen being 2
to arterial cannulation because of the risk of colonization Fr. In general, 1.1–2 Fr catheters are used in infants
of the catheter. Common sites for peripheral cannulation <2500 g and 1.9–3 Fr in those >2500 g. The PICC tip
include the radial, ulnar, dorsalis pedis, and posterior tibial should be located in the superior or inferior vena cava,
arteries, with the right radial artery selected most com- outside the pericardial reflection [80]. Common indica-
monly in one retrospective review of infants <5 kg [71]. tions for PICC placement include parenteral nutrition and
Evidence for collateral flow must be checked before can- need for long-term IV medication (antibiotics for bacte-
nulation. This can be done by using a modified Allen test rial, fungal, or viral infections). PICC has significant risks
or by Doppler ultrasound [72]. Transillumination of the and complications (such as sepsis) and must be avoided
wrist is helpful in identifying the location of radial, ulnar, when peripheral venous access is adequate and possible
dorsalis pedis, and posterior tibial arteries. Care should be [80]. Many neonatologists prefer to place a PICC after
taken not to injure the ulnar nerve during ulnar arterial 24 h of parenteral antibiotics or when the blood culture is
cannulation as it runs along the medial side of the artery. no longer positive for infection. Strict aseptic precautions
Sedation and analgesia with fentanyl are usually provided must be followed when placing the catheter
before arterial cannulation. Some also infiltrate the site
before arterial cannulation with 0.5 mL of lidocaine. After A central venous catheter is usually inserted percutane-
aseptic precautions are followed, an Angiocath is inserted ously in neonates. A cutdown or surgical technique is used
into the artery by direct puncture and advanced at a 10–15° only when percutaneous insertion has been unsuccessful.
angle to the skin with the bevel facing down [73]. When Adequate sedation and analgesia should be provided before
blood appears in the stylet, the cannula is advanced off the beginning to insert the catheter. A slow infusion of 2–4 mcg/
stylet and into the artery. Alternately, the needle stylet may kg of fentanyl is preferred, although larger doses may be
be inserted at a 30–40° angle to the skin with the bevel required for infants who have developed tolerance to opioids
facing up through the artery. The stylet is removed, and and in infants whose lungs are mechanically ventilated.
the cannula is withdrawn slowly until pulsatile arterial Infants who do not require significant respiratory support
flow is established. The cannula is then advanced into the may receive non-pharmacologic comfort measures such as
lumen of the artery [70]. A third technique is to employ a sucrose-dipped pacifier in addition to fentanyl. For catheter
guidewire that is threaded into the cannula upon accessing insertion by surgical cutdown, local infiltration with lido-
the artery. This technique increases the rate of successful caine is recommended.
cannulation compared with direct palpation [74]. With the It is important to check the position of the catheter tip
introduction of ultrasound guidance, the success rate for before commencing surgery. The use of radio-opaque con-
trast improves localization of the catheter tip. The most bating dose of propofol used as the sole anesthetic, has been
recent chest radiograph should be evaluated for catheter conflicting, although there is some evidence 2 mg/kg is gen-
position. Catheters have been reported to migrate, and these erally effective. However, the consequences have included
have been associated with complications after insertion. both profound and prolonged hypotension particularly in
Most indwelling catheters are made of silicone or poly- VLBW infants [83–85].
urethane to minimize the risk of perforation and fracture. In In our institution, the NICU team infuses 10 mcg/kg fen-
neonates, small gauges (1.1, 1.9, 2, and 3 Fr) are commonly tanyl over 20 minutes before the anesthesia team arrives in
used for percutaneous insertion. These catheters offer too order to assess the risk of hypotension and, if necessary, to
much resistance to allow withdrawal of blood or to rapidly restore euvolemia and blood pressure using balanced salt
infuse fluid boluses, anesthetic induction drugs (such as solution. If fluid boluses are needed, then euvolemia will be
propofol), or blood products during surgery. Sterile precau- established before additional fentanyl and paralysis are given
tions should be observed when breaking into a PICC circuit at the time of skin incision, thereby minimizing the risk of
during surgery. post-induction or post-incision hypotension. Our goal is to
maintain cardiorespiratory homeostasis at the time of and
after skin incision. Abdominal surgery often requires fen-
Anesthesia Requirements tanyl doses as little as 10–20 mcg/kg, whereas thoracic sur-
gery may require fentanyl doses (over the duration of the
There are several important issues that the anesthesiologist surgery) of 30–50 mcg/kg [86, 87]. It should be appreciated
should establish when planning to provide anesthesia in the that the elimination half-life of fentanyl in preterm neonates
NICU (Table 13.4). First, dedicated IV access should be is variable, with markedly prolonged elimination in neonates
available to administer drugs and fluids. A second, separate with increased intra-abdominal pressure (IAP) [86, 88].
IV access should be available to administer drugs such as Paralysis should be administered to provide adequate surgi-
antibiotics or vasopressors. Second, the anesthesia regimen cal relaxation while monitoring ventilation and oxygenation
most frequently used for neonatal surgery is an opioid-based carefully, as pre-paralysis settings may lead to hypercapnia
technique with neuromuscular blockade. Fentanyl is the once paralysis is provided or desaturation if tidal volumes
most widely used opioid in neonates. Most surgeries require are insufficient.
muscle relaxation, and rocuronium or vecuronium is the Many neonates are not paralyzed in the NICU, and as
most commonly used neuromuscular blocking agent. All such there is often some degree of spontaneous respiration
medications should be flushed through the line as medica- either with conventional ventilation or HFOV. In some cases,
tions are often administered at a site remote from the infant loss of this spontaneous respiration component will cause
and may cause an unexpected delayed effect when the IV significant hypercapnia which could result in pulmonary
line is later flushed. All fluid boluses, flushes, and infusions hypertension, hypoxia, and hypotension. To avoid surprises,
should be carefully documented to prevent fluid overdoses. paralysis with appropriate sedation should be administered
There have been some reports of the adjunct use of mid- before surgery commences to allow sufficient time to assess
azolam and propofol [81] in neonates during surgery in the any negative effects of these agents on the cardiorespiratory
NICU. The potential for profound circulatory depression systems. Otherwise, this deterioration may be confused with
after use of these drugs, especially in the septic or compro- ventilator insufficiency due to the effects of the surgical pres-
mised neonate, cannot be overstated. Midazolam has no role ence in the abdomen.
in neonatal intubation and surgery as the pharmacology of The monitoring equipment used in the NICU is often for-
this drug, especially in preterm neonates, is unfavorable and eign to the anesthesiologist. Assistance is often needed from
potentially harmful (see below, ref. 82). Most neonates are the bedside nurse or neonatologist to activate the audible
volume contracted in the NICU resulting in both direct and pulse oximetry/ECG tones, which are frequently muted in
indirect vaso−/venodilatation when anesthetics are adminis- the NICU. Blood pressure may be measured invasively via a
tered, resulting in reduced preload and afterload. The intu- radial or umbilical artery line, but in those in whom invasive
pressure monitoring is not present, a noninvasive oscillomet-
ric blood pressure monitor should be used. The reliability of
Table 13.4 Anesthesia requirements noninvasive measures of blood pressure monitoring in pre-
IV access mature infants has been affirmed by some and questioned by
Drugs others [89, 90]. Recent evidence supports applying the blood
Anesthetic technique pressure cuff in either the upper or lower extremity in infants
Monitoring >1000 g but may provide more accurate readings from the
Ventilation lower extremities in infants <1000 g [91]. Mean and systolic
Fluids blood pressures in premature and full-term neonates increase
with gestational age, birth weight, and postnatal age [92]. Of abdominal procedure. Similar data from the NICU have not
importance is the observation that the systolic and mean been forthcoming.
blood pressures measured noninvasively in premature and One major controversy regarding surgery in the NICU
full-term neonates asleep is 10–20% less than the corre- when this subject was initially considered was the potential
sponding awake values [92]. This is consistent with the risk for increased infections and sepsis. However, several
expected decrease in systolic blood pressure of 20–30% with small studies failed to demonstrate any increased risk associ-
induction of anesthesia. Because complex ICU ventilators or ated with operating in the NICU. One study that involved
HFOV/HFJV are often used in the NICU, a neonatologist repair of CDH in the NICU [57] reported an increased but
and respiratory therapist should be present throughout the not statistically significant change in the infection rate.
procedure [43] to assist with ventilation, oxygenation, and However, they did demonstrate a significant increase in the
ventilator-related issues. Changes in oxygenation and venti- inflammatory marker C-reactive protein (CRP) in the NICU
lation may occur as a result of increases in the abdominal operative group, suggesting that inflammation was present.
pressure and/or decreases in lung compliance associated Because critically ill neonates are more prone to infections
with surgery. Persistent changes in oxygenation and ventila- as well as a greater morbidity and mortality from infection
tion may require compensatory changes in PEEP, PIP, and than healthy neonates, it is imperative to adhere to OR infec-
mean airway pressure depending on the mode of ventilation tion control policies including the use of appropriately timed
as well as the inspired fraction of oxygen. If conventional (pre-incision) surgical site antibiotics irrespective of the
ventilation cannot maintain adequate blood gases, it is pos- location of the surgery [53].
sible that the strategy will have to be changed to perhaps Published reports of neonates undergoing a variety of dif-
HFOV [93]. Neonates whose lungs require HFOV are often ferent operative procedures in the NICU have included small
monitored using transcutaneous CO2 monitoring. This moni- samples and were retrospective in nature, and none were ran-
tor tracks the PaCO2 [94] although it requires recalibration domized trials evaluating outcomes. A review of the publica-
periodically; the response lags compared with end-tidal cap- tions to date suggests that the neonates in the NICU operative
nography and its accuracy should be confirmed by compar- group had a greater mortality than those operated in the OR
ing the results to an arterial blood gas before commencing [41, 48, 81, 101], although selection bias limits the external
surgery [56]. Capnography is not routinely available in most validity of these data: these neonates were sicker and required
NICUs, but the anesthesiologist should ensure that capnog- more ventilatory and inotropic support. The extent to which
raphy is available for those neonates and VLBW infants with these differences of pre-procedural morbidity were respon-
reasonable lung function and whose lungs are ventilated with sible for the increased mortality is difficult to determine. A
conventional ventilators [55, 94–96]. End-tidal CO2 does not retrospective study [41] utilizing the score for neonatal acute
provide accurate estimates of PaCO2 in neonates whose physiology (SNAP) demonstrated that neonates undergoing
lungs are ventilated with HFOV (see discussion on high- surgery in the NICU had a greater preoperative SNAP score
frequency ventilation below). than those undergoing surgery in the OR but that SNAP
Thermoregulation is a vital function in the neonate that increased by 20% in both groups during the initial 24 h
may prove challenging during surgery in the NICU. Surgery post-procedure.
is often performed in open radiant warmers with overhead Despite the lack of evidence concerning improved out-
radiant heaters in the NICU. However, these heaters may be comes after surgery in the NICU, it is difficult to determine
less effective at maintaining thermoneutrality during surgery whether the challenges associated with undertaking surgery
as the surgeons cover the neonate blocking the infants from in a foreign environment offset those associated with transfer-
the heat source. In the OR, the ambient temperature is often ring the neonate to the OR [41]. As surgery is performed more
increased to 26 °C [97–99] to prevent radiation and, to a frequently in the NICU on more stable neonates, the mortality
lesser extent, convective heat losses (see Chap. 8). This is not rate is decreasing significantly [41]. In many centers today,
usually possible in the NICU setting unless a designated pro- surgery in the NICU is regarded as routine and safe.
cedure room is used. A forced-air heating blanket, which is a
very effective method to prevent intraoperative hypothermia
[100] better than most other strategies during surgery, is usu- edation and Analgesia for Common
S
ally unavailable in the NICU. However, if it is available, it Procedures in the NICU
should be placed under the infant before surgery commences.
A fluid warmer should be used to warm all fluids, especially Critically ill neonates undergo frequent painful procedures
if blood products are required. Often, a fluid warmer must be such as blood draws, heel sticks, and intravenous catheter
supplied from the OR. Hypothermia during neonatal surgery placement in the NICU daily [102]. Other procedures that
has been associated with reduced OR ambient temperature as may cause discomfort in some neonates include tracheal
well as with major surgical procedures [57], e.g., open intubation, mechanical ventilation, and tracheal suctioning
[103]. Neonates who require mechanical ventilation are (b) Mean airway pressure recruits alveoli and is closely
often sedated with a combination of fentanyl and midazolam. related to oxygenation. When an infant is switched
The American Academy of Pediatrics (AAP) published from conventional ventilation to HFOV, it is recom-
guidelines for premedicating neonates who require nonemer- mended that the starting mean airway pressure be 2
gent tracheal intubation [82]. They recommended atropine, cmH2O above the mean airway pressure on conven-
fentanyl as a slow infusion, and vecuronium/rocuronium. tional ventilation.
These guidelines recommend avoiding midazolam in prema- (c) If a neonate is weaned from HFOV to conventional
ture neonates because of its prolonged half-life, hypotension, ventilation for surgery, adequate PEEP must be pro-
reduced cerebral blood flow, and the presence of benzyl alco- vided to maintain alveolar recruitment and
hol as a preservative. Despite these recommendations, a sur- oxygenation.
vey of NICU practices from the AAP 5 years later, in 2015, (d) Increased mean airway pressure can impede venous
reported only one-third of neonatologists frequently use pre- return and decrease blood pressure. If hypotension is
medication and less than 50% of the institutions have written encountered during HFOV, fluid boluses may be
protocols for premedicating neonates before intubation required. If hypotension persists, the mean airway
[104]. In a survey of NICU practices in 70 countries during pressure should be decreased providing the respira-
the period 2018–2019, the attitudes and practices to none- tory status of the neonate remains stable.
mergency intubations in neonates were wide-ranging, with (e) Wide fluctuations in PaCO2 (especially hypocarbia)
up to 12% reporting they used no premedication whatsoever can occur during HFOV. Frequent blood gases and/or
[105]. The authors called for an international consensus to transcutaneous pCO2 monitoring provide useful indi-
formulate optimal practices for intubation in neonates. ces of ventilation with HFOV; end-tidal pCO2 moni-
tor is unreliable. The skin at the site of transcutaneous
monitor application must be frequently checked to
High-Frequency Ventilation avoid burns. The site may have to be changed fre-
quently particularly in premature infants.
Critically ill neonates, especially premature infants, may 2. HFJV (Life Pulse, Bunnell Incorporated, Salt Lake City,
develop hypoxemic respiratory failure as a result of small UT) is the second form of high-frequency ventilation in
lung volumes, poor compliance, increased intra- and extra- the Unites States. HFJV is particularly effective for early
pulmonary shunts, and ventilation perfusion mismatch. intervention and treatment of pulmonary interstitial
High-frequency ventilation is a commonly used lung- emphysema [107]. The jet ventilator provides small, high-
protection strategy that benefits oxygenation and ventilation velocity breaths and fast rates with passive exhalation. A
[93]. Two types of high-frequency ventilators are used in conventional ventilator operates in tandem with the jet
neonates in the United States: ventilator to maintain optimal PEEP. The conventional
ventilator is attached to the regular connector of the TT,

1. High-frequency oscillatory ventilation (HFOV, Sensor and the HFJV is connected through a special adaptor to
Medics 3100A, CareFusion Corporation, San Diego CA) the side port of the tube. Mean airway pressure is adjusted
utilizes a piston pump to generate oscillations [106]. This is primarily by changing the PEEP on the conventional ven-
the only mode of ventilation in which inspiration and expira- tilator. Just as in the case of conventional ventilation,
tion are active. A constant distending pressure is applied to faster respiratory rates and greater PIP with the HFJV
the lungs (mean airway pressure), over which small tidal reduces the PaCO2. See Chap. 9 for further information.
volumes (amplitude) are superimposed at a rapid respiratory
frequency (6–15 Hz). Typically a frequency range between
10 and 15 Hz is used in neonates. Greater frequencies are Transport
commonly used in premature infants. The frequency of
oscillation influences the CO2 removal in a direction oppo- The majority of births in the United States occur in hospitals
site to that of conventional ventilation. Greater frequencies without tertiary-level neonatal intensive care units (NICUs).
decrease tidal volume and increase PaCO2. Decreasing the Neonates who are born extremely premature outside a tertiary
frequency and increasing the amplitude independently hospital may require transport to a tertiary hospital (interhos-
increase tidal volume and decrease PaCO2. The following pital transport) soon after birth because of respiratory dis-
factors should be considered if a critically ill infant who tress, congenital anomalies, and/or surgical problems. A
depends on HFOV requires surgery: transport incubator should be used for all interhospital trans-
(a) Performing surgery while the lungs are ventilated ports. Once inside the tertiary hospital, these neonates may
using a HFOV may be technically difficult for the require transport within the facility for diagnostic or special
surgeon. procedures such as radiography, cardiac catheterization, or
surgery [108] (intrahospital transport). Many of these neo- dence, congestive cardiac failure and chronic lung disease,
nates are critically ill, require mechanical ventilation, and are and necrotizing enterocolitis (NEC). In these patients, surgi-
at increased risk for cardiorespiratory instability. Increased cal ligation of the PDA may be performed [109]. More
stimulation during transport can destabilize a critically ill recently, percutaneous closure of the PDA has been per-
infant. Accordingly, appropriate sedation and analgesia dur- formed successfully in young neonates and may point to
ing transport will prevent cardiorespiratory instability. another approach to open surgical ligation [111].
For short transports within the hospital, critically ill infants Surgical ligation of a PDA in neonates has a low morbid-
are transported on radiant warmer beds. In these instances, ity and mortality. The CXR may indicate fluid overload or
the infant’s head should be covered with a hat, and the body evidence or a respiratory distress syndrome (RDS). The
wrapped in a plastic/vinyl insulated bag to prevent heat loss. echocardiogram establishes the size of the ductus and the
In neonates with abdominal wall defects (gastroschisis or degree and direction of blood flow. Although surgical closure
omphalocele) or large neural tube defects (meningomyelo- of the PDA is routinely performed in the OR, it has also been
cele and encephalocele), sterile vinyl bags should be applied performed in the NICU [112]. PDA closure appears to be the
to prevent infection, hypothermia, and hypovolemia. most common surgical procedure performed in the
Intrahospital transports are best managed by manually venti- NICU. Multiple studies from worldwide report that over 700
lating the lungs. Hand ventilation enables the operator to con- neonates have received PDA closure in the NICU without
tinuously evaluate the compliance of the lungs including major complications [113]. The outcome from surgical liga-
early detection of accidental extubation, a tube disconnect or tion appears to be related to the underlying degree of pulmo-
TT kinking, or occlusion to be detected earlier although this nary and cardiovascular disease. In a nonrandomized study
depends on the fresh gas flow and operator experience [45]. of PDA ligation in the OR and NICU, it demonstrated that
However, if the lungs are ventilated manually, it is imperative postoperative mortality (17%) was due to respiratory failure
that the operator remains focused on the ventilation (rather and sepsis, with risk factors being surgery in the NICU and
than steering the incubator) to ensure the respiratory rate and low birth weight [114]. The overall outcome of PDA ligation
peak inspiratory pressure are appropriate. was early extubation (<10 days) in 30% of neonates, late
It is recommended that the neonatal transport team carry extubation (no chronic lung disease, CLD) in 22%, and late
medications for analgesia, sedation, and paralysis [108] includ- extubation with CLD in 31%. There was no difference
ing analgesics and sedatives (fentanyl, morphine, midazolam), among the groups in terms of early incidence of extubation
neuromuscular blocking drugs (pancuronium and vecuronium), suggesting that the outcome after PDA closure in neonates
and reversal agents (flumazenil to reverse benzodiazepines, without severe cardiorespiratory disease is similar, whether
naloxone to reverse opioid-induced respiratory depression, it is completed in the OR or NICU. In another study of 41
neostigmine to antagonize neuromuscular blocking agents). In PDA ligations in neonates <1500 g with a mean gestational
addition, they must have equipment to manage a sudden airway age of 27 weeks in the NICU, none of the complications
emergency including an appropriately sized laryngoscope, were attributable to anesthesia. The five deaths were all
TTs, stylet, and ventilation circuit (Ambu bag or T-piece). related to prematurity and congestive heart failure [112].
A retrospective study of 189 premature infants compared
perioperative complications after PDA ligation in the NICU
Specific Conditions Requiring Surgery or OR. Mortality and sepsis after ligation in the NICU was
in the NICU (For Further Details, See Chap. 9 similar to that in the OR, although hemodynamic instability
“Thoracoabdominal Surgery”) was significantly more frequent during transport from the
OR to the NICU [47].
Closure of PDA In some institutions, ligation of a PDA in the NICU is
considered standard. Some regional centers have a team
Failure of the PDA to close spontaneously or in response to comprising of a pediatric cardiac surgeon, pediatric anesthe-
medical management with indomethacin or ibuprofen is siologist, and pediatric OR nurses traveling to pediatric hos-
common in ELBW premature infants. Medical management pitals to perform PDA ligation in the referring hospital’s
appears to fail in up to two-thirds of ELBW infants [109]. NICU to avoid the interhospital transfer of the neonate [115].
When medical treatment was compared with surgical closure There was no difference in either the preoperative complica-
of the PDA as first-line therapy in premature infants, the inci- tion rate or mortality between these neonates and those oper-
dence of mortality and post-closure complications were sim- ated on at the surgical institution. Most importantly, by not
ilar [110]. In some, medical treatment may be contraindicated transferring the neonates, the same neonatal team that is
because of IVH or renal failure. A PDA results in significant most familiar with the infant’s medical and social history
left-to-right shunting of blood causing pulmonary over- could provide the infant’s care, and the family is minimally
circulation, respiratory failure, prolonged ventilator depen- inconvenienced.
With the approval of a new device in 2019, transcatheter include gas in the intestinal wall (pneumatosis), air in the
occlusion of PDA is being increasingly preferred over surgi- branches of the portal vein and biliary tract, and free air
cal ligation (see cardiac catheterization section below). within the abdomen (Fig. 13.6). Indications for surgical
exploration include intestinal perforation with pneumoperi-
toneum or continued clinical deterioration despite maximal
NEC medical management. Surgical management with a perito-
neal drainage is often favored in an unstable, critically ill
NEC is the most common gastrointestinal surgical emer- premature infant with the caveat that a subsequent laparot-
gency in premature neonates, [116] affecting approximately omy may be required if the condition deteriorates.
6–7% of VLBW infants. Full-term infants rarely present Neonates who require surgery for NEC are usually criti-
with NEC. The pathogenesis of NEC remains unknown, but cally ill and require intensive resuscitation before surgery.
it is quite likely a multifactorial disease. Risk factors include Preoperative management before exploratory laparotomy
prematurity, enteral feeding (especially formula), infection, should address the following issues:
and ischemia (Fig. 13.5). Classic radiographic findings
(a) Blood pressure: Hypotension is common in NEC and is
secondary to third spacing of fluids in the abdomen, cap-
illary leak, high peak inspiratory pressures, sepsis with
Enteral nutrition poor vascular tone, and low cardiac output. Fluid boluses
(both crystalloids and colloids) may be required repeat-
edly until the vital signs stabilize. Many infants require
inotropic support with dopamine and/or epinephrine.
Preterm baby (b) Respiratory failure: Pulmonary edema and acute respira-
2-3 weeks old tory distress syndrome (ARDS) are commonly associ-
Advancing calories ated with fulminant NEC. Infants require high peak
and feeds
inspiratory pressures during conventional ventilation.
Some infants may be so ill that their lungs require HFO
(see discussion above).
(c) Electrolyte and acid–base disturbances: Fulminant NEC
results in respiratory and metabolic acidosis.
Pneumoperitoneum
Portal venous air

Areas of ischemia
and necrosis
in the ileum
Pneumatosis Sa
ty
an
Poor perfusion
Hypotension
Fig. 13.5 Pathophysiology of NEC requiring surgery. A typical patient

is a premature infant approximately 2–3 weeks of age, taking advancing
feeds. The terminal ileum is commonly involved. Areas of ischemic
necrosis and pneumatosis (intramural collection of air) are observed in
the ileum. Portal venous air can be visible on abdominal X-ray.
Pneumoperitoneum is the most common indication for surgery in these Fig. 13.6 X-ray showing pneumoperitoneum (anterior to the liver),
infants pneumatosis in a patient with NEC prior to surgery
Table 13.5 Average perioperative resuscitation requirements for NEC Table 13.6 Location, extent of disease, and mortality for NEC [117]
patients in the NICU
Location % Bowel involved % Mortality
Inotropes, e.g., dopamine Increased dose by 4 mcg/kg/min Ileum 15 15
Bicarbonate 2.5 mmol/kg Large bowel 20 35
Blood 32 mL/kg Jejunum–ileum 65 80
Platelets 12 mL/kg Large bowel–ileum 35 40
FFP 15 mL/kg Large bowel–jejunum–ileum 85 95
5% albumin 35 mL/kg
common during surgery in NEC, and many infants require

Hyponatremia is common secondary to third spacing, 50–100 mL/kg of fluid during surgery. Depending on the
and hyperkalemia due to acidosis occurs in some infants type of fluids administered preoperatively and laboratory
and may need to be corrected either before or during sur- indices, this may include balanced salt solution, colloid, or
gery. Hypocalcemia secondary to multiple blood prod- blood products (PRBCs, FFP, and platelets). Infants with
uct infusion may exacerbate hypotension and should be NEC continue to require large fluid volumes in the postop-
avoided. erative period because of ongoing third space losses, and this
(d) Hematologic disturbances: A review of 25 neonates who must be born in mind during the postsurgical period.
required surgery for NEC in the NICU required many The mortality for NEC surgery in the NICU has been
blood products perioperatively (Table 13.5) [35]. This reported to be as great as 50%. Mortality is affected by sev-
report illustrates the need to have blood products imme- eral variables including the location and extent of the disease
diately available for the anesthesiologists to administer (Table 13.6) [117]. Neonates with extensive NEC are those
during the procedure. Thrombocytopenia occurs com- in whom surgery is undertaken preferentially in the NICU,
monly in NEC. NEC associated with ischemic or and it is in those neonates that the mortality is significantly
necrotic bowel may also present with disseminated greater. In neonates with NEC who are the most unstable,
intravascular coagulation (DIC). PT, PTT, fibrinogen, placement of a peritoneal drain in the right lower quadrant is
and fibrin split products should be frequently monitored usually sufficient [42].
along with complete blood counts in neonates with
NEC. Transfusions with packed red blood cells (PRBCs),
fresh frozen plasma (FFP), and platelets are often SIP
required.
Many neonates with NEC may have received sys- A subset of premature neonates who present with intestinal
temic glucocorticoids for hypotension or management perforation without signs of NEC, such as pneumatosis
of BPD. Such patients may need a stress dose of gluco- intestinalis, are classified as focal or SIP. This condition
corticoids before surgery. presents early (7–10 days of age) in ELBW infants [118,
(e) Vascular access: At least two peripheral intravenous 119]. Prior exposure to early postnatal steroids and indo-
catheters are recommended during surgery for NEC. A methacin may be risk factors for SIP [120, 121]. Although
central venous catheter is useful to infuse inotropic these neonates are not as sick as those with advanced NEC,
agents (since most neonates will require support) and an they tend to be much younger, their lungs are often mechani-
arterial catheter to monitor blood pressure continuously cally ventilated, and they have umbilical lines secondary to
and sample arterial blood. their RDS at birth (Fig. 13.7). Surgery for SIP often involves
resection of the perforated site and reanastomosis or ileos-
General tracheal intravenous anesthesia with neuromus- tomy. This procedure is often done at the bedside in the
cular blockade is preferred for NEC surgery [39]. Lung ven- NICU because of the young gestational age.
tilation is commonly managed with a standard neonatal
ventilator, rendering an intravenous anesthetic approach
preferable over inhalational anesthetics. A high-dose opioid Gastroschisis
technique with intravenous fentanyl (20–50 mcg/kg), mid-
azolam (0.1 mg/kg), and a muscle relaxant is often used. Gastroschisis is a nongenetic, anterior abdominal defect that
Hypotension is common after induction of anesthesia but can has an unclear etiology, with one theory being it results from
be prevented in most infants by preinfusing 10–20 mL/kg of an occlusion of the omphalomesenteric artery (see Chap. 9).
balanced salt solution such as normal saline or lactated Gastroschisis, located in the periumbilical region usually on
Ringer’s solution. Persistent hypotension despite fluid resus- the left side, includes small and large intestines and other
citation may necessitate the use of inotropes such as dopa- abdominal organs that are free-floating in amniotic fluid dur-
mine and stress dose glucocorticoids. Third space losses are ing fetal life. The chronic exposure of these organs to amni-
24 - 28 wk gestation
ELBW infant Day # 7-9
(h/o early steroid
or indomethacin)
Abdominal
distension
RDS/PDA Isolated
perforation
in the
terminal
ileum
Satyan
Bluish discoloration
Bluish aspirates Pneumoperitineum of lower abdomen
(without portal and scrotum
venous gas or
pneumatosis)
Fig. 13.7 A typical patient with SIP. These patients are of extremely low or portal venous air. Many of these infants are still on respiratory support
gestational age (median—26 weeks), presenting often with asymptom- for RDS and/or PDA and may have umbilical lines from birth. Pathology
atic pneumoperitoneum by days 7–9. Some patients may present with shows a perforation in the ileum without any evidence of coagulative
bluish discoloration of the abdomen. There is no evidence of pneumatosis necrosis, a finding commonly associated with NEC and ischemia
otic fluid causes inflammation and edema on the serosal inspection of the bowel for obstructing bands, perforation,
surfaces that leads to the formation of a peel on the bowel and atresia should be undertaken before applying the silo.
surface. Preoperative management consists of reducing fluid More recent introduction of a prefabricated silo with a circu-
loss from the eviscerated organs and bowel by administering lar spring that can be placed into the fascial opening, without
adequate intravenous fluids in the form of boluses of normal the need for sutures or general anesthesia, has made it pos-
saline or lactated Ringer’s solution to replace third space and sible to insert the silo in the delivery room or at the bedside
evaporative losses and covering the bowel with sterile, in the NICU [122]. These procedures are performed with
saline-soaked dressings and placed in a sterile plastic wrap. intravenous opioid (2–4 mcg/kg of fentanyl) and midazolam
Gastric decompression is important to prevent distension of (0.1 mg/kg). A PICC line must be placed in all infants with
the stomach and intestines and reduce IAP. Reduction of gas- gastroschisis for total parenteral nutrition because intestinal
troschisis and primary abdominal wall closure is commonly hypomotility and delayed initiation and advancement of oral
performed in the OR. This procedure may be associated with feeds are common.
increased IAP. Central venous pressure > 4 mmHg, intravesi-
cal or gastric pressure > 20 mmHg, and splanchnic perfusion
pressure (mean arterial pressure, IAP, <44 mmHg) during Retinopathy of Prematurity (See Chap. 2)
the primary repair suggest decreased splanchnic and renal
blood flows. To preclude bowel and renal ischemia, it may be The surgical management for ROP may involve both laser
critical to abort the primary wall closure and opt for a staged and cryosurgery. There are numerous reports of these proce-
repair (see below) to permit the anterior abdominal wall to dures being performed in the NICU [123] and the OR. These
stretch to accommodate the increased abdominal contents neonates are not usually critically ill, thus reducing the risk
upon skin closure [122]. of transporting these neonates to the OR. Nonetheless, per-
In some patients when the volume of eviscerated bowel is forming these procedures in the OR is believed to delay their
large relative to the volume of the abdominal cavity or when care. This prompted the practice of evaluating and managing
the IAP increases during attempted primary repair, staged these infants in the NICU. In the NICU, local anesthesia and
reduction may be performed in the NICU. The staged repair IV sedation have been used, although emergent airway man-
consists of covering the eviscerated contents with a pros- agement has been common. Presently, neonatologists use a
thetic silo pouch. The pouch is serially reduced in size in the local anesthetic/sedation technique and sedation/analgesia/
NICU, allowing the abdominal cavity to gradually expand to paralysis technique with tracheal intubation or maintain their
accommodate the increased volume within, without severely present level of respiratory support to facilitate these proce-
compromising ventilation or organ perfusion. Careful dures in the NICU [124–127].
CDH require ECMO. Neonates with CDH who also present with

congenital heart defects (incidence ~10%) present a hetero-
The management of CDH now often includes NICU man- geneous group of heart defects that pose a daunting chal-
agement with HFOV, surfactant, inhaled nitric oxide, and lenge. ECMO has been used to support these infants with
possibly ECMO (in up to one-third of neonates with CDH), survival rates for single ventricle physiology that were simi-
followed by delayed surgical repair [128]. The decision to lar to those with CDH without a heart defect [130].
repair CDH in the NICU is often determined by the ventila- Retrospective data suggest that blood gases in the first 4 h
tory management required to support the infant. Despite an after birth may predict outcomes in terms of ECMO require-
increasing proportion of neonates undergoing corrective ment and mortality [131]. Those who recommend surgical
repair of CDH, present survival rates in a background of repair in the NICU do so to avoid the logistical difficulties
HFOV, iNO, and ECMO have not changed from 65% to 80% and patient safety issues associated with transferring the
[129]. Supporting the infant for several days allows the neonate, who depends on HFOV, iNO, and/or ECMO, to the
severity of the pulmonary hypertension to improve and OR. If the lungs require HFOV to maintain the pCO2 in an
vessel reactivity to wane. Although initially unstable
acceptable range and the child is scheduled for surgery in the
(Fig. 13.8), these infants can stabilize and progressively OR, converting the ventilation mode to conventional ventila-
improve resulting in better gas exchange and increased lung tion may be considered provided the respiratory settings do
compliance during postnatal adaption and correct manage- not exceed those shown in Table 13.7 [81]. If the respiratory
ment strategies. Those infants with significant pulmonary indices remain within acceptable limits after conversion to
hypoplasia (15%) or an abnormal persistence of the pulmo- conventional ventilation, the infant may be transferred to the
nary hypertension may fail to stabilize postnatally and may OR 24 h later.
Fig. 13.8 CDH. The schematic on the left illustrates the presence of present in the left chest. The diaphragmatic defect was not diagnosed
bowel in the left chest displacing the heart to the right and compressing antenatally. Feeding commenced after birth in the newborn nursery
the right lung as shown in the radiograph on the right. The radiograph before the diaphragmatic hernia was diagnosed [147]
reveals an infant whose airway was intubated and whose bowel was
Table 13.7 Recommendations for the transition from HFOV to con- of an MRI scan with anesthesia. In general, a cumulative
ventional ventilation for CDH repair radiation exposure of 100 mSv is the threshold considered to
After at least 72 h since birth, with minimal inotropic support, increase the risk for malignancy; this dose is consistent with
HFOV settings should be: multiple CT scans. However, there is also a concern that per-
FiO2 <0.4 haps any exposure above zero exposure increases the risk for
MAP <13 cm H2O
malignancy. Factors such as a variability in sensitivity to ion-
Amplitude <30 cm H2O
Oxygenation index <10
izing radiation damage, gender, and the ability to use low-
No ultrasound evidence for pulmonary hypertension dose CT scans can alter the risk–benefit ratio. The MRI itself
No difference in pre- and postductal SaO2 is generally considered safe with the appropriate use of gad-
Pulmonary/systemic pressure ratio <0.75 olinium contrast in patients with renal dysfunction. However,
Stable with above criteria for 24 h there are the short-term risks from possible peri-anesthesia
complications, as well as the potential long-term develop-
A comparison of neonates after CDH surgical repair using mental risk. Some authors now support the use of low-dose
fentanyl, pancuronium, and occasional midazolam and pro- CT scans rather than an MRI/GA combination for these rea-
pofol anesthesia in the NICU and the OR demonstrated a sons [135]. Given the growing concern over the possible
greater mortality in the former, 33%, compared with the lat- neurotoxic effects of anesthetic drugs on the developing
ter, 7% [81]. The NICU infants required more inhaled nitric brain, more centers may consider the feed and swaddle tech-
oxide, greater mean arterial pressure, greater need for inotro- nique as a first-line method for neonates to obtain brain
pic support, and a greater oxygenation index (mean airway MRIs, with sedation and GA reserved for failed feed and
pressure × FiO2 × 100 ÷ postductal PaO2, usually the umbili- swaddle attempts and special circumstances.
cal arterial PaO2). Older infants may be given chloral hydrate, ketamine,
midazolam, or several other sedatives for sedation with a
similar rate of adverse events [136], although general anes-
Other Reported NICU Surgical Procedures thesia is more frequently required with appropriate airway
management as an alternative to the complications associ-
Several additional procedures may be undertaken in the ated with chloral hydrate sedation in young infants [137].
NICU [113]. For posthemorrhagic hydrocephalus in VLBW Full-term neonates may be sedated for CT scan after stan-
infants, a VP shunt, external ventricular shunt, or more com- dard monitors are applied by simply inducing anesthesia
monly a ventricular reservoir for intermittent tapping may be with 8% sevoflurane, applying nasal prongs with 2 l/min
performed [132]. Tracheostomies have been performed in oxygen, placing a roll under their shoulders, and allowing
the NICU as reported in both pediatric and adult intensive the scan to proceed while the neonate breathes spontane-
care literature. Also, urogenital procedures including urinary ously. Present CT scan imaging is so rapid that neonates
diversion procedures such as a nephrostomy or ureterostomy often do not recover from the inhalational induction before
may be suitable to perform in the NICU. the scan is completed. These same neonates may also require
MRI, which usually lasts 1–2 h depending on the type of
scan and the strength of the magnet. The approach to anes-
Sedation for Imaging Procedures (MRI/CT) thesia in the neonate for an MRI scan begins with an inhala-
tional induction with sevoflurane and nitrous oxide, followed
Sedation is often required for neonatal patients requiring by IV cannulation and discontinuation of the nitrous oxide.
radiological procedures such as MRI or CT scan [133]. Most neonates with normal craniofacial anatomy and air-
Standard anesthesia monitors that are compatible with both ways can be sedated for the scan using a continuous propofol
MRI and CT equipment are available and should be used. infusion. The neonate is positioned supine with a small roll
However, temperature monitoring during MRI scans may under the shoulders and the neck extended. Nasal cannulae
not be available. All monitoring wires should be straight (not are applied while the child breathes spontaneously and anes-
coiled) and probes placed as far from the magnetic coil as thesia maintained with a propofol infusion. Neonates and
possible to diminish the possibility of thermal injury. those who are cognitively impaired may require greater infu-
Medications and/or procedures used for sedation depend on sion rates of propofol than toddlers (who usually require
the age and cardiorespiratory status of the infant. Many 250–300 mcg/kg/min) to stop moving during scan. Propofol
infants less than 3 months of age without any cardiorespira- infusion rates in neonates are greater than in older children,
tory compromise can be fed and wrapped snugly for an MRI reaching 400 mcg/kg/min at the beginning to transition from
and CT without sedation [134]. the sevoflurane induction and prevent movement during the
A topic for debate at present is whether the risk of a CT initial scan. Thereafter, the infusion rate of propofol may be
scan with its ionizing radiation exposure is less than the risk tapered to 250–300 mcg/kg/min. Respiration is monitored
using the baffled nasal cannula with a CO2 sample line and must remain beyond the perimeter of the scanner, and long
pulse oximetry. Dexmedetomidine has been used for seda- breathing circuit tubing must be fed through the copper hole
tion for MRI scans in infants and children with nonin the wall to ventilate the neonate during a general anes-
instrumented airways using very large doses of 3 mcg/kg thetic. Reliable monitoring is essential for all patients who
loading followed by 2 mcg/kg/h infusion [138], whereas we require anesthesia for MRI. This is a particular challenge for
have shown that a small dose of IV midazolam (0.1 mg/kg) infants as the monitors are often not optimized for very small
given at the beginning of the sedation allows for much patients. One of the more problematic monitors is the pulse
smaller infusion rates of dexmedetomidine, 1 mcg/kg load- oximeter, which often dislodges from the digit on which it
ing dose, followed by 0.5 mcg/kg/h [139]. There are no data was applied in neonates. In addition, there is often a limited
regarding dosing of dexmedetomidine for sedation in neo- choice of sizes of blood pressure cuff. Additional risks from
nates, although pharmacokinetic data suggests that the clear- the MRI environment include ferromagnetic projectiles that
ance of dexmedetomidine in neonates is one-third than in may kill the child within the scanner.
adults, which might mean that the infusion rate could be
reduced [140]. In those with craniofacial and airway anoma-
lies and in ex-premature infants (<60 weeks’ postconcep- Cardiac Catheterization Laboratory
tional age), tracheal intubation (or an LMA) may be indicated
to complete the scan [141]. One of the most common areas outside of the NICU and OR
where neonates require sedation and anesthesia is the cardiac
catheterization laboratory. Transthoracic echocardiography
Cardiac MRI in infants has a very good image window so that most cardiac
diagnoses can be undertaken using noninvasive echocardiog-
There is a growing use of cardiac MRI scans to diagnose raphy. However, infants with complex cardiac abnormalities
cardiac disease in infants, including those in the NICU [142]. may require a diagnostic cardiac catheterization procedure to
Cardiac MRIs are capable of imaging all of the thoracic accurately determine the nature of the anatomy, function,
organs, the respiratory anatomy, and cardiac function and and physiology as well as for cardiac interventions, often to
anatomy in a single technique, without radiation exposure. increase pulmonary and aortic blood flows. This is more
Other benefits include avoiding the use of IV contrast and likely to be a concern in those infants who are critically ill in
potential catheter-related complications [143]. In the criti- the NICU and may require the services of the pediatric anes-
cally ill neonate, monitoring both the arterial and venous thesiologist. In addition, MRI of the heart and lengthy elec-
pressures is important to titrate the dose of anesthesia and trophysiologic procedures such as radiofrequency ablation
volume of fluids. Although cardiac MRI scans often require of aberrant conduction pathways, pacemaker insertion, and
prolonged anesthesia, their duration is similar to that of diag- automatic implantable cardioverter defibrillator placements
nostic catheter procedures. Additional challenges during in infants have required the services of a skilled anesthesiol-
MRI in neonates include the limited access to the neonate ogist knowledgeable in cardiac anesthesia for infants [145].
while within the scanner, the need for an MRI-compatible Often in non-OR anesthesia locations there are concerns
anesthetic workstation, borderline reliable MRI-compatible that the anesthesia machine is often older and may be of an
neonatal monitors, and temperature control. The low ambi- unfamiliar brand or model. The monitoring may not be as
ent temperature required to cool the magnet combined with extensive or as up to date as in the OR. Providing anesthesia
the neonate’s inability to maintain normothermia and the in a remote location also is complicated by the anesthesiolo-
lack of MRI-compatible effective warming devices increase gist being less familiar with the location, with limited assis-
the risk for hypothermia while the neonate is within the scan- tance as well as possible inadequate communication with the
ner. Consequently, neonates must be cocooned in warm blan- off-site staff. These factors may be partly why closed claim
kets. Neonates under general anesthesia are four times more analysis has demonstrated that these remote locations are
likely to become hypothermic as compared with fed and more likely to suffer from serious complications [146]. A
wrapped patients. Propofol appears to increase this risk when plan for communication within the off-site itself for emer-
compared with sevoflurane [144]. gencies as well as with the main OR is important to facilitate
Equipment challenges present a daunting financial obsta- the best care possible.
cle if anesthetic services were included in the design of MRI Several common cardiac diagnoses that may require
units, although the capital cost of MRI-compatible anesthetic intervention are presented (Table 13.8). With the approval of
equipment is a very small fraction of the total cost of the the new Piccolo device (Abbott laboratories) for PDA occlu-
MRI unit. MRI-compatible anesthesia workstations are sion in ELBW infants >700 g, in many institutions, surgical
available for use within the MRI scanner room. If an MRI- ligation is being replaced by transcatheter closure (Fig. 13.9).
compatible workstation is not available, then the workstation This procedure for the most part is performed in the cardiac
Table 13.8 Diagnosis requiring cardiac intervention catheterization laboratory in ELBW infants. As majority of
PDA closure these infants are hemodynamically unstable requiring respi-
Balloon atrial septostomy—infants <8 weeks age for: ratory support, additional challenges are experienced by
TGA—before switch procedure if hemodynamically unstable anesthesiologists during transcatheter occlusion.
TAPVR with restrictive ASD There are several aspects of the sedation or anesthesia in
Tricuspid atresia with restrictive ASD
PV atresia with intraventricular septum neonates that must be considered in the cardiac catheteriza-
Hypoplastic left heart partially reduces gradient across atrial septum tion lab. First, the cardiologists require physiologic variables
Blade atrial septostomy > older than 8 weeks age: as close to the normal values for the neonate as possible in
Same as per balloon septostomy order to make correct diagnoses regarding the heart defect.
Balloon dilation of cardiac valves for: As a result, it is important that we provide enough anesthesia
Pulmonary valve stenosis
Aortic valve stenosis
for the neonate for the investigation but not too much anes-
Coarctation (NB., surgery is still the preferred treatment in neonate thesia to depress the myocardium. That anesthetics generally
and infants (post-dilation aneurysm risk is greater)); TGA, decrease cardiac contractility and disturb the balance of
transposition of the great arteries; TAPVR, total anomalous pulmonary shunts in a dose-dependent manner should provide a metric
venous return; ASD, atrial septal defect; PV, pulmonary valve for the amount of anesthetic that should be administered.
Intubation Warm
Significant lung a
disease often
and general mattress
makes ventilation
anesthesia
challenging during
in the cath
the procedure
lab
(may need high
frequency ventilation)
Aortic arch
PDA with device
Pulmonary
artery with
catheter
Advantages:
1. No thoracotomy/
A. Chest X-ray before occlusion of the PDA
lung collapse
2. Low incidence of Satyan
showing increased pulmonary vascularity
post-ligation and enlarged cardiac silhouette.
syndrome
3. Confirmed b
occlusion of PPA
Insertion
4. Venous access
through
femoral
vein
Disadvantages:
1. Transport to the cath lab
2. Radiation from fluroscopy
3. Complications of general
anesthesia
4. Risk of hypothermia
5. Dislodgement of device
6. Occlusion of oher vital vessels
7. Damage to tricuspid value,
chordae, papillary muscle,
pulmonic value etc., (rare) B. Chest X-ray after occlusion of the PDA (white
arrow pointing to the device) showing descresed
pulmonary vascularity and normal cardiac silhouette.
Fig. 13.9 Procedure for transcatheter occlusion of PDA in ELBW Pediatric Cardiology, UC Davis Children’s Hospital). Modified from
infants. The left panel shows the logistics of occlusion along with pro- Patent ductus arteriosus in preterm infants: is early transcatheter closure
cedural challenges, advantages, and disadvantages. The right panel a paradigm shift? Vali P, Lakshminrusimha S, Pelech A, Underwood M,
shows chest X-rays before (a) and after (b) transcatheter closure of Ing F.J Perinatol. 2019 Nov;39(11):1449–1461. https://doi.org/10.1038/
PDA in a preterm infant showing reduction in pulmonary vascularity s41372-019-0506-7. Epub 2019 Sep 27. PMID: 31562396 Review.
following the procedure (X-rays courtesy Dr. Frank Ing, Chief of Copyright Satyan Lakshminrusimha
Hemodynamic measurements recorded during a diagnostic hematocrit [150]. When the latter cardiologists are involved,
cardiac catheterization under general anesthesia may be dis- 1–2 units of PRBC should be present in the catheterization
crepant from those estimated by the awake echocardiogram lab before commencing the procedure. Blood must always
if excessive doses of anesthetics that depress the myocar- be present for balloon dilatations as a ruptured major vessel
dium and vasodilate the peripheral vasculature are adminis- or dissection of a vessel may occur. The transfusion rate for
tered. Second, the anesthetics may alter the balance of SVR interventional cases in one multicenter study (all-age
and PVR, thereby changing the amount and direction of children) was 14% [151]. It is wise to check the units to be
shunted blood resulting in changes in the shunt fraction. This certain the bags have been assigned to the neonate under
may be reflected in both the cardiac catheterization images your care, although most blood release for this purpose is
and the SaO2 measurements used to estimate the size of the type O negative.
shunt. Third, the anesthetics may decrease cardiac contractil- Procedural damage to the cardiac endothelium could cause
ity or vasodilate the peripheral vasculature altering the pres- thrombus formation resulting in embolic complications.
sure gradient across a narrowed cardiac valve or outflow Heparin is frequently used (50–100 units/kg) to achieve an
tract, thereby raising doubts about whether or not to dilate ACT of ≥200. There is a hemorrhage risk exists if the ACT is
the restricted orifice. If a balloon procedure is undertaken, too high or as a result of any mechanical injury. Hypotension
significant changes in cardiac function may occur resulting can be multifactorial; anesthesia related, hypovolemia due to
in redistribution of blood flow that can cause complications unrecognized bleeding or due to cardiac complications.
especially in a critically ill neonate with limited cardiopul- During the balloon inflation phase of valvuloplasty, there is a
monary reserve [148]. Most importantly, in the cardiac cath- dramatic fall in cardiac output due to the transient very high
eterization laboratory, access to the neonate is restricted by afterload resulting in severe hypotension, which normally
the presence of bulky radiological equipment requiring retunes to baseline with balloon deflation. If this hypotension
remote access to the IV injection ports and possibly persists, then concern for outflow tract rupture with tampon-
obstructed views of the monitors by equipment and the dark ade or very severe valve regurgitation should exist, with
lighting. Furthermore, if the anesthesiologist does not work emergent ultrasound and intervention accordingly [150].
in the cath lab frequently, the environment is unfamiliar and There are important safety factors for the anesthesiologist
the nursing assistance may be variable. None of these issues when providing anesthesia in a fluoroscopy suite: the anes-
may become important until an acute crisis occurs. thesiologist should take the appropriate steps to avoid undue
Cardiac arrhythmias are the most common major compli- radiation exposure [146]. This should include wraparound
cation during pediatric cardiac catheterization procedures lead aprons, thyroid protection, and protective eyewear. Also
[149]. Cardiac arrhythmias occur in about 7% to 11% of car- the use of portable lead shields between the radiation source
diac catheterization procedures. They may be transient, but and the anesthesia location is important. These considerations
about 25% require cardioversion and about 40% anti- are especially pertinent when using biplane imaging as this
arrhythmic therapy [150]. Often they are caused due to increases the risk of exposure. Some anesthesiologists may
mechanical stimulation by the catheters. If they persist, then wish to leave the room during the angiography runs; this
this could be due to myocardial ischemia, or damage to either obviously necessitates the ability to monitor the patient from
the myocardium or the conduction system. Arrhythmias may a remote location, even for a short period. Also the anesthesi-
be more likely if the child is hypoxic, hypercarbic, acidotic ologist should use their personal dosimeter during all cases
or has underlying electrolyte abnormalities. When anti- involving the potential for radiation exposure. Distance from
arrhythmics or pacing is required, it is usually under the source, degree of barrier protection, and exposure time
direction of the interventional pediatric cardiologist. Cardiac (including the frequent screening imaging) are the important
arrest has been reported to occur in about 2.5% of neonatal considerations. The threshold exposure for cataract formation
procedures in the catheterization lab. can occur even after a few years of unprotected exposure. The
Blood loss is infrequent during cardiac catheterizations maximum exposure for a medical worker is 5 rem/year.
(4–7%), but when procedures such as balloon dilatation are
involved, the blood loss could be catastrophic [151]. In most
centers, routine cardiac catheterizations do not involve much reanesthetic Assessment of the Neonate
P
blood loss as the only vascular access occurs at the site of in the Cath Lab
venous or arterial cannulation. Most cardiologists pay metic-
ulous attention to stopping all bleeding once their catheters The preanesthetic assessment of the neonate who is sched-
are positioned, but a minority does not, especially in cya- uled for cardiac catheterization lab procedures is exceed-
notic heart lesions that rely upon a higher hemoglobin for ingly important in neonates. The history and physical
normal oxygen delivery. Careful attention to blood loss is examination should focus on the heart defect identifying
particularly important in neonates who have a small blood limitations such as heart failure denoted by tachypnea, poor
volume and in cyanotic patients accustomed to an increased feeding, and recurrent URTI, which also may be due to
excess pulmonary blood flow. Details of every previous neonates are too great to recommend this approach in most
anesthetic and previous cardiac surgery and interventions are neonates and as such ventilation is usually controlled.
important to document. For example, the presence of a sub- General inhalational anesthesia with tracheal intubation
clavian flap for coarctation repair requires that the NIBP and and paralysis (if needed) remains the most common anes-
pulse oximetry probe should be sited on another extremity. thetic regimen for many neonates (Table 13.9). The inci-
These neonates often have a history of multiple previous dence of respiratory and/or cardiac complications secondary
admissions and procedures, which may make it difficult to to IV sedation in infants whose airways are not intubated is
establish IV access. Although drug allergies are infrequent in 5%. These adverse events during cardiac catheterization are
neonates, family history of reactions to anesthetics and poly- more likely to occur in those infants with complex or cya-
morphisms in enzyme systems should be documented. The notic heart disease, young age, and reduced body weight.
preoperative hematocrit may reflect systemic problems such The incidence of airway complications is more likely in sev-
as nutritional deficiency, feeding difficulties, chronic illness eral subgroups of infants as listed in Table 13.10.
or chronic hypoxia, and repeated blood draws. If the HCT Intravenous sedation with propofol has been used for car-
exceeds 65%, hyperviscosity may present difficulties and diac catheterization, although hypotension may present a
may require phlebotomy before commencing the procedure. concern at induction of anesthesia in premature infants who
are hypovolemic. Ketamine is also a popular anesthetic
because it maintains cardiac function (often despite hypovo-
Anesthetic Technique lemia), and side effects such as behavior problems do not
occur in neonates [156, 157]. Its use is often combined with
There is a host of different sedation and anesthesia regimens midazolam [158]. Pulmonary hypertension is associated
(Table 13.9) that have been used in neonates in the catheter- with significant perioperative risk for complications in
ization lab [152–159]. In many institutions, cardiac catheter- infants because it may cause a pulmonary hypertensive crisis
ization was historically performed using an oral [131, 152] and cardiac arrest. In adults, there is evidence that ketamine
or intramuscular sedation. Deep sedation with oral medica- increases pulmonary artery pressures, although recent stud-
tions is unreliable in onset, efficacy, and duration. As a result, ies have disputed this notion [156, 159].
IM cocktails such as the Toronto cocktail and CM3 (meperi- High-dose opioid anesthesia is considered the safest anes-
dine, promethazine, and chlorpromazine) were more com- thetic technique for neonates with cardiac disease, but it may
monly used. However, this form of IM deep sedation is now preclude tracheal extubation at the conclusion of the proce-
rare due to the unpredictable nature of sedation, the slow dure. This is true for opioids such as fentanyl and sufentanil
emergence, and the risk of sterile abscess. More importantly, because of their prolonged half-lives. However, if the high-
published reports [153, 154] of respiratory compromise and dose opioid technique were based on remifentanil, an opioid
cardiac decompensation led to recommendations from the with a context-sensitive half-life of less than 5 min in neo-
APA [155] against their use. nates, then recovery will occur within minutes after terminat-
Neonates whose airways are already intubated are often ing the remifentanil infusion, and the airway could be
sedated and ventilated by the NICU team using intermittent extubated immediately. Interestingly, some have maintained
doses of midazolam and fentanyl and neuromuscular blocking spontaneous respiration during remifentanil sedation (0.1–
agents. Although there are several theoretical benefits from 0.2 mcg/kg min) in infants for cardiac catheterization,
maintaining spontaneous respiration during a diagnostic cath- although the dose required was quite variable and the need
eterization such as avoiding circulatory depression and avoid- for supplemental sedation increased the risk of apnea [160,
ing the physiologic consequences of positive pressures within 161]. Remifentanil has also been administered in combina-
the chest. However, the risks of hypoventilation, atelectasis tion with an inhalational-based anesthetic in the cardiac
and desaturation, hypoxia, and cardiac arrest in critically ill catheterization lab [162], although the only pain that occurs
is at the initial vascular access and if balloon dilatation is
Table 13.9 Sedation techniques performed. We speculate that contribution of remifentanil
1. Inhalational anesthesia
(a) Sevoflurane Table 13.10 Risk factors for airway events
(b) Isoflurane
Sedation
(c) Desflurane
Airway abnormalities
2. TIVA
(a) Propofol GERD (gastroesophageal reflux disease)
(b) Ketamine High PVR
(c) Remifentanil IJ/SCV access
(d) Dexmedetomidine Prostaglandin infusion
3. Regional anesthesia: caudal/epidural or spinal Down syndrome
may be more for its sedative effects than analgesia. In this d esflurane, and sevoflurane, prolonged the QT interval with-
situation, remifentanil may be used more for its sedative out increasing the dispersion of repolarization and, therefore,
rather than analgesic effect. Interestingly, glycopyrrolate was without increasing the risk of torsades. The clinical signifi-
needed to prevent bradycardia in these infants; also the cance of this last effect in the presence of an intrinsic myo-
hemodynamic assessment of these neonates will be closer to cardial conduction defect remains unclear. In cases in which
baseline if the heart rate is closer to normal, rather than the neonate is hemodynamically unstable or the arrhythmias
slowed due to anesthesia. are potentially life-threatening, invasive arterial pressure
Dexmedetomidine, an alpha-2 agonist, has been advo- monitoring may be indicated.
cated for cardiac catheterization both as a solo anesthetic
[163] and as an adjunct to inhalational or IV sedation regi-
men [164]. It has been used safely in neonates when com- Complications
bined with sevoflurane for surgical procedures [165].
Although dexmedetomidine may transiently increase sys- Complications from cardiac catheter procedures have been
temic blood pressure and systemic vascular resistance (the reviewed in some detail in the literature [151, 170, 171, 173–
loading dose) in those with pulmonary hypertension, PVR 177]. The overall incidence of all complications during inter-
remained unchanged [166]. ventional procedures (10%) was almost twice that for
Some have advocated spinal anesthesia with hyperbaric diagnostic procedures [143] with airway complications com-
0.5% bupivacaine 1 mg/kg for infants undergoing cardiac prising 3% of the complications. When the risk of complica-
catheterization [167], although the failure rate was 25%, and tions after cardiac catheterization was stratified by age, the
supplemental IV sedation was required in 50% of the infants. risk in infants was twice that in older children [151, 175].
The potential benefits of this technique include stable hemo- Other risk factors included low weight and cyanotic or com-
dynamics, a reduced BIS without adding sedatives and plex congenital heart disease [176].
avoiding the need to intubate the trachea in infants who could Interventional procedures have additional potential compli-
be at increased risk for extubation failure, and prolonged cations related to the anatomy and the procedure. Complications
post-procedural ventilation due to chronic respiratory dis- from balloon atrial septostomy include transient arrhythmias
ease [168]. However, if a spinal technique were selected to with premature ventricular contractions, supraventricular
prevent postoperative apneas in an ex-premature infant tachycardia, and atrial fibrillation, the most common. Partial/
undergoing cardiac catheterization, the frequent need of complete heart block and ventricular tachycardia may also
adjunctive sedatives would result in an incidence of apnea no occur. Failure to create an adequately sized atrial communica-
different from that of a general anesthetic [158, 169]. tion, perforation, or damage to the intracardiac valve has also
Although electrophysiology (EP) studies in neonates are been reported. Balloon dilation of the pulmonary valve is one
infrequent, they may be performed for pharmacologically of the most common interventional cardiac catheter proce-
resistant tachyarrhythmias [170]. As a result of the complex dures in infants, indicated for a pulmonary valve gradient
nature of these procedures and the concern regarding the >50 mmHg. These infants are usually receiving prostaglandin
safety of prolonged deep sedation, general anesthesia is E1 (PGE1) infusions to maintain ductal patency. As a result of
often required. A study of EP cases in adults questioned the the respiratory depressant effects of the PGE1, these infants
safety of deep sedation because of the substantial (40%) risk often require tracheal intubation. Aortic valve dilation has
of airway complications [171]; however, comparable data in similar but greater risks than pulmonary valve dilation, most
neonates have not been forthcoming. notably attributed to the risk of ventricular fibrillation from
Several anesthetic regimens may be used to anesthetize which resuscitation may be a challenge. Young infants may be
neonates for EP cases [172]. However, it is best to avoid at greater risk for complications from catheter-based therapies
anesthetics that inhibit the sympathetic nervous system, such [151], although the risk is probably less than that of the surgi-
as dexmedetomidine, to minimize the risk of interfering with cal approach. In some cases, this allows a palliative procedure
the detection and treatment of the arrhythmias. Total intrave- to be performed before a safer definitive repair can be under-
nous anesthesia with continuous infusions of propofol and taken, when the child has grown.
remifentanil has been effective in this situation. Inhalational Pulmonary arterial hypertension (PAH) can lead to sig-
anesthetic may also be used; however, a rapid increase in the nificant cardiac dysfunction and is known to place the
inspired concentration of desflurane in the absence of a back- infant at an increased risk of perioperative cardiovascular
ground of opioids may induce paroxysmal sympathetic stim- complications. Baseline suprasystemic PAH is a significant
ulation, although this has never been documented in a predictor of major complications [177]. Children with
neonate. Sevoflurane maintains a stable heart rate and myo- suprasystemic PAH have a significant risk of major periop-
cardial contractility in children with congenital heart defects erative complications, including cardiac arrest and pulmo-
[169]. All three inhalational anesthetics, isoflurane, nary hypertensive crisis.
Rarely, the wire or catheter perforates a wall in the heart young children, this usually requires general anesthesia with
or a major blood vessel or the balloon ruptures a major valve intubation [146]. Removal of the femoral sheath can result in
or artery during a controlled dilatation. This potential disas- bleeding, especially if the patient will not lie still. Deep extu-
ter is best managed by increasing the inspired oxygen con- bation or the use of dexmedetomidine post-extubation has
centration to 100%, calling the cardiac surgery team for been recommended; however, an appropriate location for pro-
possible emergency bypass, stopping the procedure, and longed monitoring of the sedated child is required. Blood
leaving the perforating wire/catheter in place or the balloon pressure monitoring and control may also be necessary both
inflated. Blood should be available in the room to transfuse if during and post-procedure; this may require the placement of
bleeding persists. If the femoral venous catheter is involved an arterial line. Postoperative management may be best pro-
in the perforation, a second large bore IV should be accessed vided in an intensive care setting. This allows for sedation as
for transfusion of blood products. A blood warmer should be needed, appropriate hemodynamic monitoring and interven-
placed in-line to warm the blood during transfusion. If sur- tion as necessary, and hourly neurological assessments in the
gery is required, additional blood should be ordered and a cases of interventional procedures.
transport monitor and stretcher prepared for the rapid trans-
fer to the OR. The severity of the perforation or accumula-
tion of pericardial blood should be assessed using Conclusion
transthoracic echocardiography before transfer. If a hemo-
pericardium is forming, pericardiocentesis should be per- The provision of anesthesia in the NICU and in medical units
formed immediately to preclude a cardiac tamponade. for neonates can be a daunting challenge. These infants are
There are several cardiac diagnoses that appear to have a usually among the most critically ill neonates we are asked to
high risk of mortality during cardiac catheterization. These anesthetize, often requiring major surgery and with substan-
include a stage 1 palliation of hypoplastic left heart syn- tive mortality rates. Practicing in an unfamiliar environment
drome; induction instability is associated with procedures without access to the usual anesthesia equipment requires that
performed prior to Glenn procedure. Single ventricle physi- the anesthesiologist be proactive in deciding what is required
ology with anesthesia induction and positive pressure venti- to successfully manage the infant. Furthermore, the NICU is
lation has been reported to increase the risk of myocardial often remote from the OR, rendering the anesthesiologist a
ischemia and cardiac arrest. Also pulmonary hypertension virtual “solo” practitioner as assistance from other anesthesi-
with RVH during the induction of anesthesia with positive ologists and anesthesia technicians may be delayed or com-
pressure ventilation, decreases the right ventricular preload pletely unavailable, such as at night. Restricted access to the
and increases the afterload. Due to a lack of pulmonary blood infant and the use of unfamiliar ventilation modes and moni-
flow, resuscitation is extremely difficult. This necessitates tors also make care more difficult. The anesthetic prescription
maintaining an adequate preload along with inotropic sup- is usually relatively straightforward with most reports using
port for the failing right ventricle. Inhaled nitric oxide should an opioid-relaxant technique. It is very important to establish
be readily available to reduce the afterload if either a pulmo- excellent communication between all the physicians and
nary hypertensive crisis or cardiac arrest occurs. healthcare staff involved in the case. The anesthesiologist
In some institutions, all pediatric cardiac catheterization should use the knowledge and skills of the NICU staff includ-
procedures are anesthetized by the members of the pediatric ing the physicians, nurses, and respiratory therapists to ensure
cardiac anesthesiology team. However, this may not always the anesthetic proceeds smoothly. This will help to overcome
be possible. Those providing anesthesia care for neonates in potential difficulties that can arise during anesthesia in remote
the cardiac catheterization lab should be well acquainted and unfamiliar locations. Teamwork and planning are of para-
with concepts of neonatal anesthesia, routine and complex mount importance in order to deliver safe, optimal care for
congenital cardiac lesions, and the procedure site. these very ill neonates.
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Fetal Surgery and the EXIT Procedure
14
Marla B. Ferschl and Mark D. Rollins
Introduction Anesthetic Considerations for Fetal Surgery
The goal of fetal surgery is to correct or mitigate a severe or reoperative Evaluation of the Fetal Surgery
P
otherwise potentially lethal congenital anomaly in utero to Patient
minimize the physiologic derangements caused by the lesion
postnatally [1]. The subspecialty of fetal surgery has evolved Fetal procedures are indicated when an in utero intervention
significantly since the first fetal procedure, an intrauterine will alter the course of the pathologic process and prevent or
blood transfusion that was performed in 1963 [2]. Though mitigate otherwise predicable end-organ damage.
some fetal procedures remain investigational, prospective International multidisciplinary guidelines for performing
trials have validated the efficacy of others, leading to an fetal procedures were originally established in 1982 [3]. In
increased number of fetal procedures being performed the intervening period, these recommendations have evolved
worldwide. When providing perioperative care for these pro- and presently include the following: (1) the fetal diagnosis is
cedures, the anesthesiologist must treat two patients—the accurately established; (2) the anomaly progression is pre-
mother and the fetus. In this chapter, we evaluate the preop- dictable; (3) additional severe anomalies are not concur-
erative management of fetal surgical candidates with a rently present; (4) if untreated, the anomaly would lead to
review of maternal and fetal physiology, discuss the anes- fetal demise, end-organ damage, or severe morbidity; (5)
thetic techniques for both minimally invasive and open fetal maternal risk is low; (6) animal models have demonstrated
procedures, detail postoperative pain management consider- success with in utero lesion treatment; and (7) interventions
ations, review fetal anomalies amenable for prenatal inter- are performed at centers with specialized, multidisciplinary
vention, and examine the indications for the ex utero fetal teams, including access to bioethical care and counsel-
intrapartum therapy (EXIT) procedure with a focus on anes- ing [4]. Improvements in imaging including ultrasound
thetic management for EXIT cases. image resolution and the initiation of fetal magnetic reso-
nance imaging (MRI) as a method of evaluating fetal anat-
omy have vastly improved the field of fetal therapy, allowing
providers to develop therapeutic interventions for earlier
gestational ages [5]. Lesions presently amenable to fetal
intervention are listed in Table 14.1.
Planning for fetal surgery involves a multidisciplinary
team that consists of surgeons, anesthesiologists, ultraso-
nographers, neonatologists, maternal-fetal medicine spe-
cialists, nurses, genetic counselors, and social workers.
Anesthesiologists are a critical component of this periop-
erative process, especially the preoperative assessment of
maternal health.
M. B. Ferschl (*)
University of California San Francisco, San Francisco, CA, USA
M. D. Rollins
Mayo Clinic, Rochester, MN, USA

486 M. B. Ferschl and M. D. Rollins
Table 14.1 Fetal conditions amenable to prenatal intervention

Lesion Intervention Rationale
Fetal anemia Fetal IUT Prevent hydrops
TRAP Radiofrequency ablation of acardiac twin Prevent heart failure in viable twin
TTTS Selective fetoscopic laser photocoagulation Decrease unequal blood sharing between twins; prevent
cardiac failure and hydrops
Amniotic band syndrome Fetoscopic band ablation Prevent limb loss
LUTO Vesicoamniotic shunt placement or ablation of Improve renal function and lung growth
posterior urethral valves
Aortic stenosis with Balloon dilation of aortic valve Increase blood flow through left ventricular outflow tract;
evolving HLHS increase likelihood of biventricular outcome
CDH Fetoscopic tracheal balloon occlusion Reduce pulmonary hypoplasia
SCT Ablation of tumor vasculature or open Reduce high-output cardiac failure and fetal hydrops
debulking
CPAM Thoracoamniotic shunting or open resection Reduce hydrops, cardiac failure, and lung hypoplasia
MMC Open or fetoscopic MMC repair Reduce hindbrain herniation, hydrocephalus, and need for
ventriculoperitoneal shunting; improve neurologic function
At no time should maternal safety be significantly jeopar- Table 14.2 Cardiopulmonary changes of pregnancy
dized for a fetal intervention. Maternal risks, benefits, and Term value compared to
alternatives should be thoroughly explained, focusing on Component prepregnancy
possible outcomes from the proposed procedure and impli- Cardiovascular
cations for both present and future pregnancies [6, 7]. Cardiac output Increased 40–50%
Effective counseling is specific, thorough, realistic, and Stroke volume Increased 25–30%
Heart rate Increased 15–25%
empathetic [8, 9]. If surgery proceeds for a fetus that is of a
Intravascular volume Increased 35–45%
viable gestational age, additional discussion is necessary to Plasma volume Increased 45–55%
determine whether resuscitation is advisable or possible in Erythrocyte volume Increased 20–30%
the event of fetal distress requiring emergent delivery. Coagulation factors
Factors I, VII, VIII, IX, X, XII, VWF Increased
Factors XI, XIII, antithrombin III, Decreased
Maternal Physiology protein S
Factors II, V, protein C Unchanged
Pulmonary
During pregnancy, women undergo significant physiologic
Minute ventilation Increased 45–50%
changes that directly impact the perioperative anesthetic
Tidal volume Increased 40–45%
management [10–12]. These alterations are secondary to Respiratory rate Increased 0–15%
hormonal activity, increasing metabolic demands and bio- Oxygen consumption Increased 20%
chemical changes from the growing fetus, placenta, and Total lung capacity Decreased 0–5%
uterus. The physiologic changes of pregnancy at term are Vital capacity No change
summarized in Table 14.2. Functional residual capacity Decreased 20%
Created and adapted from information from: Page SM, Rollins
aternal Circulatory System
M MD. Physiology and Pharmacology of Obstetric Anesthesia, Chapter
37. In Hemmings HC, Egan TD (Eds.), Pharmacology and Physiology
Physiologic anemia during pregnancy (hemoglobin levels
for Anesthesia, Foundations and Clinical Application (2nd Edition).
decreasing to 11 g/dL) may be attributed to a greater increase Elsevier, Philadelphia, PA. 2019
in plasma volume (50%) than red blood cell mass (25%) by
term. The concentrations of albumin (25%) and total protein
(10%) are reduced at term, with a corresponding decrease in Increased peripheral sympathetic nervous system activity is
colloid osmotic pressure of 5 mmHg [13]. a compensatory reflex that attenuates the severity of supine
Supine hypotension occurs during pregnancy from com- hypotension in the presence of aortocaval compression to
pression of the vena cava by the gravid uterus. In the supine maintain the blood pressure despite a reduced cardiac output.
position, aortic compression occurs in 15–20% of term preg- Sympathetic tone is reduced with general or neuraxial anes-
nant women. Vena cava compression is nearly universal and thesia, further increasing the degree of hypotension in the
may occur as early as the start of the second trimester. Vena supine position. Consequently, displacing the uterus to the
cava compression causes venous blood to pool in the lower left by elevating the right hip or airplaning the table to the
extremities and increases the risk of deep vein thrombosis. left, along with administering fluids and vasopressors during
14 Fetal Surgery and the EXIT Procedure 487
anesthesia after mid-gestation, will increase the maternal of normal during pregnancy. As the plasma protein concen-
preload, cardiac output, and blood pressure. trations decrease, the free serum concentrations of highly
Cardiac output increases during pregnancy to a value protein-bound maternally administered drugs increase.
40–50% greater than the prepregnancy by the third trimester. Renal blood flow and glomerular filtration rate increase
The increased cardiac output ensures the total oxygen deliv- 50–60% by the start of the second trimester of pregnancy.
ery is maintained despite the reduced oxygen-carrying Consequently, blood urea nitrogen and serum creatinine val-
capacity secondary to physiologic anemia. The greatest ues decrease approximately 50% during pregnancy.
increase in cardiac output occurs immediately after delivery, The minimum alveolar concentration (MAC) for inhala-
which may reach ≥80% greater than the antepartum levels. tional anesthetics decreases during pregnancy. This is based
The sources of the increased cardiac output include auto- on studies in which pregnancy decreased the MAC in ani-
transfusion from the uterus, removal of aortocaval compres- mals by 40% and in humans by 28% during the first trimester
sion, and diminished lower extremity venous pressure. [10, 11, 18, 19]. However, an EEG study of the effects of
Pregnancy results in significant increases in factor I sevoflurane suggests that the anesthetic effects on the brain
(fibrinogen) and factor VII, decreases in factors XI and XIII in pregnant and nonpregnant patients may not differ [20].
and antithrombin III, and smaller increases in other factors Given these findings, it is not recommended to reduce stan-
(Table 14.2). These changes result in a hypercoagulable state dard anesthetic levels in stable obstetric patients.
with a 20% decrease in both prothrombin time (PT) and par-
tial thromboplastin time (PTT). In most cases, platelet levels
decrease minimally (10%) by term because of plasma dilu- Uterine and Placental Physiology
tion. Up to 10% of pregnancies are complicated by thrombo-
cytopenia with gestational thrombocytopenia accounting for Physiologic transfer of gases, nutrients, and drugs between
approximately 70% of cases [14]. mother and fetus occurs via the placenta. Maternal blood
flows from the uterine spiral arteries into the intervillous
aternal Airway and Pulmonary Systems
M space which lies between the basal and chorionic placental
During pregnancy, edema and tissue friability increase plates (Fig. 14.1). Fetal blood flows to the placenta via two
throughout the larynx, pharynx, and trachea. This poses umbilical arteries. After placental transfer at the chorionic
difficulty for laryngoscopy and intubation. The presence of villi, oxygen and nutrients return to the fetus through the
preeclampsia, respiratory infections, and labor also increase umbilical vein.
airway edema. The present rate of failed peripartum intuba- Uterine blood flow increases from approximately 100 mL/
tion is estimated to be approximately 1:533, based on a min before pregnancy to approximately 700 mL/min (10% of
multi-institutional database [15]. cardiac output) by term. Approximately 80% of uterine blood
Maternal minute ventilation increases approximately 50%, flow perfuses the placenta, and 20% maintains the myome-
oxygen consumption increases by more than 20%, and func- trium. Uterine vessels remain nearly maximally dilated dur-
tional residual capacity decreases by 20% at term. These ing pregnancy. Maternal hypotension and decreased cardiac
changes result in rapid desaturation during apnea and increase output can reduce uterine blood flow and result in placental
the risk of complications when combined with difficult intuba- hypoperfusion, fetal hypoxemia, and fetal acidosis. Maternal
tion. The increased minute ventilation decreases the maternal heart rate correlates closely with cardiac output during preg-
PaCO2 to 30 mmHg by the end of the first trimester. The increase nancy [21, 22]. Consequently, present recommendations for
in excretion of renal bicarbonate (HCO3, 20–21 mEq/L) leads cesarean delivery are to maintain both maternal blood pres-
to a slightly alkalotic arterial pH, at 7.42–7.44. sure and heart rate near baseline to optimize the fetal condi-
tion before delivery [22]. These recommendations should
ther Maternal Physiologic Changes
O also be strongly considered during fetal surgery. Methods to
During pregnancy, the esophageal sphincter tone is reduced, achieve these goals include the use of colloid preload or crys-
gastric pH is decreased, and gastric pressure is increased talloid co-load with initiation of anesthesia, a prophylactic
from the gravid uterus. These changes increase the fre- alpha-agonist (e.g., phenylephrine) infusion titrated as
quency of acid reflux during pregnancy and the risk of aspi- needed, and the use of left uterine displacement [22].
ration of gastric contents as general anesthesia is induced
[16]. Administration of nonparticulate antacids, H2 receptor
antagonists, and/or metoclopramide for aspiration prophy- Fetal Physiology
laxis should be considered before surgical procedures dur-
ing pregnancy [17]. Fetal surgery can disrupt both uteroplacental and fetoplacen-
Aspartate aminotransferase (AST), alanine aminotrans- tal hemodynamics and gas exchange. An appropriate under-
ferase (ALT), and bilirubin levels increase to the upper limits standing of fetal physiology is essential to ensure fetal
Maternal blood
Uterine spiral supply in
Chorionic villi artery and vein intervillus space
Placenta
Yolk sack
Amniotic fluid
Uterus Uterus
Chorion
Umbilical cord
Amnion
Umbilical arteries
Chorionic Intervillous Basal
Umbilical vein Myometrium
Plate Space Plate
Fig. 14.1 Placenta anatomy. Depiction of the placenta showing the structure and components of both fetal and maternal circulation. Figure modi-
fied from original on Wikimedia Commons. Author OpenStax College. https://commons.wikimedia.org/wiki/File:2910_The_Placenta-02.jpg
well-being. Fetal hemoglobin, which binds oxygen with All medications transfer from the mother to the fetus to
greater affinity than adult hemoglobin to compensate for the some degree, but some are significantly limited. Molecules
relative hypoxemia, is the primary oxygen carrier, although that are large, ionized, lipid insoluble, or significantly pro-
the production of adult hemoglobin begins at approximately tein bound do not readily cross the placenta. For example,
32 weeks’ gestation [23]. Fetal hemoglobin is relatively left- succinylcholine, non-depolarizing neuromuscular blockers,
shifted on the hemoglobin oxygen dissociation curve result- heparin, and glycopyrrolate do not cross the placenta to a
ing in 50% saturation (P50) at 18 mmHg compared with an significant degree. Other anesthetic agents such as opioids
adult hemoglobin P50 of 27 mmHg. Fetal acidosis promotes and inhalational anesthetics readily cross from the maternal
oxygen off-loading in times of distress [24]. With pregnancy, to fetal circulation. Sugammadex transfers, although its
the maternal hemoglobin is relatively right-shifted with a safety in terms of fetal exposure and effect on the pregnancy
P50 of 30 mmHg, which facilitates the transfer of oxygen remains unknown. Presently, it is not recommended for use
from the mother to the fetus. Fetal hemoglobin levels increase during pregnancy.
linearly throughout gestation, with a level of approximately Fetal circulation is significantly different from the circu-
11 g/dL at 17 weeks to 18 g/dL at term [25]. lation of the neonate (Fig. 14.2). Oxygenated blood from the
Two-thirds of circulating fetal blood is within the pla- placenta travels to the fetal liver via the umbilical vein (satu-
centa. After the first trimester, fetoplacental blood volume ration 70–80%) [31]. From the liver, blood enters the inferior
corresponds to gestational age and fetal weight with typical vena cava by one of two routes: either via the portal sinus
values of 100 to 160 mL/kg [25, 26]. circulation or the ductus venosus. Blood is then preferen-
Fetal PaO2 is normally 20–40 mmHg [24]. However, if tially directed to the fetal brain (carotid arteries) and heart
the mother inspires 100% oxygen, fetal PaO2 may increase to (coronary arteries) via the foramen ovale. Deoxygenated
60 mmHg. Fetal hemoglobin usually remains <65% satura- fetal blood reaches the placenta via two umbilical arteries.
tion because a significant amount of oxygen is extracted Normal fetal cardiac output is in the range of 425 to
from the maternal blood before it reaches the placenta [27, 550 mL/min/kg throughout pregnancy [32]. Heart rate is the
28]. In the presence of non-reassuring FHR patterns, supple- primary determinant of fetal cardiac output, as fluid-filled
mental oxygen for the mother improves fetal oxygenation lungs and decreased myocardial contractility prevent preload
during labor (based on fetal pulse oximetry) [29] and is from affecting cardiac output to any great extent [24, 33].
likely beneficial during fetal surgery, although this is not Sudden or significant decreases in fetal heart rate reduce
evidence-based [30]. fetal cardiac output and lead to fetal distress. Fetal lungs pro-
Fig. 14.2 Fetal circulation. Ductus arteriosus Aortic Arch Pulmonary

Fetal circulation allows vein
oxygen-rich blood from the
placenta to flow to the liver
where it divides into either the Superior vena
portal sinus or ductus venosus cava
before entering the inferior
vena cava. The majority of Pulmonary vein
flow passes through the Crista dividens
foramen ovale and enters the Left Atrium
aorta (directly perfusing the
Foramen ovale
brain and heart).
Deoxygenated blood returns
Right Atrium
to the placenta via umbilical
arteries. Figure modified from Pulmonary artery
Murphy JP. The fetal
circulation. Continuing
Inferior vena
Education in Anaesthesia
cava Descending aorta
Critical Care & Pain, Volume
5, Issue 4, 1 August 2005,
Pages 107–112 Ductus venosus
Portal Sinus Portal

vein
Inferior vena cava

Umbilical
vein
Placenta
Umbilical arteries
duce 100 mL/kg/day of fluid that flows from the trachea and for Doppler flow assessment in the ductus arteriosus and
is either swallowed or enters the amniotic cavity. umbilical artery. Absent and reversed umbilical artery flow is
Fetal hepatic synthetic and metabolic functions improve associated with increased rates of fetal demise [37]. For open
throughout gestation. Most drugs that cross the placenta procedures, when fetal hemodynamic instability is antici-
into the fetal circulation still undergo first-pass metabolism pated (e.g., open sacrococcygeal teratoma (SCT) resections,
before reaching the fetal brain or heart [34]. Coagulation EXIT procedures), fetal pulse oximetry can be employed.
factors are synthesized independent of the maternal circula- If fetal distress occurs during fetal surgery, the anesthesi-
tion and increase in concentration with gestational age, ologist should optimize maternal hemodynamics and fetal
though clot formation is immature until about 6 months perfusion. This includes augmenting maternal blood pres-
after birth. Platelet production commences at 5 weeks’ ges- sure and cardiac output, ensuring adequate uterine relax-
tation and increases to the normal adult range by 22 weeks’ ation, and altering the maternal position to optimize venous
gestation [35, 36]. return (left uterine displacement). The surgical team should
Certain procedures can significantly affect the hemody- be alerted to ensure that the umbilical cord flow is not com-
namics in the fetus. Perturbations in maternal physiology promised and that fetal manipulation and position have not
such as hypotension, hypocarbia, or uterine contractions all contributed to the distress. A decrease in the body tempera-
decrease uteroplacental blood flow, which can lead to fetal ture of the fetus can also cause bradycardia [38, 39].
distress. Umbilical cord compression and direct fetal com- Strategies should be undertaken to prevent fetal hypothermia
pression can impact the fetal blood flow. Intraoperative fetal by maintaining maternal core temperature with a warming
monitoring via direct ultrasonographic assessment of umbili- device and, in the case of open surgery, ensuring that irriga-
cal blood flow and fetal echocardiography are recommended tion fluids are warmed and the temperature of the amniotic
during fetal procedures. These monitors assess the fetal heart cavity is monitored.
rate, cardiac contractility, and cardiac filling, as well as allow
Fetal Pain Perception crosses the placenta and provides adequate fetal immobility
for fetoscopic procedures on the umbilical cord or the pla-
As early as 18 weeks’ gestation, the fetus can mount a sym- centa [57]. Inhalational anesthetic agents also cross the pla-
pathetic stress response to noxious stimuli such as pain [40, centa quickly, with studies in cesarean sections indicating
41]. However, the ability of the fetus to perceive pain remains that isoflurane has a fetal-to-maternal ratio of 0.7 after only
controversial, as the stress response is mediated at the level 10 min [58]. However, large doses of inhalational anesthetics
of the spinal cord, brain stem, and/or basal ganglia and is may depress the fetal myocardium, leading to fetal acidosis
unlikely to correlate with conscious perception of pain, [59, 60]. As a result, some institutions augment inhalation-
which is mediated by the cortex [42, 43]. However, fetal based anesthetic regimens with remifentanil [61] or a combi-
administration of opioid medications blunts the fetal stress nation of remifentanil and propofol to decrease the amount
response [40], and in preterm neonates, diminishing the of inhalational anesthetic administered to the mother [62].
stress response to surgery improves outcomes [44, 45].
Although inhalational anesthetics readily pass from the
maternal to the fetal circulation, they do not provide signifi- Anesthetic Neurotoxicity
cant analgesia or reliably suppress autonomic reflexes in the
fetus [46]. Opioids are required to reliably blunt the stress The impact of anesthetic agents on the development of the
response in the fetus. human brain is of foremost concern to providers administer-
Peripheral sensory nociceptors in the skin develop ing anesthetic agents to fetuses and neonates (see also Chap.
between 10 and 17 weeks’ gestation [47], and a fetus can 18). Animal models demonstrated profound histologic
reflexively withdraw from a painful stimulus by 19 weeks’ changes from anesthetic exposure to inhalational anesthet-
gestation, without cortical input [48, 49]. However, pain per- ics, propofol, and benzodiazepines. Furthermore, learning
ception requires intact neural pathways from the spinal cord and behavior deficits have been noted [63, 64]. Two recent
to the primary sensory cortex and on to higher cortical struc- human trials that examined the effect of a single, short-
tures. As a result, fetuses are unlikely to perceive pain before duration anesthetic exposure at a young age failed to demon-
24 weeks’ gestation [49]. This theory is supported by cortical strate any substantive early neurodevelopmental
EEG activity, which is present only 2% of the time in consequences [65, 66]; the FDA withdrew its 2011 proscrip-
24-week fetuses but 80% of the time in fetuses that are tion of anesthesia in children less than 3 years of age under-
34 weeks’ gestation [50]. going elective procedures [67]. However, long-term and
Because the exact timeline of pain perception by the fetus repeat exposure outcomes studies are ongoing. Based on ani-
is unknown, and because blunting the neural-humoral mal evidence, the U.S. Food and Drug Administration advi-
response associated with procedures in the fetus is benefi- sory committee issued a warning in 2016 that “repeated or
cial, analgesia should be provided during surgery in the fetus lengthy use of general anesthetic and sedation drugs during
[51]. Analgesia has been administered safely to fetuses for surgeries or procedures in children younger than 3 years or
over 35 years. In addition to blunting pain and the circulatory pregnant women during their third trimester may affect the
response to noxious stimuli, analgesia also promotes fetal development of children’s brains.” [67] To date, no clinical
immobility [52, 53]. studies have examined the neurocognitive effects of mid-
Opioids reach the fetal circulation by direct fetal intra- gestation fetal surgery, though an international registry has
muscular injection or maternal administration. For most been created to assess long-term neurodevelopmental out-
open fetal procedures that cause direct fetal stimulation, opi- comes in fetuses exposed to anesthetic agents during fetal
oids are administered directly to the fetus intramuscularly. surgery (Clinical Trials.gov identifier NCT02591745) [68].
The typical regimen is fentanyl 10–20 mcg/kg, administered Data are confounded by the fact that some fetal anomalies
under direct visualization or ultrasound guidance before the associated with “in utero” procedures result in developmen-
hysterotomy, although equipotent doses of alternate opioids tal delay independent of any exposure to anesthetics, and
can be used [53, 54]. In addition to opioids, many centers fetuses with congenital anomalies often require multiple
combine prophylactic anticholinergic medication (atropine anesthetics after birth [69].
20 mcg/kg) as well as a muscle relaxant (e.g., rocuronium
2.5 mg/kg or vecuronium 0.25 mg/kg) into a single injection
that is administered to the fetus [52, 55]. The onset of muscle nesthetic Management for Minimally
A
relaxation in the fetus usually occurs within 5 min and lasts Invasive Fetal Procedures
1–2 h [56].
In addition to directly administered medication to the Anesthesia for fetal procedures requires the same preopera-
fetus, maternally administered anesthetic agents cross the tive evaluation and planning process as non-obstetric surgery
placenta and affect the fetus. Remifentanil, 0.1 mcg/kg/min, during pregnancy. Patients should be medically optimized,
appropriately fasted, and maintained in left uterine displace- Table 14.3 Anesthetic approach for open fetal surgery
ment for the duration of the procedure. For most minimally Initial visit
invasive fetal procedures, monitored anesthesia care with • Fetal evaluation to exclude other anomalies and determine
infiltration of local anesthetic is sufficient, with similar extent of lesion, placental location, and estimated fetal weight.
dependability to neuraxial techniques [70]. However, for • Maternal evaluation, including complete history and physical
exam, multidisciplinary counseling, and plan for emergent
procedures involving multiple fetoscopic insertion sites, or delivery if fetus is viable.
when maternal immobility is essential for the procedure, a Preoperative
neuraxial technique may be preferred. Except in the case of • High lumbar epidural placement.
fetoscopic myelomeningocele (MMC) repair in which posi- • Maternal blood typed, cross-matched, and immediately available.
tioning the fetus as well as the possible need for uterine exte- • Fetal blood prepared and immediately available (type
riorization may require maternal general anesthesia [71], O-negative, leukocyte depleted, irradiated, cytomegalovirus
negative, cross-matched against the mother).
most minimally invasive procedures do not require a general
• Weight-based fetal medications prepared and passed to scrub
anesthetic. If immobility of the fetus is desired, it can be nurse in sterile unit doses.
assured with direct administration of a muscle relaxant, as • Maternal antacid and tocolytic (rectal indomethacin) administered.
described previously. For minimally invasive procedures that • Presurgical multidisciplinary team meeting.
directly involve the fetus (as opposed to the umbilical cord or Intraoperative
the placenta), an opioid should be administered to the fetus • Maternal normothermia maintained with forced-air warming device.
in addition to the muscle relaxant. Resuscitation medications • Sequential compression devices placed on lower extremities.
for the fetus including atropine (20 mcg/kg) and epinephrine • Left uterine displacement.
• Preoxygenation followed by rapid sequence induction and intubation.
(10 mcg/kg) should be prepared in single-dose aliquots and
• Maintain maternal Fi02 > 50% and end-tidal CO2 28–32 mmHg.
transferred to the surgical field in a sterile fashion before sur-
• Large-bore intravenous access obtained; arterial line placed or
gical incision. Should the fetus be of viable age and after all immediately available.
parties (mother and the perioperative team) are in agreement • Maternal mean arterial pressure maintained within 10% of
with the need for resuscitation, plans should be prepared for baseline with intravenous phenylephrine, ephedrine, and/or
a possible emergent cesarean section under general anesthe- glycopyrrolate.
• High-dose volatile anesthetic agents (2–3 MAC) to relax uterus;
sia in the event of fetal distress. The anesthesiologist should
alternatively, volatile anesthetic at 1.0–1.5 MAC with SIVA
be prepared for neonatal resuscitation and preoperative ste- technique.
roids previously administered to improve fetal lung maturity • Nitroglycerine prepared for administration in case of need to
if there is concern for premature delivery. Intraoperative use improve uterine relaxation.
of pressurized uterine crystalloid irrigation may lead to • Administration of fetal muscle relaxant and opioid with or
maternal pulmonary edema, and maternal intravenous fluid without anticholinergic agent. Fetal IV access can be obtained if
significant fetal blood loss is anticipated.
should be limited (<2 liters) to mitigate this risk [72]. • IV loading dose of magnesium sulfate for tocolysis.
• Maternal crystalloid limited to 2 liters to prevent pulmonary edema.
• Epidural activated with uterine closure for postoperative pain control.
nesthetic Management for Open Fetal
A • Extubate maternal trachea when fully awake.
Surgery Early postoperative
• Continue maternal tocolytic therapy.
Open fetal procedures are more complex than closed proce- • Maternal epidural analgesia for pain control.
dures as they involve a uterine hysterotomy and direct fetal • Monitor uterine activity and fetal heart rate.
• Operative team debrief.
manipulation, which is associated with greater potential for
• Plan for periodic fetal assessment and possible need for delivery.
maternal and fetal hemodynamic instability, advanced fetal
Modified from reference 54
monitoring, and an increased risk of maternal complications.
Providers must prepare for maternal and fetal resuscitation,
blood transfusion, and emergent delivery (Table 14.3). In [73]. This hybrid technique combines 1–1.5 MAC of inhala-
most instances, the mother requires general anesthesia. After tional anesthetic with either an intravenous remifentanil
tracheal intubation, anesthesia is maintained with an inhala- infusion or the combination of two intravenous infusions,
tional anesthetic to relax the uterus, as well as to provide propofol and remifentanil [59, 62].
general anesthesia for the mother and fetus. High-dose inha- Before the mother enters the operating room, the multi-
lational anesthesia has been historically used, although many disciplinary team should meet to discuss a perioperative plan
fetal centers are transitioning to a supplemental intravenous for the fetal procedure. Blood for both the mother and fetus
anesthetic (SIVA) technique to reduce fetal cardiac dysfunc- (O-negative, cytomegalovirus negative, irradiated, leukocyte
tion and umbilical artery flow abnormalities that have been reduced, maternally cross-matched) should be cross-matched
reported with these concentrations of inhalational agents and available. Weight-based unit-dose medications for the
fetus should be prepared including an opioid and a muscle pler seals the amniotic membranes to the endometrium and
relaxant (as detailed previously), in addition to resuscitation prevents hemorrhage from the relaxed uterine wall. Uterine
medications (i.e., atropine and epinephrine), and these blood loss during this part of the procedure can be abrupt,
should be transferred sterilely to the surgical field. massive, and difficult to quantify. Blood products should be
As in the case for all pregnant patients undergoing surgery, checked and readily available for transfusion. Amniotic fluid,
the patient should be fasted and given an antacid before anes- which is lost upon violation of the uterine wall, is continu-
thesia is induced. She should be positioned with left uterine ously replaced with warmed crystalloid solution, and intra-
displacement. A high lumbar epidural catheter is placed pre- uterine temperature is monitored to prevent fetal hypothermia
operatively to provide postoperative analgesia. Before induc- and associated fetal distress [38, 39].
tion of anesthesia, the well-being of the fetus should be If the fetus is at risk for hemorrhaging during the surgery
verified using umbilical artery flow patterns (abnormal flow (e.g., SCT resection), intravenous access should be estab-
patterns may be an early sign of fetal distress) [73] as well as lished in the fetus for volume resuscitation. Sterile micro-
echocardiographic evaluation. Additional monitoring modali- bore tubing can be primed, passed across the surgical field,
ties for the fetus include assessing flow across the ductus arte- and secured in a vein to facilitate administration of warmed
riosus and periodic cardiac imaging to determine systolic fluids and medications to the fetus. In an emergency, the
function [59, 74, 75]. Monitoring should continue intermit- umbilical vein can be directly cannulated in the surgical
tently throughout the procedure to ensure adequate fetal well- field. In the unlikely event of a cardiopulmonary arrest in the
being and assess the effect of maternal positioning, surgical mother, the fetus should be delivered after 4 min of unsuc-
procedure, and anesthetic technique on the fetus. cessful maternal resuscitation to increase the efficacy of
General anesthesia is induced via a rapid sequence tech- resuscitation and the possibility of maternal survival [80].
nique to minimize the risk of aspiration. Maternal For tocolysis, a loading dose of magnesium sulfate (4 to 6
hemodynamics are closely monitored during induction to grams IV) is administered to the mother over 20 min, fol-
maintain the mean arterial pressure within 10% of baseline lowed by an infusion of 1–2 g/h [81]. Typically, this is com-
and the heart rate close to the baseline measurement [22]. menced after uterine closure, although at some fetal treatment
Though maternal arterial lines are not always routinely centers, it is commenced before incising the uterus. After the
placed, one arm should remain accessible intraoperatively in bolus of magnesium, the concentration of inhalational anes-
case line placement becomes necessary. Phenylephrine is the thetic is decreased, and the epidural is initiated after a nega-
vasopressor of choice as it has been shown to improve fetal tive test dose. When surgery is completed, the trachea is
acid-base status [76], though boluses of glycopyrrolate or extubated when the patient is awake.
ephedrine can assist in maintaining maternal heart rate and
cardiac output [21, 22, 77]. An additional large-bore intrave-
nous catheter is placed for maternal resuscitation and possi- Postoperative Considerations
ble rapid blood transfusion. Intravenous fluids should be
limited to <2 liters to reduce the risk of maternal pulmonary Postoperative concerns specific to fetal surgery include the
edema associated with tocolytics [78]. The use of colloids need for continued fetal monitoring and prevention of pre-
can be considered to assist in maintaining maternal blood mature labor. Minimally invasive procedures rarely require
pressure and cardiac output while limiting overall fluid tocolysis beyond an initial dose of indomethacin. After open
administration. Maternal ventilation is adjusted to maintain fetal surgery, uterine contractions are common and are typi-
end-tidal carbon dioxide tensions in the normal range for cally monitored for at least 2 days postoperatively. The mag-
pregnancy (28–32 mmHg). nesium infusion is usually continued for 24 h postoperatively,
Before skin incision, the concentration of inhalational although it may require supplementation with additional
anesthetic should be increased to 1.0–1.5 MAC with SIVA or agents such as indomethacin or nifedipine. Indomethacin use
to 2.0 MAC without SIVA. Adequate uterine relaxation is requires periodic echocardiographic evaluation of the fetus
assessed surgically, with additional inhalational agent admin- as it may lead to premature closure of the ductus arteriosus.
istered as needed, up to 3 MAC. If further uterine relaxation Postoperative pain control in the mother is normally
is required, it can be achieved with intravenous nitroglycer- achieved using systemic oral medications in the case of
ine in small bolus doses (100–200 mcg) or as an infusion. minimally invasive procedures and via an epidural catheter
For those women in whom general anesthesia is contraindi- in the case of open procedures. Intravenous opioids can also
cated, a neuraxial technique with an intravenous infusion of be used, but large doses can decrease the variability of the
nitroglycerine (up to 20 mcg/kg/min) may be required to fetal heart rate and make the fetal heart rate tracing difficult
adequately relax the uterus [79]. To date, no single anesthetic to interpret [82]. Inadequately controlled pain can increase
technique appears to be superior to any other. oxytocin levels in the mother and result in preterm labor
Once the uterus is exposed, a small hysterotomy is made [83]. After open fetal surgery, mothers are at greater risk for
and extended with an absorbable lactomer stapler. The sta- preterm premature rupture of the membranes, preterm labor,
infection, and uterine rupture [84]. Antenatal steroids should win Reversed Arterial Perfusion (TRAP)
T
be administered to improve fetal lung maturity. Fetal well- Sequence
being is assessed by postoperative ultrasonography and
heart rate monitoring, depending on age of the fetus and the TRAP sequence occurs in monozygotic twin or triplet preg-
plan for fetal distress. Fetal complications include intracra- nancies where one fetus is not attached to the placenta and
nial hemorrhage, infection, heart failure, oligohydramnios, instead is perfused in a retrograde fashion via vascular anas-
and demise. A cesarean section is required for the delivery tomoses from the second “donor” fetus. This pattern of per-
of the present and all future pregnancies to mitigate the risk fusion results in a nonviable, acardiac, acephalic fetus,
of uterine rupture. whereas the donor twin is at risk for high-output heart fail-
ure, hydrops fetalis, and preterm delivery [91]. Untreated,
the donor twin has an intrauterine death rate of 35–55%, and
pecific Fetal Conditions Amenable to Fetal
S those that do survive are born on average at 29 weeks’ gesta-
Treatment tion [92, 93]. Effective fetal treatment of TRAP involves
abolishing the vascular anastomoses between the twins,
Fetal Anemia which leads to the death of the nonviable fetus.
The most successful therapeutic option for treatment of
Anemia in the fetus is a serious condition that may increase TRAP is either laser or radiofrequency ablation at the base of
cardiac output, tissue hypoxia, lactic acidosis, fetal hydrops, the nonviable twin’s umbilical cord [94]. After ablation, the
and intrauterine demise. The most common cause of fetal survival rate of the remaining fetus increases to 80%, with an
anemia is due to maternal alloimmunization, which leads to average delivery at 37 weeks [95]. Complications after treat-
hemolytic disease of the fetus and neonate. In this scenario, ment of TRAP include preterm rupture of the membranes,
maternal IgG antibodies cross the placenta and cause fetal preterm delivery, and fetal demise. Anesthetic management
red blood cell hemolysis. Other causes of fetal anemia for these procedures typically involves maternal local anes-
include parvovirus B19, fetomaternal hemorrhage, and thesia with minimal sedation [70].
inherited fetal anemias, such as homozygous alpha thalas-
semia and Blackfan-Diamond anemia. An increased peak
middle cerebral artery blood flow velocity, measured on non- Twin-to-Twin Transfusion Syndrome (TTTS)
invasive Doppler studies of the fetus, suggests moderate to
severe fetal anemia. Umbilical vein intrauterine transfusion TTTS is a pathologic condition seen in monochorionic
(IUT) of type O, Rh-negative, irradiated, leukocyte-depleted, twins when a significant number of arteriovenous anasto-
packed red blood cells that have been cross-matched with the moses exist between the two fetuses [96, 97]. Unequal
mother treats fetal anemia in fetuses over 18 weeks’ gesta- sharing of placental blood flow between the twins results
tion [85]. The amount of blood transfused is calculated based in discordant growth. Although some degree of shared
on a formula that incorporates the initial fetal hematocrit arteriovenous blood flow exists in 90% to 95% of all
(measured from the umbilical vein before transfusion), the monochorionic twins, normally these anastomoses are
hematocrit of the donor blood, and the estimated fetal- insignificant and partially balanced by protective arterioar-
placental blood volume based on gestational age [86]. A terial connections, which equalize the resistance and blood
post-procedure hematocrit of 45–55% is targeted, and IUTs flow [98, 99] (Fig. 14.3).
are often repeated every 1–3 weeks to maintain an adequate With unbalanced flow, TTTS results in increased blood
hematocrit until the fetus can be delivered at term [85, 87]. delivery to one twin (the “recipient”), who experiences poly-
IUT procedures are generally performed with ultrasound hydramnios, polycythemia, and polyuria, with severe cases
guidance under local anesthesia with minimal need for leading to fetal cardiomyopathy and hydrops fetalis. The
maternal sedation. Fetal movement can be prevented with decreased flow to the other twin (the “donor”) results in oli-
the use of a muscle relaxant, either injected intramuscularly gohydramnios and growth restriction, with severe cases lead-
into the fetus or directly into the umbilical vein [88]. ing to renal failure, heart failure, and hydrops fetalis [96].
Although rare, if an intrahepatic approach for transfusion is Diagnostic criteria require the presence of a monochorionic
chosen, fentanyl should also be administered to the fetus to diamniotic twin pregnancy and a discrepancy of amniotic
ameliorate the fetal stress response [89]. fluid volume, with one twin having a maximal vertical pocket
Complications occur in approximately 3% of cases. The of greater than 8 centimeters and with the other twin having
range of complications include accidental umbilical artery a maximum vertical pocket of less than 2 centimeters [100].
puncture leading to vasospasm, fetal volume overload, infec- The Quintero staging system is the most commonly used
tion, and preterm rupture of the membranes. These can result metric to quantify the severity of the disease, which when
in fetal distress that requires emergent cesarean delivery combined with fetal echocardiography is of important prog-
[90]. Fetal demise occurs in 2% of IUTs [90]. nostic value [101–103].
Fig. 14.3 SFLP for TTTS. Sonography Fetoscopy

Selective fetoscopic laser
photocoagulation is used to
treat monochorionic twin
receiving unequal placental
blood flow, resulting in TTTS.
A fetoscope is placed into the
Recipient
amniotic cavity under
ultrasound guidance. A laser
Donor
is used to ablate arteriovenous Arterial Venous
anastomoses between the
twins, resulting in more equal Laser
placental blood flow. From
Graves CE, Harrison MR,
Padilla BE.Minimally
Invasive Fetal Surgery. Clin
Perinatol. 2017
Dec;44(4):729–751. With
permission from Publisher
Arterio-Venous Anastomosis
Previous therapeutic efforts centered on amnioreduction valvuloplasty for pulmonary atresia or hypoplastic right heart
of the polyhydramniotic twin; however, survival of both with an intact ventricular septum; and (4) pericardiocentesis
fetuses is only about 60% with this technique [104, 105]. A for congenital cardiac tumors or aneurysms [109, 110].
more recent approach involves selective fetoscopic laser Of these fetal procedures, the most commonly performed
photocoagulation (SFLP), whereby abnormal arteriovenous is aortic valvuloplasty for evolving HLHS. This intervention
connections are identified by ultrasound and selectively can improve neonatal stability and allow for a biventricular
ablated in stage II–IV twins between 18 and 26 weeks’ ges- postnatal outcome [111–113]. In this procedure (Fig. 14.4),
tation [106]. A 2004 randomized, multicenter trial demon- ultrasound is used to guide a cannula through the maternal
strated improved overall survival and neurologic outcome abdomen, into the uterus, through the fetal chest wall, and
for patients treated with SFLP compared with amnioreduc- into the left ventricular outflow tract, where a balloon is
tion [107]. Unfortunately, neurologic injury remains a con- deployed at the level of the aortic valve [114]. Maternal
cern, even in treated fetuses, with major neurological neuraxial anesthesia is most typically chosen for this proce-
sequelae, such as cognitive impairment, motor delay, and dure, although general anesthesia is occasionally used to
cerebral palsy that affects 3–25% of treated twins [108]. allow for uterine relaxation for improved fetal positioning.
Additionally, preterm premature rupture of membranes Fetal immobility is ensured by administering a fetal intra-
occurs in up to 30% of SFLP-treated pregnancies [96, 106]. muscular injection of muscle relaxant with fentanyl, and
Anesthetic technique for SFLP in TTTS typically involves fetal resuscitation drugs for intramuscular or intracardiac
maternal local anesthesia with or without sedation [70]. injection must be readily available [115]. Fetal complica-
Alternatively, neuraxial anesthesia can be employed. tions include bradycardia, pericardial effusion, ventricular
thrombosis, preterm delivery, and fetal death, with technical
success present in 75% of cases [112, 116].
Congenital Heart Disease
Though congenital heart defects are common fetal anomalies, Obstructive Uropathy
few are amenable to fetal intervention. Treatment of these
lesions attempts to halt or reverse the effect of the defect Lower urinary tract obstruction (LUTO) in the fetus can
before permanent damage can occur. Present fetal cardiac occur at the level of the ureteropelvic junction, the uretero-
therapies include (1) aortic balloon valvuloplasty for treatment vesical junction, or the urethra. A high perinatal mortality
of critical aortic stenosis and evolving hypoplastic left heart rate (90%) occurs when the obstruction is bilateral or ure-
syndrome (HLHS); (2) atrial septostomy in HLHS with an thral; survivors usually exhibit significant renal impairment
intact or very restrictive atrial septum; (3) pulmonic balloon [117, 118]. LUTO is diagnosed after oligohydramnios is
maternal
abdominal wall
uterine wall
Echocardiography
Transducer
Needle
fetal chest wall
needle dilating balloon

left through
ventricle aortic value
guide
wire
spine
aorta
Fig. 14.4 Percutaneous fetal aortic balloon valvuloplasty. Percutaneous of the fetal heart. The tip of the cannula is positioned in the left ven-
fetal aortic balloon valvuloplasty is used in cases of evolving tricular outflow tract; the balloon is guided into the aortic valve and
HLHS. Ultrasound guidance is used to direct a balloon-tipped cannula inflated. From reference 113 with permission
introducer through the maternal abdomen and uterus and into the apex
noted on antenatal ultrasound; the oligohydramnios results Congenital Diaphragmatic Hernia (CDH)
from inadequate urine production [119]. LUTO is classified
by amniotic fluid index, renal imaging, and fetal urine chem- CDH is a condition where fetal abdominal contents herni-
istry. Morbidity correlates with the timing of onset, gender, ate through a defect in the diaphragm into the thoracic cav-
severity of obstruction, concentration of urine electrolytes, ity. Neonates suffer from pulmonary hypoplasia, pulmonary
and location of the obstruction [120–122]. hypertension, and respiratory insufficiency. The prognosis
Vesicoamniotic shunting involves placing a double- of infants with a CDH is often quantified based on the ratio
coiled, valveless stent between the fetal bladder and the of fetal lung area to head circumference (LHR) as well as
amniotic cavity, usually under local anesthesia with ultra- the presence of liver herniation into the thoracic cavity.
sound guidance. Shunt placement improves bladder develop- With postnatal repair, infants with an LHR < 0.7 and liver
ment, increases amniotic fluid volume, and assists with lung herniation do not survive, whereas an LHR > 1.4 is associ-
development [123]. Procedural complications include fetal ated with a 73% survival rate [130]. Because LHR varies
trauma, gastroschisis, preterm premature rupture of the with gestational age, an observed-to-expected LHR (O/E
membranes, preterm delivery, and infection [124]. A LHR) can be used to account for this difference [131, 132].
reduction in mortality has been reported after placing a fetal The MRI measurement of the fetal observed-to-expected
shunt, compared with standard of care, although long-term total lung volume is another method of antenatal assess-
morbidity and renal function are similar among treated and ment for prognosis [133, 134].
untreated survivors [125–128]. Initial attempts at fetal CHD repair were open procedures
An alternative strategy to vesicoamniotic shunting and did not improve the postnatal outomes [135]. More
involves fetal cystoscopy. Fetal cystoscopy can be used to recently, the focus has shifted to mechanically occluding the
determine if LUTO results from urethral atresia or posterior trachea to prevent the egress of fetal lung fluid and therefore
urethral valves. Ablation of posterior urethral valves with increase pulmonary hydrostatic pressure and promote lung
cystoscopy may improve renal function when compared with maturation. After a series of refinements, this technique
shunt placement [129]. involves placing a balloon into the fetal trachea using fetos-
Perfusion scope or fast-growing lesions can lead to pulmonary hypoplasia,

heart failure, and hydrops fetalis [142]. A ratio of lung tumor
volume to head circumference (CVR) is used to predict
Ultrasound hydrops fetalis and adverse postnatal outcomes, with a ratio of
<0.56 unlikely to have adverse postnatal outcome and a
ratio > 0.56 with a 33% positive predictive value for a poor
outcome [143, 144]. A ratio of >1.6 is a marker of severe mor-
bidity and can be used as an indication for fetal intervention
[145]. Betamethasone can be administered to mothers with a
high-risk fetal CPAM to improve fetal survival [146, 147].
Large macrocystic lesions or large pleural effusions lead-
Balloon ing to hydrops fetalis are managed by placing shunt cathe-
inflated
ters between the lesion and the amniotic cavity. Placing a
Balloon
thoracoamniotic shunt can improve hydrops fetalis, and
detached
lung lesions are subsequently resected after birth [148]. The
shunt is usually placed using local or neuraxial anesthesia
Fig. 14.5 Fetal tracheal balloon occlusion for CDH. Tracheal balloon for the mother with intramuscular administration of muscle
occlusion is a technique used in fetuses with CDH. The goal of occlud-
ing the trachea of fetuses with CDH is to increase lung volume, decrease relaxant and fentanyl to the fetus. Shunts can malfunction,
herniation of abdominal viscera, and improve postnatal lung function. move, and cause bleeding, infection, or premature rupture
The procedure involves a single intrauterine trocar, through which a of the membranes [140].
fetoscope is introduced into the fetal trachea. A balloon is inflated just Some solid or mixed lesions cannot be shunted and may
proximal to the carina. The balloon is usually removed at 34 weeks’
gestation with a second fetal procedure. Reproduced with permission require open fetal resection. Open resection poses significant
from Harrison MR, Albanese CT, Hawgood SB, et al. Fetoscopic tem- risks for the fetus, including hemorrhage and cardiovascular
porary tracheal occlusion by means of detachable balloon for congeni- instability, which may require resuscitation of the fetus in utero
tal diaphragmatic hernia. Am J Obstet Gynecol 2001; 185:730–3 [149]. Alternatively, in term or near-term fetuses, an EXIT pro-
cedure (see below) can be performed to facilitate tumor resec-
copy (Fig. 14.5) [136]. Initially, balloons were left in place tion in the case of severe thoracic compression [150, 151].
until delivery, which required an EXIT procedure (detailed
later), but now tracheal balloons are typically removed with
a second fetoscopic procedure, usually near 34 weeks’ ges- SCT
tation [137]. Maternal anesthesia for these procedures
involves neuraxial anesthesia or local anesthesia at the tro- SCT are usually diagnosed in the second trimester of preg-
car insertion site. Fetal anesthesia and immobility is typi- nancy and may grow rapidly. In general, the tumors them-
cally achieved with an intramuscular fetal injection of selves are benign, although the cardiovascular side effects
muscle relaxant and fentanyl. that result from the large arteriovenous shunt may cause high
A 2016 meta-analysis reported that survival in fetuses cardiac output heart failure, which in turn may lead to poly-
with an LHR ≤ 1.0 who underwent fetal tracheal occlusion hydramnios and hydrops fetalis [152, 153]. The tumors can
improved compared with a contemporary postnatal care con- also rupture, precipitating preterm delivery or urinary tract
trol group [138]. Presently, an ongoing multicenter, prospec- obstruction. Tumors are staged by the Altman criteria [154],
tive, randomized trial is comparing the outcomes after and fetal MRI can be useful for prenatal evaluation. Poor
placing fetal tracheal balloon at both 27–30 weeks and fetal outcome is associated with a tumor volume-to-fetal
30–32 weeks and removing them at 34 weeks to standard weight ratio > 0.1 cm3/g before 24 weeks’ gestation [155].
postnatal management [139]. Long-term outcome data of the Antenatal treatment of SCT is reserved for fetuses with
respiratory and neurological complications of endoscopic external tumors that are rapidly growing or diagnosed early
tracheal occlusion in the fetus are needed to better guide fetal in gestation early (<30 weeks) [156]. Both minimally inva-
therapy for the treatment of CDH. sive therapies and open fetal resection have been performed
with unclear benefits between different techniques [153,
157]. Minimally invasive intervention involves radiofre-
Congenital Pulmonary Lesions quency ablation, embolization, or thermocoagulation of the
vascular supply to the tumor and/or cyst draining. A review
Congenital pulmonary airway malformations (CPAM) consist of minimally invasive interventions in 34 patients over
of five subtypes of cystic and/or solid benign pulmonary 33 years revealed an overall survival rate of 44% in fetuses
tumors [140, 141]. Though small lesions often regress, large without preexisting hydrops and 30% in patients with
hydrops [153]. Open resection has been sucessuful [158] but distress syndrome, uterine dehiscence, and premature rup-
remains relatively rare. Open fetal resection, like postnatal ture of the membranes [163]. Analysis of long-term outcome
surgery, carries a high potential for blood loss. An intraop- data is ongoing, but the present evidence has demonstrated
erative intravenous line is essential to resuscitate the fetus improved motor and behavioral outcomes for those patients
with volume. In rare cases, maternal mirror syndrome can who underwent prenatal repair [164–166]. Results of this
develop in the case of fetal hydrops [159]. Mirror syndrome trial are limited by strict inclusion criteria and performance
is similar to elements of preeclampsia in that the mother of the procedures at one of three established fetal surgical
develops hypertension and peripheral and pulmonary edema. centers [167, 168].
The development of mirror syndrome is quite serious and More recently, the suitability of fetoscopic MMC repair to
should lead to delivery, as it does not always resolve with reduce the risk of a maternal hysterotomy and subsequent
fetal correction [159, 160]. need for cesarean delivery has begun [169]. A 2017 meta-
analysis of initial data suggested that a minimally invasive
approach for MMC repair yielded a greater rate of preterm
MMC delivery, premature rupture of the membranes, and cerebral
spinal fluid leakage but a reduced rate of preterm birth and
MMC is due to incomplete closure of the neural tube, result- uterine dehiscence [170]. Long-term outcome data are not
ing in herniation of meninges and neural tissue through a yet available to compare for these two techniques.
vertebral defect. MMC causes lifelong defects, including Regardless of surgical technique, fetal repair of MMC
loss of motor and sensory function below the level of the requires meticulous anesthetic planning. Similar to open pro-
lesion, hydrocephalus, absence of bowel and bladder control, cedures, fetal repair requires profound uterine relaxation,
and cognitive impairment [161, 162]. The deficits associated fetal analgesia, and muscle relaxation, intraoperative fetal
with MMC are likely due to two subsequent processes: first monitoring, and a plan for maternal postoperative pain man-
the abnormal neural tube formation and, second, the com- agement and maternal and fetal monitoring [54] (see
pression of the neural tissues and their exposure to amniotic “Management of Open Fetal Procedures,” previously).
fluid. By closing the defect in utero, the secondary causes of
damage are reduced, improving neurologic outcome
(Fig. 14.6). This latter benefit was first demonstrated in a he Ex Utero Intrapartum Treatment (EXIT)
T
randomized trial of 183 patients in 2011 in which prenatal Procedure
closure of MMC via open hysterotomy at 19–26 weeks was
compared with the standard postnatal closure. Fetal repair The EXIT procedure allows for partial delivery of the fetus
reduced the need for placing a ventriculoperitoneal shunt, while placental circulation is maintained to ensure adequate
decreased hindbrain herniation, and improved motor func- oxygenation and perfusion. Although initially developed for
tion at age 30 months. Complications from the fetal repair the removal of tracheal occlusive devices placed for in utero
included an increased risk of preterm delivery, respiratory CDH treatment, the EXIT procedure is now used for a mul-
titude of fetal anomalies including congenital airway
lesions, intrathoracic masses, SCT resection, separation of
conjoined twins, and as a bridge to extracorporeal mem-
brane oxygenation [171, 172] (Table 14.4). The EXIT pro-
cedure requires a profound state of uterine relaxation to
prevent placental separation from the uterus and maintain
fetal-placental perfusion. EXIT procedures are most often
performed under deep general anesthesia (>2 MAC), similar
to open fetal procedures.
The anesthetic approach for preoperative evaluation and
initial intraoperative management is similar to the approach
previously described for open fetal surgery. A detailed meet-
ing with all members from the multidisciplinary EXIT team
should be arranged before the start of the case to ensure a
uniform well-coordinated approach and availability of all
necessary equipment and supplies. Cross-matched blood is
obtained for the mother, and if a fetal surgical procedure is
Fig. 14.6 Fetal MMC. Photograph depicts a uterine hysterotomy and anticipated, compatible blood should also be available for the
fetus with a lumbar MMC undergoing open in utero fetal repair fetus. Weight-based fetal medications including epinephrine
Table 14.4 EXIT procedure indications 174]. Although nitroglycerine can cross the placenta, the
Procedure Indications majority is metabolized at the placental interface resulting in
EXIT to Any anatomical cause of anticipated airway minimal effects on the fetus [79, 173]. However, the optimal
airway obstruction, including but not limited to: anesthetic technique for the EXIT procedure has not as yet
• Congenital high airway obstruction syndrome.
been determined.
• Laryngeal atresia/stenosis.
• Tracheal atresia/stenosis. Once the uterus is exposed, a small hysterotomy is per-
• Laryngeal web/cyst. formed and extended with a stapling device. A pulse oxime-
• Cervical teratoma. ter is then placed on the hand of the fetus and shielded from
• Cystic hygroma.
ambient light. The normal range for the oxygen saturation in
• Hemangioma.
• Lymphangioma. the fetus is between 40% and 65%, before ventilation [175].
• Removal of tracheal occlusive device placed to Warmed crystalloid fluids are instilled continuously into the
treat CDH. uterine cavity to optimize the position of the fetus and to
• Severe micrognathia/retrognathia.
minimize pressure on the umbilical cord and placenta.
EXIT to Resection of lesion causing mediastinal or airway
resection compromise, including but not limited to:
Depending on the indication, the duration of the EXIT
• Bronchogenic cysts. procedure can last from a few minutes (i.e., tracheal intuba-
• Bronchopulmonary sequestration. tion) to hours (i.e., resection of a large mass); anesthetic
• CPAM. techniques have provided stability for long procedures [176].
• Mediastinal mass.
• Thoracic tumor.
Once the airway in the fetus has been secured (intubated) and
EXIT to Anticipation of severe cardiopulmonary compromise ventilation is established, the oxyhemoglobin saturation
ECMO necessitating extracorporeal circulatory support, should increase to ≥90%. Failure to increase fetal oxygen
including but not limited to: saturation represents an indication for transitioning the fetus
• CDH with severe pulmonary compromise. to ECMO before clamping the umbilical cord and delivering
• Aortic stenosis with intact/restrictive atrial septum.
EXIT to Separation of conjoined twins
the fetus. An end-tidal CO2 monitor is also helpful to confirm
separation the correct placement of the tracheal tube in the fetus.
After delivery, the anesthetic concentrations are decreased
to promote uterine contraction and hemostasis. The inhala-
(10 mcg/kg), atropine (20 mcg/kg), an opioid (fentanyl tional anesthetic is discontinued or significantly decreased,
10 mcg/kg), and muscle relaxant (rocuronium 2.5 mg/kg) and the nitroglycerine infusion is stopped, while other anes-
should be prepared and passed onto the surgical field. In addi- thetic agents such as propofol, remifentanil, and/or nitrous
tion to direct fetal cardiac monitoring, a sterile fetal pulse oxide are introduced to maintain adequate anesthesia and
oximeter is helpful to monitor the fetus and assist to confirm uterine tone [177, 178]. Oxytocin is administered, and other
that the airway of the fetus was successfully i ntubated. A ster- uterotonic medications such as Methergine and Hemabate
ile ventilation source with a pressure manometer for the fetus, may be administered as necessary to increase uterine tone.
as well as sterile laryngoscopes, tracheal tubes, and intrave- The trachea of the mother is extubated when she has fully
nous supplies, is also prepared on the sterile field. regained consciousness.
A preoperative epidural catheter should be placed for
postoperative pain control in the mother. Large-bore intrave-
nous access should be established for the mother as blood Conclusions
loss can be sudden due to profound uterine relaxation.
Though an arterial line is not mandated, invasive monitoring Fetal treatment is an innovative and maturing field with a
should be readily available and initiated in the setting of any growing number of centers worldwide. The transfer of
hemodynamic instability. General anesthesia is induced with outcomes from existing data generated from a very spe-
a rapid sequence intubation. The concentration of inhala- cific patient population at a small number of academic
tional anesthetic should be increased to ≥2 MAC to ensure centers to a larger population is unclear. Caution should
adequate uterine relaxation, with prophylactic use of phenyl- be exercised when deviating from strict inclusion criteria
ephrine to maintain the mother’s blood pressure within 10% or when minimal experience with a procedure exists. The
of baseline for adequate placental perfusion. The maternal multidisciplinary nature of fetal treatment requires coop-
heart rate should be maintained near baseline values using eration and collaboration across disciplines. Ethical,
anticholinergic agents to maintain cardiac output [22]. When social, and legal issues, such as maternal autonomy, and
general anesthesia is contraindicated, neuraxial anesthesia options for pregnancy termination further complicate the
can be combined with a high-dose infusion of nitroglycerine practice of fetal interventions [179, 180]. A bioethics
(1–10 mcg/kg/min) to relax the uterus as well as an infusion committee, spearheaded by the American College of
of phenylephrine to support the blood pressure [79, 173, Obstetricians and Gynecologists and the American
Academy of Pediatrics, has established recommendations 14. Palta A, Dhiman P. Thrombocytopenia in pregnancy. J Obstet
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Neonatal Pain: Significance,
Assessment, and Management 15
Joy M. Dawes and Richard F. Howard
Neonatal Pain Mechanisms infancy and childhood [1]. Modality-specific studies of

thresholds to mechanical stimuli (touch, pressure) in infants
Nociceptors and sensory pathways are present from embry- from preterm to 3 months of age show a clear linear relation-
onic stages of development, although they undergo substan- ship between the mechanical force needed to trigger a reflex
tial postnatal reorganization and functional change. withdrawal response and chronological age [1, 2].
Sensorimotor coordination is refined and complex integra- The response thresholds to touch, heat, and pain are
tive central processing functions develop, particularly in the reduced in neonates but gradually increase as the nervous
brain, through infancy, childhood, and adolescence, although system matures. These changes are mediated by alterations
some of the most important, rapid, and profound changes in the number, structure, and function of nociceptors, central
occur during the neonatal period. neural connections, and the balance of activity in modulatory
Plasticity of the CNS or the capacity of the CNS to change pathways; some of the most important are summarized in
and adapt is probably maximized during the neonatal period. Table 15.1.
In fact, such plasticity is essential for neural development, Painful mechanical, thermal, and chemical stimuli in
and “normal” levels of activity in nociceptive pathways are a adults are normally detected by high-threshold polymodal
mechanism by which this process is controlled. slow-conducting C and fast A-delta fiber nociceptors whose
The neonate is much more sensitive to nociceptive pain, cell bodies are located in the dorsal root ganglion (DRG) and
i.e., noxious actual or potential tissue-damaging sensory whose central terminals are mostly found in nociceptive-
inputs, than older children and adults. Stimulus-specific specific areas of the superficial dorsal horn of the spinal cord
nociceptive thresholds are reduced at birth and increase (laminae I and II, Fig. 15.1a). A-delta fibers terminate
gradually as a function of developmental age throughout directly on ascending “projection” neurons in lamina I,
Table 15.1 Factors that augment the pain responses in the neonate compared with the adult
Factor Effect
1 Low-threshold A-fiber mechanoreceptors terminate centrally on Weaker stimuli can activate pain-specific pathways
nociceptive-specific relay pathways at birth
2 Relatively larger and more overlapping cutaneous receptive fields Amplification of stimulus effect due to increased numbers of
neurons activated
3 Poorly localized and diffuse sensorimotor connections in the CNS Less anatomically specific and more generalized motor
responses
4 Weak intrinsic inhibitory mechanisms in the spinal corda Relative augmentation of pain signal
5 Intracortical circuits and arousal systems poorly developed at birth Operation of immature sensorimotor cortex is mainly reflexologic
6 Reduced descending inhibitiona Relative augmentation of pain signal
7 Combination of factors 1–6 Nociception and reflex withdrawal are activated at lower
stimulus intensity as a function of lower developmental age
Contributes to larger receptive field size
a
J. M. Dawes (*) · R. F. Howard

Great Ormond Street Hospital for Children, London, UK

506 J. M. Dawes and R. F. Howard
Fig. 15.1 (a) Adult sensory a POLYMODAL NOCICEPTORS

inputs. (b) Neonatal sensory - mechanical
inputs - thermal C fibre
- chemical
I
II
III
Aβ fibre IV
V
MECHANORECEPTORS
- low threshold mechanical Spinal cord
- touch
Periphery
b
C fibre
I
II
III
Aβ fibre IV
V
Spinal cord
Periphery
whereas C fibers generally terminate on interneurons located A-fiber input facilitates activity-dependent synaptic strength-
in lamina II. Fast-conducting A-beta fibers mostly detecting ening in the dorsal horn, but this declines with strengthening
innocuous touch and pressure normally terminate in deeper of nociceptive C-fiber input, which drives the maturation of
laminae of the cord. targeted glycinergic inhibition [6]. This lack of specificity,
However, in early development, the central terminals of organization, and control is mirrored in motor circuits such
A-beta fibers temporarily overlap with C-fiber terminals in that output responses are also more diffuse and less well inte-
pain-specific areas of lamina ll [3], withdrawing later to grated spatially and temporally [8]. Physiological studies
deeper laminae (Fig. 15.1b), thereby potentially activating have confirmed that painful inputs in preterm infants transmit
nociceptive projection neurons when activated by low- measurable responses from at least 24 weeks postconception
threshold stimuli. In addition, as spinal nociceptive with- [9]. The developing sensorimotor cortex expresses intermit-
drawal reflex pathways are also activated, the threshold for tent activity bursts that are organized as oscillations to sup-
evoking a reflex response is also reduced [4]. A reduction in port synchronization and plasticity in developing circuits
specificity due to this structural difference is augmented by [10]. Activity in the immature sensorimotor complex is pre-
lack of myelination and immature ion channel kinetics that dominantly driven by thalamic input provided by sensory
alter neuronal conduction times and synaptic strength leading feedback from spontaneous movement and passive tactile
to a more diffuse central response to peripheral stimuli. stimulation [10]. Tactile input plays an important role in
Within the spinal cord, there is a relative excess of excitation activity-dependent maturation of the CNS. Evidence that
and delayed development of both local and descending inhi- afferent nociceptive signals reach the somatosensory cortex
bitions [3, 5–7], which contribute to these low-threshold and in preterm and term neonates has been demonstrated using
generalized reflex responses. In the neonate, strong tactile near-infrared spectrometry (NIRS) [11, 12] and electroen-
15 Neonatal Pain: Significance, Assessment, and Management 507
cephalogram (EEG) recordings [9], which shown alterations anesthetic have demonstrated a massive, robust, and poten-
in cortical activity after heel lance for blood sampling [13]. tially harmful neuroendocrine stress response to pain, which
Specific postnatal functional stages in maturation of the noci- was prevented by deeper levels of anesthesia and analgesia,
ception cortex have been demonstrated using electrocortico- even at the youngest ages [25, 26]. In addition, pain relief
gram (ECoG) recordings in rat pups between 2 and 4 weeks during and after surgery improved immediate postoperative
of age [14]. Heel lance also produces spatially widespread physiological outcomes such as respiratory function in
nociceptive event-related potential (nERP) responses in the infants after major surgery [26]. As surgery in the neonatal
majority of neonates, and interestingly this widespread pat- period has been associated with changes in pain perception
tern is more likely to occur in females indicating the presence of greater duration, at least some of which can be prevented
of pain-related gender differences from birth [15]. by analgesia, it may be that unmodified and abnormally
Using fMRI, the network of brain regions that are active increased levels of activity such as during surgery without
after acute noxious stimulation in neonates has been identi- anesthesia or severe pain without analgesia contribute, in
fied and the activity compared with that observed in adults. part, to these changes. For example, boys who underwent
Significant infant brain activity was observed in 18 of the 20 neonatal circumcision without analgesia showed an
active adult brain regions but not in the infant amygdala or enhanced response to pain 3 months later during immuniza-
orbitofrontal cortex. Brain regions that encode sensory and tion compared with those who received analgesia during
affective components of pain were active in infants and their circumcision or were not circumcised [27]. Infants
showed variations with stimulus modality and intensity [16], who had abdominal surgery repeated in the same derma-
suggesting that the infant pain experience resembles that tome as a previous operation before 3 months of age exhib-
observed in adults [17]. Resting state networks of synchro- ited increased pain responses and analgesic requirements
nously active brain regions (including sensorimotor, default- compared with controls [22]. Even “minor” procedures such
mode, and salience networks) can be identified in term as heel lance blood sampling can cause significant pain in
neonates suggesting that functional connectivity is already the neonate [28]. They too can lead to augmentation of the
operational at this time [18, 19]. Secondary hyperalgesia response to subsequent pain or may even be associated with
appears to be less prominent at younger ages and is slower to more serious morbidity and poorer outcomes especially
develop [20]. Nonetheless, persistent alterations in nocicep- when repeated frequently, e.g., in NICU [29].
tive processing can occur after tissue injury in the neonate, Complex and subtle effects have occurred in cohorts of
leading to an exacerbated degree of hyperalgesia after a sub- ex-preterm children who had surgery as neonates and spent
sequent insult to the same somatotopic region [21]. time in the NICU. A relative increase in temperature and
Many aspects of maturation are subject to activity- touch thresholds near the site of surgery has been observed,
dependent developmental control, and it has therefore been a but some children also have a more generalized decrease in
concern that “abnormal” events such as severe pain in the temperature threshold [23, 30, 31]. Persistent sensory loss
neonate may alter normal development and lead to adverse and/or gain (punctate and dynamic mechanical allodynia)
long-term consequences to sensory processing mechanisms. have been demonstrated next to scars many years after neo-
In fact, surgery or injury during the neonatal period has been natal surgery [32]. Changes in somatosensory function in
associated with changes in nociceptive thresholds and the adolescents after neonatal intensive care vary depending on
response to subsequent painful stimuli, months or even years the initial exposure (e.g., gestational age at birth, require-
later, although the precise mechanisms involved and the ment for surgery, duration of intensive care), type and inten-
exact roles of pain intensity and analgesia are still not fully sity of experimental stimulus, and age at follow-up [33].
understood [8, 22, 23]. Neonatal surgical injury in an animal The degree to which persistent changes in somatosensory
model alters the postnatal development of RVM descending function correlate with altered response to future injury has
control, resulting in a predominance of descending inhibition been demonstrated in animal studies but requires further
and generalized reduction in baseline reflex sensitivity. This evaluation [34]. In the laboratory, repeated touch and needle
response was prevented by effective local anesthetic block- prick stimulation in the neonatal period can alter adult spi-
ade highlighting the importance of neonatal perioperative nal sensory neuronal sensitivity to both innocuous and nox-
analgesia [24]. ious mechanical stimulations [35]. Effects of tissue injury
include altered ion channel expression in primary afferent
and spinal cord neurons, shifts in the balance between syn-
Significance of Neonatal Pain aptic excitation and inhibition within the superficial dorsal
horn network (SDH), and priming of microglial responses
The increased sensitivity of neonates to nociceptive inputs in the adult SDH [21].
is important. Studies measuring the “stress” response to Adults who have experienced neonatal injury display
major surgery in neonates who received a “light” general increased pain and injury-induced hyperalgesia in the affected
region. Proposed mechanisms for this include peripheral • Behavioral: observation of changes in facial expression
nerve sprouting and dorsal horn central sensitization, disinhi- and body posture due to pain.
bition, and neuroimmune priming. However, mild injury can • Physiological: measurement of changes in physiological
also induce widespread baseline hyposensitivity across the arousal consequent to pain.
rest of the body surface which may be a result of altered
descending pain control systems driven, in part, by changes in Obviously, self-report is impossible in neonates, and
the stress/hypothalamus-pituitary axis (HPA) [36]. therefore an indirect measure of pain must be used. This has
In the laboratory, maturation of nociceptive reflexes can disadvantages; perceived pain intensity depends on many
be delayed or abolished by blocking sensory inputs with subjective influences apart from the degree of injury and tis-
local anesthesia (LA) for long periods [37]. NMDA receptor sue damage. Stress, anxiety, attention, and expectation,
activity is important for normal sensory development in rat which are modulated by context, mood, previous experience,
pups as chronic NMDA receptor blockade prevents the nor- and underlying personality traits, all contribute to the degree
mal withdrawal of A-fibers from lamina II described above of unpleasantness of pain; given our present knowledge of
and a consequent persistence of low sensory thresholds [38]. neurodevelopment, the extent to which such factors can
influence pain perception in the neonate is largely therefore
a matter of speculation.
Effects of Analgesics Nevertheless, in neonates, observing behaviors such as
facial expression, cry, and posture together with measuring
The pharmacodynamic profile of analgesic interventions physiological variables such as heart rate and blood pressure
may not only be affected by age but also sex and type of have been used to assess pain and gauge its intensity in the
intercurrent injury [39, 40]. A number of drugs and chemical absence of viable more objective alternatives. Physiology-
compounds may also cause long-term adverse effects when based markers such as near-infrared spectroscopy (NIRS) [42,
administered in the neonatal period over and above any 43], heart rate variability (HRV) [44, 45], and skin conduc-
altered pharmacokinetic or pharmacodynamic responses due tance have been studied but are not yet fully validated [46].
to immaturity. Neuroapoptosis, or programmed cell death, is However, these surrogate measurements and markers may
a component of normal maturation in which cells that do not not be indicative of pain to the same extent, and a statistical
form functional connections are eliminated. Drugs that are technique called the item response theory may provide use-
NMDA antagonists and/or GABA agonists, in particular, ful information regarding the informativeness of a given item
have the potential to markedly increase apoptosis to such an [46]. A recent study demonstrated that when two assessment
extent that neural development is damaged leading to mea- scales were compared, the behavioral items corresponded
surable deficits in, e.g., memory and learning. Although most closely with pain, whereas the physiological items cor-
these effects have only been demonstrated in animal models responded least closely [47]. These observations and mea-
to date, many general anesthetic agents have been implicated sures are subject to many external and internal influences
including ketamine (see below), a potent nonspecific NMDA aside from pain, which also poses difficulties for interpreta-
antagonist that is also used as an analgesic. tion. For physiological variables in particular, a reduction in
These important considerations will impact how we their reliability tends to occur over time due to homeostatic
assess and manage neonatal pain such that considerable spe- controls. In an attempt to improve accuracy, observations
cialist knowledge and skills are needed in order to deliver and measurements have been frequently incorporated into
safe, effective, and developmentally appropriate care. multidimensional pain measurement “tools” or “instru-
ments” that are generally presented as checklists or scoring
systems; the range of such observations and their validity
Assessment of Neonatal Pain and usability have been reviewed recently [48–51].
An EEG-based measure of infant nociceptive brain activ-
Assessing pain frequently is essential in order to manage ity that is evoked by acute noxious stimulation and is sensi-
pain well, although this too can present problems in imma- tive to analgesic modulation has recently been presented and
ture and preverbal infants. Accurately assessing pain, includ- validated [52]. This provides an objective outcome measure
ing pain intensity, prevents or identifies pain, as well as that can be used in clinical trials of analgesics [53].
monitors the effectiveness of administered analgesia [41].
Overall, there are three fundamental approaches to assessing
pain in children: Pain Measurement Tools
• Self-report: an individual’s personal description of pain A bewilderingly large number of pain assessment tools or
and rating of intensity. scales have been designed for use in the neonate, some
Table 15.2 Pain assessment tools Table 15.3 The PIPP [79] pain assessment toola
Validated pain assessment tools Gestational age
BIIP [58] Behavioral Indicators of Infant Pain (BIIP) > = 36 weeks 0
BPS [59] Behavioral pain score 32 weeks to 35 weeks 6 days 1
BPSN [60] Bernese Pain Scale for Neonates (BPSN) 28 weeks to 31 weeks 6 days 2
CHIPPS [61] Children’s and infant’s postoperative pain scale <28 weeks 3
COMFORT [62–64] Behavioral state
COMFORTneo [65] Active/awake eyes open facial movements 0
COVERS Neonatal pain scale [66]
Quiet/awake eyes open no facial movements 1
CRIES [67] Crying Requires Increased oxygen administration,
Active/sleep eyes closed facial movements 2
Increased vital signs, Expression, Sleeplessness
Quiet/sleep eyes closed no facial movements 3
CSS [68] Clinical Scoring System
Heart rate maximum
DSVNI [69] Distress scale for ventilated newborn infants
DAN [70] Douleur Aigue du Nouveau-ne 0–4 beats per minute increase 0
EDIN [71] Echelle Douleur Inconfort Nouveau-Ne 5–14 beats per minute increase 1
FANS [72] Faceless Acute Neonatal Pain Scale (FANS) 15–24 beats per minute increase 2
Leuven Neonatal Pain Score > = 25 beats per minute increase 3
LIDS [73] Liverpool infant distress scale Oxygen saturation minimum
NFCS [74] Neonatal facial coding system 0–2.4% decrease 0
NIPS [75] Neonatal infant pain scale 2.5–4.9% decrease 1
PAIN [76] Pain Assessment in Neonates 5.0–7.4% decrease 2
PAT [77, 78] Pain assessment tool 7.5% decrease or more 3
PIPP [79] Premature Infant Pain Profile Brow bulge
PIPP-R [80, 81] Premature Infant Pain Profile-Revised None (< = 9% of time) 0
SUN [82] Scale for use in newborns Minimum (10–39% of time) 1
N-PASS [83]
Moderate (40–69% of time) 2
Maximum (> = 70% of time) 3
examples of which are given in Table 15.2. There is a consid- Eye squeeze
erable research literature on the subject, and it is now agreed None (< = 9% of time) 0
that in order to be “fit for purpose,” a pain assessment tool Minimum (10–39% of time) 1
Moderate (40–69% of time) 2
should have undergone a rigorous process of development.
Maximum (> = 70% of time) 3
To be considered reliable, an individual tool must be vali-
Nasolabial furrow
dated in the patient population, clinical context, and the type None (< = 9% of time) 0
of pain (e.g., postoperative or procedural) for which it is to Minimum (10–39% of time) 1
be used. Despite the proliferation and availability of tools, Moderate (40–69% of time) 2
these processes have not always been completed adequately Maximum (> = 70% of time) 3
nor have they been used consistently or well including incon- Score total (0–21)
sistencies having been identified between reported assess- a
A revised version PIPP-R is also available that has undergone initial
ment practice and documented practice [54–56]. A large validation and is available in translated formats [80, 81, 85]
prospective multicenter cohort study in 243 NICUs in 18
countries (EUROPAIN) found that assessments of continu- audits of practice. Some of the most widely endorsed tools
ous pain occurred in less than one-third of NICU admissions include the PIPP [79], CRIES [67], and COMFORT [62]
and daily in only 10% of neonates [57]. Several factors may scales. The PIPP (Table 15.3) creates a score from 18 to 21
be responsible for this situation. Limitations of individual depending on gestational age and behavioral state, with 0–6
scales mean that no single one can be universally recom- reflecting no pain, 6–12 reflecting mild-moderate pain, and
mended for use in all neonates in every situation, and “usabil- above 12 indicating severe pain; it is suitable for procedural
ity” factors that lead to individual user preferences which pain and ongoing postoperative pain. PIPP has now been
might not be scientifically appropriate. revised to enhance validity and feasibility, and initial con-
struct validation of PIPP-R has been demonstrated [80, 81].
electing an Appropriate Pain Assessment Tool
S CRIES includes similar indicators to PIPP: crying, oxygen
Recommendations and guidelines have been produced by a requirements, increases in heart rate or blood pressure, facial
number of professional bodies outlining the presently avail- expression, and sleep behavior. CRIES yields a score rang-
able tools and advising on their suitability for different cir- ing from 0 to 10, similar to most self-report or observational
cumstances [48, 50, 51]. Training and support are required measures of pain. The COMFORT [63] tool is more complex
for successful implementation of the best-validated tools, than the other scales. Originally developed in 1992,
and this should be combined with ongoing monitoring and COMFORT assessed global comfort in the pediatric inten-
sive care, having undergone several validation studies for reducing their adverse effects [88]. The supporting rationale is
both procedural and ongoing postoperative pain. It is fre- that the major pharmacological groups of analgesics act on dif-
quently chosen for use in the sickest neonates, e.g., after car- ferent components of pain pathways and as such their effects
diac surgery. The tool has now been modified for neonate are likely to be complementary. This is also likely to be true in
(COMFORTneo) and showed preliminary reliability [65]. the neonate, but developmental factors influencing the effects
The EDIN scale and N-PASS tools were developed to and therefore appropriateness of many analgesics must also be
assess more prolonged pain in the neonatal period; validity considered. It is logical to use combinations of analgesics, such
and reliability studies for both scores have been described as acetaminophen, opioids, and local anesthetics in conjunction
[71, 83]. The scores used most frequently in the EUROPAIN in order to achieve the optimum effect while keeping the dose
study, a prospective cohort of practice in 243 NICUs in 18 of each, and therefore side effects, at a moderate level. Sucrose
European countries, included the EDIN scale (56.7%), and non-pharmacological pain management strategies such as
COMFORTneo behavioral scale (19.7%), N-PASS (13.2%), nonnutritive sucking (NNS), swaddling, massage, etc., also
and the COMFORT scale (10.1%) [84]. have an important place in managing neonatal pain, particu-
larly for procedural pain, and should therefore be included in a
multimodal regimen where it is appropriate
Management of Pain
I nformation and Protocols: Pain Management Pharmacological Methods

Plans
Relatively few analgesics have a clearly established role for
The provision of training and education for healthcare workers managing neonatal pain. For a detailed discussion of the
and availability of written and verbal information for families clinical pharmacology of analgesics in neonates, readers are
and caregivers are pivotal for successful pain management. referred to Chap. 3
Analgesic regimens should be pre-planned wherever possible
and implemented with supporting educational programs, pro- Acetaminophen (Paracetamol)
vision and maintenance of necessary equipment, and clear Acetaminophen is an effective antipyretic and analgesic that
developmentally appropriate management protocols. Pain has been widely used for all ages, including premature neo-
management protocols must be sufficiently flexible to allow nates. Acetaminophen is commonly used to manage pain of
for differences in analgesic requirements due to developmen- mild to moderate severity, as more severe pain is incom-
tal age and other factors; they should include a pain assess- pletely managed by acetaminophen alone. It is often com-
ment and reassessment plan, encompass management of bined with more potent analgesics to manage postoperative
background and incident (breakthrough) pain, and stipulate pain. Acetaminophen can be administered orally, rectally, or
monitoring and management of adverse effects. intravenously. Although one study showed no additional
A well-designed protocol will therefore ensure efficacy effect when rectal acetaminophen was combined with mor-
and uniformity of treatment and facilitate ongoing evaluation phine after major surgery in neonates [89], marked variations
of effectiveness. Protocols for pain management should also in plasma concentrations were noted. An RCT in neonates
be designed in conjunction with ongoing global management and infants showed a lower cumulative morphine dose over
strategies such as family-centered and developmental care 48 h with intermittent intravenous acetaminophen compared
[86]. The implementation of family-centered care involves with continuous morphine after major surgery [90].
establishing a partnership between parents or caregivers and The precise mechanism of action of acetaminophen is
nursing staff and other healthcare workers that substantially unknown, but central cyclooxygenase (COX) inhibition is
increases parents’ role in their child’s in-hospital care. probably important [91]; other mechanisms have also been
Developmental care in NICU is a strategy for reducing proposed including NMDA and serotonin antagonism [92] and
stress-related morbidity in premature neonates; stressful and a possible action of the metabolite N-arachidonoylphenolamine
painful inputs are reduced by observing individual responses (AM404) on the cannabinoid CB1 receptor [93]. Alterations in
and carefully reorganizing and planning care [87]. the pharmacokinetic handling of acetaminophen have signifi-
cant implications for safe dosing in neonates. Gastrointestinal
absorption is delayed in premature neonates, whereas rectal
Multimodal or Balanced Analgesia bioavailability is initially greater in the premature and then
decreases toward the usual value of 0.5 with increasing age
Present strategies for the treatment of acute pain are centered [94]. The volume of distribution decreases and clearance
on the concept of multimodal analgesia, which was first pro- increases from 28 weeks postconceptional age, resulting in a
posed in order to increase the efficacy of analgesics while gradual decrease in the elimination half-life.
Acetaminophen is predominantly metabolized by phase II acetaminophen is administered, except in the premature

enzymes to acetaminophen glucuronide and acetaminophen neonate.
sulfate. The remainder is metabolized to the hepatotoxic Intravenous acetaminophen is not licensed for premature
metabolite NAPQI through the action of cytochrome P450 neonates in Europe nor for those less than 2 years old in the
enzymes such as CYP2E1, CYP1A2, CYP3A4, and CYP2A6 USA, and therefore a variety of dosing regimens are used
[95]. Under usual circumstances, reduced glutathione neu- off-label.
tralizes NAPQI very rapidly [46]. Glucuronidation of acet- Comprehensive data analyses have now been undertaken
aminophen is poorly developed in premature infants and for the use of IV acetaminophen in neonates, which take into
matures during early childhood, whereas sulfation remains account size, clearance maturation, effect, and safety [100,
fairly constant [96]. CYP enzymes also mature in infancy, 104–106]. A population PK study of 158 neonates (27–
but data on NAPQI formation in neonates is lacking [46]. 45 weeks’ PMA) recommended a loading dose of 20 mg/kg
There have been cases of accidental IV acetaminophen poi- followed by a maintenance dose of 10 mg/kg every 6 h for
soning in neonates [97, 98], and concerns have been raised neonates aged 32–44 weeks’ PMA [100], which would
about the risk of accidental administration of mL rather than achieve steady-state plasma concentrations associated with
mg. However, there are few reports of hepatotoxicity after reasonable analgesia and is supported by short-term safety.
overdose, particularly when the antidote, N-acetylcysteine For premature neonates <32 weeks, increasing the interval
(NAC), is administered promptly [98]. between repeat maintenance doses to 12 hourly has been rec-
Dose guidelines based on formulation, route of adminis- ommended [107]. A more recently generated set of concen-
tration, weight, and developmental age have been determined tration time profiles for neonatal pain suggested a loading
by pooled population analysis (Tables 15.4 and 15.5). Weight dose of 12 mg/kg and a maintenance dose of 6 mg/kg/6 h in
has been shown to be the most important predictor of acet- <32 weeks’ PMA neonates. This regimen was shown to lead
aminophen clearance in neonates [99, 100]. Clearance is to target Cssmean of approximately 10 mg/L, although addi-
reduced in premature neonates than in term neonates, tional clinical studies are needed to support its safety [108].
although there is large interpatient variability [96]. For older infants and children, a dosing regimen of 15 mg/kg
Antipyretic plasma levels are 10–20 mg/L, levels required every 6 h is commonly used [107].
for analgesia are thought to be similar, and so most dosing
regimens attempt to target the trough plasma concentrations onsteroidal Anti-inflammatory Drugs (NSAIDs)
N
at 10 mg/L [101]. A greater initial dose followed by mainte- NSAIDS for analgesia are not presently used in neonates
nance doses that did not exceed the recommended maxima is because uncertainty regarding their efficacy and potential for
generally recommended. Peak plasma levels are rapidly adverse effects results in an unfavorable benefit-risk ratio.
achieved after oral ingestion, although there is a 1–2 h lag Laboratory studies have shown a reduced efficacy of
before the maximum therapeutic effect. In contrast, the onset NSAIDS in young rodents casting doubt on their value as
of analgesia after IV administration may be much faster analgesics in infants [109].
[102], with a more predictable PK profile [103]. As rectal NSAIDS act by inhibition of cyclooxygenase, enzymes
bioavailability is much poorer and more variable than oral that regulate many cellular functions by the production of
dosing, larger initial doses are recommended when rectal prostaglandins and other substances. Prostaglandins have
Table 15.4 Acetaminophen dosing guide—oral and rectal administration

Age Route Loading dose Maintenance dose Interval Maximum daily dose Duration at maximum dose
28–32 weeks’ PCA Oral 20 mg/kg 10–15 mg/kg 8–12 h 30 mg/kg 48 h
Rectal 20 mg/kg 15 mg/kg 12 h
32–52 weeks’ PCA Oral 20 mg/kg 10–15 mg/kg 6–8 h 60 mg/kg 48 h
>3 months Oral 20 mg/kg 15 mg/kg 4 h 90 mg/kg 72 h
PCA post-conceptual age
Table 15.5 Intravenous acetaminophen dosing guidea

Age Drug Loading dose mg/kg Maintenance dose mg/kg Dose interval
28–31 weeks’ PCA Acetaminophen 20 10 12 h
32–44 weeks’ PCA Acetaminophen 20 10 6 h
>44 weeks’ PCA Acetaminophen 15 15 6 h
a
Adapted from [100, 107]
multiple roles in early development, and inhibition of their Table 15.6 Morphine dosing and morphine infusion
synthesis with NSAIDs may potentially result in disruption of Morphine dosing
the sleep cycle, an increased risk of pulmonary hypertension, Preparation
alterations in cerebral blood flow, decreased organ perfusion Oral solution 50–100 mcg/kg, 4–6 hourly
and renal function, and disrupted thermoregulation [110]. Intravenous 25–50 mcg/kg initial dose (titrated according to
In premature neonates in intensive care, prophylactic response)
25 mcg/kg every 30 min to 1 h
intravenous indomethacin reduces both the need for surgical
Morphine infusion
ligation of patent ductus arteriosus and the incidence of
Preparation: Morphine sulfate 1 mg/kg in 50 mL solution
grade 3 and 4 intraventricular hemorrhage. Reductions in Concentration 20 mcg/kg/mL (0.02 mg/kg/mL)
cerebral, renal, and mesenteric blood flow velocity occur for Initial dose 0.5–2.5 mL (0.01–0.05 mg/kg)
2 h after bolus indomethacin but can be minimized by con- Infusion rate 0.1–0.6 mL/h (2–12 mcg/kg/h)
tinuous infusion. Renal effects are also less with the use of
ibuprofen compared with indomethacin. There is therefore a
potential to reduce NSAID-related adverse effects. More Table 15.7 NCA (morphine) protocol for neonates and infants
recently, oral acetaminophen has been shown to be as NCAa for neonatal use
efficacious as ibuprofen for PDA closure but with a smaller Preparation: Morphine sulfate 1 mg/kg in 50 Ml solution
risk of adverse effects [111–113]. Concentration: 0.02 mg/kg/mL
Initial dose: 0.5–2.5 mL (0.01–0.05 mg/kg)
Pump programming
Opioids Background infusion 0–0.5 mL (0–0.01 mg/kg/h)
Morphine is the prototypic opioid, which has been relatively NCA dose 0.5–1.0 mL (0.01–0.02 mg/kg)
extensively investigated in the neonate. There is considerable Lockout interval 20 or 30 min
clinical experience with morphine used to treat severe acute a
NCA is a demand-led, flexible morphine infusion system using a PCA
pain after surgery and in the NICU. Dose requirements and infusion pump [117]. It is suitable for neonates who are not receiving
clinical responses to opioid analgesics differ markedly respiratory support provided they are closely monitored by appropri-
between premature and term neonates, infants, and children. ately trained staff
There are multiple contributors to this difference including
age-dependent changes in body composition and organ func- non-ventilated premature infants [115] had to be terminated
tion influencing opioid pharmacokinetics and genetic and early due to profound respiratory adverse effects, without
developmental factors that change opioid pharmacodynam- demonstrating analgesic efficacy [116]. The authors strongly
ics. Therefore, regular and serial assessments of pain after advised caution when oral morphine is used for other acute
titrating and adjusting the opioid doses according to individ- painful procedures in non-ventilated premature infants.
ual responses are required to achieve analgesia and minimize Parenteral morphine is usually given intravenously either
adverse effects. Tolerance leading to dose escalation and by intermittent dosing, continuous infusion, or in a nurse-
subsequent physical withdrawal response if opioid infusion controlled analgesia (NCA) regimen (Tables 15.6 and 15.7,
rates are reduced too rapidly are distressingly frequent prob- Box 15.1) [117]. Subcutaneous morphine is also used. The
lems after medium- to long-term use in intensive care [114]. pharmacokinetics and clinical use of morphine in neonates
Other more lipophilic opioids such as hydromorphone, fen- have been reviewed [118–121] (see Chap. 3). The pharmaco-
tanyl, and remifentanil are also chosen to manage acute pain kinetics of IV morphine are developmentally regulated, and
on occasion in neonates and are therefore discussed briefly the neonatal period is characterized by high interpatient vari-
below along with tramadol and the morphine prodrug ability [122] and reduced clearance, making the clinical
codeine. effects of morphine less predictable than in older children. A
pharmacokinetic model for children up to the age of 3 years,
Morphine including premature neonates, showed that the capacity of
Morphine can be given orally or parenterally. Morphine morphine glucuronidation and the clearance of metabolites
solutions are generally well absorbed orally, but the pharma- are influenced by body weight in a nonlinear manner [123].
cokinetics and efficacy of oral opioids have not been clearly The clearance and glucuronidation capacity of neonates
established in neonates. Oral morphine can be given at an 1–10 days of age is approximately 50% less than that of older
effect-titrated dose of 0.05–0.1 mg/kg every 4–6 h in care- infants and children, which are less than previously reported
fully monitored non-ventilated term neonates (Table 15.6). [121, 124]. Consequently, significantly smaller doses are
However, a recent blinded randomized placebo-controlled advised, particularly in the premature neonate, than those
trial (Poppi trial) investigating whether 0.1 mg/kg oral mor- generally recommended 10–40 mcg/kg/h [125]. Using a
phine provides effective analgesia for procedural pain (reti- wider population, morphine clearance has been predicted
nopathy of prematurity screening and heel lance) in across the entire pediatric age range [126], but further studies
in patients with congenital heart disease and chronic lung dis-

Box 15.1: NCA ease. Fentanyl is also used by infusion in NICU, and it has
NCA is a demand-led alternative for patients who are some advantages for procedural pain owing to its rapid onset.
too young or unable to use PCA (patient-controlled Administered as a bolus, fentanyl has been found to be safer
analgesia). It is designed to provide safe, potent, flexi- than when administered by continuous administration [132],
ble, and convenient pain control by combining the pos- despite previous reports of a reduced frequency of apneic spells
sibility of a continuous opioid analgesic infusion with after continuous infusion compared with bolus administration
on-demand bolus doses of analgesia administered [133]. Unfortunately, fentanyl has the potential for a more rapid
according to predetermined limits. NCA was first development of tolerance with prolonged use because of the
developed for infants and those children and adults greater duration of receptor occupancy [134]. Opioid with-
who were unable to operate the PCA handset and was drawal syndromes can also occur.
subsequently adapted for neonates [117]. Suggested After intravenous administration, the duration of a single
initial NCA infusion programming for a postsurgical dose of fentanyl is 30–45 min. As fentanyl is very lipophilic,
neonate is shown in Table 15.7. its pharmacokinetic profile is context sensitive such that the
half-life progressively increases with the duration of the
infusion [135]. A predictive PKPD model of fentanyl that
are required to correct for type of pain and severity of illness, includes growth and maturation physiological changes in
in addition to differences in PK. The large variability in mor- neonates has been developed [136]. High-dose fentanyl has
phine clearance, particularly in critically ill neonates, may be been associated with chest wall rigidity [137] and subse-
attributed to variations in hepatic and renal functions and quent difficulty in ventilation, and such doses are therefore
hepatic blood flow, type of surgery, and possibly genetic dif- usually only given when respiration is controlled [138]. It
ferences. Recently, the pharmacogenetic (PG) effects of vari- can also be given neuraxially; in the epidural space, it is used
ants at the loci of organic cation transporter 1 (OCT1) and alone or in combination with local anesthetic by infusion
UDP-glucuronosyltransferase 2B7 (UGT2B7) have been after major surgery [139, 140].
studied in critically ill neonates, and a PBPK model that Alfentanil and sufentanil are fentanyl analogs with differ-
accounted for OCT1 ontogeny and PG effect adequately ent potencies and durations of effect. Their principal use is
described the observed variability in morphine PK [127, 128]. during anesthesia, but they have also been used for ongoing
Although the plasma levels associated with analgesia are pain and pain due to brief procedures, particularly on ICU
not well defined and a concentration-response profile is [141, 142]. Sufentanil is more potent (10 × fentanyl) [143]
lacking [53], a mean steady-state serum concentration of but otherwise very similar to fentanyl in clinical effect; it has
10 ng/mL is a reasonable target. This level was achieved in been used for intubation [144] and by infusion in ICU but
children in intensive care after noncardiac surgery with a probably does not offer significant advantage. Alfentanil
morphine hydrochloride infusion of 5 mcg/kg/h at birth pharmacokinetics have been studied in the neonate [145,
(term neonates), 8.5 mcg/kg/h at 1 month, 13.5 mcg/kg/h at 146]. It is less potent than fentanyl and of relatively short
3 months, 18 mcg/kg/h at 1 year, and 16 mcg/kg/h for 1- to duration after a single dose. It is also sometimes used to
3-year-old children [120]. Conversely, a common threshold facilitate tracheal intubation [142]. However, like fentanyl,
for respiratory depression in neonates, infants, and children doses effective for painful procedures can lead to chest wall
has been defined as 20 ng/mL [129]. Any differences in effi- rigidity in neonates and again, therefore, should probably
cacy observed between continuous infusion and intermittent only be used if ventilation is controlled [147].
boluses of morphine probably relate more to the age-
appropriate total dose of drug received, rather than the Remifentanil
method of administration [130, 131]. Sedation and respira- Remifentanil is an ultrashort-acting fentanyl analog that is
tory depression are the most frequently seen adverse effects metabolized by tissue and plasma esterases. As a result, its
of morphine (and other opioids); adverse effects of morphine elimination is therefore independent of liver and renal func-
can be reversed with the opioid antagonist naloxone. tion. The context-sensitive half-life of remifentanil remains
in the order of several minutes even after several hours of
Fentanyl infusion, presenting obvious advantages in anesthesia and
Fentanyl is a synthetic, high-potency (100 × morphine) lipid- sedation practice. The use of remifentanil in neonates has
soluble opioid. Its main use is for intraoperative analgesia been reviewed recently [148–150]. Given its rapid metabo-
where its rapid onset, short initial half-life, and its cardiovascu- lism, the major advantage of remifentanil remains its ability
lar stability at larger doses are an advantage. It prevents pain- to control the stress response during major surgery while
induced increases in pulmonary vascular resistance, causes less permitting a rapid recovery. The pharmacokinetic principles
histamine release than morphine, and is therefore more stable apply across all age ranges including neonates.
Although remifentanil has been used during surgery and (“slow and intermediate metabolizers”) and consequently are
to sedate neonates ventilated in the NICU, the rapid develop- less able to produce morphine from codeine, leading to unpre-
ment of tolerance and possibility of opioid-induced hyperal- dictability of effect [160]. Conversely, “rapid metabolizers”
gesia (OIH) are potential problems. In a study that compared may experience adverse effects from excess morphine result-
remifentanil- and fentanyl-based analgesia and sedation in ing in unexpected respiratory depression [161]. Several chil-
23 ventilated infants, the risk of tolerance, withdrawal, and dren with obstructive sleep apnea who received codeine for
OIH were not increased with the former [151]. It has even pain post-adenotonsillectomy were found dead and subse-
been used successfully at high infusion rates for laparotomy quently found to be rapid metabolizers [162, 163]. This led to
in extremely low birth weight premature neonates with nec- a proscription of codeine in young children in the USA. In
rotizing enterocolitis [152]. If remifentanil is used during contrast, institutions that genotyped children for 2D6 poly-
anesthesia, then longer acting opioids are usually substituted morphisms continue to use codeine safely in children by
immediately before or after awakening to prevent severe pain avoiding its use in rapid and poor metabolizers [164].
in the early postoperative period [153]. Moreover, CYP2D6 activity is developmentally regulated,
High infusion rates and large bolus dosing may result in with lower levels in the very young [165].
hemodynamic instability (bradycardia and hypotension), Traditionally codeine was chosen where respiratory
particularly in premature neonates and in patients with car- depression, sedation, or other opioid-related side effects
diac dysfunction. This is usually easily treated with intrave- were a particular concern, e.g., the neonate and after neuro-
nous fluids or decreasing the infusion rate of remifentanil. surgery, but the use of codeine for these indications was chal-
Given its short context-sensitive half-life, it can be used lenged because of uncertainties regarding its efficacy and
effectively during surgery by starting at a low infusion rate safety [161]. Regulatory agencies such as the Medicines and
and titrating up according to the hemodynamic responses Healthcare Products Regulatory Agency (MHRA), the Food
[154]. Remifentanil is also used in other clinical scenarios and Drug Administration (FDA), and the European Medicines
including tracheal intubation, brief invasive procedures, or Agency (EMA) no longer recommend its use in children
sedation during mechanical ventilation in the NICU. Chest under 12 years.
wall rigidity is a potential adverse effect, particularly with However, codeine still features in the management of pain
large or rapid boluses as has been used for tracheal intuba- in breastfeeding mothers leading to concerns for potential
tion. For example, bolus doses of remifentanil of 1, 2, or toxicity in neonates including central nervous system depres-
3 mcg/kg resulted in rigidity in 6%, 10%, and 13% of the sion and death [166–168]. To ensure neonatal safety, it is
neonates, respectively [155–157]. The rate of administration important to follow evidence-based guidelines [169].
and duration between repeat boluses may be important in Genotyping the mothers may prove useful in improving the
reducing the risk of chest wall rigidity [158, 159]. outcome of codeine therapy in this setting [170, 171].
Hydromorphone Tramadol
Hydromorphone is a potent semisynthetic morphine deriva- Tramadol is a synthetic opioid analgesic that also inhibits
tive that is popular in pediatric practice. It is used extensively serotonin and norepinephrine reuptake [172]. It has been
in PCA and epidural analgesia regimens in older children. used widely for acute and chronic pain in children, and there
Hydromorphone is approximately four to five times more is an extensive body of literature describing its efficacy and
potent than morphine and has a lipid solubility intermediate indications. Like codeine, tramadol is metabolized by the
between morphine and fentanyl. It has no active metabolites, cytochrome enzyme CYP2D6 to its major active metabolite
which is potentially an advantage in neonatal practice, but its o-desmethyltramadol, which has a 200 x increased affinity
use has not been well described or studied in this age group. for the mu opioid receptor. CYP2D6 is genetically and devel-
opmentally regulated (as is codeine metabolism above),
Codeine which may have implications for the use of tramadol in very
Codeine is a low-potency opioid that until recently has been young patients. The effect of CYP2D6 polymorphism on the
popular in pediatric practice for the treatment of mild to mod- efficacy and disposition of tramadol is not known. The phar-
erate severe pain. Codeine is a morphine prodrug; about macokinetics of tramadol in neonates and infants has been
10–15% of each dose of codeine is metabolized to morphine investigated, no relationship between post-menstrual age and
by the cytochrome P450 enzyme CYP2D6, and the morphine o-desmethyltramadol production was established, matura-
metabolite is thought to be responsible for codeine’s analge- tion of tramadol elimination occurs early (50% of adult value
sic effect as analgesia cannot be demonstrated in human vol- at term gestation) [173], and clearance reaches 80% of adult
unteers when the pathway is pharmacologically blocked. values by 1 month [174, 175].
CYP2D6 activity is genetically regulated; 5–40% of individ- Opioid side effects are less prominent with tramadol, but
uals in some populations have reduced, little, or no activity this was not confirmed when equianalgesic doses were used
[172, 176]. Although a randomized trial of fentanyl (1–2 mcg/ after cardiac surgery, it proved to be hemodynamically safe,
kg/h intravenously) or tramadol (0.1–0.2 mg/kg/h intrave- with a maximum decrease in mean HR of only 12% and tran-
nously) in neonates in the first 72 postoperative hours sient and limited decreases in diastolic blood pressure of 13%
reported equianalgesic efficacy for the two drugs, tramadol [185]. These findings were confirmed in a second study that
offered no advantages over fentanyl in terms of the duration used clonidine infusions in infants after cardiac surgery [186].
of mechanical ventilation and the time to reach full enteral However, a Cochrane Database systematic review found
feeds [177]. In another randomized trial in postsurgical neo- insufficient evidence to confirm the safety and efficacy of
nates, the addition of tramadol to a standard analgesic regi- clonidine for sedation and analgesia in term and preterm
men of intravenous acetaminophen and a morphine infusion infants who were mechanically ventilated [187].
did not affect the time to extubation, morphine or midazolam Dexmedetomidine sedation and caudal epidural anesthe-
exposure, or pain scores [178]. This study questioned the sia have been used successfully for lower abdominal and
benefit of using tramadol in postsurgical neonates, although lower limb surgery in ex-preterm and term infants with
the effects of tramadol in this study may have been masked severe comorbidities [188]. In a pilot study, dexmedetomi-
in part by the dose of morphine [179]. Conclusions about the dine at 2 mcg/kg over 10 min, followed by 1 mcg/kg over the
safety of tramadol in the neonate are limited by the small size next 10 min, was used to sedate infants to place a caudal
of the PKPD data available. block for an inguinal hernia repair [189]. A meta-analysis of
In 2017, the FDA recommended that tramadol should not perioperative analgesic effects in children, infants, and neo-
be used in the management of pain in children under 12 years nates showed intraoperative dexmedetomidine reduced post-
old and breastfeeding mothers due to the risk of serious operative opioid requirements and pain intensity without
adverse reactions. However, to date, no deaths have been effect on the frequency of postoperative nausea and vomit-
reported in breastfed neonates whose mothers used tramadol ing. The optimal bolus was 0.5 mcg/kg or more [190].
(National Library of Medicine. Drug and Lactation Database Dexmedetomidine has not been associated with neuro-
(2016)) nor have deaths been reported in neonates associated apoptosis or other neurodegenerative effects in animal stud-
with therapeutic tramadol [180]. ies involving infant rodents and fetal primates [191] and
It has been recommended that tramadol dose should be attenuates isoflurane-induced neurocognitive impairment in
limited for acute pain after tonsillectomy (e.g., maximum neonatal rats [192]. The areas of the brain affected by dex-
dose 1 mg/kg 6–8 h, maximum 400 mg/day) and starting medetomidine (primary sensory brain region) are different
with a smaller dose of 2 mg/kg daily in divided doses (e.g., from ketamine (limbic brain regions) [193]. The bulk of
0.5 mg/kg 6–8 h) [181]. A comprehensive summary of the present evidence suggests fewer consequences attributable to
literature has been published, and the authors suggest that alpha2 agonists than most other anesthetic drugs [194].
the recommendation to avoid tramadol when breastfeeding Pharmacokinetic data for dexmedetomidine are limited in
and the contraindication to use in children (including neo- neonates and infants.
nates) is inappropriate and recommendations should instead In a phase II/III safety, efficacy, and PK study of dexme-
focus on seeking medical advice and dose adjustment if detomidine in 18 mechanically ventilated term neonates
sedation is experienced in the mother or suspected in the receiving dexmedetomidine 0.05–0.2 mcg/kg/h, clearance
breastfed infant [168, 180]. was 0.9 (0.2–1.5) L/kg/h and even less in 24 premature neo-
nates (0.3 L/kg/h) [195]. Dexmedetomidine undergoes
Non-opioid Analgesics almost complete hepatic transformation, and so these lower
clearances are likely to reflect their decreased hepatic enzyme
Clonidine and Dexmedetomidine activity compared with adults [196]. In an open-label single-
Clonidine and dexmedetomidine are alpha2 adrenergic ago- center PK study, younger infants (with a PMA of 33–61 weeks
nists capable of producing analgesia both systemically and and a body weight of 2–6 kg) and those with a history of
neuraxially. Clonidine has analgesic, sedative, and antiemetic cardiac surgery were significant predictors of reduced clear-
properties; it can also cause hypotension and bradycardia. It ance and may therefore require relatively lower doses to
is used as a sedative infusion in ICU areas and for the symp- achieve exposure similar to older patients [197]. There were
tomatic treatment of effects due to the rapid withdrawal of no significant associations between dexmedetomidine con-
opioid analgesics [182]. Both agents have been found to have centrations and hypotension. In a PK study in 23 neonates
opioid-sparing effects when used as adjuncts to sedation and and 36 infants after open heart cardiac surgery, continuous
analgesia in neonates [183]. Clonidine infusions at 1 mcg/ infusions of up to 0.3 mcg/kg/h in neonates and 0.75 mcg/
kg/h in ventilated neonates reduced fentanyl and midazolam kg/h in infants were well tolerated [198]. It has found a niche
requirements with deeper levels of analgesia and sedation in critically ill neonates and infants with congenital heart dis-
without substantial side effects [184]. When clonidine (in ease because of its minimal effects on respiratory function at
doses of 0.5–2 mcg/kg/h) was used to sedate small infants sedative doses, facilitating early extubation and fast-track
postoperative care. However, there is a potential risk for inter-utero and in the first few days of life [211]. The role of
withdrawal seizures after dexmedetomidine sedation for car- ketamine varies not only on the basis of the dose and fre-
diac surgery, particularly with greater cumulative doses and quency of exposure but also the intensity of the noxious
abrupt discontinuation [199]. stimuli [212]. Repeated ketamine usage may be neurotoxic
Neonates appear to be more susceptible to the effects of to immature brains in the absence of noxious stimuli, whereas
clonidine including side effects. After severe delayed respira- it may be neuroprotective in the same brains in the presence
tory depression was reported in a neonate given 2 mcg/kg of strong painful stimuli [213, 214]. The significance of
caudal epidural clonidine, several similar cases were pub- these findings in humans and implications for clinical prac-
lished resulting in a warning of caution in neonates for all tice are not known [215]; however, taken together, they raise
routes of administration [200–203]. Epidural dexmedetomi- concern regarding the use of ketamine in premature infants
dine analgesia was also found to be developmentally regu- and term neonates [208].
lated and relatively greater in neonates in a rodent laboratory Spinally (epidural) preservative-free ketamine has not been
model and may be better tolerated, but when administered clinically implicated as a cause of neurotoxicity, although
caudally in children it showed no advantages over clonidine, recent research in rodents has led to a conclusion that the ben-
and there has been limited spinal safety evaluation [204, 205]. efit-risk ratio is unlikely to be favorable in neonates and young
children and so it should be avoided [200, 216].
Ketamine
Ketamine is a glutamate NMDA receptor antagonist that pro- Local Anesthetics
duces a state of “dissociative” anesthesia. It has been used for LA is very important in infant acute pain management, par-
many years as an intravenous general anesthetic with several ticularly during and after surgery and for procedural pain
advantages: profound analgesia, relative preservation of res- where opioid requirements and opioid-induced side effects
piration and respiratory reflexes, and cardiovascular stimula- such as depression of respiration can be reduced or avoided
tion. At low doses (<1 mg/kg), it is an effective analgesic; in by the use of LA. Topical LA, LA infiltration, and peripheral
particular, it appears to reduce the hypersensitivity due to and central regional analgesia are all used extensively for
central sensitization after injury or surgery in both inflamma- acute pain indications in neonates. The detailed pharmacol-
tory and neuropathic conditions. Although numerous publica- ogy of local anesthetics and regional anesthetic techniques
tions describe the analgesic effects of ketamine, a systematic are detailed in Chaps. 3 and 16.
review concluded that its role in the management of postop-
erative pain in the adult remains unclear [206]. Ketamine has Lidocaine, Bupivacaine, Levobupivacaine,
been effective in resetting opioid requirements in patients Ropivacaine, Chloroprocaine
who chronically abused opioids. The disadvantages of ket- The amide-type LAs lidocaine and bupivacaine have been
amine include infrequent emergence phenomena such as hal- the most commonly used in neonates for several decades,
lucinations and unpleasant dreams and nausea and vomiting. and there is considerable clinical experience of their effi-
The NMDA receptor is known to undergo developmental cacy and safety at all ages. Lidocaine has a rapid onset and
changes in distribution, structure, and function and is thought is of short to intermediate duration; it is used for local infil-
to be important in regulating neuronal plasticity during the tration and regional nerve blocks, particularly where a rapid
developmental period [3]. The precise impact of this on the response is required. EMLA (eutectic mixture of local anes-
efficacy or toxicity of ketamine (or other NMDA antago- thetics) is a combination of lidocaine and prilocaine for
nists) in neonates is still not fully understood. The principal topical analgesia – see below for a detailed description.
uses of ketamine in neonates include for intravenous induc- Bupivacaine has a slower onset and long duration, 4-h anal-
tion of anesthesia in high-risk patients with cardiovascular gesia or longer can be expected after a single dose in a cen-
disease and for procedural sedation. The potential for neuro- tral nerve block, and consequently it has been the first choice
toxicity from systemically or spinally administered NMDA for postoperative analgesia. Their pharmacology and phar-
antagonists is also a concern that is widely debated [207, macokinetics have been well investigated and reviewed
208]. Systemically administered ketamine, and a number of [217]. Bupivacaine is a racemic mixture. The S(+) enantio-
other substances including some sedatives and anesthetic mer, levobupivacaine, has a slightly improved in vivo and
agents, can produce damaging neurodegeneration in rodent in vitro safety profile compared to bupivacaine but is other-
brains during a critical period of rapid synaptogenesis in the wise similar [218, 219]. Ropivacaine is an amide LA with
early postnatal period [209] (see Chap. 18). Ketamine has similar clinical properties to bupivacaine except that motor
more recently been found to alter neurogenesis from neural block is slower in onset, less intense, and shorter in duration
stem progenitor cells in the developing rat brain [210]. Early [200]. Ropivacaine and its active metabolite 2′,6′-pipeco-
studies in primates indicate that similar histological damage loxylidide (PPX) unbound clearance depends on body
is possible but critically dependent on age at exposure, drug weight and age [220]. Ropivacaine may have theoretical
dose, and duration of treatment, with the greatest risks being advantages during prolonged infusion in neonates and
infants as unlike bupivacaine context-sensitive half-life does re-established appears to be a sensible approach at this time
not increase with increased duration of infusion [200]. Most (see Chap. 16).
recently, 2-chloroprocaine has seen a resurgence in use in
neonates and premature infants for caudal blocks in awake EMLA, Amethocaine Gel, and Other Topical LA
neonates for open (and closed) hernia repair and lower Preparations
abdominal surgery [221, 222]. Since chloroprocaine is Topical LA has revolutionized the practice of minor needle-
spontaneously degraded by plasma esterases, it has a very related procedures such as venipuncture, venous cannula-
brief half-life even in neonates with reduced pseudocholin- tion, and lumbar puncture [230]. A number of preparations
esterase activity. This precludes accumulation of the local are available, and the most frequently studied and in clinical
anesthetic and reduces the risk of toxicity even after pro- use are EMLA and Ametop (amethocaine gel).
longed regional blockade. Lidocaine forms a eutectic mixture with prilocaine such
Toxicity of LAs depends on the age of the patient, the that the combination has a lower melting point than either of
local anesthetic, dose, and route of administration. the constituents. This mixture, formulated as a cream, can
Neurotoxicity and cardiotoxicity have been reported in neo- produce LA when applied to intact skin. When applied for
nates who have a reduced threshold for toxicity, but pro- about 60 min under an occlusive dressing, the duration of the
vided the recommended doses are observed, toxic events are resulting cutaneous analgesia is several hours. EMLA is
rare [223]. LAs are extensively protein bound (>90%), with suited for use in the neonate in single doses; multiple doses
the free, unbound, fraction being the pharmacologically should be limited to a maximum of four applications per day
active fraction. AAG (alpha-acid glycoprotein) and albumin and under close supervision to preclude methemoglobin-
are the most important plasma proteins that bind drug; AAG emia. Measurement of blood methemoglobin concentrations
concentrations in the blood are reduced in the neonate has been advised if multiple applications or large doses of
resulting in increased unbound fractions of lidocaine and EMLA are applied [231, 232]. A metabolite of prilocaine,
bupivacaine [224]. Plasma bupivacaine concentrations o-toluidine, can increase the blood levels of methemoglobin,
>3 mcg/mL are associated with neurotoxicity in the awake an oxidized form of hemoglobin which has a reduced
adult and cardiotoxicity >4 mcg/mL; the equivalent concen- oxygen- carrying capacity. Methemoglobin reductase, the
trations in neonates are unknown, although toxicity has enzyme which catalyzes reduction to hemoglobin, is also
been reported after bupivacaine infusions at doses >0.3 mg/ developmentally regulated, rendering neonates susceptible
kg/h, leading to a reduction in recommended doses and to methemoglobinemia because fetal hemoglobin is more
infusion durations in the neonate to ≤0.2 mg/kg/h [225]. easily oxidized [233]. Minor side effects of transient pale-
When transversus abdominis (TAP) blocks were performed ness or redness and edema of the skin may occur following
in ten neonates using 1 mL/kg or 0.125% levobupivacaine, application. Tetracaine is a potent ester-type LA. Due to its
the greatest plasma concentration, 0.26 mcg/mL, was sig- high systemic toxicity, it is only used for surface anesthesia
nificantly less than the potentially toxic plasma threshold (not on mucus membranes), with about 15% bioavailability
(1.5–2 mcg/mL) suggesting a low risk of LA toxicity [226]. after application to intact skin.
In contrast to bupivacaine infusions, plasma concentrations Four percent tetracaine gel (Ametop) produces surface
after ropivacaine infusions in infants <1 year did not con- anesthesia in about 30 min with an absorption and elimina-
tinue to increase with time, although absolute concentration half-life of about 75 min. Its duration of analgesia is
tions and free fraction were similarly increased at younger 4–6 h. Ametop therefore produces a more rapid onset of
ages [227]. In a comparison of epidural bupivacaine and action and greater duration than EMLA. It has been shown to
ropivacaine, boluses and infusions in neonates and young be effective in the neonate [234]. Mild erythema at the site of
infants showed that epidural infusions of 0.2 mg/kg/h bupi- application is seen frequently but of little consequence;
vacaine or ropivacaine were well tolerated and efficacious edema of the skin, itching, and even blistering have been
with no accumulation of unbound drug [228]. reported in older children but are rare in the neonate.
2-Chloroprocaine overdose has not been reported in neo-
nates or older infants. Sucrose
Intralipid 20% has been used to treat inadvertent local Sucrose solutions may reduce physiological and behavioral
anesthetic toxicity of amide local anesthetics in neonates and signs of pain in neonates during brief painful procedures
children [229]. This lipid emulsion is distinguished from such as heel lance blood sampling [235].
propofol, which is an emulsion of a general anesthetic in a Volumes of 0.05–2.0 mL of a 12–24% solution of sucrose
10% suspension of long-chain triglycerides that should not administered 1–2 min before a painful stimulus appears to be
be used for said purpose. Although a dosing regimen for effective [235, 236]. It can be administered using a pacifier
Intralipid to treat local anesthetic toxicity in neonates has not or dripped directly onto the tongue using a syringe, with the
been forthcoming, titrating doses of 1 mL/kg Intralipid and number of drops titrated to the infant’s response. Coughing,
monitoring the circulatory responses until a stable rhythm is choking, gagging, and transient oxygen desaturation can
occur. The safety of multiple administrations in very small analgesia is commenced intraoperatively as part of the plan
premature infants has been questioned as changes in neu- of anesthesia using combinations of local anesthetics, opi-
robehavioral responses were observed after repeated sucrose oids, and acetaminophen and suitable ongoing analgesia
administration in this group [237, 238]. administered orally, rectally, or parenterally as indicated.
It is important to note however that sucrose has not been
found to significantly affect activity in neonatal brain or spi-
nal cord nociceptive circuits, suggesting that it should not be roup 1: Inguinal Hernia Repair, Circumcision,
G
considered an effective analgesic drug [239]. There was also Pyloromyotomy, etc.
no difference in the cortical response to pain during veni-
puncture in neonatal infants who were administered sucrose Neonates presenting for this type of surgery are usually
versus those who were breastfed [240]. healthy. The surgeries are generally relatively brief and are
sometimes performed using minimally invasive laparoscopic
techniques.
Postoperative Pain Management LA: Caudal epidural analgesia or simple LA nerve
blocks such as ilioinguinal block and penile block are often
Postoperative pain management should always be planned indicated. If these techniques are not suitable, then subcuta-
before beginning surgery [241]. Initiation of postoperative neous infiltration at the surgical incision or laparoscope port
pain relief is usually considered to be part of the plan of sites with a relatively long-acting LA such as levobupiva-
anesthesia; patients should not normally be discharged from caine is an option.
the PACU (postanesthesia recovery unit) or returned to the Opioid analgesia: Fentanyl or other suitable intravenous
ICU until they are comfortable, and an ongoing pain man- opioid administered as part of anesthesia can be continued
agement plan is established. Pain management protocols into the postoperative period if necessary. Oral intake is usu-
should include pain assessment, monitoring, criteria for ally rapidly resumed, therefore oral morphine solution can
additional analgesia, management of side effects, and criteria be given every 4 h as required. However, it is unusual for
for transition to simpler, usually oral, analgesia when appro- neonates to require more than one or two doses following
priate. Neonatal surgery may be relatively minor, such as this group of procedures.
circumcision or uncomplicated inguinal hernia repair on oth- Acetaminophen: A loading dose should be administered
erwise well neonates, or major interventions in life- during surgery; it is convenient to give it intravenously. Oral
threatening circumstances carried out on very sick infants. and rectal dosing are options; the first dose can be given prior
Appropriate analgesia depends on the exact prevailing cir- to surgery, but rectal absorption is less predictable in neo-
cumstances, which depends on the type of surgery, physical nates. Acetaminophen can be continued orally at appropriate
state of the child, and available facilities for postoperative doses for 2 or 3 days as needed.
care and level of staff training. Some of the more commonly
encountered procedures, divided into three groups of increas-
ing complexity, are listed in Table 15.8. Conventionally, Group 2: Major Gastrointestinal or
Genitourinary Surgery
Table 15.8 Common surgical procedures Although surgery can be quite prolonged and relatively inva-
Neonatal surgery sive, the majority of neonates presenting for these proce-
Group 1 dures are well and can be expected to recover rapidly. A
Inguinal hernia repair potential problem is that high doses of intraoperative opioid
Pyloromyotomy may be required to obtund physiological responses to s urgery
Orchidopexy, orchidectomy leading to delayed recovery and possibly necessitating post-
Group 2 operative respiratory support.
Duodenal atresia LA: Continuous epidural analgesia should be considered
Intestinal malrotation
for this group as it allows early postoperative tracheal extuba-
Colostomy formation
tion and reduces the need for ongoing respiratory support.
Urogenital malformations
Group 3 Opioid: High-potency analgesics such as parenteral opi-
Bowel resections NEC oids or local anesthetic infusions may be needed as part of a
Esophageal atresia “balanced analgesia” approach. Intravenous opioid infusion
Congenital diaphragmatic hernia may be needed postoperatively, and NCA (see above) should
PDA repair be considered because it is easier to adapt dose requirements
Congenital heart surgery to individual patients and circumstances.
Acetaminophen: It is somewhat unclear whether acet- ratory stability in ventilated neonates and possibly neuro-
aminophen significantly contributes to analgesia in conjunc- logical outcome [245]. However, this benefit was not
tion with these more potent analgesic techniques although a confirmed in a subsequent large study, which initially
recent systematic review concluded that it might reduce mor- reported an association between bolus morphine administra-
phine requirements after major surgery [242]. Rectal acet- tion and worse outcome [246]. Reanalysis of those data dem-
aminophen did not reduce morphine requirements in onstrated that poor neurological outcomes were related to
neonates after major abdominal surgery in one study [89]. preexisting hypotension and morphine therapy was not a
But as rectal absorption is unreliable and pain assessment is contributory factor [247]. However, morphine infusions can
difficult in these infants, further study would be required produce hypotension, and the safety, efficacy, and long-term
before firm conclusions can be drawn. Acetaminophen, and outcomes of analgesia and sedation in ventilated neonates
particularly intravenous acetaminophen, should not be given require further evaluation. A follow-up study of ventilated
at full dose for more than a few days because of potential preterm neonates who were randomized to either morphine
toxicity, and therefore its use may usefully be delayed until or no morphine failed to show any serious long-term conse-
epidural or IV opioid infusions are being withdrawn follow- quences in the neonates who received morphine [248]. In
ing the second or third postoperative days. contrast, midazolam, frequently used for sedation in older
patients in intensive care, has been strongly associated with
an increased incidence of poor neurological outcome in neo-
roup 3: Cardiothoracic Surgery or Complex
G nates [245]. Midazolam exposure was associated with
Gastrointestinal/Genitourinary Surgery macro- and microstructural alterations in hippocampal
development of premature neonates and poorer outcomes
These infants are frequently unwell, in poor clinical condition, consistent with hippocampal dysmaturation. The authors
or critically ill. Sepsis, cardiorespiratory insufficiency, and sig- cautioned the use of midazolam in preterm neonates, particu-
nificant blood loss can complicate the perioperative period. Few larly those not undergoing surgery [249]. A Cochrane
of these neonates are extubated within the first postoperative Systematic Review including three trials (148 neonates)
day. Preterm neonates with necrotizing enterocolitis who need reported a greater incidence of adverse neurological events at
GI surgery or ventilator-dependent neonates with PDA are often 28 days’ postnatal age (death, grade III or IV IVH or PVL)
too immature or too unwell to tolerate procedures such as place- with midazolam compared with morphine infusions (RR
ment of an epidural unless strongly indicated. Potent intrave- 7.64, 95% CI 1.02 to 57.21; RD 0.28, 95% CI 0.07 to 0.49;
nous opioid analgesia by continuous infusion or NCA with or NNTH 4, 95% CI 2 to 14, one study, 46 infants) [250]. The
without acetaminophen is the mainstay of analgesia in this group concluded that data was insufficient to promote the
group. Neonates having surgery for NEC need greater doses of use of intravenous midazolam infusion as a sedative for neo-
morphine postoperatively than neonates operated on for other nates undergoing intensive care, and the review raised con-
conditions [243]. Postoperative pain management after cardiac cerns about the safety of midazolam in neonates. It behooves
surgery in neonates has previously been reviewed [244]. us to carefully assess the risk/benefit ratio of such drugs in
neonates to avoid adverse sequelae. Although there is
presently insufficient evidence to support the routine use of
Analgesia for Neonates in ICU opioid infusions in ventilated neonates, morphine appears to
be safer than midazolam to sedate neonates [251]. As the
The EUROPAIN study of 6680 neonates in 243 NICUs in risks involved are often subtle and difficult to measure and
Europe showed wide variations in sedation and analgesia their mechanisms not well understood, the selective use of
practices among NICUs [84]. Neonates who have undergone opioids based on the assessment of pain, clinical judgment,
surgery require analgesia; this is usually given in the form of and the present best available evidence has been recom-
an opioid infusion in ICU settings. Preterm and other neo- mended [252, 253]. It may be that the concomitant use of
nates in ICU who need respiratory support may also require dexmedetomidine infusions confers benefits in terms of
pain relief, but there is ongoing and presently unresolved reduced sedation requirements and earlier introduction of
debate regarding whether the use of opioid infusions in neo- enteral feeding, but this notion requires further study [254].
nates who are ventilated in ICU should be routine. Typically,
these infants undergo numerous painful medical procedures
such as heel lance blood sampling, insertion of arterial lines, Procedural Pain
lumbar puncture, and many others, and in addition the pres-
ence of the endotracheal tube may itself be painful. Aside A number of documents including reviews, guidelines, and
from humanitarian and ethical reasons for giving analgesia, policy statements have been published on the subject of pro-
routine use of morphine infusions has improved cardiorespi- cedural pain management in the neonate [51, 255–260].
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Regional Anesthesia for Neonates
16
Adrian Bosenberg
Introduction defined. Even the spinal cord can be visualized in neonates,

since ossification of the vertebrae is limited [17, 18]. Despite
Although technically challenging in neonates, regional anes- these innovations, overall experience with neuraxial blocks
thesia has wide ranging benefits. Effective pain relief after sur- in neonates remains relatively limited (Table 16.1).
gery plays a significant role in the surgical outcome. Most
major surgery is performed in the first few days of life – a time
when critical physiological transitions are taking place. The
Table 16.1 Neonatal epidural risk based on data accumulated from
challenge is to provide safe and effective analgesia [1–3]. publications worldwide. Caudal catheters are included
Even though it may be impossible to completely elimi- Number of Number
nate postoperative pain particularly in spontaneously breath- Author institutions cases Complications Ref
ing neonates, much can be done to reduce the intensity of Murrell Sydney 20 0 [36]
pain. Traditionally, intravenous opioids have been the pri- (1992) Australia 1
mary therapeutics to blunt the stress response and provide Van Niekerk Utrecht 20 V1 [73]
(1990) Netherlands 1
analgesia [4]. However, these analgesics may require venti-
Bosenberg South Africa 2 240, 11, DP 1, C 1, V [35,
latory support and monitoring in an intensive care unit. In (1998, 2005) 35 1 52,
contrast, regional anesthesia is the closest intervention to 76]
achieving complete analgesia in both ventilated and sponta- ADARPEF France 43 0 [64]
neously breathing neonates without requiring either ventila- (1994) Belgium Italy
38
tory support or intensive care admission [1–5].
Yamashita Japan 1 950 DP 7 [68]
Most regional blocks are placed during general anesthesia to (1992–2000)
ensure an immobile patient. In specific situations, however, Webster Ontario 18 V2 [200]
spinal blocks [6–9], caudal blocks [7], epidurals [10, 11], (1992) Canada1
caudal catheters [12], and peripheral nerve blocks [13, 14] Williams Vermont 1 17 with 0 [37]
have been placed while the neonates were “awake.” However, (1995) spinal
Courreges France 1 45 0 [72]
sedation or conversion to general anesthesia is generally
(1996)
required for major abdominal or thoracic surgery [7, 10, 11]. Tobias Columbia 25 0 [105]
Specialized equipment is required to perform regional (1999) USA 1
anesthesia in neonates [2, 15, 16]. Portable high frequency Hasan London 1 12 0 [70]
ultrasound has improved our ability to place epidural and (1994)
peripheral nerve blocks safely and with greater efficacy in Vas (1999, Bombay 1 20 0 [71]
2001,2003)
children. Neonates are ideal subjects for ultrasound-guided
National UK UK 21 529 C 1 DE 3 [63]
blocks [17, 18] given that most peripheral nerves are superfi- audit (2007)
cial and the nerves and surrounding structures can be readily Frawley Melbourne 50 with 0 [256]
(2000) Australia 1 spinal
Somri Israel 1 24 with 0 [11]
A. Bosenberg (*) (2007) spinal
Department Anesthesiology and Pain Management, Faculty Health Valairucha Boston 1 115 A-1 [171]
Sciences, University Washington and Seattle Children’s Hospital, (2002) caudal
Seattle, WA, USA cath
e-mail: [email protected] (continued)

530 A. Bosenberg
Table 16.1 (continued) inhibit the hormonal stress response more effectively than
Number of Number opioids [21, 23, 24]. The stress response also varies directly
Author institutions cases Complications Ref with the degree of surgical stress [2, 19] and is activated even
Krishnan Birmingham 1 20 0 [53] by minor surgery. Thus, all neonates require a strategy to
(2006)
attenuate the nociceptive responses after surgery. There is
Willschke South Africa 1 85, 20 0 [17]
(2007)
also some evidence that severe stress may be pathological
Raghavan Birmingham 1 22 0 [47] and increase postoperative morbidity and mortality with
(2008) extreme catecholamine responses associated with worst out-
Schenkman Israel 1 44 V 5 M1 [54] come [2, 16]. Hence, regional anesthesia is particularly
(2009) suited to attenuate the stress response and reduce adverse
Kost-Byerly Baltimore 23 0 [174] outcomes associated with opioid administration in neonates.
(2002–2007) USA 1
Bailey Philadelphia 28 0 [212]
Neonates, and in particular preterm infants, exposed to
(2001–2002) USA 1 caudal the deleterious effects of pain are also at risk of neurodevel-
cath opmental impairment and altered pain sensitivity [26–31].
PRAN USA 20 307 DP 2 V 6 A 1 [7] Long-term effects may include emotional, behavioral, and
(2007–2014) caudcath learning disabilities. In theory, regional anesthesia may
167
avoid or, when used in combination with anesthesia, attenu-
ADARPEF France, Tunis, 46 DP 1 [65]
(2010) Quebec, Swiss, ate the neurotoxicity associated with general anesthetics [4,
Belgium 45 28–31] when administered to newborn rodents and primates.
Willschke Vienna 1 20 0 [10] The GAS (General Anesthesia and Spinal) study, which
et al. (2010) compared the neurodevelopmental outcome in young chil-
Martin Seattle 20 0 [4]
dren at 2 and 5 years after either a general or spinal anes-
Total ~102 2811 DP11 DE 3
institutions C2 V 15 M 1 thetic, found similar outcomes with the two anesthetic
A2 techniques [32, 33].
DP dural puncture, V intravascular, S total spinal, B bloody tap, DE There are additional advantages that should be recognized
drug error, H hypotension, C convulsion, M meningitis, A aberrant pre- when regional and general anesthesia are combined in neo-
sacral placement nates [2, 5, 17, 34, 35]. As a distinct population, neonates are
vulnerable to the effects of general anesthesia given their
immature cardiovascular, central nervous, and respiratory
Risks and Benefits systems, which are very sensitive to the depressant effects of
general anesthetics. Neonatal myocardial function is particu-
Before implementing any new pain management strategy, larly sensitive to both inhalational and intravenous anesthet-
the risks and benefits of that strategy must be carefully evalu- ics. When combined with general anesthesia, regional
ated to ensure the benefits do outweigh the risks and to avoid anesthesia provides profound analgesia with minimal hemo-
exposing the neonate to complications and adverse events [1, dynamic effects [8], even in those with congenital heart dis-
2]. Potential benefits of regional anesthesia must also be ease [3, 35, 37–48]. A successful regional block reduces the
weighed against a provider’s ability to perform the block concentrations of inhalational agents needed to achieve a
successfully as well as the ability of the staff to manage con- successful outcome [3–5, 35], thereby attenuating the sever-
tinuous infusions of local anesthetics and/or opioids safely. ity of cardiovascular and respiratory depression [3] and facil-
Benefits: Surgically induced pain causes a spectrum of itating emergence and recovery. Inhalational agents also
autonomic, hormonal metabolic, immunologic/inflamma- provide a reciprocal protective effect by increasing the
tory, and neurobehavioral consequences that may have detri- threshold for local anesthetic toxicity [49].
mental effects [2, 19–25]. Acute pain can also have negative Regional anesthesia also reduces the requirement for
physiological consequences that include depressing respira- muscle relaxants by providing a degree of motor blockade.
tion and systemic and pulmonary vasoconstriction that nega- Neuraxial blockade facilitates the reduction of abdominal
tively influence compromised or immature organ function [2, organs in gastroschisis [47], omphalocele, and diaphrag-
19–22]. matic hernia [29, 38] by providing analgesia and relaxation
In the late 1980s, Anand et al. first demonstrated that neo- of the abdominal musculature, independent of the mode of
nates, including preterm infants, are capable of mounting ventilation [5, 6, 35, 37]. Similarly, caudal blocks facilitate
both hormonal and metabolic stresses in response to surgery reducing incarcerated inguinal hernia before surgery, restor-
[19]. They demonstrated that opioids inhibit the stress ing blood flow to ischemic bowel or preventing ischemia of
response to surgery. Regional anesthesia has been shown to the bowel until surgery can be performed [44].
16 Regional Anesthesia for Neonates 531
Neuraxial anesthesia may stimulate respiration and alter testinal motility [48, 59, 60], particularly after gastroschisis
respiratory mechanics. [50, 51]. The effects of neuraxial repair [23, 35, 47]. In necrotizing enterocolitis, the vasodila-
blockade on ventilation depend on the level and intensity of tory effects of autonomic blockade may improve splanchnic
the block, as well as the clinical scenario. Neuraxial block- perfusion [35, 59], whereas opioids increase intestinal
ade may diminish abdominal and intercostal muscle activity, smooth muscle tone that may increase the risk of anasto-
particularly in the compliant chest wall of neonates. motic leaks [59]. Lastly, oral feeding may resume earlier,
Alternately, blockade may improve diaphragmatic activity and the speed of recovery after minor surgery reduced after a
and excursion, thus offsetting a loss of accessory muscle regional block [6, 37, 56].
function [36–38, 40]. The ventilatory response to CO2 is also The immunosuppressive effect of regional anesthesia is
improved with a regional block, improving the efficiency of attenuated compared with that reported with opioids [23, 24,
ventilation so that normocapnia can be maintained [50, 51, 60]. Local anesthetics, but not opioids, stimulate natural
54, 55]. The pain relief provided by epidural analgesia killer cells, which play an important role in nonspecific cel-
improves ventilatory mechanics [37, 47, 51] and reduces the lular mediated and antitumor immunity [25, 60]. Local anes-
need for and duration of assisted or controlled ventilation thetics (e.g., bupivacaine) also confer antimicrobial action
after major abdominal or thoracic surgery [5, 37, 52–55]. As and inhibit bacterial growth [60].
a consequence, ventilator associated morbidity and mortality Finally, regional anesthesia also confers economic bene-
is reduced [45, 52–55]. fits that include reducing the anesthetic costs, reducing the
Spinal anesthesia was reintroduced into pediatric anes- number of days in the neonatal intensive care, and facilitat-
thetic in the mid-1980s in an effort to reduce the respiratory ing earlier discharge and more efficient use of the ward
complications, especially apnea, after surgery in preterm and nurse’s time. However, to realize these benefits, the staff
ex-preterm infants. The impact on the outcomes from anes- must be trained to care for neonates with epidural infusions
thesia was significant [6, 38, 56, 57]. As a result, spinal anes- and other regional blocks.
thesia and, more recently, caudal analgesia have been Risks: Although the efficacy of regional anesthesia is not
advocated for high-risk neonates at risk for perioperative disputed, opinions remain divided on our ability to safely
apnea after surgery [1, 3, 7, 9, 56, 57]. A recent Cochrane perform regional anesthesia in neonates [34, 61]. Some con-
review that investigated the perioperative risk of apnea in sider the risks of regional anesthesia in this age group too
infants anesthetized with spinal or general anesthesia (sevo- great for routine use by individuals who do not have the req-
flurane, desflurane) demonstrated that the incidence of post- uisite expertise [34, 48]. Even though the risks associated
operative apnea after spinal anesthesia for inguinal hernia with opioid and epidural analgesia in children are similar
surgery in preterm infants is reduced by 47% and in infants [61, 62], the risks associated with epidural analgesia and
without a history of apnea by 66% compared with that after peripheral nerve blocks in neonates are small [7, 61]. The
general anesthesia [56–58]. Overall, oxygen saturation, bra- numbers of neonates in published surveys of regional anes-
dycardia, and the need for respiratory support and analgesics thesia are relatively small when compared with the numbers
were similar for spinal and general anesthesia. A recent sys- of children and adults who were given the same anesthetics
tematic review of spinal versus general anesthesia in prema- [38, 62–77]. The aggregate of published series from approxi-
ture infants undergoing inguinal hernia repair reported mately 102 institutions yielded only 1 serious complication,
significantly fewer episodes of apnea and bradycardia and meningitis, in the 2811 published cases (Table 16.1). Serious
the need for mechanical ventilation in the spinal group com- complications, as rare as they are, usually occur early “at the
pared with general anesthesia [57]. However, there were no end of the needle,” i.e., when the anesthesiologist is still
differences in the postoperative oxygen requirements, fre- present. For example, the risk of a dural puncture is approxi-
quencies of prolonged apnea and oxygen desaturation <80%, mately 1:255, and convulsions 1:1405 in neonates
and hospital stay. Distinguishing these two anesthetic tech- (Table 16.1). Every effort should be incorporated in the anes-
niques has been hampered by a paucity of studies and their thetic plan to eliminate drug errors, a feature in the UK audit
poor study design. [63]. Anecdotal reports of spinal cord injuries bear testimony
Ex-premature infants today differ from those from the that these unfortunate disasters can occur [78]. In general,
1980s. Improved neonatal intensive care, ventilation strate- we recommend that neonatal epidurals should only be per-
gies, and surfactant have reduced the incidence and severity formed by those with the technical expertise to place these
of bronchopulmonary dysplasia. blocks, despite the advent of ultrasound that may reduce the
Regional anesthesia may have salutary effects on gastro- risks and with the safeguards to select the correct drug and
intestinal function. It enhances the early return of gastroin- dose [7, 79].
532 A. Bosenberg
Anatomical Considerations [80–87] cervical curve appears when head control is achieved, usu-
(Table 16.2) ally by 6 months, and the lumbar curve develops with
weight bearing by ~1 year. In neonates, the spinous pro-
Ultrasound and anatomical studies have demonstrated that cesses are parallel and horizontal facilitating a midline
the conus medullaris (the terminal end of the spinal cord) lies approach to the epidural space at all levels. The largest
between L1 (first lumbar vertebrae) and L2 in the majority of intervertebral spaces are found between T12 and L1 (12th
neonates including preterm infants [17, 82–84]. The conus is thoracic vertebrae) and L5 and S1 (first sacral vertebrae),
not fixed but moves with changes in body position [86], respectively.
although rarely does it extend caudad to L3. A conus that The sacrum is narrower and flatter, ossification is incom-
extends below L3 suggests the presence of a tethered cord plete, and the vertebrae are separate facilitating sacral inter-
[17, 82–87]. The dural sac usually terminates between S2 vertebral epidural blocks. Sacral dimples or pits may reflect
and S4 but may lie within millimeters of the sacral hiatus an occult spina bifida, which should be excluded using ultra-
[17, 84, 87]. sound, CT, or MRI before attempting a neuraxial block.
The shape of the vertebral column develops over the A posterior midline approach to the epidural space in neo-
first year of postnatal life. At birth, the vertebral column nates is regarded as the safest approach for several reasons.
has a single shallow anteriorly concave curve extending With a triangular spinal canal, the widest aspect of the epi-
from the C1 (first cervical vertebrae) to L5. A secondary dural space is the midline where the epidural veins and arter-
ies are less dense [87]. The epidural space is narrow
(0.9–2.4 mm; median 1.5 mm) [17, 88, 89] and less compli-
Table 16.2 Important anatomical and physiological similarities and ant, whereas the ligamentum flavum is thinner and less dense
differences between neonate and adolescents (adults) and offers less resistance to the advancing epidural needle
Anatomy Neonate Adolescents (adult) than in adults. Pressures generated during the passage of an
Conus L1–L2 L1 epidural needle through the ligamentum flavum range from
medullaris 35 to 105 mmHg (mean 70 mm), and the epidural pressures
Dural sac S2–S4 S2–S4
range from 1 to 10 mm Hg [88].
Intercristal L4 L4
line The epidural fat consists of spongy gelatinous lobules
Vertebral Concave C1–L5 Secondary curves with distinct spaces and offers minimal resistance to the pas-
column sage of local anesthetic or an epidural catheter [5]. The epi-
Main cartilaginous Ossified dural veins have no valves and connect directly with
Spinous Lumbar more horizontal, Lumbar angled intracranial veins. As a consequence, air or drugs inadver-
processes parallel caudad
tently injected into the epidural veins can easily reach the
Orientation T10–T12 similar All thoracic spines
to lumbar angled caudad brain without impediment.
Midline approach easy The effective concentration of local anesthetics in neo-
Intervertebral Largest T12–L1; L5–S1 nates is less than in older children as the nerves are thinner
space and less myelinated. The nerve trunks to the lower extremi-
Ligamentum Thinner, less dense Thicker, fibrous ties do not reach full myelination until the second year of
flavum
Epidural space 1–2 mm; less compliant Compliant
life. The degree of myelination influences the pharmacody-
spongy gelatinous fat Densely packed namic effects of local anesthetics.
lobules lobules fibrous The CSF volume in neonates <1.5 kg is 4 mL kg−1, rela-
strands tively large compared with adults and older children,
Sacrum Flatter; less ossified Fully ossified by 2 mL kg−1. CSF production in neonates, 0.35 mL min−1, is
30y
Nerves Thinner less myelination
greater than in adults. This explains in part why neonates
CSF volume 4 mL/kg 2 mL/kg require proportionately larger doses of local anesthetic for
Physiology spinal block than in older children.
Blood Stable Hypotension In terms of peripheral nerve blocks, it is important to
pressure appreciate that the muscle layers of the thoracic and abdomi-
Pulse rate Stable Bradycardia nal wall are thinner, less well defined, and more compliant in
Respiratory Diaphragmatic function Similar neonates than in older children. The sciatic nerve divides
improved, ventilatory
response CO2 enhanced within the popliteal fossa [90], the ilioinguinal and iliohypo-
CNS Cortical arousal reduced Similar gastric nerves lie 3–5 mm medial to the anterior superior
Lower BIS iliac spine [91], and the musculocutaneous nerve is easily
Endocrine Inhibition stress response Similar included in an axillary block because of its proximity to the
GIT function Earlier return Similar divisions [92] (Fig. 16.1).
as a safer local anesthetic than the amide anesthetics in neo-

nates because it is very rapidly metabolized by the ubiqui-
tous enzyme, pseudocholinesterase, even if administered
inadvertently intravascularly [2, 38, 105–108].
Vascularity of the injection site and regional blood flow
influence the rate of uptake of local anesthetics. The rate of
absorption and therefore the peak serum concentration is
reduced by vasoconstrictors. Epinephrine prolongs the dura-
tion of action of local anesthetics [109–111] by up to 50% in
neonates [6, 110–112]. In the author’s experience, the dura-
tion of caudal bupivacaine is virtually doubled by the addi-
tion of epinephrine 1:400,000 (unpublished data). However,
during continuous epidural infusions of lidocaine with or
without epinephrine, the blood concentration of lidocaine
within the first hour is reduced in the presence of epineph-
Fig. 16.1 Anatomical dissection of the axilla in a neonatal cadaver
rine, whereas after 2 h, the blood concentrations of lidocaine
demonstrates the brachial plexus (j) and related structures within the are similar [109]. Hence, epinephrine is recommended for
axilla and at the root of the neck. Note the close relationship between single-shot caudal epidural blocks but not for continuous
the axillary artery and the cords and branches of the brachial plexus. infusions of lidocaine.
The musculocutaneous branch is easily included even with small vol-
umes of local anesthetic. Structures identified include the (a) pectoralis
Lung function also plays an important role in modulating
major and (b) pectoralis minor muscles, (c) coracoid process, (d) cora- the duration of action of local anesthetics. Approximately
cobrachialis muscle, (e) axillary artery, (f) anterior and (g) middle sca- 60–80% of an intravenous lidocaine bolus is absorbed on the
lene muscles, (h) common carotid artery, (i) vagus nerve, and (k) first pass through the lungs. However, in neonates with right
clavicle
to left intracardiac shunts, the reduced uptake by the lungs
may increase the peak blood concentration by up to 100%,
increasing the risk of local anesthetic toxicity [113].
Pharmacological Differences Little is known about the pharmacokinetics of longer-
acting local anesthetic agents in neonates [2, 75, 76, 94, 95,
The pharmacological differences in neonates vary with ges- 99]. Guidelines for epidural infusions of bupivacaine in neo-
tational age-related changes in body fluid compartments, nates and infants <6 months of age based on anecdotal
plasma protein levels, distribution of cardiac output, and the reports of toxicity recommend 0.2 mg.kg−1 h−1 bupivacaine
functional maturity of the liver and kidneys [93]. Other or ropivacaine and in infants >6 months of age recommend
contributing factors include less body fat (15% body weight) up to 0.4 mg.kg−1 h−1. The blood concentrations recorded in
and skeletal mass (25% body weight), a proportionally larger neonates were greater than in infants, although the concen-
brain and liver, and greater cardiac output and regional blood trations in both groups were <2–3 mcg.mL−1, i.e., well below
flow to vessel-rich organs resulting in more rapid uptake of the threshold for toxicity in humans [75, 76, 99]. Plasma
drugs. concentrations of bound bupivacaine accumulate after a 48-h
Neonates are at greater risk for intravenous drug toxicity infusion [75], whereas concentrations of bound ropivacaine
than older children [2, 93–98]. With smaller concentrations are independent of the duration of infusion up to 72 h [76].
of albumen and α1 acid glycoprotein [76, 94–100], the free Thus, ropivacaine appears to be the safer local anesthetic for
fraction of circulating intravenous drugs in neonates is epidural infusions 48–72 h in duration in neonates [76, 99].
increased [101, 102]. Plasma concentrations of α1 acid gly-
coprotein, an acute phase protein, increase in acute illness
and after surgical stress [76, 96]. This difference protects Neuraxial Blockade
against a local anesthetic overdose by attenuating the free
fraction of the local anesthetic, particularly the amides. Spinal
Furthermore, a greater fraction of local anesthetic is excreted
unchanged in the urine because of the reduced hepatic blood Bainbridge described the first spinal anesthetic on an infant
flow and immature cytochrome P450 (CYP) enzyme system in 1899, and early in the twentieth century, Lord H Tyrell
[76, 96]. The plasma cholinesterase activity in neonates is Gray suggested that spinal anesthesia “would occupy an
50% that in young children and adults, which may delay the important place in the surgery of children in the future.”
clearance of ester local anesthetics such as chloroprocaine Although the popularity of spinal anesthesia waned as the
[103, 104]. However, on balance, chloroprocaine is viewed safety of general anesthesia improved, these prophetic words
534 A. Bosenberg
may still be realized considering the current controversy early leg raising (e.g., when placing the electrocautery pad),
regarding the neurotoxicity of general anesthetics in neo- or “top-ups” when the dermatome level is inadequate.
nates. The popularity of spinal anesthesia was rekindled in Unilateral spinal blockade in neonates has also been
the early 1980s when Abaijan proposed its use for ex- described [131]. Plasma concentrations of local anesthetics
premature infants undergoing inguinal hernia repair. after spinal anesthesia are small (0.2–0.3mcg/mL) and unaf-
Currently, spinal anesthesia remains limited to selected fected by the addition of epinephrine [132].
high-risk infants in whom general anesthesia may pose a Technique: Using a sterile technique, a spinal anesthetic
major risk [114]. is placed using a 25ga or styleted 22ga 1.5inch (3.8 cm) spi-
Spinal anesthesia has been used alone or in combination nal needle in the sitting or lateral decubitus position.
with an epidural for a wide variety of surgeries including Currently, chlorhexidine in 70% alcohol is the recommended
inguinal hernia repair, ligation of patent ductus arteriosus, skin preparation. The usual puncture sites are L3–L4 or L4–
pyloromyotomy [42, 49], gastrostomy, gastroschisis [115], L5. A prior ultrasound scan is useful but not required, to
omphalocele, exploratory laparotomy, lower abdominal sur- determine the exact location of the dural sac and to exclude
gery (colostomy, anoplasty, rectal biopsy, circumcision) any central nervous system or bony anomalies. Once free
meningomyelocele repair, or orthopedic surgery [6, 116]. flow of CSF is obtained, the local anesthetic can be adminis-
Spinal anesthesia has a much shorter duration of action in tered using a 1 mL syringe. The onset of the block is her-
neonates than in adults despite the relatively larger doses alded by profound motor block in the lower extremities
used in the former. The duration of action appears to be within seconds of completion of the spinal. Care should be
directly correlated with age [112, 117, 118]. For practical taken to avoid positioning the infant head-down, i.e., when
purposes, an effective plane of surgical anesthesia after spi- placing the electrocautery pad on the back, before the block
nal block lasts ~40–60 min with bupivacaine, levobupiva- height is set to avoid a high spinal block. Instead, the child
caine [119, 120], and ropivacaine [120, 121], up to 1.5 h with should be log-rolled to apply monitors, cautery pads, and
tetracaine plain or 2 h with tetracaine with epinephrine [6, other devices.
112], and up to 1 h after lidocaine 3 mg.kg−1 with epineph- Gentle stroking, soothing, or dextrose water on a pacifier
rine [112]. calms most neonates. Intravenous sedation may be necessary
Spinal anesthesia has been used to facilitate placement of in ~25% of cases [6, 116, 130] but may be associated with
an epidural block [11] in order to prolong the duration [11, apnea [9, 116].
12]. Intrathecal clonidine (1 μg.kg−1) may also be used to
perform surgery, although it is associated with more sedation Dose guidelines:
and apnea than the local anesthetics alone [117]. Hyperbaric tetracaine 0.5% 0.6–1 mg.kg−1.
Spinal anesthesia rarely produces significant changes in Isobaric bupivacaine or ropivacaine 0.5% 0.1 mg.kg−1.
heart rate or blood pressure in neonates, even with blockade Hyperbaric bupivacaine 0.75% 0.1mL.kg−1.
to thoracic levels and in infants with congenital heart disease Hyperbaric lidocaine 3 mg.kg−1.
[7, 48, 122–124]. Reduced cortical arousal caused by periph-
eral deafferentation [41, 125] or a decrease in cerebral blood Adjuvants:
flow [126] should be considered when concomitant sedatives Epinephrine 5–10 mcg.kg−1 to prolong the duration of action
are administered [125]. Furthermore, a single dose of seda- Clonidine 1 mcg.kg−1 to prolong analgesia [118].
tion (ketamine 1–2 mg.kg−1, midazolam 0.2 mg.kg−1, or pro-
pofol 1 mg.kg−1) increases the risk of perioperative apnea [6,
116, 127]. Caudal Block
Complications: The incidence of serious complications
(nerve injury, meningitis, arachnoiditis) [128, 129] after spi- Caudal analgesia is frequently used to provide analgesia for
nal anesthesia, based on two large series, is small [6, 116]. surgery below the umbilicus [7, 43, 81, 133]. The popularity
Failure rates for effective spinal anesthesia in neonates range of caudal blockade stems from its simplicity, safety, and effi-
from 5–10% (in experienced hands) [6, 130] to 17% (train- cacy, but more importantly, that additional local anesthetic
ees) [5, 28] with a bloody tap rate of 10% [116]. Failure was can be administered if the anesthetic begins to wane before
associated with bloody taps in the GAS study [130]. the procedure is completed. This block is usually combined
Bradycardia (<100 bpm) and apnea can be treated with tac- with general anesthesia [7]. Larger doses of local anesthetics
tile stimulation, atropine 0.1 mg.kg−1, or ventilatory support are required for upper abdominal surgery [134], although
as indicated. The incidence of bradycardia ranges from 1.2 to achieving this level of block is less predictable unless a cau-
1.8% [6, 116]. A high spinal (0.1–0.6%), heralded by apnea dal catheter is introduced. Caudal blocks are effective as the
but uncommonly associated with hypotension or bradycar- sole anesthetic, particularly for ex-premature infants under-
dia, has been associated with large doses of local anesthetic, going inguinal hernia repair, thereby preventing periopera-
tive apneas. They have also been used to reduce incarcerated

inguinal hernia [44], to improve compromised perfusion
after umbilical catheterization [135] and penile block [136],
or to facilitate PICC line placement in extreme preterm
infants [137].
Anatomy: The sacral hiatus lies between the sacral cornu,
two prominences that represent the remnants of the fifth
sacral arch, and extends to the fused arch of the fourth sacral
vertebra. The sacrococcygeal membrane, an extension of the
ligamentum flavum, covers the sacral hiatus separating the
caudal space from the subcutaneous tissue. Considerable
variation in sacral hiatal anatomy exists mainly due to incom-
plete posterior fusion of other sacral vertebrae. However, a
few important surface landmarks can be used to enhance suc-
cess in both normal and abnormal sacra. The sacral hiatus
virtually always lies at the apex of an equilateral triangle
which has the line drawn between the posterior superior iliac
spines as its base (Fig. 16.2). The intersection of a line drawn
from the patella through the greater trochanter (with the hips Fig. 16.3 Caudal block. The knee chest position may be used to facili-
flexed at 90 degrees) to meet a line drawn down the vertebral tate placement of the caudal in awake neonates
column is another useful landmark (Fig. 16.3).
Technique: Caudal block can be performed in the lateral skin [140] – this has become this author’s preferred approach!
decubitus position or prone knee chest position—a useful A “give” can be felt as it enters the caudal space and can be
position for an “awake” caudal block [138] (Fig. 16.3). confirmed by loss of resistance. Penetration of the sacrococ-
Under sterile conditions, a short bevelled needle, held cygeal membrane just above the sacral cornua carries a
between the thumb and index finger, is introduced at approx- smaller incidence of bloody tap in the author’s experience.
imately 30–45° to the skin and advanced until it pierces the The dural sac lies within 5–10 mm of the sacral hiatus in the
sacrococcygeal ligament [139]. Some advocate up to 90° to majority of neonates [17], and thus changing the angle and
advancing the needle, as described in adults, are unnecessary
as it may result in a dural puncture or bloody tap [43]. Using
a 22 g IV cannula is another popular approach [43, 141], but
in the author’s experience, it carries a greater incidence of
failure (subcutaneous injection) and bloody taps in untrained
hands.
Aspiration should be gentle since strong negative pressure
may cause the low-pressure epidural vessels to collapse
before a positive aspiration test can be elicited [43].
[Editor’s Note. Our practice includes only IV catheters to
achieve several purposes. First, once the needle tip punctures
the sacrococcygeal ligament and advances 1–2 mm, only the
catheter is advanced into the caudal space. If the needle has
punctured the thin bony table of the sacrum, the catheter will
accordion rather than advance smoothly confirming immedi-
ately that the needle/catheter is not in the caudal canal.
Second, limiting the needle tip to traversing only the sacro-
coccygeal ligament reduces the risk of an intravascular or
subarachnoid puncture. Third, we remove the needle leaving
the catheter in place and observe for passive blood or CSF
backflow. We do not aspirate the catheter at this time because
the vein will collapse due to the negative pressure leading to
a false-negative detection of an intravascular cannulation.]
Fig. 16.2 Caudal block. The sacral hiatus lies at the apex of an equilat- After negative aspiration for blood and CSF, the required
eral triangle with the line drawn between the posterior superior iliac
spines as the base volume of local anesthetic can be injected [Editor’s Note. We
536 A. Bosenberg
recommend that the entire volume of local anesthetic that Bupivacaine 0.125–0.25% [159, 160], ropivacaine 0.1–
will be administered be treated as a test dose, injecting 0.2% [161–164], levobupivacaine 0.25% [165], chloropro-
10–15% of the predetermined volume at a time while palpat- caine 3% [38, 105–107], or lidocaine 1% with 1:200,000
ing the soft tissues just cephalad to the sacral hiatus to detect epinephrine has been effective as a single dose. The duration
swelling from a subcutaneous injection and watching the of analgesia depends upon the dose (concentration and vol-
ECG for conformational changes described above.] In the ume) and specific local anesthetic administered, the use of
event of a “bloody tap,” the needle should be redirected or epinephrine, the site of surgery, and whether a continuous
removed and reinserted more cephalad. Local anesthetic catheter is used [38, 81]. Increasing the concentration of
injection should proceed with caution after a bloody tap con- local anesthetic does not offer additional advantage com-
sidering the greater risk of an intravascular injection under pared with standard concentrations but may increase the
these circumstances [142]. Ultrasound can be used to “visu- incidence of side effects and/or complications and reduces
alize” the spread of local anesthetic within the caudal epi- the volume that may be administered, which itself may limit
dural space [143]. the height the block achieves. Despite numerous publica-
Complications: Dural puncture and subsequent injection tions that provide guidelines for the optimal dose and vol-
may lead to a total spinal and respiratory arrest (apnea). ume of bupivacaine (or equivalents of other local anesthetics)
Systemic toxicity after accidental intravascular or sacral for caudal analgesia in infants <1 year of age, a review of
intraosseous injection may be heralded by ECG changes (ST more than 14,000 infants in the pediatric regional anesthesia
segment elevation, peaked T waves or arrhythmia) from network documented large variability in the dose and volume
injection of epinephrine, cardiovascular collapse, or convul- used [166]. Clonidine has been added to prolong the duration
sions. Intrapelvic injections [144, 145] are avoided with the of analgesia but is associated with an increased risk of seda-
correct technique. Urinary retention does not occur when tion and apnea [167, 168].
only local anesthetics are used [146]; urinary retention is,
however, associated with coadministration of opioids [147].
Nerve injury and neurological deficits have not been reported Caudal Catheter Techniques
in neonates. Historically, inclusion dermoid tumors have
been reported but only anecdotally [148, 149]. The risk of An epidural catheter can be introduced via an IV catheter
introducing nucleated epidermal cells from stratum spino- in the sacral hiatus to prolong the duration of the caudal
sum during caudal block is extremely small and is similar block [12, 38] or to access the sacral, lumbar, or thoracic
with 22 g hollow needles and styleted 22 g caudal block epidural space for a block at a more cephalad level [5, 73,
needles [148, 149]. 169–181]. Specialized equipment is not required to per-
One peculiar complication associated with caudal blocks form this block [4]. This technique was developed before
in infants undergoing hypospadias repair is a postoperative the introduction of pediatric epidural needles. The risk of
ureterocutaneous fistula, a finding that occurred more com- dural puncture or spinal cord injury may be less than with
monly than after a penile block, was recently reported [150]. direct lumbar or thoracic epidural placement in less expe-
The accompanying editorial elegantly articulated the flaws in rienced hands [5, 18].
this retrospective review [151]. Despite reports of an associa- A caudal block of “intermediate” duration (for a sur-
tion in a systematic review which acknowledged publication gery of prolonged duration and for a brief period postop-
bias [152], recent evidence has focused on the surgery as the eratively) may be achieved by administering supplemental
cause and dispelled an association between caudal analgesia doses of local anesthetics (ropivacaine, lidocaine, or chlo-
and urocutaneous fistulae [153, 154]. roprocaine) through a caudal IV catheter with a 5 cm or
Dosage: Many formulae have been proposed for caudal longer Luer lock IV extension or through an epidural cath-
block based on the neonate’s weight, age, and length with eter threaded caudally. The catheter and extension should
insufficient consideration to the increased free fraction of be padded to prevent kinking the tubing and secured with
drug due to reduced protein binding, especially in the case of a Tegaderm and/or tape. At the end of the surgery or in
bupivacaine [101, 102, 133, 142, 155–158]. The most practi- PACU, a final dose of local anesthetic may be administered
cal is that suggested by Armitage [142]: before the catheter is removed. [Editor’s Note. In our expe-
rience, some IV catheters are flimsy and prone to kinking
0.5 mL.kg−1 of local anesthetic for sacro-lumbar if left in the sacral hiatus for 1 or more hours. We have had
dermatomes. mixed success administering a top-up dose of local anes-
1.0 mL.kg−1 for lumbar thoracic dermatomes thetic through a 22 ga IV catheter at the end of surgery
(sub-umbilical). because the lumen was occluded (possibly kinked). If a
1.25 mL.kg−1 for mid-thoracic dermatomes (upper top-up is essential in such a case, either an epidural cathe-
abdominal). ter should be inserted in the first place or the IV catheter
must be removed and a new IV cannula is inserted through recent study suggested that catheters can migrate one to two
the sacrococcygeal ligament.] vertebral levels and that the level of the tip should be verified
Technique: An 18 or 20G IV cannula, Crawford needle, if the catheter is left in situ postoperatively in neonates and
or purpose designed kits [18, 170] can be used to access the infants [183]. [Editor’s Note. We use 19 ga epidural cathe-
caudal space in order to site an indwelling catheter. A ters, do not verify the level of the tip, and have had complete
19–24G epidural catheter that passes easily through the can- success with analgesia up to 3 days in neonates, infants, and
nula is measured along the neonate’s back from the sacro- children without verification.] Nonetheless, smaller gauge
coccygeal puncture site to the level of the planned surgical (24G) flexible catheters are more likely curl in the sacro-
incision. The catheter can then be introduced gently into the lumbar epidural space and fail to reach their target derma-
caudal/epidural space to this predetermined length tome level compared with larger diameter catheters [184].
(Fig. 16.4). It is important to avoid applying force to the This problem can be overcome by using styleted catheters,
catheter should resistance be encountered while threading it which are expensive [174, 176, 177].
as the catheter tip may impinge on a nerve root or exit We prefer to use larger volumes of local anesthetic in neo-
through a foramen, puncture a blood vessel or dura, or form nates rather than force catheters to reach the target derma-
a loop or knot in the catheter. tome level within the epidural space, although this is a
Flexion or extension of the infant’s spine [5, 54], flushing trade-off between the degree of dilution of the local anes-
the catheter with saline [5, 169], or twisting/rolling the cath- thetic and the maximum volume that could be administered
eter between the operator’s fingers [5, 54] can be used to to preclude toxic blood concentrations during a continuous
further advance the catheter. It is important to position the tip infusion.
of the multi-orifice (closed tip) catheter at the most cephalad The preferred method used to confirm the dermatome
dermatome level to achieve an adequate block as only the level of the tip of epidural catheters varies. Techniques used
proximal orifice is perfused at the usual (small) epidural to identify the location of the tip include epidurography [5,
infusion rates (although local anesthetic boluses delivered 73, 171, 185], fluoroscopy, electrocardiography [177, 186],
manually perfuse all three orifices) [182]. Even if the cathe- nerve stimulation [180, 181], and ultrasonography [143, 172,
ter is threaded to the “optimal level” for effectiveness, a 178, 187]. In contrast, some practitioners do not verify the
position of the catheter tip after inserting a predetermined
length of catheter to reach the desired dermatome level but
depend on the effectiveness of the epidural block to confirm
a satisfactory catheter position.
Recently, two studies shed light on catheter tip migration
in neonates and infants. When the final position of the cath-
eter tip verified with ultrasound was compared with land-
mark based measurements to reach the desired dermatome
level (lumbar and thoracic levels) in neonates and infants,
ultrasound documented the catheter tip 4.2 cm more cepha-
lad than that based on blindly passing the predetermined
length of catheter [187]. In a study of caudally passed tho-
racic radio-opaque catheters, fluoroscopy and epidurograms
demonstrated that almost two-thirds of the catheter tips were
either caudad or cephalad ≥1 vertebral levels and 27% of the
catheter tips reached T4 level [183]. Of particular concern
was that catheter tip migration ≥2 vertebral levels occurred
only in infants <6 kg in weight and <73 days of age. These
data emphasize the need to document the level of the catheter
tip in neonates. Electrical stimulation with wired catheters
allows real-time adjustment of the catheter level but requires
specifically designed equipment [167]. In the author’s expe-
Fig. 16.4 A predetermined length of catheter can be inserted via the
sacral hiatus and threaded up the epidural canal to reach the desired rience, a 20 g nylon catheter (Portex®) passed through the
dermatome level. An epidurogram or ultrasound can be used to confirm epidural space to within one vertebral body of the intended
the position of the tip of the catheter. Here, an epidurogram demon- dermatome level achieved the desired level of analgesia in
strates contrast in the epidural space at the L1 level (upper arrow) at the more than 500 neonates. Difficulties have been described
tip of the catheter. In addition, the contrast filled caudal catheter intro-
duced at the sacral hiatus (lower arrow) can be followed up in the spine when threading the catheter in premature infants and when
to the level of the tip at L1 (arrows) using a Tuohy needle [12, 73]. The curve of a Tuohy needle
538 A. Bosenberg
may cause the catheter to curl if the lumen is not properly risk of spinal cord trauma, thoracic epidurals should only be
aligned within the long axis of the caudal canal. performed by experienced providers familiar with placing
Complications: Complications include failure to position epidural blocks in neonates.
the catheter at the desired level, dural puncture, intravascular Technique: Using a sterile technique, the skin should be
placement [54, 175], catheter colonization (30%) [188, 189], punctured with a needle to facilitate smooth insertion of a 19
and one reported case of meningitis [54]. Careful aseptic or 20 g Tuohy needle. A midline approach is preferred since
technique with chlorhexidine, rather than povidine-iodine, the epidural space is widest at this point and the epidural ves-
for all catheter techniques carries a smaller risk of coloniza- sels less dense. The interspace chosen should be as close to
tion [190]. Tunneling the catheter subcutaneously, away the dermatome of the surgical incision as possible. The nee-
from the anal region, may further reduce the risk of coloniza- dle angulation is dependent on the level of epidural puncture
tion [189, 191] especially for prolonged infusions [188]. and is greatest in mid-thoracic region. Below this level, a
However, it is crucial to appreciate that colonization does not more perpendicular approach can be used since the spinous
progress to infection or abscess formation in the nervous sys- processes are almost horizontal when the back is flexed [194,
tem; epidural abscesses depend on hematogenous spread and 195] (Fig. 16.5). T12–L1 and L1–L2 interspaces are the larg-
seeding of bacteria (most often Staphylococcus aureus) or est and most easily palpable processes. The skin-epidural
fungus [192]. distance ranges from 5 to 12 mm depending on the gesta-
Dosage: Commonly used local anesthetic doses include tional age and weight of the neonate [35]. The depth of the
0.5–1.0 mL kg−1 0.175–0.25% bupivacaine, 0.15–0.2% epidural space can be accurately measured using ultrasound
ropivacaine, or 1.5–3% chloroprocaine loading dose; the [17].
volume of each solution depends on the number of derma- Both air and saline have been advocated for the loss of
tomes required to be covered [5]. Continuous infusion resistance test to identify the epidural space [195, 196].
rates at 0.3 mL/kg/h maintains the height of an established Saline is more popular according to recent survey [196], but
block. In the case of bupivacaine, the concentration of the air is perhaps more sensitive [35, 194]. A recent practice
infusion fluid must be restricted to preclude toxic plasma advisory has suggested that either air or saline could be used
concentrations in neonates beyond 24 h: 0.1% concentra- [197]. Both techniques have issues—saline dilutes the local
tion is usual at a volumetric infusion rate of 0.2–0.25 mL/ anesthetic and air may embolize (and cause acute neurologic
kg/h [193]. This has proven to be an issue with bupiva- injury via the artery of Adamkiewicz) [198]. The volume of
caine in neonates who appeared jittery as a result of an both saline and air that is used to identify the epidural space
increased free fraction in this age group [102]. In the case should be restricted to 0.5–1 mL. A “drip and tube” method
of 0.2% ropivacaine, toxic plasma concentration is not has also been described [67].
achieved with these doses after 48–72 h of infusion [76]. A catheter should be introduced at least 2 cm into the epi-
[Editor’s Note. We infuse 1.5%–3% 2-chloroprocaine dural space for continuous infusion or intermittent “top-ups”
(1 mL/kg) as an epidural solution in awake neonates for depending on whether an open tip or closed tip catheter is
lower abdominal superficial surgery as it is the least toxic
of the local anesthetics. Subsequent infusion rates are 0.5–
1.5 mL/kg/h [38]].
Lumbar and Thoracic Epidural
Lumbar epidurals are most effective for lower abdominal,

pelvic, and lower limb surgery, whereas thoracic epidurals
are effective for upper abdominal or thoracic surgery [189],
particularly in high-risk patients with respiratory disabilities
[194]. Experience with these epidural techniques in neonates
is limited [4, 7, 35, 54, 55, 63, 76, 77].
Few dermatomes are involved in the transverse abdominal
incision favored by pediatric surgeons and thus can be easily
covered by an accurately placed epidural. Most epidural
blocks are performed after the neonate/infant has been anes-
thetized, although if general anesthesia is to be avoided, it Fig. 16.5 The epidural needle can be introduced almost vertically to
the skin in neonates when the back is flexed in the lateral decubitus
can also be performed with sedation [10] or after initial spi- position. Loss of resistance to air is considered more sensitive for
nal blockade when indicated [11]. In view of the potential detecting the 1–2-mm-wide epidural space
used [182]. This is best done after the “test dose” has tact bone and then “walked” off cephalad or caudad on the
“opened” the epidural space to facilitate the passage of the sacral vertebra till the interspace is identified.
catheter [5, 169]. The length of catheter introduced is impor- After skin preparation, the skin should be punctured to
tant. An excessive length of catheter runs the risk of unilat- facilitate insertion of the 19 or 20 g Tuohy needle. No flexion
eral blockade or vascular or subarachnoid puncture, whereas is required since the spinous processes of the sacrum are
an insufficient length could result in a failed block or rudimentary. The epidural space can be identified using a
increased leakage of local anesthetic solution. Ultrasound “loss of resistance” technique. The Tuohy needle may be
can confirm the placement of the catheter as well as the loca- inclined to facilitate threading the catheter.
tion of the tip [178]. Dosing guidelines: These are the same as for caudal
Complications: No serious complications, except dural block.
puncture, have been reported in large published series [35,
54, 55, 63, 76, 77, 194, 199, 200] (Table 16.1). Anecdotal
case reports of spinal cord injury and air embolus bear testi- Continuous Epidural Infusions
mony to the potential for this disaster [201].
Dosing guidelines: An initial bolus dose of 0.5 mL/kg Postoperative analgesia can be maintained using intermittent
followed by an infusion of 0.1–0.3 mL/kg/h 0.15–0.2% ropi- “top-ups” [7, 35] or continuous infusions of local anesthetic
vacaine or 0.1% bupivacaine provides satisfactory analgesia [35, 63, 68–72, 75, 76, 99, 105–107]. As significant hypoten-
[35, 76]. A recent study suggested that 0.6 mL/kg is the opti- sion is unlikely, swings in blood pressure—a problem in
mal bolus dose for abdominal surgery [202]. A smaller initial adults—are not a feature in neonates. Intermittent “top-ups”
bolus 0.33 mL kg−1 0.25% bupivacaine or 0.2% ropivacaine are therefore a useful alternative when infusion pumps can-
is suggested for thoracic epidurals [203]. In the author’s not deliver small hourly volumes of local anesthetic agents
experience, larger volumes of up to 0.5 mL kg−1 may be accurately.
required in small infants. “Top-up” doses should be half the There is no consensus on the optimal local anesthetic
original dose. agent or concentration in clinical practice [7, 208, 209].
Dosing guidelines for racemic bupivacaine (i.e., 0.2 mg/kg/h
for neonates and infants under 3 months) have proven to be
Sacral Epidural Block safe and effective for both ropivacaine and levobupivacaine
[7, 63, 75, 76, 99, 164, 193, 210]. No complications have
Busoni described two approaches to the sacral epidural space been reported using this dosing guideline in more than 1400
[204, 205]. The sacral intervertebral block [206, 207] is pos- neonates, infants, and children [193]. Similarly, no compli-
sible in neonates since the sacral vertebrae are not fused. cations have been reported in neonates from both the PRAN
This block is particularly useful in neonates in whom the data [7] and in over 500 neonates, ranging from 0.5 to 5 kg
sacral hiatus cannot be identified and thus a caudal approach (author’s unpublished experience).
is not possible, e.g., obese neonates or high anorectal malfor- Some have recommended a smaller loading dose of
mations with associated sacral abnormalities [207]. The 0.5 mL kg−1 0.25% bupivacaine followed 30 min later by a
modified Taylor approach [173, 204] between L5 and S1 is similar infusion dose of 0.08 mL kg−1 h−1 delivered by a vol-
possible because of the large space between spinous process umetric infusion pump [211] (Table 16.3). For simplifica-
of the fifth lumbar vertebra and the rudimentary spinous pro- tion, ease of calculation, and an adequate volume to ensure a
cess of the first sacral vertebra. These approaches are less complete block, an infusion of 0.1 mL kg−1 h−1 works well in
risky for spinal cord injury or dural puncture [17, 87]. neonates in the author’s experience provided the catheter tip
Furthermore, indwelling catheters for continuous infusions lies close to the dermatome of the surgical incision; others
at these sites are less likely to become contaminated because use dilute concentrations (0.1% bupivacaine or 1.5% chloro-
of the greater distance from the anus than caudal catheters procaine) at 0.2 mL/kg/h [Editor’s Note]. Smaller infusion
[204]. rates (0.06 mL kg−1 h−1) have been advocated for thoracic
Technique: The posterior superior iliac spines are identi- epidurals [186] (Table 16.3). For neonates <2 kg, the author
fied with the neonate in the lateral decubitus position with reduces the concentration of local anesthetic, to 0.1% ropiva-
the hips flexed. A line between the posterior superior iliac caine or bupivacaine.
spines bisects the second sacral vertebral arch (S2). The larg- The editor uses primarily 2-chloroprocaine or lidocaine
est sacral intervertebral space (S2–S3) is easily identified for all continuous epidural infusions in neonates for safety
0.5–1.0 cm caudad to this line. The L5–S1 interspace is reasons. Once a particular infusion rate has been selected,
located 0.5–1.0 cm cephalad of this line and is also easily regular assessment of the level of blockade, as well as an
palpable provided the overlying sacral fat pad is thin. If dif- assessment of the degree of motor blockade, should be per-
ficult to palpate, an epidural needle can be introduced to con- formed. Adjustments to the infusion rate should be made as
540 A. Bosenberg
Table 16.3 Epidural infusions of bupivacaine and ropivacaine in neonates

Drug Dose Additive Ages Site Author Ref.
Bupiv 0.2 mg/kg.h Neonate Berde [193]
Bupiv 0.2 mg/kg.h Neonate, infant L Schenkman [54]
Bupiv 0.2% 0.1 mL/kg/h Neonate L,T Bosenberg [35, 52]
Bupiv 0.2% 0.1 mL/kg/h Neonate Larsson [75]
Bupiv 0.1% 0.2 mL/kg/h F 1mcg/mL Neonate, infant L Murrell [36]
Bupiv 0.125% 0.2–0.3 mL/kg/h Neonate, 4 m L Wolf [257]
Bupiv 0.125–0.25% 0.25 mL/kg/h Neonate, 6y L,T Luz [102]
Bupiv 0.2% 0.2 mL/kg/h Neonate, infant L Meunier [101]
Ropivacaine 0.2% 0.1–0.2 mL/kg/h Neonate, 1y L,T Bosenberg [76]
L lumbar epidural, T thoracic epidural, F fentanyl
Note: Text highlighted in bold where the dose infused was described in mg/kg/h
necessary (Table 16.3). If the maximal infusion rate is Ultrasound Imaging of the Spinal Cord
reached and the child still remains agitated, a manual “top-
up” dose of lidocaine may prove effective to increase the der- Incomplete ossification of the posterior elements of the spi-
matome level of the block and establish whether the epidural nal canal in neonates allows accurate ultrasound evaluation
block can be salvaged. If the block remains inadequate, then of spinal cord structures with high frequency 7–12 MHz lin-
supplementation with a systemic opioid or epidural a djuvants ear array transducer probes [83, 84, 178, 179, 215, 216]. The
should be considered. A check of the insertion site for signs best acoustic views are obtained in preterm infants.
of infection should also be included in the regular Information about the anatomical relationships of the spinal
assessment. cord, dura mater, and epidural space (size, depth) can be
applied effectively [83, 84, 215, 216]. The skin-epidural
depth can be measured and serve as a guide at which loss of
Epidural Adjuvants resistance can be expected. The exact location of the conus
can also be determined [86, 217].
Few adjuvants have been used extensively in neonates In axial scans (Fig. 16.6a), the spinal cord is a hypoechoic
despite the variety used in older children [212–214]. Most of (black) oval structure with a central hyperechoic (white) area
these additives have been studied in inguinal surgery as the representing the base of the paramedian sulcus. The
model to evaluate their efficacy and risk/benefit ratio. hypoechoic spinal cord tapers to the conus medullaris. At
Whether these findings can be extrapolated to major abdomi- this level, the rest of the vertebral canal is filled with multiple
nal or thoracic surgery is debatable. The potential risk seems small rounded hyperechoic structures representing the cauda
unjustified for relatively minor surgery since oral or rectal equina seen in cross section. The dura mater forms a hyper-
analgesia with less risk appears equally effective. echoic (white) ring bordering the spinal canal; the pia mater
Epidural fentanyl carries a significant dose-dependent is a hyperechoic ring surrounding the spinal cord. The cere-
risk of respiratory depression without substantial analgesic brospinal fluid is hypoechoic. The paraspinous muscles
benefit [212]. Moreover, it causes urinary retention, pruritus, appear as an ovoid hypoechoic structure in either side of the
and ileus. Nausea, vomiting, and pruritus are difficult to midline.
assess in neonates and preterm infants but may be expressed In sagittal longitudinal scans (Fig. 16.6b), the spinal cord
as irritability, fussy, or “unsettled.” When administered via a elements are bounded by the pia appearing as hyperechoic
thoracic epidural, fentanyl is absorbed systemically and acts parallel lines that converge at the conus. The cord is homoge-
on the central nervous system. In the lumbar region, fentanyl neously hypoechoic with a central hyperechoic line (central
probably acts locally as well as systemically. sulcus). The dura mater is the hyperechoic line closely
Clonidine has been used as an adjuvant for caudal or epi- applied to the bony elements. The spinous processes can be
dural infusions in neonates. At the recommended bolus dose identified by the “saw tooth” effect at regular intervals above
(0.5–1 mcg/kg) or infusion rate (<0.1 mcg/kg/h), the hemo- the spinal canal and its contents.
dynamic effects are mild. Clonidine provides synergistic Using real-time imaging, ultrasound can verify the cor-
analgesia and, unlike epidural opioids, produces little or no rect placement of a Tuohy needle, the injection of local anes-
ileus, nausea and vomiting, itching, or urinary retention. thetic, and the position of the catheter within the epidural
Even at doses that cause sedation, the respiratory drive with space [178, 215, 217]. The epidural space in neonates ranges
clonidine is better preserved than with opioids. from 1 to 3 mm in depth [17]. The orifice of a 19G (Portex®)
a
a b
b
c
d
Fig. 16.6 Ultrasound image of the vertebral column (cross section—a; sagittal section—b). The depth the epidural space can be measured before
placing the catheter. Abnormalities and normal variants of relevant anatomy can be excluded before placing an epidural block
542 A. Bosenberg
or 20G (Arrow®) Tuohy needle is 2 and 3 mm, respectively. bifida, can be identified using ultrasound. Anatomical abnor-
This suggests that dural tenting must occur at the time of malities of the spinal cord (e.g., syrinx, diastematomyelia)
either needle placement or epidural catheter insertion in neo- can also be identified [216, 218].
nates or infants. Ultrasound can determine the location of the
catheter tip introduced via the sacral hiatus [178, 215].
Anatomical abnormalities [216, 218], particularly in Peripheral Nerve Blocks
those neonates with vertebral anomalies, unusual pits
(Fig. 16.7), or tufts of hair suggesting an underlying spina Peripheral nerve block can be performed in neonates [13, 14,
219–229] to provide analgesia postsurgery, for sympathetic
blockade to facilitate PICC line placement [13, 14], or as
part of the management of vascular complications [13, 14,
221, 225–227]. Nerve blocks can been placed using anatomi-
cal landmarks, a nerve stimulator [222], or ultrasound guid-
ance [18, 220, 223]. These blocks are almost always placed
under anesthesia or infrequently under awake/sedation in
selected cases [7, 197].
Ultrasound guidance is the most accurate particularly
when purely sensory nerves need to be blocked [215].
Peripheral nerves are less myelinated in neonates, and thus
smaller concentrations of local anesthetic may be used to
achieve a rapid onset of a block. For practical purposes, a
dose of 0.1–0.2 mL/kg is sufficient to block most peripheral
nerves.
Axillary blocks can be used to vasodilate veins to facili-
tate PICC line placement [13, 14] or to salvage an ischemic
limb after misadventures with arterial catheterization [221,
224]. Larger concentrations speed the onset and provide
motor block useful for PICC line placement in awake neo-
nates [14], whereas smaller concentrations are adequate for
sympathectomy and analgesia. Dose guidelines are 0.5–
1.0 mL of a 0.125–0.5% bupivacaine, depending on the
aim.
A stellate ganglion block, using a paratracheal approach
onto Chassaignac’s tubercle at the cricoid level, has also
been used for this purpose [226, 227].
Femoral nerve blocks can also be used for PICC line
placement in the lower limbs, muscle biopsy [219], skin
graft, and clubfoot repair in infants. Successful placement of
local anesthetic just lateral to the femoral arterial pulse can
be achieved using anatomical landmarks, nerve stimulation,
or ultrasound guidance. This block is relatively free of com-
plications, but the hip’s joint capsule deep to the artery may
be entered.
Infraorbital nerve block: Although neonatal cleft lip
repair (cheiloplasty) remains controversial (and is no longer
performed in many institutions because the cosmetic result is
not as good as originally thought) [228], an infraorbital nerve
block provides excellent analgesia without the risk of respi-
ratory depression [228–230]. This block may be particularly
Fig. 16.7 Skin dimples or pits may indicate underlying spina bifida or
cord abnormalities. Ultrasonography can be used to exclude these useful in infants with airway anomalies that could be com-
anomalies before placing either a caudal or epidural block promised by opioids when used for cleft lip repair [230].
The infraorbital foramen is difficult to palpate in neonates ment when introduced subcostally or above the iliac crest.
and small infants. Two approaches have been described—a The muscle layers are thin and compliant, and the risk of
transcutaneous and an intraoral transmucosal approach. The penetrating the peritoneal cavity, liver, or spleen is substan-
nerve exits the infraorbital foramen, which is midway (15– tial if the needle is not advanced with caution. The needle tip
17 mm) along a (30–34 mm) line drawn from the angle of the must be visible at all times (see Fig. 16.8).
mouth to the midpoint of the palpebral fissure, approximately Dose: 0.2–0.5 mL.kg−1 of 0.25 bupivacaine or 0.2%
7–8 mm from the alae nasi [228]. Using a 27–30 g needle, ropivacaine.
the nerve can be blocked by introducing a needle perpen- Intercostal blocks can be placed under direct vision at
dicular to the skin to make bony contact close to, but not into, surgery or using ultrasound guidance to provide analgesia
the foramen. The intraoral approach relies on the ability to after thoracotomy or chest tube placement in both cyanotic
palpate the foramen. A needle is introduced through the alve- and acyanotic neonates.
olar mucosal margin beneath the palpating finger. Both Dosage: 0.6 mL/kg (1.5 mg/kg) of 0.25% bupivacaine
approaches provide analgesia with minimal risk of respira- with epinephrine [236]. Epinephrine should be added to all
tory depression compared with fentanyl [229, 230]. local anesthetics when used for intercostal block in order to
Dosage: 0.5–1 mL 0.25–0.5% bupivacaine [228, 229], or minimize the risk of toxic plasma concentrations of local
ropivacaine, with 1:200,000 epinephrine. anesthetics (due to rapid absorption) and to prolong the dura-
Ilioinguinal nerve block provides comparable analgesia tion of the intercostal blocks. Plasma concentrations using
to caudal blockade for inguinal herniotomy or orchidopexy this dose are variable, but adverse events have not been
[231–233]. The ilioinguinal and iliohypogastric nerves lie reported [241].
between the transversus abdominis and internal oblique Paravertebral block: Direct paravertebral placement of
muscles 3–5 mm medial to the anterior superior iliac spine a catheter for continuous paravertebral block is technically
[91]. Under sterile conditions, a needle is introduced under difficult in neonates. [242, 243]. Extrapleural paravertebral
ultrasound guidance in a medial to lateral direction, i.e., placement under direct vision immediately before chest clo-
toward the iliac muscle and bone. The muscle layers in neo- sure is a viable alternative for management of post thoracot-
nates are thin and compliant. The risk of penetrating the peri- omy pain. After an initial bolus of 0.5 mL.kg−1 of 0.25%
toneal cavity is much greater than in children if the needle is bupivacaine, a continuous infusion of 0.125–0.25% bupiva-
not advanced with caution [65]. caine at 0.2 mL.kg−1 h−1 with epinephrine provides satisfac-
When ultrasound is not available, identification of the tory analgesia.
“pop” as a short bevel needle penetrates the external oblique Erector spinae plane block (ESPB): This novel
aponeurosis and internal oblique muscles is needed. These ultrasound- guided regional technique involves injecting
“pops” can be facilitated by introducing the needle at an local anesthetic deep to the erector spinae muscle at the lum-
angle—the greater the angle, the “thicker” the aponeurosis bar or thoracic transverse process (Fig. 16.9) [244–246]. The
becomes. Large plasma concentrations of local anesthetics spinal nerves are blocked as they leave the paravertebral
have been reported [231, 232], although this block is rela- space. Some retrograde spread to dorsal and ventral rami
tively free of complications. Transient femoral nerve block within the paravertebral space is thought to occur. ESPB is
[234, 235] and colonic perforation have been described [65, technically easier to perform and covers more dermatomes
236]. than a paravertebral block using the same dose (0.5 mL.kg−1
Dosage: 0.1–0.2 mL.kg−1 0.25–0.5% bupivacaine or 0.2– of 0.25% bupivacaine). ESPB has been used successfully for
0.5% ropivacaine. both thoracic and abdominal surgery [244–246].
Transabdominal plane (TAP) block is becoming an Topical anesthesia: During the past two decades, there
increasingly popular alternative for intraoperative and early has been a substantial increase in the number and types of
postoperative analgesia for selected procedures (ileostomy topical anesthetics [247]. Options for the prevention of neo-
closure [237], colostomy [238] involving the abdominal wall natal pain associated with skin-breaking procedures were
[239, 240]. Under sterile conditions and using “in plane” previously limited to injections of lidocaine. Topical anes-
ultrasound guidance, the lateral branch of the intercostal thetics are now available as creams and gels and a heat-
nerves can be blocked in the tissue plane between the inter- activated patch system [247]. The onset time varies for each
nal oblique and transversus abdominis provided the spread modality, and careful planning is needed to coincide with the
of local anesthetic extends posterior to the midaxillary line. peak effect. Indications range from peripheral IV placement,
Hydro-dissection of this tissue plane confirms correct place- lumbar puncture, circumcision, and heel sticks.
544 A. Bosenberg
Fig. 16.8 Ultrasound images of the rectus sheath block through a com- the aorta and inferior vena cava. (c) With pressure from the probe and
pliant abdominal wall. (a) Before application of any pressure with the the needle (visualized), the proximity of the needle tip as it approaches
probe or needle. (b) With minimal pressure during needle insertion, the the posterior sheath to the aorta and vena cava is apparent
abdominal wall and rectus muscles can be pushed dangerously close to
Fig. 16.9 Ultrasound image

of the back muscles in a
neonate. Muscles of the
posterior chest are very thin.
The trapezius is most
superficial, the rhomboids are
visible above T7, and the
erector spinae muscle is
deepest. The transverse
process should not be
confused with a rib since the
ribs are flatter in neonates
Management of Local Anesthetic Toxicity Table 16.4 Management of LAST

1 Stop the local anesthetic infusion and call for help
Neonates are more susceptible to local anesthetic systemic 2 Hyperventilate immediately with 100% oxygen
toxicity (LAST) than are older children. Prevention is there- 3 Suppress seizures if present (midazolam, thiopentone, propofol)
fore better than the cure since management of LAST in neo- 4 Begin external cardiac massage
5 Administer epinephrine 1mcg/kg or 0.1 mL/kg of 1:1000
nates may be difficult. A variety of drugs have been used
6 Administer 1.5 mL/kg of 20% intralipid intravenously over
with limited success in the past [248]. Recent reports of suc- 1 min. Follow it immediately with an infusion at a rate of
cessful management using 20% lipid emulsion are encourag- 0.25 mL/kg/min. Lipid emulsion in propofol should not be used
ing [249–251]. in lieu of intralipid
Initial resuscitation should always proceed according to a. Continue chest compressions (lipid must circulate)
b. Repeat bolus every 3–5 min up to 3 mL/kg total dose until
PALS guidelines, aiming to secure the airway, provide 100% circulation is restored
oxygen, hyperventilate (to reduce the free fraction by induc- c. Continue infusion until hemodynamic stability is restored
ing respiratory alkalosis), and provide circulatory support. d. Increase the rate to 0.5 mL/kg/min if BP declines
Lipid emulsion (20% Intralipid®) should be given as soon as e. A maximum total dose of 10 mL/kg in first 30mins is
recommended
possible [252, 253]. An initial bolus of 1 mL/kg over 1 min,
7 If no response, consider ECMO if available
repeated at 3–5 min intervals (i.e. a total dose of 3 mL/kg),
converting at that point, or earlier with evidence of recovery,
to 0.25 mL/kg/h infusion once cardiovascular stability has
been restored. Drugs (such as propofol) that are formulated trapping lipophilic local anaesthetic agents (ii) at the mito-
in a lipid emulsion are not appropriate substitutes for chondrial level (interrupts fatty acid transport into cardiac
Intralipid® particularly in the presence of cardiovascular col- mitochondria) and Intralipid supplies new energy (iii)
lapse [254] (see Table 16.4). activation calcium channels increasing intracellular calcium.
There are a number of theories as to the mechanism of To date, there have been in the order of ten case reports of
action of the lipid emulsion works: These include “(i) lipid intralipid use for LAST in children of which nine were
sink” i.e. a distinct lipid compartment in the blood stream successful.
546 A. Bosenberg
Conclusion 12. Peutrell JM, Hughes DG. Epidural anaesthesia through caudal
catheters for inguinal herniotomies in awake ex-premature babies.
Anaesthesia. 1993;48:128–31.
The benefits of regional anesthesia are significant, but safety 13. Messeri A, Calamandrei M. Percutaneous central venous catheter-
should remain our primary concern particularly with today’s ization in small infants: axillary block can facilitate the insertion
high expectations and zero tolerance for morbidity after rate. Paediatr Anaesth. 2000;10(5):527–30.
14. Keech K Bosenberg A. Axillary block for PICC Lines in critically
anesthesia. While most regional anesthetic techniques are ill neonates Abstract Society Pediatric Anesthesia (SPA) Annual
simple to perform, they should never be considered routine meeting 2010, San Antonio, TX.
because of the risks involved [7, 74]. Careful consideration 15. Bosenberg AT, Lonnqvist P. The potential future or just a way
of the indications and contraindications together with the of trespassing the safety limits of pediatric regional anesthesia?
Pediatr Anesth. 2011;21:95–7.
setting (day case or hospital) should influence the decision. 16. Sethna NF, Berde CB. Pediatric regional anesthesia equipment.
Continuous infusions and nerve blocks have limited dura- Int Anesthesiol Clin. 1992;30:163–76.
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multimodal approach [255]. In general, the more peripheral placement in neonates: sonoanatomy and feasibility of ultrasono-
graphic guidance in term and preterm neonates. Reg Anesth Pain
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performed by, or under the guidance of, an experienced 18. Marhofer P, Willschke H, Kettner S. Imaging techniques for
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Anesthetic Complications
in the Neonate: Incidence, Prevention, 17
and Management
Mary Lyn Stein, Robert F. O’Donnell, Monica Kleinman,

and Pete G. Kovatsis
Introduction eri-anesthetic Mortality and Adverse

P
Events
The neonate is at risk for increased peri-anesthetic complica-
tions attributed, in part, to factors such as the transitional cir- The first reviews of perioperative morbidity and mortality in
culation and the immaturity of many organ systems and infants and children, which date back to the 1950s, reported
metabolic processes. Advances in perinatal and neonatal care a greater incidence of adverse events when compared with
together with the growing field of fetal interventions have that in adults [1, 2]. In the first edition of Smith’s text on
increased the number of medically complex, preterm neo- pediatric anesthesia in 1959, he noted that greater than one-
nates presenting for anesthetic care. In the preterm neonate, third of the deaths in children under 10 years of age occurred
incomplete maturation of all organ systems, particularly the in neonates during the first week of life [3]. Reaching a simi-
pulmonary, cardiovascular, and neurologic, has further mag- lar conclusion, a report in 1961 suggested that the greater
nified the perioperative risks. Surgical or interventional pro- rate of cardiac arrest in children compared with adults could
cedures in neonates, such as repair or palliation of major be attributed primarily to the greater frequency of arrest in
congenital anomalies and management of life-threatening infants [4]. In 1964, the Baltimore Anesthesia Study
complications of prematurity, are rarely elective. Despite Committee estimated an anesthesia-related mortality rate of
preparation, experience, and best intentions, peri-anesthetic 3.3 per 10,000 children under 15 years old, with neonates
adverse events confront all practitioners who care for neo- accounting for a staggering 20.4% of these deaths [5].
nates. Excellent communication and collaboration among The literature has consistently identified a greater rate of
the neonatal, anesthetic, and procedural teams are essential adverse events in infants compared with that in older chil-
to optimize the outcomes for neonates. dren [4, 6–27]. However, most publications relied on self-
reporting of the incidents and grouped the events that
occurred in neonates with those in infants, without explicitly
detailing the rate of adverse events in neonates.
Underreporting is a common problem with self-reported
events, which results in an underestimation of the true fre-
M. L. Stein (*) · P. G. Kovatsis quency of peri-anesthetic adverse events in the literature
Division of Perioperative Anesthesia, Department of [28–31]. Some epidemiologic studies have relied on report-
Anesthesiology, Critical Care and Pain Medicine, Boston ing critical incidents to a national database or reviewed
Children’s Hospital, Harvard Medical School, Boston, MA, USA
closed claims. However, because these reports do not include
e-mail: [email protected];
[email protected] a denominator, the frequency of critical events involving
neonates remains elusive. Additionally, the lack of uniform
R. F. O’Donnell
Division of Pediatric Anesthesia, Department of Anesthesia, definitions of clinical complications, regional differences in
F. Edward Hebert School of Medicine, Naval Medical Center, clinical practice, and the inability to control for or identify
Uniformed Services University, Portsmouth, VA, USA confounding variables can complicate the interpretation of
adverse event studies. Studies from single institutions have
M. Kleinman the added challenge of accruing an adequate sample size to
Division of Critical Care Medicine, Department of Anesthesiology,
accurately reflect the frequency of rare adverse events. This
Critical Care and Pain Medicine, Boston Children’s Hospital,
Harvard Medical School, Boston, MA, USA may require collecting data for a greater duration. These
e-mail: [email protected] issues limit the external validity of the data from individual

554 M. L. Stein et al.
institutions and direct comparisons among the studies. In cardiovascular instability during transport between the neo-
2015, a meta-analysis recommended a standardized r eporting natal intensive care unit (NICU) and the ORs (operating
system for future studies of adverse events in pediatric anes- rooms) in neonates <1 kg and modified their practice to per-
thesia given the heterogeneity of existing data [32]. However, form selected procedures in the NICU [9].
even with improved reporting, it is important to recognize The Canadian Pediatric Adverse Events Study described
that “there is probably an unknown and unquantifiable num- the epidemiology of adverse events among children in 8 aca-
ber of errors which may or may not be involved in a chain of demic pediatric centers and 14 community hospital in
events resulting in morbidity or mortality, but which go Canada between April 2008 and March 2009, selected ran-
unnoticed and therefore unreported” [33]. domly and evenly distributed across 4 age groups (0–28 days;
The first prospective survey of pediatric anesthesia- 29–365 days; >1–5 years; and >5–18 years) [34]. There were
related morbidity and mortality in 1988 included data from 651 neonates of whom 29 (4.5%) experienced a total of 63
40,240 anesthetics in children younger than 15 years from adverse events. Five of those neonatal adverse events (12.8%)
440 randomly chosen institutions in France between 1978 were classified as surgically related adverse events.
and 1982 [8]. This survey included 27 major complications Anesthesia-related events were not specifically identified.
that were defined as fatal, life-threatening, or resulting in Thus, it remains unclear if the anesthesia-related events were
severe sequelae through the first 24 h after an anesthetic. The included in the surgical or the “other” group. Adverse events
observed incidence of morbidity was 7 per 10,000 anesthet- in the surgical category occurred less often in neonates when
ics with a mortality rate of 0.25 in 10,000. The risk of signifi- compared with all other age groups, and neonates in the
cant morbidity in infants (43 per 10,000) was greater than NICU experienced significantly greater rates of adverse
that in children 1–14 years old (5 per 10,000). Neonates were events than those not in a NICU. The latter may be related to
not analyzed as a group distinct from infants. Respiratory the increased complexity of care associated with NICU
failure was identified as the most common cause of major patients, which parallels other reports [35, 36].
complications in the infants, whereas respiratory failure and In a review of >100,000 anesthetics in children over a 5.5-
cardiac failure were equally responsible for major complica- year period, the 24-h mortality from any cause was 13 per
tions in older children. Higher ASA physical status, coexist- 10,000 anesthetics, with a 15-fold greater rate in neonates
ing diseases, prior anesthetic exposure, and emergency (180 per 10,000). Analysis of all deaths suggested that the
surgery were all associated with an increased risk of rate attributable to anesthesia-related factors was small,
complications. ~1/10,000, with only one neonatal death in this category
In a retrospective review of anesthetic morbidity and mor- [26]. In another retrospective review of 45,182 anesthetics
tality data from a single pediatric institution in Canada over 7 years at a tertiary pediatric hospital in the Netherlands,
between 1982 and 1987, adverse events were collected for 72 neonatal deaths occurred within 30 days of 1862 neonatal
up to 72 h postoperatively in children less than 16 years of procedures, with only 1 death attributable to anesthesia. This
age. They included events that required an intervention intra- resulted in a 30-day anesthesia-related perioperative mortal-
operatively by the anesthesiologists, selected events in the ity rate of 5.4 per 10,000 in neonates [27].
recovery room reported by the recovery room nurse, and any Pediatric perioperative mortality associated with major
additional occurrences noted on chart review within 72 h of surgical procedures (excluding cardiac and trauma opera-
the procedure but without distinguishing if the events were tions) has been reported from the Pediatric Participant Use
related to the surgical procedure or the anesthetic. Of the Data File (PUF) collected between 2012 and 2015. The over-
29,220 anesthetics that were reviewed, only 361 (1.2%) all 30-day perioperative mortality rate in infants and children
involved neonates, yet neonates experienced 41.5% of all was 70 per 10,000. The results were not stratified by age.
events reported. Neonates experienced the greatest incidence Given that the procedures necrotizing enterocolitis (NEC)
of adverse events (83 per 10,000), 3 of which were intraop- and congenital diaphragmatic hernia (CDH) were associated
erative deaths. Neonates with complications were more with the greatest proportion of perioperative mortality (19%
likely to be ASA physical status 3 or greater and scheduled and 5%, respectively), we can deduce that this mortality
for major surgical procedures. In neonates, respiratory com- most likely occurred in neonates and infants. Additionally,
plications accounted for the majority of intraoperative events 67% of perioperative mortality associated with NEC occurred
(54%), whereas blood pressure derangements (44%) and within 24 h of the procedures. Perioperative mortality of
respiratory events (38%) accounted for the majority of events NEC was strongly associated with sepsis along with the need
in the postoperative period. Of note, some events occurred for inotropic support and blood transfusion within 48 h of
more than once, and/or multiple events were observed in the surgery [37].
same child but additional details were not provided. The A single-center quality improvement study demonstrated
researchers identified increased risks of hypothermia and that the incidence of adverse events in neonates and infants
17 Anesthetic Complications in the Neonate: Incidence, Prevention, and Management 555
was greater than in older children, irrespective of the loca- most common causes of arrest being medication-related and
tion (OR versus nonoperating room). Respiratory events cardiovascular. ASA physical status 3–5 and emergency sur-
were the most common cause of adverse events [24]. gery were predictors of mortality, but age was not. In a fol-
The Pediatric Risk Assessment (PRAm) score is a tool low-up analysis of the POCA Registry between 1998 and
devised to predict the perioperative risk of mortality in pedi- 2004, neonates accounted for 11% (21/193) of all anesthesia-
atric patients undergoing noncardiac surgery. The PRAm related cardiac arrests, which was similar to the incidence
score originated from the pediatric database of the American reported previously [19]. Specific analyses of neonatal cases
College of Surgeons (ACS) National Surgical Quality were not performed. ASA physical status 3–5 and emergency
Improvement Program to predict 30-day mortality in patients surgery remained predictors of mortality with medication-
18 years of age and younger [38]. The score, which ranges related causes of cardiac arrest decreasing significantly,
from 0 to ≥9, is the sum of surgical urgency (one point); attributable to the decreased use of halothane.
presence of any significant comorbidities (two points); fac- In a single-institution retrospective review of anesthetics
tors of critical illness such as mechanical ventilation, inotro- between 2000 and 2011, cardiac arrest occurred in 5.1 of
pic support, or cardiopulmonary resuscitation (three points); 10,000 anesthetics, with 2.6 per 10,000 classified as
age less than 12 months (three points); and the presence of a anesthesia-related [43]. Age ≤6 months was significantly
neoplasm (four points). A PRAm score ≥ 6 confers an eight- associated with the incidence of anesthesia-related cardiac
fold increase in 30-day mortality for patients with an arrest.
American Society of Anesthesiologists physical status (ASA In 2017, a prospective cohort study (the Anaesthesia
PS) of ≤3 [39]. The PRAm score may contribute to the pro- PRactice In Children Observational Trial (APRICOT)) from
spective assessment of risk during the peri-anesthetic care of 261 participating facilities in 33 European countries cap-
neonates, but this remains to be established. tured 31,127 anesthetics in 30,874 children over a defined
Despite differences in study design, data sets, and analy- 2-week period [44]. The cases were assessed for severe peri-
ses, a large body of research [10–12, 14–18, 20, 22, 40] sup- operative critical events that required immediate intervention
ports the general findings of the studies discussed in detail in that (may have) led to death or major disability. The overall
the proceeding section, leading to the following incidence of severe perioperative critical events was 5.2%,
conclusions: with an increasing incidence with decreasing age. Respiratory
events were the most likely proximate cause. In our interpre-
1. Risks are greater in infants and more specifically in tation of the published data from the neonatal subgroup, the
neonates. overall rates of critical events were greater in this age group,
2. Respiratory and airway-related events are the leading cat- with a primary cardiovascular etiology four times greater
egories of adverse events. (12%) than a respiratory etiology (3%). The data demon-
3. Factors such as comorbid disease (ASA physical status strated a large variability in pediatric anesthetic practice
3–5) and emergency surgery increase the risk in the peri- among institutions as well as a relatively high rate of critical
operative period. events. The incidence of critical events for providers with a
greater experience (in terms of years in anesthesia practice)
was statistically significantly less than for those with less
Peri-anesthetic Cardiac Arrest experience. The APRICOT study supports further education
and quality improvement strategies targeting pediatric anes-
Cardiac arrest during pediatric anesthesia is a sentinel event. thesia care teams. The study also supports the benefit of uni-
Depending on the population studied, the reported incidence versal practice standards, active support of peripheral
is between 1.4 and 147 per 10,000 anesthetics, with an asso- hospitals by specialized pediatric centers, and matching
ciated mortality rate between 5 and 28% [1, 13, 19, 21, 23, complex and high-risk cases with anesthesiologists with
25, 41–45]. The Pediatric Perioperative Cardiac Arrest commensurate experience and training [44, 46].
(POCA) Registry, a voluntary reporting system of intraop- Wake Up Safe (WUS) (http://wakeupsafe.org/) is a patient
erative cardiac arrests in children, was established in 1994 by safety organization and quality improvement initiative spon-
the ASA Committee on Professional Liability and the sored by the Society of Pediatric Anesthesia (http://www.
American Academy of Pediatrics Section on Anesthesiology pedsanesthesia.org/) and certified by the Agency for
[13]. In their initial review of submitted data of the first Healthcare Research and Quality (AHRQ). The WUS regis-
4 years, neonates accounted for 15% (22/150) of all try collects serious adverse events associated with pediatric
anesthesia-related cardiac arrests and 26% (75/289) of all anesthetics from its member institutions [47]. This registry
cardiac arrests [13]. Their analysis concluded that cardiac overcomes many of the limitations of single-institution stud-
arrest occurred most often in infants, <1 year of age, with the ies and other databases that do not include reliable demo-
graphic information. Reports from WUS have substantiated of the airway are the most common adverse events associated
the notion that infants are at a greater risk for a variety of with anesthesia in neonates and infants [53]. Laryngospasm is
adverse events including transfusion-associated hyperkale- the leading cause of cardiac arrest in the respiratory subgroup
mic cardiac arrest [48] and cardiopulmonary arrest in the from the POCA registry [13, 19]. A study of the incidence of
PACU [49]. An analysis of the WUS cases submitted between laryngospasm in all ages reported that the greatest risk
2010 and 2015 revealed that the incidence of cardiac arrest in occurred in infants 1–3 months of age [6]. An observational
infants <6 months of age was threefold greater than in those analysis of NICU patients recovering in the PACU found a
>6 months of age and children. Neonates, who comprised significant association of serious adverse events with birth
only 17% of the total number of cardiac arrests, appeared weight less than 1.58 kg and post-menstrual age at surgery
less likely to survive the cardiac arrest, accounting for 31% <41 weeks. If a patient had both factors, the risk of a serious
of the non-survivors [45]. adverse event increased by a factor of 7. All the serious
Postoperative cardiac arrest is a significant risk factor for adverse advents were respiratory [54].
mortality among many subgroups including neonates with The POCA registry identified that 27% of reported car-
congenital heart disease. Researchers used the POCA regis- diac arrests were respiratory-related and most commonly
try to compare cardiac arrest in children with and without associated with laryngospasm and airway obstruction [19].
heart disease. Those with cardiac disease were more likely to Recognizing this, Cincinnati Children’s Hospital imple-
experience an arrest from a cardiac cause (50% vs. 38%), mented a quality improvement project over 2.5 years to
and the arrest was more likely to occur in the general OR increase the availability of airway emergency drugs (succi-
(54%) than in the cardiac OR (26%) or catheterization labo- nylcholine and atropine), the use of non-depolarizing muscle
ratory (17%). There were no data related specifically to neo- relaxants for endotracheal intubation in children 2 years of
nates, although a significant number of events occurred in age and younger, and the presence of anesthesia providers
infants <6 months of age [25]. A single-institution, retro- until emergence from anesthesia in high-risk patients. By the
spective review of cases from 1988 to 2005 reported that the end of the project, the incidence of serious airway events was
frequency of cardiac arrest and associated mortality in neo- reduced by 44%, and that of airway cardiac arrests was
nates undergoing cardiac surgery was more than nine times reduced by 59% compared with the preceding 2 years [55].
the rates in neonates undergoing noncardiac surgery [21]. In In neonates and young infants, the combination of pro-
another single-institution study of infants with congenital nounced airway protective reflexes, smaller airway caliber,
heart disease who suffered perioperative cardiac arrest dur- and noncalcified chest wall increases the risk of airway
ing cardiac surgery, the risk of anesthesia-related cardiac obstruction during inspiration [56]. Even during “normal
arrest was greater than reported in the general pediatric pop- breathing,” the compliant chest wall of neonates and infants
ulation. In this study, neonates with congenital heart disease lowers transpulmonary pressures and lung volumes, which
had a greater incidence of anesthesia-related cardiac arrest increases the tendency toward airway collapse. Because of
than older children [23]. When cardiac arrest occurs after this propensity for obstruction at static functional residual
complex cardiac surgery, mortality was almost twofold capacity (FRC), infants (and neonates in particular) need to
greater in low-birth-weight (LBW) neonates (defined as maintain a dynamic FRC. Early diaphragmatic contraction
<2.5 kg) than in the general population of neonates (12.1% and laryngeal “braking” (vocal cord adduction) during expi-
vs. 6.8%, respectively) [50]. ration generate dynamic FRC by supporting a greater lung
There is scant literature on the rate of postoperative car- volume during the respiratory cycle. These developmental
diac arrest in the NICU. In a large series of pediatric inten- mechanical properties, coupled with high oxygen consump-
sive care unit patients who suffered cardiac arrest, survival to tion, increase the risk of perioperative hypoxemia and hyper-
discharge for neonates was 27% [51]. A more recent single- capnia and postoperative respiratory events in neonates [9].
center report found an incidence of cardiac arrest in a quater- Sedatives and anesthetics impair or ablate the neonate’s
nary NICU to be 1.2 events per 1000 patient-days or 2.2% of capacity to sustain respiratory adaptations. During the deliv-
admitted patients. Survival to discharge was 61% [52]. ery of anesthesia, the provider can compensate by using con-
tinuous positive airway pressure (CPAP), assisted ventilation,
or controlled ventilation with positive end-expiratory pres-
Respiratory and Airway Complications sure (PEEP) to avoid respiratory deterioration. Extremely
preterm infants who require mechanical ventilation should
Studies have consistently demonstrated that airway and respi- be closely monitored to maintain FRC without overdisten-
ratory events are among the most common complications tion. If the alveoli are overdistended, then it could lead to
during pediatric anesthesia, with laryngospasm and/or “air- lung injury, resulting in respiratory distress syndrome and
way obstruction” occurring most frequently [11, 15, 17, 22, lasting bronchopulmonary dysplasia (BPD) and chronic lung
24, 25]. Not surprisingly, respiratory complications and loss disease [57]. A Cochrane review concluded that lung-
protective ventilation with volume targeted ventilation in infants less than 44 weeks postconceptional age and ex-
preterm infants less than 44 weeks corrected gestational age premature infants less than 60 weeks postconceptional age
decreased the incidence of BPD and death when compared be admitted postanesthesia for a minimum of 12 h apnea-free
with pressure-limited ventilation [58]. continuous monitoring. If the infant experiences an apnea,
Many neonates exhibit periodic breathing, that is, relative he/she should continue to be monitored. Others recommend
tachypnea with interspersed periods of apnea not associated that all infants less than 46 weeks postconceptional age be
with bradycardia and/or significant hypoxemia [59, 60]. admitted for a minimum of 12 h of apnea monitoring postop-
Significant or pathological apnea is defined by the cessation eratively and those between 46 and 60 weeks postconcep-
of breathing for more than 15 s or for any duration when it is tional age be evaluated and if comorbidities such as a history
accompanied by bradycardia or cyanosis. This is particularly of apnea, chronic lung disease, neurological disorder, or ane-
common in preterm neonates [60, 61]. Respiratory control in mia are present, then they too should be monitored continu-
the neonate is characterized by blunted responses to hypoxia ously for 12 h [67]. All other healthy neonates beyond
and hypercarbia. The hypoxic response is biphasic with the 4 weeks postnatal age should be scheduled first on the sur-
initial response being hyperventilation followed by hypoven- gery list and monitored for 6 h postoperatively for apnea.
tilation, bradycardia, and apnea if the hypoxia is not reme- Regional anesthesia (spinal, caudal, or spinal and caudal
died quickly (see Chap. 2). Residual trace concentrations of without additives other than epinephrine) in ex-premature
inhalational anesthetics may abolish the initial hyperventila- infants is an effective alternative to general anesthesia.
tion response to hypoxia in the neonate. The risk of periop- However, if any sedation is administered, the incidence of
erative apnea is increased when hypothermia, metabolic perioperative apnea will be similar to that after a general
derangements, sepsis, lung disease, and residual anesthetics anesthetic [68–71]. In a direct comparison of spinal and gen-
are also present. Anemia remains controversial with a recent eral anesthesia, spinal anesthesia did not reduce the risk of
study failing to demonstrate an association with apnea, central apnea in preterm infants, although there was less
although that study was not powered to demonstrate an effect desaturation and bradycardia in the perioperative period
of anemia [62]. Adaptive responses to hypoxia and hypercar- [72]. Spinal anesthesia that requires supplemental sedatives
bia are further blunted in the perioperative period and in pre- or a partially failed spinal that requires general anesthesia
term infants, increasing the risk of respiratory complications may be associated with a high risk of postoperative apnea
in the form of apnea and hypoxemia. [73, 74]. These publications also postulated that infants with
Postoperative apnea in the preterm neonate and infant a postconceptional age of approximately 41 weeks or less
may also exhibit an obstructive component since residual have an increased risk of delayed postoperative apnea, par-
anesthetic agents depress upper airway muscle tone as well ticularly when comorbidities are present. A more recent
as the respiratory coordination needed to maintain the upper study of apnea using data from the General Anesthesia com-
airway [63]. Neonates are also more prone to upper airway pared with Spinal Anesthesia (GAS) study determined that
obstruction related to head and neck position, which is more the overall incidence of apnea after regional and general
likely to occur with residual anesthetics and analgesics. anesthesia were similar. However, apnea was a secondary
In 1982, a retrospective analysis of the risk of periopera- outcome in the GAS study, and the study excluded many
tive apnea after hernia surgery in preterm and full-term neo- infants who were extremely premature and those with
nates and infants reported a 20% incidence of perioperative comorbidities, was not powered to differentiate the incidence
apnea in preterm neonates compared with zero events in full- of apnea between general and regional anesthesia, and did
term neonates [64]. This prompted eight prospective trials not require a uniform monitoring strategy for apnea postop-
that culminated in a combined analysis in 1995 that deter- eratively. Nonetheless, a subgroup analysis revealed that
mined that “apnea was strongly and inversely related to both apnea with regional anesthesia was less than with general
gestational age and postconceptional age” with associated anesthesia in the early postoperative period, from 0 to 30 min
risk factors of ongoing preoperative apnea and anemia [65]. after surgery [62]. The incidence of postoperative apnea was
The authors concluded that the incidence of apnea decreases 6% in ex-premature infants, consistent with the literature
to less than 1% beyond a postconceptional age of [65]. Interestingly, interventions including positive pressure
54–56 weeks, but the external validity of this conclusion has ventilation and CPR were required in 1.3% of infants, with
been questioned [66]. six of the nine interventions occurring in PACU, within
It is well established that neonates, preterm neonates, and 30 min of the end of surgery and all in infants who received
ex-premature infants require postoperative monitoring for general anesthesia. Prematurity was the strongest predictor
apnea and bradycardia. Many clinicians advocate regional of apnea in the GAS study as 96% (24/25) of infants with
anesthesia without parenteral or oral sedation in neonates, apnea were born preterm.
especially premature neonates, to minimize the risk of post- The least-soluble, potent inhalation agent, desflurane,
operative apnea. Most institutions recommend that term facilitates a rapid emergence from anesthesia and may
decrease the risk of postoperative apnea when combined odds in neonates [88]. The Pediatric Difficult Intubation
with a regional technique [75–77]. However, the evidence Registry (PeDI-R) reported that >2 intubation attempts and
remains insufficient to support such a claim. Given the fail- infants who weigh <10 kg correlated with a significantly
ure rate and relative stress of awake regional techniques, increased risk of complications [41]. Subsequently, the
using dexmedetomidine as a sedative to facilitate the place- PeDI-R concluded that each additional intubation attempt
ment of the regional anesthesia and possibly reduce the stress increased the risk of complications by twofold [89].
response may be an alternative technique without increasing Neonates can develop stridor after tracheal extubation,
the need for peri-anesthetic respiratory intervention [78, 79]. although the incidence is not well-documented. Systematic
In a prospective study of general anesthesia (GA) versus reviews, including neonatal studies, have consistently shown
combined spinal-epidural anesthesia (CSEA) in 50 infants at that neither IV steroids nor nebulized racemic epinephrine
a mean age of approximately 6 weeks and postconceptional prevents post-extubation stridor [90–93].
age of 48.5 (GA) and 46.1 (CSEA) for gastrointestinal sur- Acquired subglottic stenosis is also a known complication
gery, the incidence of adverse cardiorespiratory events in the of prolonged tracheal intubation in the neonate. The inci-
first eight postoperative days in the GA group was signifi- dence of subglottic stenosis after tracheal intubation in the
cantly greater than in the group receiving CSEA [80]. Of neonate ranges from 1 to 8% [94–96], with a gradual decrease
note, the infants who received GA were treated with a fen- in the incidence over time [97–99]. Prolonged duration of
tanyl infusion for postoperative analgesia, whereas the CSEA intubation and reduced birth weight increase the risk for sub-
group received a continuous infusion of bupivacaine via the glottic stenosis [96, 100]. In a large series of pediatric
thoracic epidural catheter. The postoperative analgesic regi- patients undergoing cardiac surgery, the incidence of sub-
men may have contributed to the increased incidence of glottic stenosis was 2.3% in infants <1 year of age. The dura-
adverse cardiorespiratory events in the GA group. tion of tracheal intubation being >96 h was a risk factor for
Methylxanthines such as caffeine reduce but do not elimi- subglottic stenosis. However, the incidence of subglottic ste-
nate the risk of postoperative apnea in preterm infants. They nosis in neonates undergoing congenital heart surgery whose
may be administered when neonates present to the OR with airways were intubated with cuffed versus uncuffed tracheal
continued apnea or have apnea postoperatively [81, 82]. tubes did not differ significantly [101]. A retrospective, case-
Methylxanthines also reduce the rate of extubation failure in control study from a single institution reported an overall
preterm infants in the NICU, but not specifically in the post- incidence of subglottic stenosis that required surgical inter-
anesthetic period [83]. A systemic review of meta-analyses vention in children without genetic syndromes to be 0.93%.
which were considered limited in quality showed the non- The incidence was nearly 4% in infants <28 weeks’ gestation
inferiority of caffeine to doxapram or other methylxanthines compared with 0.13% in those ≥28 weeks. Multivariate
in the management of apnea of prematurity [84]. analysis identified the following three factors that were asso-
Polymorphisms in the adenosine1 receptor gene may ciated with the development of subglottic stenosis: more
explain interindividual variability in response to caffeine: than five previous intubations (aOR 3.74; 95% CI 1.15 to
infants >28 weeks’ gestation who responded to caffeine car- 12.19), a traumatic intubation (adjusted OR (aOR) 3.37;
ried the rs16851030 C/C A1 genotype [85]. A large, retro- 95% CI 1.01 to 11.26), and a ratio of the internal diameter
spective study concluded that sex-based differences occur in (mm) of the tracheal tube/gestational age > 0.1 (aOR 6.40;
apnea of prematurity such that females may have more rapid 95% CI 1.65 to 24.77) [99].
maturation of the respiratory system [86]. Further studies are Oral or airway stimulation may lead to vagally mediated
warranted to explore the possible role of adenosine polymor- mild or severe bradycardia and even to asystole and apnea
phisms and sex in a larger population of preterm infants as [102–104]. This response may be further enhanced in the set-
they relate to the risk of apnea of prematurity. ting of hypoxia [105]. In early reports, the use of halothane
The pediatric airway literature strongly suggests that mul- likely contributed to the incidence and severity of bradycar-
tiple attempts at tracheal intubation in infants and neonates dia at induction of anesthesia and with airway management.
increase the frequency of complications. A retrospective Now that halothane has been supplanted with sevoflurane,
analysis of 1341 infants revealed that 16% required two or anticholinergic pretreatment is generally unnecessary unless
more laryngoscopy attempts to achieve tracheal intubation a vagotonic medication such as succinylcholine is also
and those who required additional attempts had a signifi- administered [106, 107]. There have been reports of a
cantly greater rate of hypoxemia than infants who required a decreased incidence of intraoperative bradycardia in infants
single attempt [87]. Similarly, in another retrospective study from pre-2000 (127 per 10,000 anesthetics [16]) to post-
in which induction techniques for pyloromyotomy were 2000 (33 per 10,000 anesthetics [13]), which may be attrib-
compared, multiple attempts at tracheal intubation were utable to the transition from halothane to sevoflurane;
associated with an 11-fold increased odds of hypoxemia however, establishing causality is difficult based on the avail-
compared with a single attempt and an 18-fold increased able data.
Pulmonary aspiration of gastric contents in the peri- the ability to provide and maintain such an environment, and
anesthetic period is a rare but potentially fatal complica- the preservation of a familiar, comfortable surgical setting.
tion. The reported incidence of aspiration in infants ranges Over the past few decades, the practice of performing sur-
from 3.6 to 10.2 per 10,000 [8, 17, 20, 108–110]. One study gery in neonates in the NICU has gained favor by mitigating
reported that the incidence of pulmonary aspiration during the risk of transport, especially for preterm neonates and
emergency procedures exceeded that of non-emergent those more critically ill. Procedures performed in the NICU
ones, with the majority occurring at induction of anesthesia include abdominal procedures for NEC, cryotherapy for reti-
[109]. In contrast, an analysis of over 50,000 anesthetics nopathy of prematurity (ROP) [114], cannulation for extra-
demonstrated that although the risk of aspiration was mar- corporeal membrane oxygenation (ECMO), and less
ginally increased under emergency conditions, it correlated commonly, balloon atrial septostomy [115] and ventriculo-
most closely with ASA physical status [108]. These studies subgaleal shunts for posthemorrhagic hydrocephalus [116].
found no instances of aspiration in neonates. Neither study Transporting neonates, particularly critically ill neonates,
considered any of the infants and children who aspirated to between hospital locations has many potential dangers, par-
have had serious morbidity, despite a few requiring pro- ticularly for the extremely preterm infant and those who
longed post-aspiration ventilator support. While severe depend on high frequency ventilation (see Chap. 13,
morbidity and mortality were unlikely after aspiration, Anesthesia Outside the Operating Room). During transport
closed claims analysis and national databases revealed that from the stable, safe environment of the NICU or OR, the
aspiration is a reported cause of serious untoward compli- critically ill neonate is vulnerable to a number of mishaps
cations [10, 22, 111]. including equipment failure, disconnections from drug infu-
Residual muscle weakness after antagonizing the neuro- sions and equipment, temperature instability, and even pro-
muscular blockade may also pose a significant risk of adverse vider distraction as they deal with navigating through doors,
events in neonates. This risk may be exaggerated in neonates elevators, and hallways. If sophisticated NICU ventilators
with respiratory disease or congenital and acquired anatomic are not available for transport, the critically ill neonate is left
airway abnormalities. The use of a safe and effective agent to with less than ideal ventilation techniques during transfer. A
antagonize neuromuscular blockade would minimize the single-institution study reported a 27% incidence of compli-
adverse events that may result from residual neuromuscular cations in 1197 intrahospital NICU transports. Increased risk
blockade. Sugammadex may be an optimal drug to antago- for complications was associated with surgical transports,
nize aminosteroid neuromuscular-blocking agents. It is capa- pre-transport assisted ventilation, pre-transport supplemental
ble of completely antagonizing even profound neuromuscular oxygen, central nervous system malformations, and longer
blockade by trapping the aminosteroid in a cyclodextrin duration of transport [117]. A WUS review reported that 5%
toroid; it has a compelling and growing safety profile com- of the reported pediatric events were transport-related and of
pared with using both an anticholinergic and an anticholines- these transport-related events, nearly 40% occurred in infants
terase. A 2019 retrospective review found that the incidence <6 months of age, even though this age range represented
of adverse events such as bradycardia and anaphylaxis only 7% of the database [118]. They found 13 transport-
between neostigmine and sugammadex was not different related deaths, 3 of which were in neonates, underscoring the
[112]. Although all children recovered after sugammadex vulnerability of neonates. The study authors found that a per-
more quickly than after neostigmine, the greatest difference sonal and institutional learning curve occurred over the study
in the speed of recovery occurred in neonates with an almost period with ongoing improvements in human and environ-
12-min faster recovery time after sugammadex. Today, the mental factors.
use of sugammadex in neonates remains off-label. Evidence In many institutions, surgical procedures are either rou-
supports the use of sugammadex in children >2 years of age; tinely performed in the NICU, or the option exists if the risk
however, evidence of sugammadex’s safety and efficacy in of transporting the patient outside of the NICU is deter-
neonates remains limited [113]. mined to be excessive. A 1993 report described the charac-
teristics and outcomes of 193 neonates who underwent
surgery either in the NICU or in the OR. Not unexpectedly,
Additional Considerations infants with a greater acuity of illness, as evidenced by the
preoperative requirement for mechanical ventilation, under-
Location of Operative Procedures went surgery in the NICU [119]. Likewise, surgical proce-
dures performed in the NICU, as opposed to the OR,
The traditional location for providing anesthesia and per- involved neonates with reduced birth weights and gesta-
forming major surgical procedures has been the OR. The tional age. Overall, the mortality in the NICU surgical group
purported benefits and advantages include the OR team, effi- was greater than in the OR group (14% vs. 2%, respec-
ciencies in care and supplies, a more aseptic environment or tively), which may be attributed to sicker neonates undergo-
ing procedures in the NICU versus the OR. Of note, neonates 2. Prewarming the OR temperature to >23.3 °C (74 °F). Of
were more likely to become hyperthermic (> 37.5 °C) in the note, the frequency of hyperthermia increased signifi-
OR than in the NICU likely due to the presence of forced air cantly but not clinically from 1.1% to 2.2%, without any
warmers and other external heating devices in the OR. In sequelae.
two reviews comprising >80 neonates who underwent a
variety of surgeries in the NICU, there were no anesthesia- The Consortium concluded that interdisciplinary team
related deaths [120, 121]. In a single-center retrospective engagement and high compliance to processes throughout
study, the surgical complication rate for patent ductus arte- the procedure period together with identifying the opportuni-
riosus ligation in the NICU (9%) did not differ significantly ties and barriers within each system were essential.
from the same surgery performed in the OR (8%), with no In a retrospective study of infants in a tertiary care NICU,
deaths related to the procedure [122]. The surgeons traveled surgical site infections occurred in 4.3 per 100 interventions
to off-site NICUs for the procedures, which avoided the (CI 95% 3.2 to 5.7), a rate similar to the general pediatric
complexity of transporting NICU infants between hospitals. population. Very low-birth-weight (VLBW) infants and
In another series of 42 neonates with congenital diaphrag- those undergoing gastroschisis closure are at greater risk for
matic hernia who required HFOV, the mortality associated surgical site infections [128]. A single-institution, prospec-
with surgical repair performed in the NICU did not differ tive, cohort study found the overall incidence of surgical site
from that in the OR [123]. In a retrospective analysis of 233 infections in neonates was 43/319 (13.5%) and identified a
neonates who required laparotomy for NEC, the mortality in preoperative NICU stay of ≥4 days and gastrointestinal pro-
infants <1500 g who underwent surgery in the NICU cedures as independent risk factors [129]. Concerns have
because they were judged to have significant risk if trans- been raised about the ability to create and maintain an asep-
ported to the OR did not differ from those who were oper- tic environment for surgical procedures in the NICU envi-
ated on in the OR [124]. In the previously discussed, ronment compared with the OR. Retrospective analyses of
single-center, retrospective Dutch study, the majority of the rates of infection and sepsis in infants undergoing proce-
deaths (84%) occurred during procedures in the NICU or dures in the NICU or the OR yielded mixed results [119,
PICU despite making up less than 10% of the overall proce- 123]. Evidence for periprocedural antibiotic use in neonates
dures reflecting the severity of illness in such patients remains inadequate. Moreover, data suggest that antibiotics
deemed too ill to transport to the OR [27]. are overused [130]. Institutions should consider forming
In a prospective, case-control study that included 108 interdisciplinary antimicrobial stewardship teams to develop
infants from a single institution who were sequentially appropriate plans to identify and treat at-risk infants using
scheduled for an operative procedure in the OR (55) or the local data to select, monitor, and optimize the therapy
NICU (53), clinical perioperative hypothermia in neonates [130–132].
undergoing surgery in the OR (65%) occurred 7 times more Between 1999 and 2009, general surgical cases in the
frequently than in those undergoing surgery in the NICU NICU at a single institution were reviewed. Neonate whose
(13%) [125]. The hypothermic neonates in both groups airways were already intubated and were ventilated remained
required more interventions for respiratory and cardiac sup- in the NICU for their surgeries; the remainder traveled to the
port. Instituting a multidisciplinary transport protocol that operating room. The authors reported that more than one-
included a discrete checklist, team education, ongoing moni- third of the general surgeries or 36% of the 859 total surger-
toring with periodic feedback, and rapid cycle reiterative ies were performed in the NICU compared with almost
improvement decreased the frequency of perioperative hypo- two-thirds or 64% that were performed in the operating
thermia in those transferred from the NICU [126]. The room. There were no surgical complications noted in the
Children’s Hospitals Neonatal Consortium developed the NICU cases with only a single adverse event of an operative
Perioperative Euthermia Clinical Practice Recommendations delay while awaiting equipment. For the last 6 months of the
to maintain euthermia in neonates undergoing procedures study, the team compared operations performed in the NICU
[127]. The recommendations include establishing euthermia (n = 21) with those in the ORs (n = 7) prospectively and
before the procedure and standardizing practice to maintain evaluated temperature, infectious complications of surgery,
the neonate’s temperature during transport to and from the and adverse events related to transfers. They found no differ-
NICU and during the surgery. These 19 institutions were ence in these parameters except for one event in which intra-
able to reduce postoperative hypothermia by 48% by employ- venous access was lost during transfer back to the NICU
ing two key strategies: [127] [133], although the sample size for the prospective portion of
the study was insufficient to identify differences between the
1. Compliance with ensuring neonatal euthermia defined as outcome variables.
36.1–37.9 °C on transfer and arrival to and departure Before traveling between the NICU and a procedural
from the OR. area, providers should ensure that the appropriate equipment
and supplies are present and functional, including an ade- then separated into components immediately before admin-
quate supply of supplemental oxygen. The transport team istration. The leak of potassium from red blood cells is accel-
should review roles and plans for potential adverse events. erated by storing the blood in cool temperatures and by
Physiologic monitoring should be maintained at a level simi- irradiation. Risk factors for hyperkalemia in the neonate
lar to that in the NICU/OR environment to facilitate early include the transfusion of old blood, cold blood, and irradi-
detection of any clinical issues. The use of a transport incu- ated blood, rapid and/or massive transfusion, hypocalcemia,
bator supports thermoregulation but may impair the team’s renal dysfunction, and transfusion through central venous
ability to visualize and access the infant. Given these risks, in
access [48, 145–147]. Washing the blood can minimize
the case of extremely ill neonates, a multidisciplinary team transfusion-induced hyperkalemia and the associated cardiac
meeting should be convened to determine the location and arrhythmias, particularly if the blood has been stored for a
details relative to the surgical procedure to optimize the careprolonged period. However, the greater the interval between
provided. washing and administering the RBCs, the more potassium
will leak out of the cells. Rapid administration of cold,
hyperkalemic red blood cells through a central line directly
Transfusion of Blood Products into the right atrium may cause the atrium to become irrita-
ble and trigger atrial and then ventricular arrhythmias or car-
Transfusions are frequently required for critically ill neo- diac arrest [48]. To preclude such devastating complications,
nates undergoing anesthesia for surgical conditions. Although blood products should be warmed before transfusion to pre-
the measured volume of blood loss may be small, any blood vent hypothermia, and they should be infused through a
loss is a proportionally greater fraction of the circulating peripheral IV line to prevent the associated dysrhythmias.
blood volume in neonates. Thus, meticulous attention must Ideally, fresh units of blood and blood that has been stored
be paid to the amount of blood harvested for laboratory stud- for the briefest time since irradiation should be given to neo-
ies and the amount lost during surgeries. Red blood cell nates to minimize the concentration of potassium in the cell-
transfusion may be considered for preterm neonates who free fraction of the red cells. Other strategies include
require mechanical ventilation for hemoglobin levels of less monitoring and maintaining ionized calcium blood concen-
than 12 g/dL while allowing for reduced thresholds in neo- trations within a normal range [145, 146].
nates who do not require mechanical ventilation, specifically Citrate is used as an anticoagulant in most transfused
hemoglobin transfusion thresholds of 7–10 g/dL, with varia- products, binding calcium and magnesium. Frozen plasma,
tion for gestational and postnatal age as well as underlying whole blood, and platelets have the greatest quantities of
disease process [134, 135]. Children with preoperative ane- citrate followed by red blood cell units and cryoprecipitate.
mia demonstrated an increased risk of in-hospital mortality, Washing the units of red blood cells dramatically reduces the
but whether any correction of preoperative anemia improves concentration of citrate in the acellular fraction. The metabo-
patient outcomes and if this finding also applies to neonates lism of citrate (in the liver) is diminished in neonates, render-
remain unclear [136–138]. For procedures that are associ- ing neonates prone to the prolonged effects of circulating
ated with significant blood loss (e.g., >40 mL/kg), we advise citrate compared with older children and adults [145].
the following processes to minimize exposure and known Clinically, the rapid administration of citrate-containing
complications: use blood conservation techniques such as blood products binds ionized calcium and causes bradycar-
cell salvage and antifibrinolytic medications; transfuse the dia and hypotension that are magnified in the neonatal myo-
freshest units of packed red cells possible (<7 days old) or cardium (see Chap. 2, Physiology and Development of the
use washed units; and minimize the interval between irradia- Term and Preterm Neonate). Hence, citrate-containing
tion of the blood to its administration (less than 24 h) plasma should be infused at rates <1 mL/kg/min along with
[139–144]. concomitant administration of calcium to maintain normal
Neonates are particularly vulnerable to transfusion- plasma calcium concentrations [145]. Exposure to large vol-
related complications including hyperkalemia, hypothermia, umes of citrate through a massive transfusion may also lead
and citrate-induced electrolyte alterations (ionized hypocal- to metabolic alkalosis as the citrate is metabolized in the
cemia and hypomagnesemia). Hyperkalemia has been a liver.
leading cause of cardiac arrest under cardiovascular causes Blood transfusions in neonates lead to both beneficial and
in the POCA registry [19]. Potassium accumulates in the pathologic associations that are poorly understood. In a large
acellular fraction of packed red blood cell units as it leaks series of VLBW neonates, the mortality in those who received
from red blood cells that have been stored for a prolonged >1 blood transfusion increased, although the factors that were
period, increasing linearly with the number of days of stor- responsible for the increased mortality remained elusive [148].
age. Hyperkalemia may also be present in plasma if the The possibility of transfusion-associated NEC and BPD in
blood was stored as whole blood for a prolonged period and VLBW infants has been described, but the pathogenesis is
poorly understood [149, 150]. An important outstanding ques- In stable, non-bleeding, preterm neonates, reduced con-
tion that remains unanswered is whether enteral feeds at the centrations of platelets have been accepted as safe for sur-
time of blood transfusions predispose to transfusion-associated gery, thus reducing the need for platelet transfusions [134].
NEC [150, 151]. In the absence of randomized controlled In a randomized trial of preterm infants with thrombocytope-
studies, a Cochrane review could not determine whether halt- nia in the NICU, the use of a platelet transfusion threshold of
ing enteral feeds at the time of transfusion affected the fre- 50,000 per microliter was associated with a greater risk of
quency of NEC or death [152]. Nonetheless, red blood cell mortality or severe bleeding within 28 days compared with a
transfusion in extremely low-birth-weight (ELBW) infants reduced transfusion threshold of 25,000 per cubic millimeter
(birth weight < 1000 g) may be a risk factor for ROP as well as [164], although the generalizability of this finding to surgical
untoward effects on late neurodevelopment, suggesting cau- neonates remains unstudied. The presence of major hemor-
tion when choosing an appropriate transfusion threshold in rhage in preterm infants is not primarily associated with the
this population [153]. Transfusion practices vary widely due severity of thrombocytopenia [165].
to the lack of any consensus on the thresholds to transfuse Thromboelastographic (TEG) and thromboelastometry
[154]. More restrictive transfusion practices may result in a (TEM) are potentially useful tests of coagulation that reflect
decreased incidence of associated morbidities of prematurity, multiple factors involved in hemostasis, including fibrinoly-
but the evidence is still emerging [135, 155–157]. The results sis. Such viscoelastic tests can provide more information
of the first of two large trials to address this complex topic about the functional status of platelets as well as other com-
[157] have been published. The results of the ETTNO (Effects ponents of the coagulation process even in preterm neonates
of Transfusion Thresholds on Neurocognitive Outcome of [163]. The greatest experience with neonatal TEG has been
extremely low-birth-weight infants) trial which included 1013 in infants undergoing cardiopulmonary bypass or receiving
VLBW infants almost equally between liberal and restrictive extracorporeal membrane oxygenation (ECMO), but further
transfusion strategies revealed no difference in mortality or evaluation of incorporating viscoelastic tests in transfusion
disability (cognitive impairment or cerebral palsy) at algorithms is ongoing [166].
24 months after birth [156]. The results of the second trial, the
TOP (Transfusion Of Prematures: NCT01702805) trial, are
pending [157]. Vascular Access
Transfusion-related acute lung injury (TRALI) and
transfusion-associated circulatory overload (TACO) may be Reliable vascular access is vital to the management of criti-
underdiagnosed in neonates, particularly in those with preex- cally ill neonates but can also be a significant challenge to
isting developmental lung disease [154, 158]. TRALI pres- obtain, secure, and maintain. Vascular access is associated
ents as the sudden onset hypoxemic respiratory failure within with a wide variety of complications and requires constant
6 h of transfusion, associated with non-cardiogenic pulmo- surveillance to diagnose and minimize the potential for
nary edema and bilateral lung infiltrates. Although life- harm. Common issues with vascular access include infec-
threatening TRALI has rarely been observed in neonates, it tions, disconnections, phlebitis, and extravasations.
should be considered in the clinical setting of a sudden dete- Extravasations can lead to significant complications includ-
rioration in pulmonary function after blood component ing tissue necrosis and compartment syndrome. Less com-
transfusion [159, 160]. A less well-known transfusion- mon complications include nerve damage, thrombosis, and
related morbidity is transfusion-related immunomodulation embolism. Arterial lines have the added concerns of isch-
(TRIM), which is a new area of transfusion research seeking emic injury, formation of an arteriovenous fistula, and inad-
to understand how blood products modulate immune cell vertent injection of IV drugs [167]. Proper labeling of lines
function in neonates [159]. and access ports should minimize the chance of intra-arterial
The indications to transfuse fresh frozen plasma (FFP) in administration of a medication.
neonates are variable as common laboratory studies are poor Neonates are at particularly high risk for vascular access-
metrics of potential clinical issues in neonates. Neonates related complications. During the perioperative period, the
have a different balance of coagulation factors compared incidence of thrombophlebitis and adverse events after arte-
with older children, which still results in adequate global rial line cannulation in neonates was 185 and 148 per 10,000,
hemostasis despite laboratory abnormalities [161–163]. The respectively, whereas the incidence in infants, the group
transfusion of FFP in neonates should be clinically based, closest to neonates for these complications, was 20 and 49
targeting evidence of bleeding rather than as a theoretic or per 10,000 respectively [9]. Studies that investigated the tim-
prophylactic measure, except in cases of large volume blood ing of replacing peripheral IV catheters favor clinically based
loss [134]. In contrast, the transfusion of cryoprecipitate algorithms rather than routine, timed replacement, which
should be based on laboratory measures of the fibrinogen have been associated with increasing costs without decreas-
concentration if massive blood loss is anticipated. ing adverse events [168–170].
Central venous access is essential for many critically ill Oxygen Toxicity
neonates while introducing a wide range of potential compli-
cations [171–173] (see Chap. 7, Monitoring). Analysis of The relationship between oxygen therapy and organ injury in
children with heart disease published from the POCA preterm neonates and infants has been well-known for
registry showed that central venous catheters were most fre- decades. Exposure to increased concentrations of oxygen in
quently associated with equipment-related arrests, and 78% the first few weeks after birth is associated with an increase
of arrests that were attributed to central venous catheters in the risk of ROP and BPD [184–186]. Efforts to reduce
occurred in neonates [25]. Ultrasound is commonly used to these sequelae in preterm infants born at ≤28 weeks’ gesta-
increase the rate for the successful placement of central tion led to several studies that examined the impact of a
venous catheters as well as to confirm the location of the range of oxygen saturation targets on neonatal outcomes.
catheter tip [174–176]. Ultrasound can also assist in rapidly Initial reports indicated that a reduced oxygen saturation tar-
diagnosing catheter complications. Large vessel or right get (85–89%) was associated with fewer sequelae of oxygen
atrial perforation may occur either during attempts to place a toxicity in survivors [181, 182, 187–190]. However, in 2016,
central venous catheter or after it is placed due to erosion the UK and Australian Benefits of Oxygen Saturation
through the wall of the atrium. Emergent and potentially life- Targeting (BOOST)–II trials (BOOST-II) reported that this
threatening conditions associated with central venous cathe- reduced target oxygen saturation range of 85–89% was asso-
ters include pneumothorax, hemothorax, and cardiac ciated with a significantly increased incidence of the com-
tamponade. These must be considered in any neonate with a bined outcomes of death and disability at a corrected
central venous catheter who suddenly develops cardiopul- gestational age of 18–24 months, and of dying alone, in post
monary instability. Other complications include thrombosis hoc combined analyses compared with the greater oxygen
(vessel and/or line), embolism, infection, hydrothorax, chy- saturation range of 91–95% [191]. The Neonatal Oxygen
lothorax, and unplanned displacement. In a retrospective Prospective Meta-analysis (NeOProM) Collaboration was
review of 587 central venous catheters in neonates and comprised of five international, comparative effectiveness
infants, the complication rate was 28% (dislodgement 12%, trials and included the two trials from BOOST–II to further
perforation 5%, obstruction 5%, infection 4%, thrombosis evaluate the impact of these two oxygen saturation ranges
1%), with two deaths due to cardiac tamponade [177]. [188, 191–193]. NeOProM analyzed almost 5000 neonates
The combination of an underdeveloped coagulation sys- in two prospectively planned publications that concluded
tem and small-caliber vessels containing a proportionately there was no overall difference in the primary composite out-
larger access catheter in the setting of an underlying critical come of major disability or death in those treated with the
illness predisposes the neonate to thromboembolic events. A reduced (85–89%) versus greater (91–95%) oxygen satura-
Canadian, multi-institutional registry reported that even tion target range by a corrected age of 24 months [192, 193].
though thrombosis occurred infrequently in 97 neonates over However, the reduced oxygen saturation range (85–89%)
more than 3 years from 64 centers, it was strongly associated was associated with a significantly greater incidence in the
with indwelling catheters (89%) and/or the presence of a sys- secondary outcomes of mortality by 18–24 months, death
temic infection (29%) [178]. The registry also concluded that before hospital discharge, NEC, and patent ductus arteriosus
the greatest mortality occurred in neonates with an aortic, that required surgical ligation while significantly reducing
right atrial, or SVC thrombosis. In neonates who were sched- the incidence of ROP and BPD. The net result is that the
uled for or undergoing cardiac surgery, the incidence of cen- optimal target oxygen saturation for preterms infants in the
tral venous line thrombosis was 3 to 10% [179, 180]. NICU remains unclear with many outstanding questions
In addition to the common complications associated with [194, 195]. In the future, advancing technologies such as
chronic indwelling vascular catheters such as infection and closed-loop, automated oxygen control may prove effective
thrombosis [181, 182], peripherally inserted central catheters in maintaining more consistent target oxygen saturations and
(PICC) introduce a greater risk of rupture and potential identifying the optimal target oxygen saturation in these neo-
embolization of a catheter fragment. In a series of 1650 nates [196–198] (see Chap. 2).
PICCs, 11 fractures (0.67%) occurred, requiring invasive When anesthetizing preterm neonates for surgery, anes-
retrieval of fragments via a percutaneous intravascular thesiologists strive to avoid the extremes of hypoxia and
approach [183]. Several factors were associated with cathe- hyperoxia to minimize the contributions of either insufficient
ter fracture including the duration of its placement, line or excessive oxygen exposure to adverse sequelae, even after
occlusion, and leaking at the insertion site. Unless otherwise a brief exposure. We advocate a multidisciplinary discussion
stated by the manufacturer, syringes ≥10 mL are recom- to determine the acceptable peri-anesthetic target oxygen
mended for injections into PICC to preclude excessive intra- saturation or range of saturation together with the minimum
luminal pressure. inspired concentration of oxygen to achieve this goal. In the
absence of confounding variables, the authors and the editor National Confidential Enquiry into Perioperative Deaths
recommend that the inspired oxygen fraction be adjusted to emphasized three ideals [212, 213]:
achieve a midrange oxygen saturation of 90–92% during
anesthesia in preterm neonates. Even though a precise target 1. Surgeons and anesthesiologists should not undertake
saturation is not supported by the current evidence, we can occasional pediatric practice.
state categorically that an oxygen saturation of 100% is not 2. Anesthesiologists who care for children must keep them-
only unnecessary but is potentially harmful, especially if it selves up to date and competent in pediatric anesthesia.
requires a large fraction of inspired oxygen to achieve. 3. Consultant supervision of trainees needs to be kept under
Concerns related to the impact of oxidative stresses in scrutiny.
neonates have led to changes in delivery room resuscitation
guidelines. Two meta-analyses of randomized, controlled tri- These recommendations promoted the concept of region-
als that compared the initial resuscitation with 100% oxygen alization for pediatric and, in particular, neonatal surgical
with room air resuscitation showed greater survival with care in the United Kingdom [213]. The United States does
room air [199, 200]. However, the methodologies used in not have any formal system of regionalization despite the
these studies have been criticized, leading to much weaker clustering of pediatric institutions staffed with pediatric sub-
evidence of the benefit of reduced oxygen concentrations for specialists [214, 215]. Increased volume of cases, specialty-
resuscitation of the neonate [201]. In the case of the preterm specific training and experience, and triaging high-risk and
neonate, best practice and neonatal resuscitation program rare cases to specialty centers are additional strategies that
(NRP) guidelines currently suggest using a FiO2 of 0.21–0.30 decrease the risk and human error [12, 13, 215–221].
to initially resuscitate these neonates and titrate the FiO2 Emphasizing the importance of continuous, competent
thereafter to achieve age-appropriate oxygen saturation tar- practice in the preterm and term neonates, evidence suggests
gets [202]. If the bradycardia persists after ventilation with that many modifiable perioperative factors may contribute
room air, then the neonate should be administered increasing synergistically to neonatal neurological injury. Systemic
concentrations of oxygen up to 100% [203, 204]. hypotension or hypertension outside the autoregulatory
Although there is no consensus on the ideal oxygen con- range, hypocapnia, hypercapnia, increased intracranial pres-
centration for use during neonatal anesthesia, preventing sure, or obstructed central venous drainage may adversely
hypoxemia is an indisputable goal for every pediatric anes- affect cerebral perfusion. Neuronal cell death may also be
thesiologist. We also recommend avoiding hyperoxia to min- promoted by insufficient metabolic or oxidative fuel, such as
imize the risks of adverse effects [205–207] (see Chap. 2) hypoglycemia or hypoxia, especially in times of increased
demand during hypermetabolic states such as pain, fever,
seizures, or other physiologic stressors. Neurotoxic media-
Prevention of Adverse Events tors may also cause brain injury from the sequence of
hypoxia and ischemia, followed by reperfusion and free radi-
Human Factors cal oxidative stress from hyperoxia [222].
A retrospective analysis from a single pediatric institution
The human dynamic in adverse events plays a significant investigated the role of human factors in 668 reported anes-
role in patient safety in the peri-anesthetic period. As stated thetic incidents, representing 2.4% of the total anesthetics
by Allnutt [208]: provided. The analysis concluded that human factors
accounted for 284 (42.5%) of the incidents with the two most
…all human beings, without any exception whatsoever, make
common errors being judgment and failure to check equip-
errors and that such errors are completely normal and necessary
part of human cognitive function. For a … doctor to accept that ment, tracheal tubes, and lines [18].
he or she is as likely as anyone else to make a catastrophic error The following processes decreased severe critical inci-
today is the first step towards prevention; whereas to claim dents of death and coma in a large, multicenter adult popula-
exemption on the grounds of being a … senior professor, … or
tion [223]; their implementation would be expected to have a
consultant [attending]…, is the first step on the road to disaster.
similar impact on safety in neonates:
The Institute of Medicine publications To Err Is Human
and Crossing the Quality Chasm identified the annual cost of 1. Routine use of an equipment protocol and checklist.
more than 40,000 lives and 2 billion dollars lost by the US 2. Availability of an anesthesiologist for additional help and
healthcare system due to failures of safety and quality [209, insight.
210]. This information has prompted dramatic quality 3. Use of full-time anesthesia team members.
improvement initiatives, including in the practice of pediat- 4. Presence of two anesthesia team members at emergence
ric anesthesiology [211]. Over 30 years ago, the 1989 and transfer.
5. Reversal of muscle relaxants at the end of an anesthetic perioperative period reported to the UK National Reporting
before extubation. and Learning System over 3 years revealed that medication
issues predominated at 35.6%, nearly double the next closest
In addition to checklists, targeted feedback and updating category, airway, and respiration at 18.8% [111]. The major-
protocols decrease the role of human factors in adverse ity of these were administration errors, including unintended
events [18]. Recognizing that anesthesia provider who is dis- additional dosing in which an anesthesiologist was one of the
tracted is a patient safety hazard, a 2017 process improve- healthcare professionals involved but may not have made the
ment project implemented at the Vanderbilt University error. As this review included the hospital course, a greater
Medical Center decreased environmental distractions such overall percentage of medication errors points to increased
as music, loud noises, and unnecessary conversation during concerns for appropriate perioperative communication
induction of anesthesia in pediatric otolaryngology ORs between healthcare providers during the transition from the
from 61% to 10% [224]. OR to the postanesthesia care unit and intensive care unit.
A 2016 review of the Wake Up Safe database revealed
that medication errors were the third most frequent category
Medication Errors of events only behind cardiac- and respiratory-related events.
Errors during administration accounted for 65% of medica-
Human factors play a pivotal role in medication errors. tion errors, and nearly 31% of the errors were due to admin-
Medication errors are among the most frequent critical event istration of the wrong dose, followed by an accidental syringe
in anesthesia and are underreported [225–230]. Anesthesia swap in 18%. Over 80% of the errors were conveyed to the
providers are unique in terms of managing medications, pre- patients, and more than 50% caused harm with 5% of the
scribing, identifying, dispensing, calculating, diluting, pro- patients requiring a life-sustaining intervention. The review
graming, administering, and recording the drugs given, most determined that 97% of errors were likely or certainly pre-
often without verification by other personnel. Drug calcula- ventable [240].
tion errors have been reported by staff and resident anesthe- In 2017, the Pediatric Anesthesia Trainee Research
siologists [231–233]. The incidence of drug errors in Network conducted a survey of 162 anesthesia trainees and
anesthesia is 1–5%, with untoward outcomes reported staff, of whom 60% described they made pediatric drug
including death [226, 231]. In 2010, the Anesthesia Patient errors at least once a year and 15% reported an error at least
Safety Foundation convened a summit that produced a new once a month [229]. Of those surveyed, 36% stated that they
paradigm of standardization, technology, pharmacy/pre- would only report drug errors if they resulted in patient harm,
filled/premixed, and culture to reduce drug errors in the OR which limits individual and systemic education from unre-
area [231]. ported near-miss events. Drug calculation and dilution errors
Despite recent advancements in neonatal pharmacokinet- constituted half of all reported errors, while 16% resulted
ics, pharmacodynamics, and clinical outcome measures, sig- from failure to flush the intravenous catheter, and 11% were
nificant knowledge gaps persist [234–238]. Neonatal dosing due to administering the wrong drug. Evaluation of drug
requires dose calculation and administration of drugs from dilution performed by pediatric anesthesiologists revealed
concentrations and volumes that are generally manufactured that irrespective of the practitioner’s experience, the mea-
for adults. Developmentally immature organ and metabolic sured drug concentration is in error by >10% from the tar-
processes in the neonate, amplified in the preterm neonate, geted concentration in 70% of the samples and > n 30% off
together with the lack of methods to measure medication the target in 23% of the samples [241]. These data support
effects quickly and reliably, contribute to the complexity of the use of standardized, prefilled syringes for neonates,
determining appropriate doses and dose frequency. A variety infants, and children.
of disease states further alter metabolism during complex A single-institution, retrospective study showed the rate
and high-risk procedures that demand rapid decision-making of medication errors in pediatric anesthesia started at 7 per
and intervention. 10,000 cases and then, after implementing a series of inter-
Research indicates that medication errors as a percentage ventions to decrease drug errors, decreased to 1.7 per 10,000
of incidents in pediatric anesthesia have remained relatively over 8 years [242]. In a prospective study from a single insti-
unchanged over the last three decades (~2% to 6%) [9, 15, tution that captured data from 73% of its cases over 3 months,
17, 18, 20, 24, 239]. Prior reviews of critical incidents in the authors reported a medication error rate of 264 per 10,000
pediatric anesthetic demonstrated that medication errors cases [243]. The results of a meta-analysis of medication
accounted for 4.4% of all errors, with anaphylaxis as the errors in pediatric anesthesia yielded an error rate of 8 per
most common event in this category [15]. In contrast, a 10,000 cases, a rate that was much less than the published
review of critical incidents in children during the extended data from adults, approximately 75 per 10,000 cases. As a
result, the authors expressed concern about the validity of the record (i.e., documentation of the medication administered
published research methods and the reliance on self-reporting and wasted) [255]. In addition to these “rights,” additional
of drug errors in pediatric anesthesia [244]. systems must be designed and implemented to further
Few studies have addressed the risks of medication errors diminish the chance of an error occurring. Methods to
specifically in neonates; however, the consequence of decrease medication-related errors can include stringent
adverse drug events may be significantly greater in neonates drug labeling on syringes and vials, barcoding all vials,
than older children [245]. In both neonates and children, the color-coding by class of drugs, removing dangerous drugs
incidence of drug errors is similar; however, the risk of a 10- from “open” anesthesia carts and drawers, and not storing
to 300-fold error has led to serious or potentially serious similar appearing drug containers near each other [15, 53,
adverse sequelae, which is particularly concerning given that 256]. Table 17.1 includes strategies to decrease the risk of
many drugs administered to neonates are off-label and medication errors in anesthesia, some of which are directed
incompletely studied [238, 246, 247]. Adverse and potential toward the individual practitioner since no system com-
drug events in the NICU as part of a larger study in a pletely eliminates medications errors [255]. In 2017, Seattle
university-affiliated pediatric occurred in 19 and 27 per 1000 Children’s Hospital instituted a project to reduce medication
hospital days, respectively, of which 14 adverse drug events errors [253] in which they identified 5 targeted countermea-
per 1000 hospital days were deemed preventable. sures that decreased the error rate from 1.56 to 0.95 per
Interestingly, the frequency of adverse drug events in the 1000 anesthetics: medication tray reorganization, medica-
NICU was less than the average for all hospital areas studied, tion top cart template, syringe labeling, infusion double-
with the pediatric surgical ward leading with the most events, check, and medication practice guideline posted in every
65 per 1000 hospital days [248]. In contrast, another study room.
reported that neonates in the NICU had the greatest risk of
calculation errors compared with older children [245]. A
recent review of medication errors and adverse events in the Table 17.1 Strategies to decrease medication errors
NICU showed that error rates varied from 4 to 35 per 1000 Labels
patient-days and from 6 to 78 per 100 medication orders with Similar packaging and presentation of medications should be
avoided where possible.
prescribing and medication administration errors as the most
The legibility and contents of labels on ampules and syringes
common medication errors and dosing errors the most fre- should be optimized according to agreed standards.
quently reported error subtype [249]. This study reported The label on any drug ampule or syringe should be read carefully
preventable adverse drug event rates were 0.9 per 1000 doses before a drug is drawn up or injected.
and 0.5–14 per 1000 patient-days in NICUs. Syringes should always be labeled.
The technique of administering bolus and continuous IV Organization
medications plays a central role in neonatal care. Undiluted Medication drawers and workspace should be formally organized
into a known and consistent template.
or minimally diluted formulations of bolus medications Any changes in presentation should be notified ahead of time.
result in small administration volumes (tenths of a milliliter), Potentially hazardous medications (e.g., concentrated epinephrine,
which can be easily lost or captured in the dead space of IV concentrated phenylephrine, insulin, bupivacaine) should be
tubing, syringes, and access ports, significantly delaying or separated, either visibly with specific colors or another identifier or
decreasing the intended drug effect. This can also lead to spatially from those that are routinely used.
Strongly consider designating a pharmacist to the operating
accidental dose stacking with risk for ensuing complications. theaters.
The administration of extra or even excessive volume may Calculations
occur when more diluted infusions are used or with the need Reduce calculation errors by accessing weight-based references,
for repeated medication flushes [250, 251]. Only preservative- and integrate systems that provide such support.
free flush solutions should be used for neonates to prevent Resources need to be allocated to employ prefilled syringes in the
the excessive accumulation of potentially toxic preservatives appropriate concentrations for neonates rather than individuals
diluting concentrated medications.
such as benzyl alcohol [250, 252]. The setup of the IV and
Independent double-checks
infusion lines together with the drug concentration and flow Labels should be checked with a second person or with a device
rates plays an important role in the lag time to achieve (such as a barcode reader linked to a computer) before any
steady-state blood concentrations of the drug and in the medication is prepared or administered.
amount of drug in the system architecture that may be avail- Medication infusions require a second individual to verify
concentration and dose.
able for an inadvertent bolus [251].
Reporting
Systematic countermeasures should aim to decrease the
Errors in intravenous drug administration during anesthesia should
number of drug administration errors in anesthesia. The “six be reported and regularly reviewed to identify areas for
rights” of medication administration to avoid errors are veri- improvement, both individual and systemic.
fying the correct patient, dose, medication, time, route, and Adapted from the following references: [226, 228, 240, 253–255]
Another key strategy to prevent drug errors is to add mul- revealed that clinicians override most alerts, resulting in
tiple barriers to the error pathway such as standardized inappropriate overrides 40% of the time, although more
concentrations for continuous infusions, standardized pack- than 75% of the overrides on warnings of significant harm
aging of pediatric medications rather than relying on adult were inappropriate [266].
formulations, prefilled syringes, use of barcodes to verify Despite decades of recognizing drug errors in anesthesia
medications before their administration, and reengineering as a substantial patient safety issue, there has been insuffi-
drug delivery systems such that intravenous, intra-arterial, cient progress in reducing medication errors and insufficient,
and regional syringes or infusion lines cannot be inter- robust studies to uncover the complex mechanisms involved
changed [53, 256, 257]. Ready-to-administer products such and the potential solutions. When institutions, industry, and
as prefilled syringes have been found in a recent study to be regulatory agencies mandate that the formulation, distribu-
associated with significantly fewer errors than traditional IV tion, and administration of pediatric and neonatal medica-
injection practices [258]. Barcode assisted labeling systems tions are standardized, and clinicians are given support to
have improved medication safety in the ORs [259], emer- implement the updated, standardized systems at the bedside,
gency departments [260], and inpatient units [261–263], only then will adverse drug events finally be harnessed and
although further study in the OR environment is warranted. substantially reduced.
As with most solutions to complex problems, these steps are
likely to add extra costs while still requiring the provider to
remain fully engaged and diligent. Equipment-Related Incidents
In 2014, an observational, single-institution study on
weight-based infusion calculations in children reported that Equipment-related incidents in pediatric anesthesia contrib-
only 15% of the written responses were error-free and the ute a small but important role in adverse or “near-miss”
observed mean time for the calculation exceeded 3.5 min events. Comparing the outcomes from studies is difficult
[264]. The calculations ranged from 50 times too small to because some only report critical events and others report
56 times too large of the correct dose. In 2019, a study both critical and potentially critical events. The actual defini-
involving seven academic training institutions in the United tion of equipment-related incidents is not always stated or
States explored computational drug error rates by anesthe- consistent among the studies. Pediatric closed claims cases
siology residents and faculty by administering a written in the United States [10] and the Australian Incident
test. They identified a mean error rate of 17%, with the Monitoring Study [11] reported that equipment-related
more junior residents and more experienced faculty both events comprised 13% and 14% of total claims or incidents,
making more frequent errors, with the magnitude of the respectively. In a more recent pediatric closed claims analy-
residents’ errors more extreme than the other groups. Only sis, equipment-related issues were cited in 15% of claims
20% of residents and 25% of faculty correctly answered all [22]. Data from the POCA registry from 1994 to 1997 and
of the questions [233]. 1998 to 2004 reported equipment-related events in 7% and
Considering the narrow therapeutic index of many anes- 5% of total events, respectively, with central venous catheter
thetic drugs, the occasional 10-fold to 1000-fold computa- complications the most frequent complications followed by
tional errors observed in this study suggest the need for a problems with the tracheal tube or breathing circuit [13, 19].
process improvement initiative to decrease this risk. The POCA registry also reported the rate of equipment-
Suggested mechanisms have included didactic sessions and related arrests as 9% in children with congenital heart dis-
testing in computational competency as core requirements ease [25]. A review of critical incidents affecting or
for anesthesiology residents [265]. A study of 277 anes- potentially affecting the perioperative anesthetic manage-
thetic cases at the Massachusetts General Hospital reported ment in children under 16 years of age reported to the UK
a drug error or adverse drug event rate of 1 in 20 medica- National Reporting and Learning System from 2006 to 2008
tions administered [226]. The most common type of error showed equipment-related incidents to be 15.7% of the total
identified was improper drug labeling. The event rate across without any associated deaths or reports of severe harm
house staff, CRNAs, and attending anesthesiologists did not [111]. As this review included potential harm, the greater
differ significantly, which suggests that these errors are not rate is not surprising even though venous access complica-
simply attributable to a lack of experience or to distracted tions were not included in the equipment category.
care providers. These data support the exploration of tech- Equipment-related events in institutional or multi-
nologies designed to enhance safety in the OR, where institutional studies ranged from approximately 1% to 10%
redundant, multiple checks before drugs are administered of total events reported [8, 15, 17, 18, 20, 43]. Most of these
remain an uncommon practice. An analysis of allowing involved the anesthesia machine or the breathing circuit and
overrides of medication-related decision support alerts tracheal tube.
Addressing Risks and Adverse Events The Task Force for Children’s Surgical Care convened its
first meeting in May 2012, originally with representatives
Ideally, reconstructing the course that led to a critical inci- from several pediatric surgical disciplines and the Society for
dent such as with a root cause analysis may provide a broader Pediatric Anesthesia. It was subsequently expanded to
overview of the processes that combined to result in an include additional representatives from the full array of pedi-
adverse event. Prospective collection of such information for atric surgical specialties as well as neonatology, pediatric
adverse events is essential yet exceedingly difficult, particu- radiology, pediatric critical care, and pediatric emergency
larly for rare events. Analysis of the contributing factors medicine. The task force produced a white paper [270] and
should then lead to strategies and tactics to manage and con- consensus statement [215] which stated that neonates are a
trol potential safety threats, to improve safety and outcome. pediatric subpopulation with differential outcomes in spe-
As neonates are a high-risk anesthetic population and are at cialized versus nonspecialized surgical environments. The
greater risk for perioperative complications [53], both insti- task force unveiled the Children’s Surgery Verification pro-
tutional and individual stakeholders must focus on identify- gram in January 2017 with the intent of establishing multi-
ing the root causes of adverse events and developing disciplinary standards for pediatric perioperative care [267].
outcomes research to appropriately implement or modify Hospitals applying for verification are designated as Level I,
processes to prevent or reduce their occurrence [53]. II, or III based on resource allocation, such as the on-site
Stakeholders must also critically review findings to appropri- presence of pediatric anesthesiologists and other pediatric
ately address patient safety during anesthesia, which may surgical and medical subspecialists. The American Society
require implementing new strategies or redeploying resources of Anesthesiologists has expressed concern that this program
[219, 223]. may have the unintended consequence of reduced access to
Optimizing patient care by verifying anesthetic equip- care and increased burdens on families, particularly in rural
ment and medications with appropriate dilutions, labels, and areas [271]. The Global Initiative for Children’s Surgery was
double-checks before induction is essential and should be formed to help low- and middle-income countries to develop
routine. Setting parameter limits and appropriate alarms is and implement regional- and national-based standards in an
vital in such a complex environment. As anesthesia informa- attempt to optimize care for pediatric surgical patients, which
tion systems, monitors, machines, and equipment advance in also will improve surgical and anesthetic care for neonates
capacity and integration, preset alarm limits based on the age globally [272, 273].
of the child and adjusted for various periods of an anesthetic Although medical errors are classically associated only
could be tied to an anesthesia information management sys- with patient harm, a spectrum of consequences may occur
tem such that as the case progresses from induction to emer- with a medical error ranging from tangible harm to real ben-
gence, so do appropriate alarms settings. Concerning alarms efit. Many medical errors have no positive or negative patient
can also be forwarded to all providers covering the case via impact and might be referred to as a near miss, whereas a
the institution’s integrated communication system to alert smaller yet not insignificant number have important conse-
those not at the bedside. quences. In an unplanned extubation after a surgical proce-
Asking for help, either by a consultation with another dure, wherein the patient remains safely extubated, the
pediatric anesthesiologist or having an extra team member patient may indeed benefit from both the medical errors of
present when needed, is an excellent strategy to decrease planning, i.e., inappropriate continuation of mechanical ven-
adverse events [223]. Providers who are specifically trained tilation, and execution, i.e., unplanned extubation. Learning
for and experienced in high-risk subpopulations can decrease from the unexpected and even beneficial consequences of
the risk of adverse events [12, 215–217, 219, 221, 267, 268]. medical error may improve the quality of care and aid in
This holds true for all areas of care, from the preoperative to redefining optimal care [274].
the postoperative setting. Practitioners must engage in self- Incident reporting systems are patient safety mechanisms
reflection and seek feedback. Institutions and departments that are capable of identifying risks and improvement oppor-
must provide mechanisms and processes for feedback such tunities. While they can be a valuable tool for gathering inci-
that the appropriate steps may be taken to understand and dent data, underreporting remains a major limitation likely
prevent further mishaps. Continuing medical education and due to barriers such as concern for punitive repercussions,
implementing evidence-based practices are essential to feelings of incompetence, insufficient understanding regard-
maintain skills and provide safe, appropriate care, for exam- ing what constitutes an event, lack of feedback, and the per-
ple, by incorporating the Enhanced Recovery After Surgery ception of irrelevance of reporting. An analysis of
guideline for surgical neonates which included 17 recom- perioperative adverse events reported by pediatric anesthesi-
mendations developed by an international team using a rig- ologists determined that these barriers were optimally
orous, evidence-based, consensus-driven process [269]. addressed through education, encouraging reporting as part
of a culture of safety, feedback from those reporting, and from the interaction between humans and complex systems,
increasing the involvement of anesthesiologists in patient Wake Up Safe aims to improve the quality of delivered care
safety initiatives [239]. Clinical outcomes research must pro- by designing safer systems. The database resulting from this
ceed with the goal of identifying common parameters to process has already led to published advisories regarding
measure, maintaining universal definitions for parameters wrong-site procedures, medication errors, and cardiac arrest
and their assessment, and aggregating data from multiple associated with blood transfusion in young children [47].
sources to better assess both the more common minor adverse As pediatric anesthesiology designs, studies, and imple-
events and the rare yet potentially devastating major events. ments high-reliability science to move toward reducing error
Many organizations are advancing this ideal including the rates, simulation is playing a prominent role [279–284].
Society for Pediatric Anesthesia, through its support of vari- Simulation can provide an excellent learning environment
ous safety registries and collaboratives (Table 17.2). without putting patients at risk. Simulations can help teams
WUS member institutions apply a root cause analysis prepare for events, practice new models of care, as well as
model to serious safety events that result in moderate to uncover and address individual, team, and system
severe patient harm, precursor safety events that reach the vulnerabilities.
patient but result in minimal or no detectable harm, as well Helping practitioners avoid cognitive errors is essential to
as near-miss safety events that do not reach the patient [278]. avoid errors during patient care [285]. Cognitive aids provide
The goals are to identify how the event occurred (active benefit in ORs for routine processes including the presurgi-
error) and why the event occurred (latent error) and then to cal time-out such that there are reasons to anticipate their
prevent future errors. Recognizing that errors often result benefit during critical events [286]. Checklists increase both
the accuracy and speed of responses during critical events
that may otherwise be limited by cognitive-processing limi-
Table 17.2 Selected organizations dedicated to improving the anes-
thetic care of pediatric patients tations and confusion [287, 288]. A study on the implemen-
Society for Pediatric Anesthesia (SPA)
tation of an emergency manual conducted from 2013 to 2016
https://www.pedsanesthesia.org/ at a large academic anesthesia practice found that anesthesi-
Sections ology attending physicians, resident physicians, CRNAs,
Congenital Cardiac Anesthesia Society (CCAS) – ccasociety.org and SRNAs using their institution’s customized version of
Pediatric Regional Anesthesia Network (PRAN) [275]: pranetwork. the Stanford Emergency Manual consistently performed bet-
org ter in the verbalization of critical actions during simulated
Society for Pediatric Pain Medicine (SPPM): pedspainmedicine.org crisis events [289]. However, a review of anesthesia-specific
Wake Up Safe [45, 47, 49, 118, 240, 276]: wakeupsafe.org
checklist found them limited and heterogeneous [288]. To
SPA Pedi Crisis Critical Events Checklist (SPA Quality & Safety
Committee) [277]: https://www.pedsanesthesia.org/ address the need for cognitive aids, the Quality and Safety
critical-events-checklist/ Committee of the Society for Pediatric Anesthesia developed
Special Interest Groups the SPA Critical Event Checklists (SPA-CECs) [290].
Biomedical Informatics & Technology The evolving field of clinical genomics is expected to
Pediatric Craniofacial Collaborative Group (PCCG) [139, 142–144] improve the diagnosis of and care for critically ill children
Pediatric Critical Care Medicine including neonates as many may have undiagnosed, underly-
Pediatric Difficult Intubation Collaborative (PeDI Registry) [41]
ing genetic conditions [291, 292]. The Australian Genomics
Pediatric Liver and Intestinal Transplant (PLIT)
Acute Care Study showed the feasibility and blueprint of
Pediatric Perioperative Surgical Home
Simulation
implementing ultrarapid genomic testing in critically ill
Task Force for Children’s Surgical Care infants and children of which 57% were from NICUs [293].
Children’s Surgery Verification (CSV) Quality Improvement They found the ultrarapid genomic testing influenced the
Program clinical management in 87% of tested patients. Hopefully, an
https://www.facs.org/quality-programs/childrens-surgery/ improved ability to rapidly diagnose neonates with previ-
childrens-surgery-verification ously unconsidered genetic conditions will allow more tar-
Optimal Resources for Children’s Surgical Care
geted anesthetic and surgical care and decrease the potential
International Anesthesia Research Society
for adverse events.
Smart Tots: https://smarttots.org/
American Society of Anesthesiologists Adverse events must also be studied by utilizing multidis-
Anesthesia Quality Institute: https://www.aqihq.org/introduction-to- ciplinary improvement measures that identify not only
nacor.aspx specialty-specific factors but also specialty-related and
American Academy of Pediatrics shared factors [214]. For any of these to be achievable, the
Section on Anesthesiology and Pain Medicine: https://services.aap. development of uniform pediatric standards, central pediat-
org/en/community/aap-sections/anesthesiology-and-pain-medicine/
ric registries, appropriate benchmarks, and a robust infra-
structure must occur. To borrow from Peter Davis and the 7. Olsson GL, Hallen B. Cardiac arrest during anaesthesia. A
national security and intelligence communities, only then computer-aided study in 250,543 anaesthetics. Acta Anaesthesiol
Scand. 1988;32(8):653–64.
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Perioperative Cardiac Arrest (POCA) Registry. Anesthesiology.
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Do Anesthetic Drugs Harm Neonates?
A Global Perspective 18
Tom G. Hansen, Steen W. Henneberg,
and Thomas Engelhardt
Table 18.1 Receptor activity of commonly used anesthetic agentsa

Introduction
NMDA GABA- μ-Opioid
Anesthetic agent antagonist mimetic agonist
There is still much to be discovered regarding how expo- Volatile anesthetics
sure to anesthesia affects the immature and developing Halothane −/0 +++ 0
brain. Given that the commonly used anesthetic agents Isoflurane −/0 +++ 0
exert their actions via N-methyl-D-aspartate (NMDA) and Desflurane −/0 +++ 0
gamma-aminobutyric acid (GABAA) receptors, it is bio- Enflurane −/0 +++ 0
logically plausible that exposure during periods of vulner- Sevoflurane −/0 +++ 0
able brain development may affect long-term outcomes Injectable anesthetics
(Table 18.1) [1, 2]. Propofol 0 +++ 0
The provision of anesthesia for surgery in neonates and Barbiturates 0 +++ 0
infants is a medical necessity. In addition to the humanitar- Etomidate 0 +++ 0
ian and ethical reasons to provide anesthesia, surgical and Benzodiazepines 0 +++ 0
Ketamine −−− −/0 0
medical procedures should be performed safely and effec-
Medical gases
tively, minimizing the stress of surgery [3]. However,
Nitrous oxide −−− +++ 0
numerous studies in newborn animals suggest that anesthet- Opioid analgesics
ics lead to both short-term and long-term neurological Morphine −/0 0 +++
changes [4, 5]. It is unclear whether this evidence translates Methadone − 0 +++
in whole or in part to the human experience given the physi- Meperidine −/0 0 +++
ological and developmental differences between animals Fentanyl −/0 0 +++
and humans. Studies of neurocognitive function in young Other sedative hypnotics
children after anesthesia are emerging slowly, and the results Chloral hydrate −−− +++ 0
from those studies demonstrate far less consistent and, in Trichloroethanol − − − +++ 0
some instances, directly conflict with those in newborn ani- Ethanol −−− +++ 0
mals. Translating the results of animal studies to the human Key: (− − −), strong antagonism within the clinically relevant range
clinical context is fraught with known pitfalls [6]. How do based on available in vitro data; (+++), strong potentiation within the
clinically relevant range based on available in vitro data; (−/0), little
antagonism within the clinically relevant range based on available
in vitro data; (+/0), little potentiation within the clinically relevant
T. G. Hansen (*) range based on available in vitro data; (0), no compelling data to sup-
Department of Anesthesiology and Intensive Care—Pediatric port activity at this site within the clinically relevant range
Section, Odense University Hospital, and University of Southern NMDA N-methyl-D-aspartate, GABA γ-aminobutyric acid
Denmark, Clinical Institute—Anesthesiology, Odense, Denmark Reproduced with permission from Mellon RD, Simone AF, Rappaport
e-mail: [email protected] BA. Use of anesthetic agents in neonates and young children. Anesth
S. W. Henneberg Analg 2007:104;509-20 [7]
Copenhagen University Hospital, Copenhagen, Denmark
a
Receptor activity as noted in the table does not imply mechanisms of
action; rather it indicates potential to neurological injury. The table was
Uppsala University, Uppsala, Sweden adapted, in large part, from reviews by Krasowski and Harrison (9) and
e-mail: [email protected] by Dilger (10); for more detail, please refer review articles
T. Engelhardt
Department of Anesthesia, McGill University Health Center,
Montreal Children’s Hospital, Montreal, Canada

582 T. G. Hansen et al.
various stages of brain development in animal models trans- subtypes, with the GABAA receptors themselves comprised
late into comparable stages in humans? Given the numbers of three of their subtypes, 𝛼, 𝛽, and 𝛾. Both NMDA and
of neonates, infants, and young children who are anesthe- GABAA receptors are integrally involved in mediating the
tized annually, if the animal evidence of neurocognitive dys- trophic factors that cause neuronal cell migration, differen-
function also held for humans, then these data would have tiation, proliferation, and dendritic maturation during this
already had demonstrable and significant effects on infants period. During rapid synaptogenesis, the NMDA receptors
and children together with widespread public health impli- are hypersensitive and if stimulated will trigger excitotoxic
cations. The subject of anesthesia-induced neurotoxicity in cell death. Additionally, they are indirectly involved in the
neonates, infants, and children continues to come under modulating trophic factors that mediate programmed cell
increasing scrutiny by both healthcare providers and the death or apoptosis, which is defined below. If during the
public after recent public health announcements from the same period the NMDA receptors are blocked, then apopto-
Food and Drug Administration (FDA) in the USA regarding sis will be activated. As the nervous system develops, an
the neurocognitive risks of anesthesia in infants and chil- abundance of neurons is formed. Those neurons that form
dren including the parturient [7, 8]. functional synapses and integrate fully into the neural net-
The purpose of this chapter is to summarize the available work survive, whereas those that fail in these respects are
scientific evidence regarding the effects of anesthetics on pruned by apoptosis [13]. As many as 50% of the cells in any
neurodevelopment in animals, summarize the current pre- one organ may undergo apoptosis during growth and devel-
clinical and clinical human data, highlight specific areas of opment, although only 1% of the cells undergo apoptosis at
concern in the clinical care we provide neonates and infants, any one time. Since most anesthetics either antagonize
and outline potential strategies that may minimize the poten- NMDA receptors or activate GABA-ergic receptors, the
tially harmful effects of anesthetics on neonates and young same receptors that mediate apoptosis, investigators discov-
children. ered totally by serendipity that massive neuroapoptosis
occurred in newborn rodents who were anesthetized for but a
brief period, uncovering a potentially serious and previously
Animal and Preclinical Data unforeseen risk of neurocognitive dysfunction after anesthe-
sia if the same held in humans. This discovery fostered an
Brain development begins with the embryonic period, from enormous number of investigations and funded research
conception until the eighth week of gestation [9]. At this activity that explored the how, when, and why this occurs
time, the major structures that form the central and periph- and its implications for humans. Below, we summarize those
eral nervous systems are completed. From 8 weeks to the end findings.
of gestation, this period of rapid brain development wit- The biologic phenomenon known as physiological cell
nesses the formation of cortical and subcortical structures death follows one of two paths: necrotic or apoptotic [14,
complemented by cellular changes that create major fiber 15]. Necrotic or excitotoxic cell death usually follows a trau-
pathways. Gyri and sulci form in sequence between 8 and matic, toxic (drug-related), or inflammatory event that causes
22–26 weeks gestation. Brain growth continues throughout the affected cell to swell and rupture, releasing its cellular
gestation and after birth, with the brain increasing fourfold in contents. The contents, which include inflammatory prote-
size during the preschool-age period, reaching 90% of adult ases and lysozymes, trigger an acute inflammatory process
size by 6 years of age. Throughout childhood and adoles- locally that causes characteristic edema, swelling, and
cence, both white and gray matter continue to develop. From inflammation well-known after head injuries. During the
the third trimester (27 weeks gestation) until 3 years of age, period of rapid synaptogenesis, this results from activation of
the period known as rapid synaptogenesis, extensive connec- NMDA receptors during the period of hypersensitivity. In
tions between neural cells explode with neuronal migration, contrast, programmed cell death or apoptosis is the orderly
synaptogenesis, and differentiation and maturation of the removal of ineffectual and redundant cells in an organ by
cells, all mediated by glutamate, the excitatory neurotrans- phagocytosis, preventing the release of intracellular enzymes
mitter. Both glutamate and GABA effect their actions in the that might trigger an inflammatory response. Apoptosis is a
nervous system via one of two receptors: ionotropic normal process that occurs during organ development in all
(ligand-
gated ion channels) or metabotropic (G protein- tissues including the brain. Central to distinguishing these
coupled) receptors. Here we focus on the ionotropic recep- two processes is the relative contributions of the NMDA and
tors. The ionotropic glutamate receptors are named after GABAA receptors. When NMDA receptors are stimulated or
their agonists: 𝛼-amino-3-hydroxy-5-methyl-4-isoxazole triggered during rapid synaptogenesis, a period of rapid
propionic acid, kainite, and NMDA (N-methyl-D-aspartate), growth of synapses in the brain results in excitotoxic cell
the last forming three subunits, NR1, NR2, and NR3 [10– death, whereas when these same receptors are blocked, they
12]. The ionotropic GABA receptors are comprised of eight trigger apoptotic cell death [16]. This latter phenomenon was
18 Do Anesthetic Drugs Harm Neonates? A Global Perspective 583
elegantly simulated by administering the NMDA-receptor ing on these two receptors. However, if GABAA receptors
antagonist, MK-801, which like ketamine led to widespread were activated and/or NMDA receptors were antagonized,
neuronal apoptosis, exceeding the naturally occurring apop- cells would undergo apoptosis. Thus, it appeared as if anes-
tosis by several orders of magnitude [1]. Additionally, inves- thetics could interfere with normal brain development, trick
tigators discovered that when GABAA receptors are activated, neurons that were not destined to undergo apoptosis, and
it also triggered neuronal apoptosis (Fig. 18.1). impair neurocognitive development, at least of the develop-
The earliest animal studies that reported anesthesia- ing newborn rodent. The importance of the activity of these
related neurotoxicity in the developing brain arose from nei- receptors during this period of rapid synaptogenesis cannot
ther clinical concerns nor anecdotal suspicions that general be overstated.
anesthesia impaired neurocognitive function in neonates. When these same researchers conducted parallel studies
Anesthetic-induced neurotoxicity was discovered by seren- on concussive brain injury in newborn rats, they surprisingly
dipity during studies of fetal alcohol syndrome and neuronal found widespread apoptosis in the brain contralateral to the
injury after head trauma in newborn rats [17]. Alcohol site of the excitotoxic head injury [18]. Suspecting that the
ingested during pregnancy is known to injure the brain of the anesthetic was responsible for these findings, they adminis-
developing fetus proportional to both the amount of and fre- tered NMDA-receptor antagonists to otherwise normal new-
quency that alcohol is ingested, as well as the timing during born rats and found widespread apoptosis in the brain [1,
pregnancy. Alcohol causes widespread apoptosis and neuro- 18]. They speculated that as in the case of alcohol, other
cognitive dysfunction by inhibiting NMDA receptors and/or NMDA-receptor antagonists such as ketamine and nitrous
augmenting GABAA-ergic activity. During the period of oxide could induce similar injury in the form of apoptosis in
rapid synaptogenesis, synaptogenesis is rapid, and dendritic the brains of human infants who received anesthesia. In addi-
spin density increases, with both of these processes depend- tion, they postulated that GABAA-mimetic anesthetics might
Fig. 18.1 Apoptotic
neurodegeneration occurs via Extrinsic pathway Intrinsic pathway
activating both the intrinsic
and extrinsic pathways. The
intrinsic pathway disrupts Death receptors
Intrinsic lethal stimuli:
synaptic signaling via NMDA (e.g TRAILR and FAS)
FADD DNA damage, ER stress,
receptor antagonists, which
hypoxia and metabolic stress
upregulates Bax and increases Pro-caspase-8 and
mitochondria permeability, pro-caspase-10 Mitochondrion
releasing cytochrome c into
the cytoplasm, which in turn
activates caspase-9 and then
caspase-3, the final common BH3-only
pathway to apoptosis. The BCL-2 proteins
alternate pathway is the BCL-XL or
extrinsic pathway, which MCL1
MOMP
triggers cell surface death Cytochrome c
Activated
receptors that activate FAS BAX and BAK
and FADD, which in turn
convert caspase-3 to its active
form, initiating apoptosis. Caspase-8 and
Inflammatory mediators such caspase-10
as TNF-alpha are one such BID tBID
mediator. Anesthetics may
activate this pathway via SMAC
GABAA, thereby activating APAF1
oligomerization Apoptosome
caspase-8, which then cleaves
caspase-3 and initiates
apoptosis. The final common
pathway and the most XIAP
important biomarker for the
Caspase-3 and Caspase-9
identification of apoptosis are
caspase-7
caspase-3 levels in tissues.
Downloaded from http:// Apoptosis
biologydictionary.net/
apoptosis/ (accessed July 12, Caspase-3 and
2021) caspase-7
also induce widespread apoptosis in humans [19]. Since In humans, the period of rapid synaptogenesis is thought
most anesthetic agents exert their anesthetic effects via to span development from the third trimester of pregnancy
antagonism of NMDA receptors and activation of GABAA- until 3 years of age [23, 26, 27]. However, the period of vul-
ergic receptors, researchers raised the biologically plausible nerability to anesthetics may well extend beyond this period
notion that the short- and long-term neurocognitive dysfunc- as evidence from animals suggests that rapid brain develop-
tion reported in newborn animals may cause similar effects ment or the period during which anesthetics may induce
in human neonates and infants during rapid synaptogenesis. widespread apoptosis may occur in stages, that is, some
More than 1000 studies that investigated the relationship regions of the brain (from the caudate nucleus to olfactory
between anesthetics and neurotoxicity in neonatal rodents, nucleus) are more vulnerable than others at specific times
mammals, and primates have been published. The majority throughout development [21]. Although investigators have
of these studies demonstrated that anesthetics impair cogni- focused on specific areas of the brain in rodents such as the
tive development in newborn animals. Here, we summarize thalamus, hippocampus, and dentate gyrus on PND7, other
the animal evidence regarding neurotoxicity during areas of the brain develop more slowly and may be affected
anesthesia. by anesthetics at later ages. The same almost certainly holds
for humans with the period of rapid synaptogenesis extend-
ing over a much greater period, possibly increasing the
At What Age Are Animals Particularly period of vulnerability to anesthetics in some parts of the
Vulnerable to or Safe from Neurocognitive brain beyond even the 3-year limit. Thus, if apoptosis exists
Effects of Anesthetics? in humans, it may be relevant not only during fetal exposure
but also during neonatal, infant, and throughout childhood.
Normal human brain development is a complex process that To compare the relative developmental ages of different
occurs over many years, which contrasts with the much- animals, data from core developmental stages in animals and
abbreviated brain growth in rodents and nonhuman primates. mammals were integrated into an up-to-date statistical model
Normally, neurons grow, migrate, and establish vital connec- known as “translating time,” which can be accessed for free
tions throughout the growth period, although those neurons at the website www.translatingtime.net [29, 30]. For exam-
that are identified to be redundant or nonfunctional are ple, the website indicates that the developmental stage of a
“pruned” and removed by a naturally occurring process rodent cerebral cortex at PND7 corresponds to the matura-
called apoptosis. During rapid synaptogenesis or rapid brain tional stage of the human brain at the very beginning of the
growth spurt, exposure to compounds that interact with third trimester [29, 30]. Hence, studies of anesthetic-induced
NMDA or GABAA receptors is known to trigger apoptosis at apoptosis and neurocognitive dysfunction in PND7 rodents
rates that exceed the naturally occurring pattern or interrupt correspond to anesthetizing preterm neonates. However,
dendritic arborization, which results in nonfunctional neuro- rapid synaptogenesis is not a homogeneous process, affect-
nal connections by several orders of magnitude. If extensive, ing all areas of the brain similarly at the same time. Thus,
this leads to neurocognitive impairment in the short term as translating the animal evidence to humans fails to account
well as long term into adulthood [20]. The age at which ani- for the fact that different areas of the brain undergo rapid
mals are particularly vulnerable to blockade of NMDA growth and pruning at different times throughout early child-
receptors or activation of GABA-ergic receptors, i.e., during hood. In contrast to research in animals where brain biopsies
the period of rapid synaptogenesis, varies among animals. In and cellular and subcellular brain studies are possible,
the case of young rodents, rapid synaptogenesis occurs research in humans is limited to test only functional human
between postnatal days (PND) 4 and 10, with the maximum responses for ethical reasons.
vulnerability reported to be on PND7 [21]. Evidence sug- To date, no clear cutoff (translated) age can be identified
gests that anesthetics induce apoptosis via blockade of at which there is no risk of structural or functional abnor-
NMDA blockade or GABA-mimetic activity by triggering malities. Thus, if this problem exists in humans, it may not
both the intrinsic and extrinsic intracellular pathways, with only be relevant to intrauterine exposure but go beyond early
the former activated earlier than the latter [21]. In rhesus infancy.
monkeys, this period of greatest synaptogenesis corresponds Similarly, no defined duration of exposure can be identi-
to the period from the third trimester until PND35 [3, 22, fied in in vivo animal studies. These studies examine sub-
23]. In terms of the GABAA receptor, some evidence sug- stantially longer exposure times than ever necessary in
gests that neurocognitive impairment is more likely to occur clinical practice and suggest abnormal structural and detri-
in early development while GABA is an excitatory neu- mental cognitive outcomes after prolonged exposure includ-
rotransmitter rather than in later development when it is ing in nonhuman primates [21, 24, 25, 31–35]. The need to
inhibitory. In humans, this occurs prenatally whereas in rats, either combine or separate interventions also remains
it occurs at approximately PND7 [8, 21, 24, 25]. unanswered.
oes the Duration of Exposure Impact Long-

D sum, the effects of the potentially neurotoxic anesthetics
Term Effects? depend on the dose, duration, and frequency of administra-
tion to maximize their proapoptotic effects and neurocogni-
The minimum duration of exposure to putative anesthetics tive impairment.
beyond which widespread apoptosis occurs has not been Ketamine. Ketamine, the best known NMDA-receptor
defined in newborn animals, but the evidence shows that antagonist, has been extensively studied in newborn animals.
brief exposure to proapoptotic anesthetics including It causes widespread apoptosis and neurocognitive dysfunc-
ketamine and sevoflurane does not trigger widespread apop- tion [22, 38, 43]. However, the dose of ketamine (as well as
tosis, even in PND7 rodents [36]. In most animal studies, most other intravenous anesthetics) required to induce anes-
anesthesia was administered for periods two- to threefold thesia in animals is five- to tenfold greater than the dose in
greater than the duration of most anesthetics in human humans [38, 44]. For example, the plasma concentrations of
infants <1 year of age [32, 37–42]. We speculate that the ketamine that induce anesthesia in newborn animals, 14 μg/
purpose of exposing newborn animals to prolonged anesthe- mL, are five- to tenfold greater than those in humans, 2–3 μg/
sia was to achieve extensive apoptosis and ensure cognitive mL [44]. Since these large doses of ketamine are required to
impairment to report neurocognitive dysfunction, irrespec- induce anesthesia in animals, the same doses were adminis-
tive of its relevance to the human anesthetic experience. tered to assess the severity of the apoptosis and neurocogni-
Moreover, anesthetics induce the maximum harm to the tive dysfunction in newborn animals; whether these same
brains of newborn animals if it is administered during the effects are present in neonatal humans at much smaller doses
most vulnerable period of brain growth, the period of rapid of ketamine has not been forthcoming.
synaptogenesis. The duration of synaptogenesis in newborn In rats, when ketamine was given on PND7 and repeated
rodents is approximately 1% of that in human neonates, ren- thereafter, it caused neurodegeneration and apoptosis [44]
dering these precocial rodents/animals much more vulnera- within the laterodorsal thalamic nucleus of rats. Indeed, the
ble to the effects of anesthesia on synaptogenesis than in apoptotic effects of ketamine likely are regionalized to the
humans. limbic areas of the brain as NMDA receptors are highly
expressed in this region of the brain in PND7 rats [45].
Ketamine exerts multiple effects in the hippocampal dentate
Do All Anesthetic Agents Cause gyrus including inhibiting neuronal differentiation, prolifer-
Neurocognitive Dysfunction? ation, and migration, which may explain how ketamine given
to newborn rodents on PND7 leads to neurocognitive dys-
Except for xenon, opioids, neuromuscular blocking drugs, function in adult rodents [46]. In the long term, a single dose
and possibly alpha2 agonists, all other anesthetic agents of 20 mg/kg s/c ketamine in PND7 rats not only causes apop-
cause neuroapoptosis as well as neurocognitive dysfunction tosis in the hippocampus within 24 h but leads to impaired
in the brains of animals from newborn rodents (mice, rats, short-term memory and enhanced motor performance in
and guinea pigs) to nonhuman primates and mammals. In adults [47]. In mice, ketamine-induced apoptosis depended
animals, a single anesthetic exposure may be insufficient to on both age and activity, the latter attenuating the severity of
trigger massive apoptosis or demonstrable short- and long- the apoptosis and resultant neurocognitive dysfunction as
term neurocognitive changes, but when multiple drugs are has been reported in other models [48]. In rhesus monkeys
administered concurrently or larger doses are administered between PND5 and PND35, ketamine-induced neuronal cell
over a period, the probability that they cause neurocognitive death depended on age and the duration of exposure [38, 39].
changes increases dramatically. Hence, exposing children to Specifically, when ketamine was infused for ≥6 h, neurocog-
a single putative anesthetic may not cause neurocognitive nitive changes were demonstrable; however, when it was
dysfunction at least in small doses, whereas when exposing administered for ≤3 h, there was no evidence of apoptosis
them to a combination of anesthetics, either repeatedly or [40]. In fetal macaque exposed to ketamine infusion for 5 h,
after prolonged exposure, the severity of the defect increases apoptosis was 2.2-fold greater than it was in the neonatal
substantively. brain [24]. A single 24-h exposure to a ketamine infusion in
PND5 or PND6 monkeys demonstrated neurocognitive dys-
Intravenous Anesthetics function for up to 3.5 years of age [49]. Interestingly, ket-
With the exception of the alpha2 agonists, all intravenous amine demonstrates antiapoptotic and anti-inflammatory
anesthetics can cause neuroapoptosis and neurocognitive roles via some growth factors (known as neurotrophins)
dysfunction in newborn animals by their known interactions attenuating neurocognitive impairment after isoflurane expo-
with NMDA and GABAA receptors. These putative anesthet- sure [36]. Consequently, it is difficult to translate the neuro-
ics confer their effects on neuronal tissue in similar regions apoptotic effects of large doses of ketamine for prolonged
of the central nervous system and by similar mechanisms. In periods in rodents to humans, who require but a fraction of
the dose for a relatively brief period to achieve comparable peritoneal for 5 days demonstrated no response at 50 mg/kg
levels of anesthesia for surgeries. in a single daily dose, whereas the larger doses (100 and
Benzodiazepines: Enhancing the gamma-aminobutyric 150 mg/kg) did upregulate cytokines and impair cognition
acid at GABAA receptors also increases neuronal apoptosis [58]. Repeated but not single doses of IP propofol in mice
and impairs neuronal differentiation [22]. Examples of ani- PND7–PND11 impaired neurocognitive and behavioral
mal studies that demonstrate this include a study which abilities in adulthood [59]. The contribution of hypoxia to
showed that midazolam blocks calcium oscillations, which propofol-induced apoptosis should not be underestimated.
themselves mediate neuronal differentiation and In PND7 mice, 18% oxygen exacerbated the severity of
synaptogenesis. The net effect is reduced synaptic integrity apoptosis and cognitive learning deficits compared with
[50]. When diazepam was administered to rats on PND7, it those who remained normoxic [60]. Quantifying the loca-
induced widespread apoptotic neurodegeneration [51]. In an tion of apoptosis in monkeys revealed an age-related effect:
early study, midazolam in a dose of 3–9 mg/kg or nitrous exposing the fetus to propofol resulted in apoptosis in the
oxide 50–150% failed to induce widespread neuroapoptotic subcortical and caudal regions of the brain, whereas expos-
degeneration, whereas when midazolam was followed by ing the newborn monkey resulted in apoptosis in the neocor-
0.75% isoflurane or combined with ketamine (≥20 mg/kg), tical regions [32]. Overall the severity of the apoptosis after
widespread apoptosis ensued [2, 43]. 5 h of propofol was less than comparable doses of isoflurane
Propofol: Propofol exerts both NMDA-receptor antago- [61]. A recent study suggested that the addition of propofol
nism and GABAA-ergic potentiation (as well as activation of to a ketamine anesthetic attenuates ketamine-induced cogni-
GABAA receptors at larger concentrations). In newborn ani- tive dysfunction [62]. Several factors may affect the extent
mals, propofol causes widespread apoptosis, impaired neu- of apoptosis during propofol anesthesia. Propofol, particu-
ronal differentiation, and behavioral changes compared with larly in repeated doses in newborn rodents and monkeys,
no anesthesia [22, 32]. In PND7 mice, 6 h of IP propofol was triggered apoptosis and impaired cognition that persisted
more likely to cause apoptosis in the cerebral cortex and hip- into adulthood.
pocampus than in other regions of the brain [52]. Apoptosis α2 agonists: α2 agonists are not proapoptotic anesthetics
occurred only in neurons, but not in astrocytes, oligodendro- because they neither antagonize NMDA receptors nor poten-
cytes, or neural stem cells. In PND5 and PND7 rats, repeated tiate GABAA receptors but exert their actions on the locus
doses of propofol for three consecutive days triggered sig- coeruleus (specifically the ventrolateral preoptic nucleus) via
nificant decreases in dendritic spine density in the hippocam- α2 receptors and the sympathetic nervous system [63]. α2
pus that persisted into adulthood with cognitive deficits [53, agonists are neuroprotective (via intracellular brain-derived
54]. A single dose of 50 mg/kg intraperitoneally in PND7 rat neurotrophic factor), and in the presence of proapoptotic
pups yielded apoptosis and cognitive deficits on PND9, anesthetics such as isoflurane or midazolam in PND7 rats,
whereas multiple doses induced significant neuronal apopto- they attenuate the severity of the apoptosis by increasing
sis and synaptic loss at PND9 to PND35 and spatial learning Bcl-2 (B-cell lymphoma/leukemia-2 regulatory proteins)
and memory impairment at PND36 to PND41 [55]. In PND5 and expression of the mitogen-activated protein kinases
rats anesthetized with propofol for 6 h, structural changes in (MAPK), JNK (c-Jun N-terminal kinase), P38 MAPK, and
neural circuitry (dendritic arborization and synaptogenesis) ERK (phosphorylated, extracellular signal-regulated protein
occurred during rapid synaptogenesis [31]. Repeat dosing of kinase) [63–65]. In a systematic review of the neuroapop-
propofol to PND7 rats induced greater apoptosis (in the cor- totic effect of dexmedetomidine in animals, dexmedetomi-
tex and hippocampus) and neuronal loss as well as learning dine did not cause apoptosis but attenuated the injury of
and memory deficits compared with a single exposure [56]. coadministered proapoptotic agents [66]. α2 agonists attenu-
To define the timing of maximum apoptosis during propofol ate sevoflurane, isoflurane, and propofol-induced apoptosis
administration in mice brain, continuous caspase-3 activa- in newborn rats by upregulating Bcl-2 expression and revers-
tion was measured in hippocampus CA1 neurons in vitro ing the proapoptotic suppression of Bcl-2 [67–70].
[57]. Caspase-3 activation was significant 5 h after the start Dexmedetomidine exerts a biphasic effect on neurotoxicity:
of exposure and not before. It is tempting to conclude that in PND7 rats, small or clinically relevant doses of dexme-
activation of apoptosis is a time-dependent process that detomidine 50–100 μg/kg intraperitoneally (IP) alone was
requires a startup period that may exceed the duration of not proapoptotic, whereas large doses ≥250 μg/kg IP over
anesthetic exposure in most surgeries in neonates and young 6 h was proapoptotic, similar to ketamine alone [71]. In addi-
children. If this holds in humans, it may explain the rarity of tion, dexmedetomidine did not attenuate ketamine-associated
adverse neurocognitive outcomes in humans. The cytokine apoptosis. These results are consistent with the neuroprotec-
(inflammatory, caspase-3) and apoptotic responses in the tive effects of small doses of dexmedetomidine (1 μg/kg IP)
hippocampus in PND7 rats who underwent appendectomy during sevoflurane anesthesia reducing the severity of the
or sham surgery to propofol between 0 and 100 mg/kg intra- apoptosis by 84% in the thalamus and 50% in the hippocam-
pus and cortex, but increasing mortality with larger doses Studies of IV fentanyl with or without xenon in newborn
>5 μg/kg IP [72]. In contrast, repeat doses of dexmedetomi- pigs failed to produce evidence of apoptosis (using caspase-3
dine up to 20 μg/kg IP during sevoflurane or even 100 μg/kg immunostaining) after a 24-h infusion of fentanyl [85].
IP 2-hourly failed to substantively attenuate apoptosis in However, a subsequent study documented apoptosis in the
PND7 rats anesthetized with sevoflurane in other studies [73, cerebellum of newborn pigs after a similar infusion [86].
74]. Dexmedetomidine also attenuates propofol-induced Remifentanil is known to induce postoperative hyperalge-
apoptosis and neurocognitive impairment in newborn rats sia, an effect mediated through μ-opioid receptor activation
[36]. The inconsistency of the effects of dexmedetomidine of NMDA receptors [87]. Hence, it follows that during rapid
among these studies raises questions regarding the use of the synaptogenesis, remifentanil (which contains glycine) may
neonatal rat as a model to extrapolate its effects on vulnera- promote necrotic and/or apoptotic cell death in vulnerable
ble infants and children [75]. animals. In PND2 mouse brain slices ex vivo, a 5-h infusion
Clonidine, an older α2 agonist with less affinity for the α2 of remifentanil increased necrotic cell death in the deep lay-
receptor than other α2 agonists, shares many of the effects of ers of the neocortex and decreased apoptosis in the superfi-
dexmedetomidine. Similar to dexmedetomidine, clonidine cial immature layers [87]. Remifentanil decreased both the
also confers neuroprotective effects in at least one preclinical intrinsic and extrinsic apoptotic pathways as evidenced by
study [76]. the caspase-3, caspase-8, and caspase-9. The effects of remi-
Opioids: Opioids act via mu, kappa, and delta receptors fentanil on apoptosis have also been studied in the presence
to exert their primary action, not on NMDA or GABAA of isoflurane anesthesia in newborn (PND7) rats. Remifentanil
receptors. However, some cells in the central nervous system did not augment apoptosis during isoflurane anesthesia but
such as oligodendrocytes express opioid receptors and thus demonstrated neuroprotection in the hippocampus [88].
may respond to opioids if they are administered during peri- Hence, acute, brief exposure to opioids during anesthesia
ods of rapid growth. and the perioperative period likely holds minimal risk for the
Methadone and buprenorphine cross the placenta expos- neonate. Further research is warranted to identify the possi-
ing the fetus to opioids. Prenatal exposure to methadone has ble neurocognitive effects of prolonged exposure to opioids
been associated with microstructural changes in major white in neonates.
matter tracts in the fetus at birth, although a cause and effect
relationship remains to be established [77, 78]. The mecha-
nism postulated for methadone- and buprenorphine-induced I ntravenous vs. Inhaled Anesthetic
neurodysfunction is through their interactions with dopa- Neurocognitive Effects
mine, serotonin, and cholinergic receptors as well as through
oligodendrocyte-expressed opioid receptors. The latter may When comparing the physiologic effects of intravenous and
impair and alter myelination and white matter microstruc- inhalational anesthetics, the greatest challenge to overcome
tures in the developing brain [77–79]. In a clinical study of is to ensure that equivalent levels of anesthesia are present
women who abused opioids throughout their pregnancy, nal- for both. Although the depth of anesthesia with the inhala-
trexone offered an alternative to these two opioids although tional anesthetics can be estimated by measuring the end-
it should be withheld 60 h before delivery [80]. tidal concentration, a comparable metric for intravenous
The evidence that the opioids, morphine, fentanyl, and anesthetics has not been forthcoming. The depth of anesthe-
remifentanil may be associated with apoptosis in newborn sia with intravenous agents can only be estimated using
rodents depends on the duration of exposure. Newborn electroencephalography.
rodents that received morphine for <24 h and did not undergo The only study that compared the severity of apoptosis
surgery sustained no irreversible structural changes in their with an intravenous and inhalational anesthetic [4] included
brains, whereas rats that received opioids for 5 days sus- two trials in nonhuman primates that compared 5 h of propo-
tained irreversible structural changes (in microglia or oligo- fol [32] with 5 h of isoflurane [33]. The results yielded
dendrocyte) and apoptosis [81, 82]. In a similar study, PND7 slightly less apoptosis with propofol than isoflurane.
rats that received morphine for the first 6 days after birth
developed increased apoptosis only in the cortex and amyg-
dala, but not in the hippocampus, hypothalamus, or periaq- Inhalation Agents
ueductal gray matter and almost exclusively in neurons, not
glial cells [83]. Long-term exposure to morphine resulted in All inhalation agents except for xenon [85, 89] trigger neuro-
significant apoptosis in microglia and neurons, an effect apoptosis and neurocognitive dysfunction in neonatal ani-
reversed by naloxone [84]. This evidence supports the mals. Isoflurane, sevoflurane, and desflurane all increase
hypothesis that prolonged opioid exposure can induce wide- neuroapoptosis in animals from newborn rodents to mon-
spread apoptosis in newborn rodents. keys, in proportion to the dose, duration of exposure, and
frequency if repeated [33, 34, 41, 85, 89–103]. However, dif- stantive apoptosis primarily limited to the cerebral cortex
fering doses and single anesthetic administrations have made [93]. In a similar study, the same group determined that the
it difficult to compare the relative risk of neurocognitive dys- apoptosis after 5-h isoflurane was evenly divided between
function after the current anesthetics, isoflurane, sevoflurane, glial cells and neurons [94]. To determine whether isoflurane
and desflurane. The minimum alveolar concentration (MAC) induces neuroapoptosis in young nonhuman primates and, if
or the end-tidal concentration of inhalational anesthetic, the it does, the spatial distribution of the apoptosis in the gray
effective dose that prevents movement in 50% of the animals and white matter, PND6 rhesus macaques were anesthetized
or patients (ED50), is the clinical metric widely used to com- with isoflurane at a surgical depth of anesthesia for 3 h [95].
pare equipotent concentrations of inhalation anesthetics. The Apoptosis occurred fourfold more frequently in those anes-
MAC values for inhalation anesthetics are stable across spe- thetized with isoflurane compared with controls. Moreover,
cies [104]. Hence, many studies report “MAC” multiples or the distribution of the apoptosis differed: neuroapoptosis
fractions of anesthetics to provide equipotent concentrations occurred primarily in the cortex, caudate, putamen, and thal-
among studies. amus, whereas oligodendrocyte apoptosis was evenly dis-
tributed throughout the white matter [95]. In terms of the
ingle Inhalational Agents
S behavioral follow-up after an anesthetic exposure, long-term
Multiple studies examined the neuroapoptotic and neurobehavioral changes in both motor and socioemotional func-
cognitive effects of individual anesthetics in rodents and tions were demonstrated in PND6 rhesus macaques that were
nonhuman primates during the period of rapid synaptogen- anesthetized with isoflurane for 5 h on three occasions, find-
esis. Isoflurane, the first inhaled agent studied, in PND7 ings that were not present in either controls or those exposed
mice (not in PND4 or 14 mice) at sub-MAC concentrations to a single anesthetic [108].
0.75% for 4 h, 1.5% for 2 h, or 2.0% for 1 h, and in separate Sevoflurane, the most widely used inhaled agent in chil-
studies, 0.75% and 1.5% isoflurane for 6 h triggered wide- dren, has also been shown to induce apoptosis in PND7 rats
spread apoptosis compared with controls while maintaining together with spatial learning deficits 6 weeks after exposure
euglycemia [90, 92, 103]. However, a prior study reported [109]. In PND7 rats, 2.3% sevoflurane for 6 h induced wide-
that 1.5% isoflurane for <6 h did not cause widespread spread neuroapoptosis in the hippocampus but not for ≤1.3%
apoptosis in hippocampal slices from PND7 mice, but did at for the same period [110]. These results were supported in a
durations ≥6 h [41]. Investigators posited that hypercapnia second study in which 3% for 6 h in PND7 rats induced
may explain the inconsistency in these results, as hypercap- widespread apoptosis in the frontal cortex and CA1 region of
nia itself leads to apoptosis in a similar distribution in the the hippocampus but not 2% sevoflurane for 3 h [111] and a
brain as 4 h of 1 MAC isoflurane, although only the latter, second study that showed 3% sevoflurane for 6 h impairs
not hypercapnia, exposure resulted in long-term neurocog- synaptic plasticity in the hippocampus and learning and
nitive dysfunction [105]. memory deficit compared with a 1-h exposure [112].
Recent evidence also suggested that brief exposure to iso- Curiously, in a study that investigated the effects of low con-
flurane once at differing ages, PND3, PND5, and PND7 as centrations of sevoflurane on cognitive development, 1.8%
well on pairs of days or all 3 days, yielded neuroapoptosis of sevoflurane promoted hippocampal neurogenesis and facili-
varying severity in different regions of the brain: PND3 tated performance in learning tasks [113].
affected the thalamus, PND5 affected the hippocampus and To compare the neuroapoptotic and long-term cognitive
striatum, and PND7 affected the cortex [106]. This likely effects of a single prolonged exposure to multiple brief expo-
reflects the distribution of NMDA and GABAA receptors in sures of sevoflurane, several studies were undertaken. In the
the different parts of the brain on different postnatal days. first, PND7 rats were anesthetized for either 2 or 6 h in a
Repeated exposure to isoflurane-induced apoptosis as well single exposure or repeated 2 h exposures on PND7, PND10,
as behavioral dysfunction. In PND7 rats anesthetized with and PND13 (total 6 h) or no sevoflurane [96]. Repeat expo-
1.8% isoflurane for 2 h either once or repeated on PND10 sure to sevoflurane causes greater postsynaptic losses than a
and PND13, those after a single exposure demonstrated single exposure. In the second, the long-term cognitive
improved spatial memory, whereas those after multiple effects of sevoflurane in newborn mice, PND3 to PND14,
exposures experienced impaired cognitive dysfunction [107]. that were exposed to sevoflurane between 1 and 4% for inter-
In fetal rhesus macaques at 120-day gestation, 5 h of vals between 1 and 4 h were investigated [114]. After a single
1–1.5% end-tidal isoflurane administered to the pregnant exposure, younger mice yielded worse cognitive dysfunction
rhesus macaques caused substantive apoptosis of neurons in adulthood than did older mice; greater concentrations of
(primarily in the cerebellum, caudate, putamen, amygdala, sevoflurane and more frequent exposures also yielded worse
and other regions) and oligodendrocytes (diffusely over sev- cognitive dysfunction in adults. Lastly, the smaller the inter-
eral white matter areas) [33]. In PND6 rhesus macaques, 5 h val between repeat exposures, the worse the cognitive dys-
of isoflurane between 0.7 and 1.5% isoflurane yielded sub- function. In contrast, PND7 rats that were exposed to 2.5%
sevoflurane for 2 h once or also on PND10 and PND13 for to older animals. PND16 rats administered with 1 MAC iso-
the same duration failed to demonstrate cognitive impair- flurane, sevoflurane, and desflurane for up to 2 h increased
ment in adulthood [115]. These results suggest that very dendritic spine density without inducing widespread apopto-
young rodents are particularly susceptible to the long-term sis or changes in dendritic arbor patterns, thereby interfering
effects of sevoflurane if exposed to a threshold with brain circuit assembly in the cerebral cortex [35]. These
concentration. authors suggested that PND7 in the rodent model may cor-
respond more closely to the first to the second trimester of
Pairwise Comparisons pregnancy in humans and that PND16 more closely approxi-
Do the inhalational anesthetics differ in their propensity to mates the first few years of postnatal life on the human scale,
induce widespread apoptosis or cognitive dysfunction in the a thought that merits consideration when extrapolating non-
short and long term? In pairwise comparisons, isoflurane human primate data to humans [29, 30].
was compared with sevoflurane at 0.5 MAC in PND7 mice All three inhalation anesthetics are considered equally
for 6 h. Apoptosis in the hippocampus and cortex was signifi- neurotoxic in young rodents, although whether desflurane
cantly greater with isoflurane than sevoflurane, but neither has a greater propensity to trigger apoptosis than the other
altered memory nor learning abilities [91]. Using the same two anesthetics at equipotent concentrations remains unclear.
model, isoflurane at 1 MAC for 6 h caused both short-term Nitrous oxide: In an early study, PND7 rats that were
and long-term memory impairment, whereas sevoflurane exposed to only nitrous oxide for up to 6 h experienced no
caused only long-term impairment [102]. Recent evidence neurocognitive dysfunction [2]. The same holds for isoflu-
indicates that while both isoflurane and sevoflurane induce rane alone. However, when the combination of midazolam,
apoptosis, they act via different mechanisms. Isoflurane but nitrous oxide, and isoflurane was administered, the last
not sevoflurane induces neuroinflammation and alters the two for 6 h in PND7 rats, the severity of the neuroapopto-
expression of proteins that impact synaptic transmission and sis was 28-fold greater than either nitrous oxide or isoflu-
memory in mice suggesting a differential effect between rane alone [2].
these two agents [103]. Xenon: Xenon is a rare noble gas with a very small
To study the effects of repeated dosing, isoflurane 1.5% blood/gas partition coefficient (0.007) that equilibrates rap-
for 2 h/day for 3 days caused greater cognitive impairment at idly within the brain when administered by inhalation. It is
30 days compared with sevoflurane 2.2% with the same regi- a weak anesthetic with a MAC of 70%. Xenon (75%) atten-
men, although both cause similar apoptosis of hippocampus uates isoflurane-induced apoptosis [89, 119], although it
neurons and neuronal damage [116]. may trigger apoptosis [119]. In contrast, when xenon (50%)
When PND7 rats were administered with either sevoflu- was given to newborn pigs for 24 h, it did not induce apop-
rane or the combination of sevoflurane and nitrous oxide at 1 tosis compared with fentanyl [85]. Xenon’s mechanism of
MAC for 4 h, only rats who were exposed to the combination action is thought to involve partial antagonisms of the
of anesthetics displayed impaired memory and behavior in NMDA receptor (differently from other anesthetics).
adults [117]. These results supported the notion that combi- Nonetheless, it is either weakly or non-apoptotic during
nations of anesthetics are more toxic than exposure to indi- rapid synaptogenesis. The major drawbacks with xenon are
vidual agents. The same investigators administered 1 MAC its expense, limited availability (it is a naturally occurring
isoflurane or desflurane to PND7 rats for 4 h [118]. Apoptosis gas), and the fact that it must be administrated in a closed
was present in the thalamus, hippocampus, and dentate circuit to be economical [63].
gyrus. At PND48, both anesthetics caused memory impair-
ment and cognitive dysfunction, but isoflurane appeared to I s There a Difference Between Single
produce worse memory and cognitive dysfunction. and Multiple Exposures or the Duration
of Exposure on Apoptosis?
omparison of Three Inhalational Anesthetics
C Most, but not all, laboratory investigations have reported
Two studies compared the neurocognitive effects of equipo- apoptosis and neurocognitive dysfunction after a single
tent concentrations of inhalational anesthetics in PND6/ exposure to anesthetics. Although experimental deficiencies
PND7 mice. In the first study, desflurane yielded greater including insufficient doses or duration of exposure may
apoptosis and spatial long-term memory impairment than explain the false-negative results, in most cases, a single
both sevoflurane and isoflurane [100]. In a second study, the exposure causes neurological deficits in animals (albeit tran-
three inhalational anesthetics yielded similar neurotoxic siently). For ketamine, propofol, isoflurane, and sevoflurane,
effects [101]. Slight differences in the methods of the experi- multiple exposures resulted in greater apoptosis and neuro-
ments may have accounted for these differences. cognitive dysfunction than single exposures. In the case of
Further evidence suggested that inhalational agents may ketamine, a single dose of 10 mg/kg intraperitoneally or even
interfere with neural development even when administered 3 h of infusion in rats and subhuman primates failed to trig-
ger apoptosis (using caspase-3 as the marker of apoptosis) A bevy of pretreatments has been effective in attenuating
compared with controls, whereas continuous infusions of both apoptosis and neurocognitive dysfunction in newborns
20–50 mg/kg/h for 24 h or repeat doses of 20–40 mg/kg trig- and the elderly [36]. These include ketamine precondition-
gered widespread apoptosis [38, 43]. Interestingly, even ing, lithium, budesonide, NAP (neuroprotective peptide,
seven repeat doses of 10 mg/kg failed to trigger apoptosis in davunetide), vitamin C, bumetanide, melatonin, and TRP-
the laterodorsal thalamus and medial amygdala, whereas 601 [36, 120, 122–131].
seven repeat doses of 20 mg/kg did trigger apoptosis in these
two regions [44]. Although animals require doses of intrave- ranslation and the Effects of Surgery
T
nous drugs that are severalfold greater than in humans to Despite the large volume of animal studies available that
induce anesthesia, the blood concentration of ketamine in demonstrate structural and behavioral changes after exposure
animals (14 mcg/mL) is three- to sevenfold greater than that to various anesthetic agents in vitro, we lack comparable evi-
in humans (2–5 mcg/mL). In newborn rodents and subhu- dence from human studies. The translational relevance of ani-
man primates, very large anesthetic doses, multiple doses, or mal studies is challenging to define due to several factors.
doses administered for prolonged periods induced apoptosis Whether the immature brain in the animal is comparable to
(Table 18.2), although how this evidence translates to humans the developing human brain at various stages of childhood
remains unclear. has been debated. Numerous compounds that were identified
in the laboratory as poisons proved to be safe in humans
re There Any Preventative Measures or
A [132]. Only two of the hundreds of animal studies that inves-
Treatments That May Attenuate This Insult? tigated neuroapoptosis in animals included animals undergo-
During studies of head injury in rodents, investigators ing surgery; in humans, anesthesia is most commonly
reported that injured rats performed poorly when compared administered to facilitate surgery and infrequently for nonin-
with the sham controls; however, if they exercised the rats vasive procedures (such as CT or MRI scanning). The results
after the head injury, the injured rats performed as well as the of those two studies yielded conflicting effects in the presence
sham controls [120]. This prompted a multifaceted investiga- of surgery. Although 100% of newborn animals are adversely
tion into the beneficial effects of exercise and socialization and demonstrably affected by exposure to anesthesia in these
after exposing newborn animals to anesthesia. The authors studies, serious neurocognitive adverse outcomes in humans
determined that if the newborn rats were exercised and are so exceedingly rare that it has neither been recognized
socialized after anesthesia, the neurocognitive effects were after anesthesia in young children after almost a century of
drastically attenuated. If rats in many of these earlier studies providing general anesthesia nor recognized in long-term
were isolated, not exercised, and not socialized, widespread studies [132]. To further compound this issue, the time lag
neurocognitive effects may have been exaggerated [121]. between anesthetic exposure and the development of frank
Most neonates and infants are held by parents, cuddled, and cognitive dysfunction may further complicate the issue. Many
stimulated after sedation or anesthesia, which may contrib- have questioned the relevance of the neurocognitive effects
ute to the difficulty in identifying adverse effects in humans after intravenous anesthetics in newborn animals as the doses
after anesthesia. and duration of exposure have been several orders of magni-
Table 18.2 Effects of anesthetic agents on rodents and nonhuman primates

Agents Cellular effects Neurobehavioral findings
Rodents Ketamine Neuroapoptosis Neurodegeneration • Learning
Isoflurane/ Neuroinflammation • Spatial memory
sevoflurane Defects in: • Motor activity
Propofol • Neurogenesis • Attention
Combined agents • Growth cone polarization • Social behavior
Modifiers (+) • Cytoarchitecture • Behavior
Modifiers (−) • Dendritic density Not available
Noxious stim (+) isoflurane (−) Sevoflurane
Noxious stim (−) ketamine • Anti-inflammatory agent
• Environment enrichment
Nonhuman Ketamine Neuroapoptosis Neurodegeneration Learning, memory, motivation, response speed, color
primates discrimination
Isoflurane Neuroapoptosis Not available
propofol Apoptosis in neurons and Not available
oligodendrocytes
Reproduced with permission Ref [141]
tude greater in the animal studies (10- to 20-fold greater doses assessment of neurocognitive outcomes recently, ambidirec-
of ketamine in animals than in humans) and approximately tional studies, and most recently, a single multicentered, ran-
5.5 h ±4 h than in routine surgery in young children [4, 133]. domized controlled trial of spinal versus general anesthesia
Stimulating neonates and infants as most nurses and parents as summarized in two reports [140, 141]. Given the inherent
do after surgery may attenuate the neurocognitive effects in weaknesses in these studies, most can provide only associa-
humans. The newborn animal is a delicate preparation with tions among the variables, anesthesia, and the cognitive met-
up to 30% of the animals succumbing during the first several rics. Confounding factors that limited the external validity of
hours of the study; [121] such a mortality rate suggests the these initial studies included pain, (neuro-) inflammation,
model is quite unstable and in no way reflects the human surgical trauma and sequelae, the underlying indications for
under general anesthesia, whether it is 26 weeks gestation or surgery, and comorbidities, which weighed heavily in our
50 weeks postnatal age. Difficulties in translation from ani- assessment of their impact on neurological structure and
mals to humans due to the differences in physiology includ- function [3].
ing accelerated “pace of life” and sexual maturation in rats Serious criticism of the studies in humans has focused on
preclude experimental equivalence in humans [134]. the imprecision in the outcome variables that were used to
Numerous laboratory issues may bias the evidence from assess and quantify possible defects in cognition. A review
animal studies rendering them not applicable to humans. itemized the psychometric and nonpsychometric tests that
Initial concerns regarding the effects of anesthesia on PND7 have been used to diagnose neurocognitive impairment after
rodents were attributed to hypoglycemia, acidosis, and anesthesia in young children (Table 18.3).
hypoxia, which were subsequently corrected in follow-up
studies. However, other issues persisted including high mor-
tality rates [40–50%] reported in the newborn rodent studies, Retrospective Cohort Studies
without clear explanations for the large percent of deaths
[114, 121]. Whether this speaks to the fragility of the rodent A large number of retrospective cohort studies investigated
model is unclear, but similar mortality rates do not occur in whether exposure to general anesthesia in infants and young
neonatal humans under anesthesia. Additional issues may children is associated with neurocognitive deficits assessed
explain the discrepant results including the breeds of rodents, using a range of metrics at a later age, some of which are
feeding, local infection risks, and handling or other as yet cited here [142–163]. With two exceptions [142, 143], over-
unidentified factors. In none of the studies has surgery been all these studies reported (1) no association between a single
performed, the primary indication for general anesthesia. exposure to anesthesia and later neurocognitive deficits and
Some have reported that surgery itself may increase apopto- (2) an association between multiple exposures (≥2 or more)
sis, further complicating the interpretation of research into and a range of neurocognitive deficits. Although these were
the effects of anesthesia on apoptosis in humans [135]. retrospective studies with well-recognized weaknesses, they
Nociceptive stimulation in the presence of a proapoptotic also suffered from multiple sources of heterogeneity and bias
anesthetic such as isoflurane augmented neuroapoptosis but including the age of exposure to general anesthesia, age at
in the case of ketamine attenuated neuroapoptosis [136, which the neurocognitive outcome was assessed, widely dis-
137]. Curiously, social isolation and enrichment deprivation crepant outcome variables (including learning disability, IQ
have been shown to exacerbate neurocognitive deficits in testing, academic performance, early development index,
newborn rodents after anesthesia [138]. Correcting these ADHD diagnoses, and the Ages and Stages Questionnaire),
deficiencies attenuated the impaired neurobehavioral out- and the absence of baseline measurements [164]. Using the
comes from the anesthetics [121]. A mechanism for this Raine cohort from Western Australia, which included exten-
effect has been elucidated and may offer a target for prevent- sive and repeated neurodevelopmental testing, the authors
ing neurotoxicity [139]. asserted that group testing such as academic achievement
may lack sufficient sensitivity to detect smaller, minor, or
more subtle neurocognitive impairment between children
Human Studies exposed and not exposed to anesthesia in early life [153,
154]. Nonetheless, studies from multiple countries reached
In comparison with the numerous studies in animals, there is similar conclusions that multiple anesthetic exposures are
a dearth of clinical studies in humans. Given the ethical chal- more likely than not to be associated with some degree of
lenges of undertaking clinical trials on neurocognitive dys- neurocognitive deficits at a later age and that a single anes-
function in children, the majority of the initial studies in thetic exposure is unlikely to be associated.
humans were retrospective and/or observational. These were Confounding variables that are associated with cognitive
followed by large population studies providing a more robust deficits have precluded investigators in some studies from
Table 18.3 List of different neurocognitive and sensorimotor function outcomes used to assess outcome in children exposed to general anesthesia
(alphabetic order) and the domain to which the test was assigned
Psychometric test Domain of testing
ABAS-II Adaptive Behavior Assessment System—Second Edition Development
AIMS Alberta Infant Motor Scale Development
– Albert Einstein College of Medicine Neonatal Neurobehavioral Development
Assessment Scale
AVLT Rey Auditory Verbal Learning Test Intelligence/cognition
ASQ Ages and Stages Questionnaire Development
BDS Backward digit span test Intelligence/cognition
BRIEF Behavior Rating Inventory of Executive Functions Development
BSID-II Bayley Scales of Infant and Toddler Development—Second Edition Development intelligence
BSID-III Bayley Scales of Infant and Toddler Development—Third Edition Development intelligence
CAT California Achievement Test Academic achievement
CBCL Child Behavior Checklist Development
CDI Child Depression Inventory Screening/diagnosis (psychiatric
disorder)
CELF Clinical Evaluation of Language Fundamentals Development
CELF-E Clinical Evaluation of Language Fundamentals—Expressive Language Development
Score
CELF-R Clinical Evaluation of Language Fundamentals—Receptive Language Development
Score
CELF-T Clinical Evaluation of Language Fundamentals—Total Language Ability Development
CHQ50 The Child Health Questionnaire 50 Development
CPM Raven’s Colored Progressive Matrices Intelligence/cognition
CPT-II Continuous Performance Test II Development
CTRS-R Conners’ Teacher Rating Scale—Revised Development
CVLT-C California Verbal Learning Test—Children Academic achievement
DKEFS Delis-Kaplan Executive Function Systems/Trail Making Subtests Academic achievement
DSM-IV Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition Screening/diagnosis (psychiatric
disorder)
DSM-ADH DSM—Attention Deficit Hyperactivity Scores Screening/diagnosis (psychiatric
disorder)
EDI Early Development Instrument Development
FDS Forward digit span test Intelligence/cognition
FSIQ Full-Scale Intelligence Quotient Intelligence/cognition
G-TVPS Gardner Test of Visual-Perceptual Skills—Revised Development
GDQ General Developmental Quotient Development
GDS Gesell Developmental Schedule Development
GMDS Griffiths Mental Development Scale Development
GMFCS General Motor Function Classification Score Development
HAWIVA-III Hannover-Wechsler Intelligence Scale, third Edition Intelligence/cognition
GPT Grooved Pegboard Test Intelligence/cognition
ICD-9 International classification of Disease—Ninth Edition Screening/diagnosis (psychiatric
disorder)
ICD-9-CM 299.00 International Classification of Disease—Ninth Autistic Disorder Screening/diagnosis (psychiatric
Diagnoses disorder)
ICD-9-CM 314.01 International Classification of Diseases—Ninth Edition Attention Deficit Screening/diagnosis (psychiatric
Hyperactivity Disorder disorder)
IEP-EBD Individualized Educational Program—Disorders of Emotion and Academic achievementa
Behavior
IEP-SL Individualized Educational Program—Speech and Language Academic achievementa
K-ABC Kaufmann Assessment Battery for Children Intelligence/cognition
KET-KID Kognitiver Enwicklungstest für das Kindergartenalter Intelligence/cognition
LD Learning Disability Screening/diagnosis
MAND McCarron Assessment of Neuromuscular Development Development
Table 18.3 (continued)
Psychometric test Domain of testing
MacArthur-Bates CDI MacArthur-Bates Communicative Development Inventory Development
MRI Magnetic resonance imaging Screening/diagnosis (somatic
disorder)
NEPSY Developmental NEuroPSYchological Assessment Academic achievement
NEPSY-2-NL NDevelopmental Neuropsychological Assessment Development
Development Battery—Second Edition, Dutch Version
OLSAT Otis-Lennon School Ability Test Cognition
OWLS Oral and Written Language Scales Academic achievement
PDMS Peabody Developmental Motor Scales Development
– Phonemic verbal fluency test Intelligence/cognition
PIQ Performance Intelligence Quotient Intelligence/cognition
PPVT Peabody Picture Vocabulary Test Academic achievement
RDLS Reynell Developmental Language Scales Development
PSLE Primary School Leaving Examination Academic achievement
SDMT Symbol Digit Modality Test Development
Semantic Verbal Fluency Test Intelligence/cognition
SON-R Hogrefe/Snijders-Oomen Nonverbal Intelligence Test—Revised Intelligence/cognition
– Stanford Academic achievement
SB-5 Stanford-Binet Intelligence Scales—Fifth Edition Intelligence/cognition
Stroop Color and Word Test Intelligence/cognition
TCS Total cognitive skills Intelligence/cognition
TIQ Total Intelligence Quotient Intelligence/cognition
TEA-Ch NL Test of Everyday Attention for Children, Dutch Version Intelligence/cognition version
TMT—A Trail Making Test—Part A Intelligence/cognition
VABS The Vineland Adaptive Behavior Scale, Second Edition Development
VIQ Verbal Intelligence Quotient Intelligence/cognition
VMI Beery-Buktenica Developmental Test of Visual Motor Integration, Fifth Intelligence/cognition
Edition
Wallin BP Wallin B pegboard Development
WAMSE Western Australian Monitoring Standards in Education Academic achievement
WASI Wechsler Abbreviated Scale of Intelligence Intelligence/cognition
WJ III Woodcock-Johnson III Academic achievement
WJ III—Visual Matching Woodcock-Johnson Test—Visual Matching Academic achievement
WeeFIM Functional Independence Measure Developmentb
WPPSI-R Wechsler Preschool and Primary Scales for Intelligence: Revised Intelligence/cognition
WISC-III Wechsler Intelligence Scale for Children—Third Version Intelligence/cognition
WISC-III-NL Wechsler Intelligence Scale for Children—Third Version, Dutch Version Intelligence/cognition
WISC-IV Wechsler Intelligence Scale for Children—Fourth Edition Intelligence/cognition
Nonpsychometric tests/means to assess cognitive, developmental outcome, or both of children exposed to general anesthesia
Serum biomarkers of Neuron damage
brain-derived neurotrophic
factor (BDNF), S100B
Neurological examination Neurologic deficit

Surrogate measures of Sensorineural deficit
visual function (visual
acuity, refractive error,
thickness of retinal nerve
fiber layer)
Reproduced with permission, reference [164]
a
Individualized educational program (IEP) is not a psychometric test but the intervention applied for a child with special needs. The IEP is meant
to address each child’s unique learning issues and includes specific educational goals. It is a legally binding document, sanctioned by the US fed-
eral law called the Individuals with Disabilities (IDEA). The IEP describes the goals the team (e.g., teachers, parents, school psychologists) sets
for a child during the school year, as well as any special support needed to help achieve them
b
Functional Independence Measure is used in follow-up of rehabilitation
detecting an effect of anesthesia on neurocognitive deficits. In a recent and powerful sibling cohort design, 2346 sib-
The type of surgery, which has not been a restriction in most ling pairs were evaluated using the Early Development
studies, may impact the power of the study to identify the Instrument (EDI), a population-based measure of child
specific effect of anesthesia on cognitive function. In two development in five domains at ages 5–6 years [167]. (EDI is
such studies, one in infants undergoing neurosurgery [149] a validated 103 item teacher completed the assessment of
and the second in infants undergoing craniofacial surgery development in the child in five domains: physical health,
[150], ninth-grade exam scores were compared with con- social competence, emotional maturity, language/cognitive
trols. In the former study, the exam scores in those with development, and communication skills/general knowledge.
hydrocephalus and craniotomy were less than controls, Vulnerability was defined as a score below the tenth percen-
although those with myelomeningocele repair were similar tile in one of the domains.) In this study, development out-
to controls. The anesthetic did not impact the scores. In the comes in exposed children did not increase compared with
latter study, the ninth-grade exam scores depended on the nonexposed biological siblings or in those siblings who were
type of cleft rather than the number and timing of the discordant for exposure to anesthesia. Importantly, all twin
anesthetics. In designing studies to investigate the neurocog- studies were mitigated for unmeasured biological vulnerabil-
nitive effects of general anesthesia in infants, it is prudent to ity and home environmental influences on child develop-
exclude populations at risk for neurocognitive deficits based ment. These findings lend further support to the notion that a
on their underlying comorbidities (e.g., neurological, plastic, single exposure to anesthesia in early childhood is not asso-
and reconstructional facial and cardiac defects). ciated with detectable adverse child development [167].
To investigate the effect of general anesthesia on the sub-
win and Sibling Studies
T sequent development of ADHD, the Swedish twin database
To reduce the heterogeneity among children, parental educa- extracted those twins who had been exposed to general anes-
tion, and socioeconomic status, several studies focused on thesia before the age of 12 years [168]. Of the 68 twins who
associations between the exposure of identical twins or sib- were discordant for anesthesia, the association (1.02)
lings and subsequent neurocognitive deficits. The identical between anesthetic exposure and ADHD was very weak.
Twin Registry in the Netherlands yielded 1143 monozygotic However, it should be noted that the children were not tod-
twin pairs including 71 twins who were discordant for anes- dlers at the age of exposure but were as old as 12 years and
thesia and surgery before 3 years of age [165]. Standardized 88% of the children received only a single anesthetic, reduc-
testing and teacher ratings of all the twin pairs showed sig- ing the power of the study.
nificantly lower scores in those exposed to anesthesia com-
pared with those who were not exposed. However, when the
same scores were compared in twins who were discordant Large Databases
for anesthesia, they did not differ. This supported the notion
that exposure to anesthesia at a young age may be a marker To further clarify the impact of early exposure to general
for a child’s vulnerability to developing learning difficulties anesthesia on cognitive development in children, four large
at a later date, but anesthesia per se does not substantively databases were searched; two studies were conducted in
result in cognitive dysfunction. A major limitation of the Canada [169, 170] and one each in Sweden [171], Australia
study was the small sample size, the absence of details [153, 154], and the UK [172].
regarding the type of surgery, and the type of anesthesia and In 2016, the EDI was measured in 3850 children who
its duration. were exposed to a single anesthetic preschool and 620 who
In a retrospective sibling cohort study of children with were exposed to 2 or more anesthetics, and both of these
New York Medicaid insurance, the incidence of develop- groups were compared with 13,586 matched but nonexposed
mental and behavioral disorders in 304 children <3 years of children in Ontario, Canada [169]. Overall, the children’s
age who received anesthesia was compared with that in developmental vulnerability increased slightly based on the
10,146 unexposed children [166]. Disorders in children EDI metric in the exposed versus unexposed children, with
exposed to anesthesia were twice as frequent compared with an odds ratio (OR) of 1.05. In addition, the developmental
those siblings who were unexposed. Furthermore, the risk of vulnerability in children age > 2 years at the time of their first
disorders in the exposed group was 1.1 after one anesthetic anesthetic was greater than in controls, OR 1.05. In contrast,
exposure, 2.9 after two exposures, and 4.0 after three or more developmental vulnerability after single and multiple anes-
exposures. When the 138 sibling pairs who were discordant thetic exposures at <2 years of age did not increase com-
for anesthesia were controlled for age, environmental, and in pared with controls [169]. These data indicate that although
utero conditions, the matched relative risk for disorders was developmental vulnerability in preschool-age children who
0.9 [166]. were exposed to general anesthesia is greater than in those
unexposed, the difference was quite small. Moreover, those anesthesia. Long-term deficits in language and abstract rea-
children <2 years of age at the time of a single or multiple soning were greater in those exposed to anesthesia (whether
exposures were at no greater risk for developing cognitive single or multiple exposures) compared with unexposed chil-
defects. dren, although other domains did not differ between the
In a second cohort study from Manitoba, 3850 children exposed and unexposed. Even within the language domain,
exposed to a single GA and 620 exposed to ≥2 GA were higher-order language skills such as the clinical evaluation of
matched to 13,586 unexposed children, using the EDI as language fundamentals and the Peabody Picture Vocabulary
their outcome tool to quantify the children’s developmental Test did not differ suggesting that not all aspects of language
vulnerability [170]. Developmental vulnerability after either are affected by exposure to anesthesia [153]. This study has
a single or multiple anesthetics at <2 years of age was not several limitations including the varied type of surgeries that
increased, whereas it was increased for those exposed to a were included (e.g., neurosurgery and cardiac surgery, sur-
single anesthetic between 2 and 4 years of age, with deficits geries known to adversely impact neurocognitive develop-
noted in communication/general knowledge and language/ ment). In addition, almost 25% of the children underwent
cognition. However, developmental vulnerability after myringotomies and tubes that required a general, albeit brief,
multiple exposures between 2 and 4 years of age was not anesthetic (< 15 min), although chronic hearing loss is a rec-
increased [170]. ognized primary source of poor language development and
In 2017, the largest and most robust retrospective cohort learning problems [155]. Moreover, multiple paired com-
study used academic school grades and IQ test scores in parisons introduced a possible Type 1 statistical error that
33,514 children (male to female ratio of 2:1) after single or remained unaccounted for.
multiple anesthetic exposures before 4 years of age (e.g., The most recent longitudinal, cohort study comprised
preschool) to compare with the same metrics in 159,619 age- 13,433 children from the UK who were exposed to general
and gender-matched controls [171]. The academic or cogni- anesthesia before 4 years of age and were evaluated for cog-
tive performance on a population level demonstrated that nitive and behavioral development between 7 and 16 years of
general anesthesia reduced the school grade scores to a small age [172]. After adjusting for confounding variables, no neu-
extent, 0.41% (95% CI, 0.12%–0.70%), and IQ test scores, rocognitive deficits in terms of cognitive ability, memory,
0.97% (95% CI, 0.15%–1.78%), compared with unexposed attention, reading, spelling, and behavior difficulties on
children. Furthermore, the types of surgery yielded signifi- national exam performance were identified to be either clini-
cant heterogeneity: children who underwent ear, nose, and cally or statistically significant, although motor and social
throat procedures reported lower scores compared with those linguistic performance were significantly lower in the
who underwent abdominal procedures. Children with exposed group, worse after multiple anesthetics. The authors
chronic ear infections are known to suffer behavioral and issued a cautious reassurance that exposure to general anes-
learning difficulties rendering the effect of anesthesia on thesia does not seriously impact global neurodevelopment
developing cognitive deficits difficult [155]. Those who with the two exceptions above noted [172].
underwent urological procedures reported higher school
grades and IQ scores. Also, the differences in scores associ-
ated with sex, maternal education level, and month of birth Prospective Human Trials
during the same year (December versus January) were sev-
eral orders of magnitude greater than the effect of exposure The General Anesthesia vs. Spinal (GAS) study was an inter-
to anesthesia [171]. Cognitive scores were lower after mul- national prospective randomized controlled trial that com-
tiple (>3) exposures to anesthesia, although these were pared the Bayley III Scales of Infant and Toddler Development
smaller than the difference noted between the months of evaluated at 2 and 5 years after either a 1-h sevoflurane anes-
birth. thetic or spinal anesthesia in infants undergoing inguinal her-
A cohort of 2868 pregnant women whose children were nia repair. At both follow-up ages, the Bailey Scales were
born between 1989 and 1992 was enrolled in the Western similar [173, 174]. The proportion of with the number of
Australian Pregnancy Study (Raine) to evaluate the long- participants The GAS study provides the strongest available
term effects of prenatal ultrasound [153]. All children under- evidence to date that approximately 1 h of a single anesthetic
went neuropsychiatric tests through the first 10 years after (sevoflurane) exposure in early life is safe and does not lead
birth and at 13 and 16 years of age. The testing was com- to cognitive dysfunction in either the short or long term.
prised of four domains: language, cognition, behavior, and Limitations of this prospective study included the brevity of
motor function. To test for the effects of anesthesia before the anesthetic exposure, the limited exposure to a single pro-
the age of 3 years, exposed children were tested at 10 years apoptotic anesthetic, the absence of repeated exposures to
of age. Males were twice as likely as females to undergo sevoflurane, and the proportion of participants in both groups
who were lost to follow up, 30 and 42%, using an ITT or elevant Human Outcome Measures,
R
APP approach, respectively. Population Migration, and Sample Sizes
The Pediatric Anesthesia Neurodevelopment Assessment
(PANDA) trial was an ambidirectional cohort study that It must be emphasized that the potential phenotype of
compared the neurocognitive and behavioral outcomes from anesthesia- related neurotoxicity in young children is
105 healthy sibling pairs who were discordant for exposure unknown [156, 164]. But if such a phenotype exists, it is
to anesthesia before the age of 3 years [175]. essential to ascertain a meaningful outcome metric for the
Neurocognitive and behavioral outcomes were collected possible effects of anesthesia on cognitive function in
prospectively, although the data on the anesthetic exposure humans including when and how to best evaluate the child.
were collected retrospectively. The primary outcome, global Current crude outcome measures such as developmental dis-
cognitive function (IQ) at age 8–15 years, did not differ orders in preschool, learning disabilities (LD) in elementary
between siblings. Secondary outcomes including domain- school, attention-deficit hyperactivity disorder (ADHD),
specific neurocognitive functions and behavior also did not social disturbances in adolescence, psychiatric disorders in
differ between siblings [175]. adulthood, loss of various cognitive functions, or early
The Mayo Anesthesia Safety in Kids (MASK) study, a dementia in the elderly are influenced by a multitude of fac-
second ambidirectional study, compared a matched cohort tors. Large population studies identify associations but can-
study of 997 children who were unexposed, singly exposed, not identify causality. More importantly, it also remains to be
or multiply exposed to general anesthesia before 3 years of established how well a single short-term interim outcome
age based on their medical charts [176]. These children metric performed in early childhood or adolescence ade-
underwent comprehensive late neuropsychological testing at quately predicts the outcome later in life. Extensive and
ages 8–12 years or 15–20 years. The primary outcome mea- repeated neurodevelopmental testing may be more likely to
sure, the Full-Scale Intelligence Quotient Standard Score of identify any potential phenotype (e.g., abnormalities in
the Wechsler Abbreviated Score of Intelligence, was similar speech and language neurocognitive impairment) [156].
among the unexposed, singly exposed, and multiply exposed Importantly, it is unknown under what circumstances
children [176]. repeated individual cognitive testing is meaningful human
Using the data from the MASK study, the same cohort of outcome measures. Assessment of academic performances
children was reanalyzed using the Operant Test Battery has a pragmatic advantage as an outcome measure in that
(OTB)—the battery of tests used to investigate deficits in parents are likely to be more interested in their child’s aca-
infant macaque monkeys after anesthesia [177]. In the pri- demic standing in school [179] and importantly good aca-
mary analysis, there was no association between exposure to demic achievements require good speech and language skills
anesthesia and neurocognitive deficits after correcting for [180].
multiple comparisons. In this exploratory factor analysis, the The use of ADHD as an outcome measure for anesthesia-
OTB scores loaded onto four factors, and the score for one related neurotoxicity requires further evaluation [152] as the
factor was significantly less in multiply exposed children, diagnosis and treatment of this disorder are contentious
but significance did not survive a sensitivity analysis account- [157]. ADHD is afflicted by ascertainment bias as demon-
ing for outlying values. strated by the large variation in its prevalence among coun-
The TREX (Trial Remifentanil and dEXmedetomidine) tries, states, races, sexes, and ethnicities. In 2011, two million
pilot study is a multicenter study that assessed an alternative more children were diagnosed with ADHD in the USA com-
anesthetic technique for infants (1–12 months) undergoing pared with 2003, with one in five adolescent males in the
lower abdominal/lower extremity surgical procedures that USA labeled with ADHD. More than two-thirds of these
were expected to last for more than 2 h. The protocol speci- children were prescribed long-term medication such as dex-
fied an inhalational induction with sevoflurane, a caudal amphetamine [181, 182]. Additionally, ADHD is associated
block, and maintenance of anesthesia using both remifent- with an array of psychiatric disorders and LD. For these rea-
anil and dexmedetomidine infusions. The pilot study reported sons, ADHD seems to be of limited value as an outcome
that 87.5% of the 56 infants achieved a satisfactory depth of measure for anesthesia-related neurotoxicity. Autism spec-
anesthesia. Based on the pilot study, this anesthetic prescrip- trum disorder has also served as an outcome measure in
tion seemed to be potentially beneficial for infants undergo- anesthesia-related neurotoxicity studies [158] with similar
ing surgery as it reduced the time the infants would be arguments as those mentioned for ADHD applied to question
exposed to inhaled anesthetics [178]. This pilot study laid the the validity of this outcome measure. In the case of autism, it
groundwork for subsequent studies that will investigate is important to appreciate that it affects up to 1% of children,
alternative anesthetic regimens to minimize infant’s expo- beginning in early childhood or later and progressing
sure to proapoptotic drugs. throughout adulthood.
The degree of migration of study subjects is of major dren [188]. Limitations of this study included the absence of
concern in many of the human cohort studies [151, 152, baseline measurements due to the urgent need to commence
183]. Therefore, sufficiently large sample sizes are required cancer treatment. Importantly, the sicker a child with cancer
to detect even modest associations of perioperative factors is, the more likely he/she is to require repeated anesthesia.
that impact neurocognitive outcomes. Too many studies As a final thought, anesthesia was required in this study and
included small cohorts that limited the power of the studies will be required in the future in analogous situations if we are
to identify differences and associations. Multiple (individ- to ethically and successfully treat cancer in children.
ual) testing has also been employed to compensate for this; To further understand the magnitude of the impact of the
however, this approach introduces the risk of Type 1 statisti- FDA warning regarding prolonged anesthesia in children, a
cal error, particularly considering that many of such tests are retrospective review of 1.5 million anesthetics from the
interrelated [180]. National Anesthesia Clinical Outcomes Registry reported
the duration of anesthesia in children undergoing elective
surgery. The authors reported that the median duration of
ge at Exposure, Duration of Surgery/Number
A anesthesia was <1 h in all age groups except those <1 year
of Exposures, and Impact of Surgery for whom the median duration was 79 min (upper 90th %ile
was 210 min) and 13–18 years for whom it was 70 min
Neurogenesis in infants and children peaks at different ages (upper 90th %ile was 170 min) [189]. Overall, 94% of the
within brain regions [28, 184]. Surprisingly, neurogenesis anesthetics were ~ 1 h in duration. Only 6% of the anesthet-
continues in some regions (e.g., dentate gyrus and olfactory ics fell into the category considered “prolonged” by the
bulb) into adulthood far beyond the previously suggested FDA. Using a much smaller database from a tertiary referral
window of vulnerability [20, 28]. The belief that the young- center in the USA, the authors reported that less than 4% of
est and most immature infants are at the greatest risk of anes- the anesthetics administered to young children that exceeded
thetic agent-induced neurotoxicity is not reflected in the >3 h in duration were multiple exposures before 3 years of
currently available human studies [143, 144, 146, 169–171, age or both [190]. Children who require prolonged anesthet-
185]. In a summary of the neurocognitive sequelae after ics almost certainly had illnesses that require repeat anes-
exposure to anesthesia in infants and children by age, there thetics to treat or cure the underlying illness or required
were no age-associated changes in either the severity or surgery of prolonged duration to remove a tumor or treat
nature of the neurocognitive defects identified [186]. some other potentially life-threatening condition. In those
In 2016, the FDA in the USA issued a notice cautioning small numbers of children with chronic diseases who require
that prolonged anesthetic exposure may increase the risk of prolonged exposures to anesthesia, clinicians should design
long-term cognitive dysfunction, without defining the term their anesthetic prescriptions to minimize the duration, num-
“prolonged.” This was based primarily on animal data. The ber, and/or dose of proapoptotic anesthetics and include non-
very few studies that focused on prolonged exposures and apoptotic strategies including regional anesthesia where
procedures suggest that confounding variables other than the possible to minimize the risk of neurocognitive deficits.
mere exposure to anesthetic agents may be critical in devel- The effects of surgery including the stress response, pain,
oping cognitive dysfunction [149, 187]. However, a recent and neuroinflammation cannot be disentangled from that of
cohort of 212 children who were more than 5 years after the anesthetic agent itself [191], with inconsistent results
being diagnosed with acute lymphoblastic leukemia for from two studies of the effects of pain on neurocognitive
which they received 5699 anesthetics demonstrated different deficits in rodents [135, 136]. Both surgery and underlying
results [188]. The cohort underwent a comprehensive battery pathology independently influence the subsequent neurocog-
of neurocognitive tests after 8 years of age to determine the nitive outcome. The single most important cofactor may be
neurocognitive and neuroradiological effects of multiple the effects of surgery. The impact of stress responses, noci-
anesthetics over a prolonged period. After adjusting for conception, and neuroinflammation on (long-term) neurocogni-
founders, the authors determined that increasing cumulative tive function requires further exploration [149, 187, 191].
exposure to and duration of propofol or isoflurane anesthesia
resulted in neurocognitive impairment and neuroradiological
abnormalities beyond those associated with the chemothera- Sex, Parenting, and Low Birth Weight
pies. This small but focused sample of cancer survivors
raises concerns about the effects of exposure to a large dose Another factor that may confound the long-term neurode-
of anesthetics over a prolonged period in chronically ill chil- velopment is sex. Male sex can influence the need for sur-
dren, and the authors rightly caution that we minimize the gery, as inguinal hernia repair and pyloromyotomy are far
dose and duration of exposures to anesthetics in such chil- more common in males than females [25, 29]. Sex is known
to independently impact the neurobehavioral outcome and adverse neurocognitive outcomes, although they face
[192, 193]. Evidence from PND7 rats indicates that when insurmountable obstacles: an enormous commitment of
males and females were exposed to isoflurane, apoptosis time, substantive budget, and an international cooperative of
and simple object recognition were similarly affected at pediatric centers.
PND38, although social memory and object recognition in
novel locations in the males were impaired compared with
females [193]. Other Aspects
Maternal age and, more importantly, higher socioeco-
nomic status are strongly associated with better neurobehav- Many other perioperative factors may impact later neurode-
ioral outcomes and with enhanced capacity to recover from velopment and may affect the neurodevelopment to a much
any injury. Of note, the level of parental education is more larger extent than anesthetic exposure early in the child’s
important than parental occupation and socioeconomic sta- young life [196]. These include a series of (small) physiolog-
tus as these are subject to changes over time, whereas, after ical, metabolic, and biochemical factors induced by general
the age of 30 years, the level of parental education rarely anesthetics and surgery that are known to impact survival
changes [194]. Low birth weight (prematurity) is strongly and morbidity [197]. Likely, the aggregate of several rela-
associated with negative neurobehavioral outcomes as are tively small and consistent improvements in clinical care
other comorbidities such as congenital defects [195]. may very well substantively influence the overall outcome
(“aggregation of marginal gains”) [3].
The conduct of anesthesia by skilled practitioners in an
Future Studies appropriate pediatric environment supported by sufficient
resources will improve the overall perioperative care for
Unmeasured confounding factors limit large observational infants and children. For example, it is crucial to maintain
retrospective cohort studies. For example, the effects of sleep normal physiological and metabolic indices including oxy-
duration, relationships with peers, and levels of physical genation, normo-capnia, normo-natremia, blood pressure
activity are difficult to disentangle from the exposure to within the normal limits, euglycemia, and normo-thermia
anesthesia when using academic performance as the only and to minimize fear and anxiety. These are listed in the safe-
outcome measure of cognitive dysfunction. Furthermore, tots.org initiative as the 10 N model for safe anesthesia
given that multiple metrics have been used to assess develop- (Fig. 18.2) [197]. Although deviations in physiologic vari-
ment, cognition, intelligence, academic achievement, and ables have not been directly linked to neurocognitive defi-
neuropsychological diagnoses, our ability to merge and col- cits, ensuring physiologic homeostasis in the neonates
late the results of the studies has become increasingly chal- eliminates confounding variables from being implicated
lenging [60]. Future observational studies will only yield should neurocognitive deficits occur. In the European Apricot
meaningful results if they are sufficiently powered, include study of clinical morbidity in pediatric anesthesia, neonates
infants and children with comparable surgeries, comorbidi- experienced the greatest frequency of critical cardiovascular
ties, indication for exposure, follow up and consistent out- and respiratory adverse events, the age group at great risk for
come metrics [165]. Several questions need to be answered if neurocognitive deficits due to rapid synaptogenesis [198]. In
we are to unravel the true effect of general anesthetics on a retrospective case series of seven infants who underwent
vulnerable young infants and children (Table 18.4). Large relatively minor surgery at a major pediatric institution, all
international, randomized controlled trials with standardized seven developed postoperative encephalopathy (including
outcome measures are needed to discover possible associa- seizures) that appeared to be consistent with cerebral hypo-
tions between prolonged anesthesia or multiple anesthetics perfusion [199]. During the anesthetic, hypotension was
observed in the majority, only one was given glucose intra-
Table 18.4 Further questions that should be answered in future clini- operatively, and two-thirds exhibited mild hypocapnia. How
cal research each or all of these physiologic deviations possibly contrib-
Is there a particular phenotype of the patient that is at risk of uted to the neuropathology remains unclear. Hypotension
neurotoxicity? has been reported previously in neonates and infants under
Are there periods of significant vulnerability to neurotoxicity, and if general anesthesia and is known to occur more frequently in
so when are these?
neonates than older children, although the definition of
Which anesthetic agents confer the most harmful effects and at
what dose range? hypotension in infancy remains elusive and ill-defined [200–
Are short multiple exposures, for example, staged procedures, safer 203]. In the European Nectarine study of morbidity in neo-
than one long exposure? natal anesthesia, 35% of neonates and infants <60 days
Is there a dose-response curve? postnatal age experienced either hypotension or hypoxemia
Which outcome measures are most affected by neurotoxicity if any? (SpO2 < 85%) during general anesthesia [204]. In a review of
Fig. 18.2 Maintenance of physiological homeostasis is key for the safe conduct of anesthesia in children, as stated by the safetots.org initiative
(www.safetots.org)
infants undergoing pyloromyotomy, hypotension was com- fluoride, and phthalates, to name a few [207], and poverty
mon particularly in preterm infants and in neonates [205], and low socioeconomic status [208].
and desaturation occurred in 18–30% postintubation depend-
ing on the type of rapid sequence induction that was used
[206]. Strict maintenance of these physiological variables Important Issues to Consider
may be aided by advances in monitoring technology such as
near-infrared spectroscopy (NIRS) allowing regional perfu- With conflicting evidence regarding the effects of exposure
sion and oxygenation to be continuously assessed and main- to anesthetic agents on neurodevelopment in humans, clini-
tained throughout prolonged exposure to anesthesia. In cians face an ethical dilemma: how, when, if, and to what
addition, the conduct of anesthesia by skilled practitioners in extent these issues should be discussed during the consent
an appropriate pediatric environment supported by sufficient procedure with parents and caregivers? Knowing there is a
resources also needs to be addressed. The important ques- panoply of factors that may affect a child’s neurodevelop-
tions of who, where, when, and how young infants and chil- ment, it is daunting to quantify the impact of exposure to
dren should be anesthetized will need to be addressed. For anesthesia on an individual child’s neurodevelopment, given
more information and further updates about these issues, the that anesthesia is required on compassionate grounds to
readers are referred to www.safetots.org [197]. facilitate surgical and diagnostic procedures in young chil-
Finally, concerns about the long-term neurocognitive out- dren. In some institutions, pamphlets are available in sur-
comes after surgery and anesthesia in early life are further geon’s offices and in clinics that address the issue of
complicated by several environmental factors that are poten- anesthesia and its possible effects on the neurodevelopment
tially hazardous to the neurodevelopment of children. Of of children. Would such a discussion at an inopportune time
particular concerns are the effects of chronic exposure to (as anesthesiologists often are given) immediately before
lead, methylmercury, pesticides, perfluorinated compounds, surgery garner excessive concerns for parents when there are
few or no alternatives? If the parents raise direct questions the observed pathology. The research focused on anesthetic
regarding the risks of anesthesia on neurocognitive outcomes neurotoxicity (GABAA, NMDA receptors) during periods of
in their child, then the questions should be answered in an rapid synaptogenesis, attracting generous funding, aca-
honest and forthright manner. Since most children who pres- demic merit, and publicity (https://www.smarttots.org).
ent for surgery are healthy, the risk of neurocognitive adverse Interestingly, attention to improving the safe conduct of
outcomes after a single brief anesthetic is exceedingly small. general anesthesia (by maintaining blood pressure, PaCO2,
However, if the child presents with multiple comorbidities or electrolytes, temperature, and blood glucose concentration
has experienced multiple anesthetics, the perioperative expe- within physiologic norms) in the vulnerable infant and child
rience may increase the risk of neurocognitive adverse remained largely neglected and ignored. Although it is com-
effects, although it is far more important to reassure the par- mon knowledge that the risk for perioperative morbidity in
ents that their pediatric anesthesiologist is experienced and infants and children particularly by inexperienced pediatric
will deliver a “first-class anesthetic” maintaining vital signs anesthesiologists is not insignificant, several national anes-
within normal limits to optimize their child’s outcome and thesia societies were unwilling initially to accept and/or
minimize their perioperative risks. If the parents are pursue specialized certification of pediatric anesthesiolo-
vacillating over delaying surgery until their child is older, it gists. Subspecialty training in pediatric anesthesiology is
is important to remind them that this decision should not be available in many regions, although in many other regions,
taken lightly; the parents or legal guardians should be fully standardized pediatric anesthesia certification remains elu-
aware of and understand that the risks of delaying surgery or sive [210].
a medical procedure that may introduce undesired sequelae As outlined above, prospective studies and worldwide
must be balanced against the biologically plausible, but cur- collaborations such as the PANDA, MASK, and GAS studies
rently unknown, risk of neurotoxicity in the child. have focused on the need for excellence in perioperative
It should be noted that the neurocognitive outcome stud- quality of care [173–177]. The plausible negative effects of
ies from both Europe and North America varied in the met- the anesthetic agent on neurodevelopmental outcomes have
rics they used to assess long-term cognitive function, which highlighted the importance of the safe conduct of anesthesia
may explain discrepant results among studies. Although big to minimize perioperative critical events and improve out-
data epidemiological studies yielded tenuous associations comes [199, 211, 212]. In addition, the safetots.org initiative
between anesthetic exposure and neurocognitive deficits has galvanized global support from experts in pediatric anes-
[169–171], they serve to identify associations, not causa- thesia. Although it remains important to continue to investi-
tions, between the variables. Since clinicians on both conti- gate anesthetic-related neurotoxicity, we should not lose
nents use similar anesthetic regimens and techniques and sight of the need to guarantee the delivery of high-quality
perform similar surgeries on children with similar disease and consistently safe anesthesia to neonates, infants, and
processes, the fact that studies in one region reported positive children at all times.
associations whereas those in the second region did not
raises several possible explanations for the discrepancy
including that the neurocognitive outcome metrics in one Conclusion
region were less sensitive than those in the other regional
and/or that the general provision of healthcare, specialist There is incontrovertible evidence that general anesthetics
care, standards of anesthesia care, and, most importantly, adversely affect newborn animals from rodents to subhuman
education and support differed resulting in the conflicting primates both histologically and neurocognitively. These
outcomes [209]. effects become apparent in the early postexposure period and
The history of anesthesia-induced apoptosis and neuro- persist as the animals mature to adulthood. The quintessen-
cognitive dysfunction differs from other serious issues that tial question is how does this evidence translate into the vul-
anesthesiologists have confronted previously. Such issues nerable human?
were primarily clinical dilemmas and unexpected morbidity It has proven difficult to find a human correlate to the ani-
and mortality that spurred extensive research to understand mal model that demonstrated anesthesia-related neurotoxic-
and resolve. Examples of these include halothane hepatitis, ity in the developing brain (Table 18.5). In the only
malignant hyperpyrexia, methoxyflurane-induced renal fail- prospective, controlled, randomized study that exposed
ure, and rapacuronium pulmonary complications and death. young infants and children to ~1 h of a single anesthetic,
However, in the case of anesthetic-associated cognitive dys- sevoflurane, for inguinal hernia repair, neurobehavioral defi-
function, it was discovered first by serendipity in animals, cits 5 years after exposure were similar to those in a matched
[1, 18] not humans. This spurred basic (animal and labora- cohort who received only regional anesthesia for the same
tory) science research to elucidate the putative agents and surgery [174]. Weaker evidence suggests that repeated expo-
the plausible cellular mechanisms for anesthetics to cause sures to anesthesia and surgery may be associated with mar-
Table 18.5 Further questions that should be answered in future clini- tion in the developing rat brain and persistent learning deficits. J
cal research Neurosci. 2003;23:876–82.
3. Hansen TG, Engelhardt TC. Long-term neurocognitive out-
• General anesthesia is neurotoxic to the developing brain in
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Anaesthesiol. 2018;31:297–301.
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4. Lin EP, Lee JR, Lee CS, et al. Do anesthetics harm the developing
human context presents enormous challenges
human brain? An integrative analysis of animal and human stud-
• A single, brief general anesthetic is not harmful to young ies. Neurotoxicol Teratol. 2017;60:117–28.
children. Recent large-scale observational studies found minimal 5. Vutskits L, Zhongcong X. Lasting impact of general anaesthe-
neurocognitive impairment after anesthesia and surgery sia on the brain: Mechanisms and relevance. Nat Rev Neurosci.
• The recent FDA warning regarding potential harm to fetuses and 2016;17:705–17.
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Conflicts of Interests None. nerability of neurons to anesthetic toxicity. Ann Neurol.
2013;73:695–704.
21. Yon JH, Daniel-Johnson J, Carter LB, Jevtovic-Todorovic
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Neonatal Resuscitation
for Anesthesiologists 19
Satyan Lakshminrusimha and Payam Vali
Key Points for Neonatal Life Support in the Delivery • Inflation and ventilation of the lungs are a priority for
Room (Fig. 19.1) infants who need support.
• Risk factors—Review maternal and fetal risk factors; • Thoracic (chest) compressions if poor response to posi-
anticipate and prepare. tive pressure ventilation (PPV).
• Evaluation—Ongoing assessment. • Adrenaline/epinephrine—IV reasonable if poor response
• Skin-to-skin contact with mothers can help with tempera- to chest compressions.
ture management. • Tension pneumothorax—Rule out if poor response to
• Umbilical cord management—Deferring cord clamping adrenaline.
for >30 s. • Expand volume with normal saline or blood if history or
• SpO2 monitoring is used to guide oxygen therapy if exam is consistent with blood loss.
needed. • Direction of care—Discuss with family and team if no
• Cardiac monitoring (preferably with EKG if extensive response by 20 min.
resuscitation is needed)—increasing heart rate is the most
important indicator of response to resuscitative
interventions.
Fig. 19.1 Twelve key points

to remember during neonatal
resuscitation. Based on Aziz
et al. [18]. Mnemonic—
RESUSCITATED Copyright
Satyan Lakshminrusimha
S. Lakshminrusimha (*) · P. Vali

Department of Pediatrics, UC Davis Children’s Hospital,
Sacramento, CA, USA

608 S. Lakshminrusimha and P. Vali
Introduction
Anesthesiologists are often called to help in neonatal resus-

citation. These situations may include (i) in the delivery
room (DR) when an infant is born unexpectedly depressed,
(ii) emergent delivery when the neonatal team has not
arrived, (iii) when the neonatal or obstetric team has diffi-
culty in resuscitation and needs help, and (iv) during code
situations in the operating room. Anesthesiologists are
experts in airway management and resuscitation. However,
when the anesthesiologists are resuscitating a neonate, it
would be good to be aware of the basic principles of the neo-
natal resuscitation program (NRP) established by the
American Academy of Pediatrics (AAP) and the American
Heart Association (AHA) [1] so that there is synchrony with
the participating neonatal and pediatric resuscitators [2].
Equipment
As delivery may occur in situations and locations that are not

completely organized for resuscitation of a newly born
infant, a quick equipment and personnel checklist as shown
in Fig. 19.2 is beneficial.
Fig. 19.2 Equipment and personnel checklist before neonatal resusci-

tation at delivery. Every birth is TO BE BLESSED is a mnemonic for
this checklist. Copyright Satyan Lakshminrusimha
19 Neonatal Resuscitation for Anesthesiologists 609
Physiology of Transition at Birth (Fig. 19.3) ransition at Birth and Deferred Cord

T
Clamping (DCC)
Fetal Circulation (Fig. 19.3a)
As the infant is born and cries, air enters the alveoli increas-
The fetus depends on the maternal circulation for gas ing the partial pressure of alveolar oxygen (PAO2) leading to
exchange [3]. The fetal lung is filled with liquid. It has a a decrease in PVR and pulmonary vasodilation. Consequently,
small blood flow that does not participate in gas exchange. pulmonary venous return increases (Fig. 19.3b) and
Pulmonary vascular resistance (PVR) is high due to hypoxic contributes to increasing the left ventricular preload. During
pulmonary vasoconstriction. The pulmonary arterial blood is this process, deferring umbilical cord clamping (DCC) until
diverted across the ductus arteriosus (DA) to the placenta. respiration becomes established (physiological cord clamp-
Oxygenated blood from the umbilical vein streams across ing) will provide umbilical venous flow as a source of left
the right atrium through the foramen ovale (FO) to the left ventricular preload as pulmonary venous flow is gradually
atrium and supplies the coronary and cerebral circulation. increasing. DCC for at least 30–60 s is recommended in all
Although the fetal PaO2 is low (~ 25 mm Hg), it compensates births where immediate resuscitation is not required [6].
through four mechanisms: (i) presence of fetal hemoglobin Once the umbilical cord is clamped, due to removal of the
(HbF) with strong oxygen affinity, (ii) large ventricular blood low-resistance placental circuit, systemic vascular resistance
flow (combined ventricular output of ~450 mL/kg/min as (SVR) increases. An increase in SVR/PVR ratio leads to
compared with 150 mL/kg/min in an adult), (iii) diverting reversal of shunts across the DA and FO from right-to-left
more oxygenated blood to the brain and heart (preductal), (pulmonary to systemic) to left-to-right (systemic to pulmo-
and (iv) increased hemoglobin values (15–19 g/dL in term nary; Fig. 19.3c). These shunts contribute to a rapid and
neonates) [3–5]. eight- to tenfold increase in pulmonary blood flow after birth.
a b c
Fig. 19.3 Transition from fetal to neonatal physiology. (a) Fetal circu- umbilical vein and the pulmonary veins (by oxygenation through the
lation with liquid filled lungs. The placenta serves as the organ of gas newly ventilated lungs) enters the left atrium and contributes to the left
exchange with deoxygenated blood coming from the umbilical arteries ventricular (LV) preload. (c) Neonatal circulation after removal of the
(UA) and oxygenated blood leaving the placenta to the fetus through placenta is characterized by reduced pulmonary vascular resistance
the umbilical vein (UV). Oxygenated blood enters the right atrium (RA) (due to ventilation of the lungs) and increased systemic vascular resis-
and crosses through the foramen ovale (FO) right-to-left (R → L) to tance (due to removal of the placenta) resulting in a left-to-right
perfuse the cerebral and coronary circulations. Deoxygenated blood (L → R) shunt at the patent ductus arteriosus (PDA) and eventual clo-
from the systemic veins enters the RA and the right ventricle (RV) to sure of the PDA and patent foramen ovale (PFO). Ventilation of the
the pulmonary artery (PA). As the pulmonary vasculature is constricted lungs is the key step in this transition. Lungs are established as the site
with high resistance, blood enters the aorta through the ductus arterio- of gas exchange. (Modified from Maheshwari Evidence Based
sus (DA) and reaches the placenta. (b) Transitional circulation during Neonatology, Copyright Satyan Lakshminrusimha)
deferred (physiological) cord clamping. Oxygenated blood from the
Asphyxia tion with stimulation, respiratory effort can improve during

primary apnea. However, if the asphyxial insult continues,
Classic studies by Dawes et al. have described the course of the fetus suffers from secondary apnea and will require posi-
respiratory and hemodynamic changes that occur with fetal tive pressure ventilation (PPV) to recover. During secondary
asphyxia (Fig. 19.4) [7]. Soon after fetal asphyxiation, there apnea, hypotension and bradycardia occur, and if asphyxia
is an increase in respiratory rate, heart rate, and blood pres- persists, cardiac arrest follows necessitating circulatory sup-
sure followed by primary apnea. If there is prompt interven- port with chest compressions.
Onset of Ischemia of Global hypoxia

asphyxial “expendable” and ischemia
insult organ systems
Brain Resuscitation
Satyan
Satyan
Heart Satyan
Satyan
with
Adrenal sparing PPV and
circulatory
Sa
tyan
Satyan support as
needed
Sat
yan
Sat
Sat
yan
yan
n
Satyan
a
an
an
ty
Satyan
Satyan
ty
Sa
ty
Sa
Sa
Satyan
Satyan
Satyan
Respirations
Rapid Primary Irregular Secondary

respirations apnea gasping apnea
Heart
pressure rate
e
Blood
Asphyxia b Resuscitation ROSC

Airway maintenance Breathing c
Circulatory Drugs
a and Agitation/ PPV (Stimulation
alone-inadequate) Support d
stimulation
Fig. 19.4 Pathophysiology of asphyxia and resuscitation showing hypotension occur. (b) Breathing with positive pressure ventilation
respiratory rate (green line), heart rate (purple line), and systemic blood (PPV) is required in the presence of secondary apnea as global ischemia
pressure (red line). Soon after an asphyxial insult, rapid respirations are can deprive blood flow to the brain and heart. The hyphenated blue line
observed as a compensatory phenomenon. Subsequently, primary overlapping respirations depicts PPV. (c) Circulatory support in the
apnea associated with bradycardia is noted. At this phase, blood flow to form of chest compressions is necessary in the presence of persistent
nonexpendable organs such as the brain, heart, and adrenals is pre- bradycardia in spite of effective PPV. (d) Drugs—epinephrine (or vol-
served, and blood pressure remains within normal limits. (a) ume)—are indicated when PPV and chest compressions are ineffective.
Maintaining the airway and agitation (stimulation) is required at this (e) Effective resuscitation results in return of spontaneous circulation
stage. However, if stimulation is not provided or if asphyxial insult is (ROSC). (Modified from Maheshwari Evidence Based Neonatology,
severe and ongoing, irregular gasping followed by secondary apnea and Copyright Satyan Lakshminrusimha)
Physiology of Resuscitation Gestational age—What is the expected gestational age?

Risk factors—Are there any additional risk factors (e.g., dia-
The key step during neonatal resuscitation is effective venti- betes, hypertension, preeclampsia, and obesity)?
lation of the lungs. During assessment, increasing heart rate Amniotic fluid—Is the amniotic fluid clear? Presence of
is the best sign of response to resuscitation [2]. The steps of meconium or blood can be associated with the need for
resuscitation include clearing the airway and stimulation for resuscitation.
primary apnea, PPV for secondary apnea, and chest com- Single/multiple—How many babies are expected?
pressions and epinephrine for circulatory collapse (Fig. 19.4). Placental transfusion—Are there any plans for delayed cord
clamping or cord milking? Factors that influence placen-
tal transfusion are shown in Fig. 19.6. With an intact cord,
Preparation for Delivery maternal blood gases and some anesthetic agents will
continue to cross the placenta and reach the fetus/neonatal
The anesthesiologist has primary responsibility for the infant.
mother. It is important to anticipate the need for neonatal
resuscitation using the mnemonic GRASP by posing five
questions (Fig. 19.5).
Fig. 19.5 Pictorial flow diagram of

neonatal resuscitation. Resuscitation
begins before delivery with team assembly,
equipment check, and briefing. Initial
questions follow the GRASP mnemonic
(Table 19.1). After delivery, gestational
age, muscle tone, and breathing should be
recorded for the initial assessment. If the
infant is full-term with good tone and
normal respirations, the infant should stay
with the mother and routine resuscitation
should be provided. If these three criteria
are not met, routine resuscitation is
provided in addition to further assessment.
Additional respiratory support can be
provided to infants who have breathing
difficulty or cyanosis via oxygen or
pressure, but an infant who remains apneic
or bradycardic requires support with
positive pressure ventilation. Monitoring
oxygen saturation and heart rate with pulse
oximetry (SpO2) and ECG, respectively,
should also be considered at this point.
The target preductal (right upper
extremity) SpO2 values at each time point
should be the range between the numbers
above and below the time point in the
inset. Positive pressure ventilation (PPV)
should continue for an infant who remains
bradycardic or apneic. The effectiveness of
ventilation should be assessed, and
ventilation corrective steps (mnemonic—
MRSOPA) should be performed as
needed. Finally, if the heart rate (HR)
decreases to <60 beats per minute (bpm)
and does not improve with adequate
ventilation, then tracheal intubation, chest
compressions, and 100% oxygen should
be provided. At this time, further therapy
with medications and assessment for
additional confounding issues such as
pneumothoraces or hypovolemia
(correcting with normal saline—NS)
should be considered. (Modified from
Maheshwari Evidence Based Neonatology
and Textbook of Neonatal Resuscitation
[2], Copyright Satyan Lakshminrusimha)
Table 19.1 ETT size for babies based on estimated gestational age Positioning
(GA—weeks) or birth weight (kg)
GA Weight ETT Suction catheter Laryngoscope The majority of neonates only require routine care and can
(weeks) (kg) size size blade
be held by the mother. Non-vigorous infants and preterm
>34 >2 3.5 8 F No. 1
neonates without good tone and with poor respiratory effort,
28–34 1–2 3.0 6 F or 8 F No. 0
<28 <1 2.5 5 F or 6 F No. 0 or 00 apnea, or grunting need to be placed under a radiant warmer.
These infants initially need positioning, stimulation, and
warmth. The baby should be positioned supine with the head
and neck slightly extended in the “sniffing position.” A
shoulder role may be useful for infants with a large occiput
from molding. If secretions are obstructing the airway, the
mouth should be cleared first followed by the nares by gentle
suction.
Temperature Management
Wet skin increases evaporative fluid loss (Fig. 8.6, Chap. 8).
Removing fluid from the skin by drying with a warm, dry
blanket is the first step in reducing heat loss. If more drying
is required, discard the wet towel and use a new dry towel
(Fig. 19.7). In preterm infants, placing them immediately in
a polyethylene plastic before drying is also effective in
reducing heat loss by evaporation. A combination of inter-
Fig. 19.6 Factors that influence a placental transfusion. Modified from ventions such as increasing the environmental temperature to
[6] to indicate the importance of uterine contractions, gravity (although 24–26 °C (75–80 °F) and using warm blankets, a plastic cov-
this plays a small role in the presence of vigorous uterine contractions), ering without drying, and a thermal mattress (Fig. 19.7) is
and presence of spontaneous respirations (crying). (Copyright Satyan effective in preventing hypothermia. It is important to avoid
Lakshminrusimha)
hyperthermia in asphyxiated infants as it may predispose to
poor outcomes [8].
Fig. 19.7 Mechanisms of heat loss during resuscitation. The neonate contact with a warmer surface such as a heated mattress. Heat can also
has the potential to gain or lose heat by four mechanisms: radiation, be transferred via convection by air passing over the infant. The tem-
conduction, convection, and evaporation (See Chap. 8, Fig. 8.6). Heat is perature in the DR is cooler than the infant, so the infant loses heat by
lost to surrounding surfaces that are not in direct contact with the infant this mechanism. This source of heat loss can be minimized by increas-
via radiation and is proportional to the temperature difference between ing the DR temperature and ensuring the sides of the radiant warmer are
the infant’s body and the environmental sources. A radiant warmer pro- up and surrounding the infant to minimize convection heat loss. Finally,
vides a source of radiant heat to counteract heat losses. Increasing the the infant can lose heat by evaporation. This can be reduced by drying
temperature of the DR can also decrease the amount of heat loss by the neonate immediately after delivery or with the use of a polyurethane
radiation and convection. Conduction is the route by which neonates hat placed on the head and polyurethane bag or wrap covering the
gain or lose the least amount of heat. Conduction heat energy is trans- infant’s body in premature infants. Modified from Mathew et al. [55]
ferred between surfaces that are in direct contact. An infant can lose (Copyright Satyan Lakshminrusimha)
heat via conduction if placed on a cooler surface and gain heat if in
Stimulation Monitoring
In addition to stimulation by positioning, clearing secretions In infants that require resuscitation beyond stimulation,
if needed, and drying, gently rubbing the back, trunk, or assessment of oxygenation, respiration, and heart rate is
extremities will assist in initiating and supporting spontane- important. Assessment of color is not accurate, whereas
ous breathing. If a neonate remains apneic despite stimulation placement of a pulse oximeter on the right upper extremity to
for a few seconds, PPV should be initiated without delay. monitor preductal SpO2 is vitally important (Fig. 19.8).
Fig. 19.8 Methods to assess the heart rate in the DR. There are four rate is displayed and requires adequate perfusion. Pulse oximeter moni-
methods to assess heart rate in the DR, each with advantages and disad- tors are not immediately available in every DR. Both umbilical cord
vantages. The method chosen should be based on the availability of palpation and auscultation with a stethoscope are not as accurate as
equipment and training of providers. Electrocardiography is the most pulse oximetry or electrocardiography and do not provide continuous
accurate method and is most widely recommended for use in the DR, monitoring. However, these approaches use equipment that is readily
but this resource is not always available. Pulse oximetry is more reliable available in most DRs. Modified from Vali et al. [9] (Copyright Satyan
than other methods, but there may be a lag time before an accurate heart Lakshminrusimha)
Heart rate can be monitored by pulse oximetry, palpation of 2000 mother-infant dyads in each trial, tracheal suctioning
pulsations of major arteries (including the umbilical stump), for vigorous infants, suctioning before the delivery of
auscultation, EKG, and Doppler/echocardiographic mea- shoulders, and amnioinfusion all failed to impact the inci-
surements (Fig. 19.8). Placement of EKG leads is a quick, dence of meconium aspiration syndrome (MAS) [13].
reliable method to measure the heart rate in the DR [9]. Before 2015, non-vigorous infants born through MSAF
underwent routine tracheal suction [13]. Based on the
results from four small randomized controlled trials from
pproach to an Infant Born Through
A India [14–17] that showed no difference in mortality or the
Meconium Stained Amniotic Fluid (MSAF— incidence of MAS among non-vigorous infants with tra-
Fig. 19.9) cheal suctioning, NRP now recommends initiation of PPV
without routine immediate direct laryngoscopy with tra-
In the 1990s, amnioinfusion, suctioning at the perineum, cheal suctioning in non-vigorous neonates delivered
and tracheal suctioning for both vigorous and non-vigorous through MSAF [1]. MSAF remains a significant risk factor
infants were steps in the management of an infant born for needing advanced resuscitation. If meconium obstructs
through MSAF (Fig. 19.9). With evidence from three large the airway and prevents chest rise with PPV, suctioning
randomized controlled trials [10–12] involving close to may be needed [1].
Fig. 19.9 Management of

infants born through
meconium stained amniotic
fluid (MSAF) in the 1990s.
Randomized controlled trials
(n = number of mother-infant
dyads enrolled in these trials)
evaluating various indications
for these interventions are
shown. See text for details.
Modified from Rawat et al.
[13]—Copyright Satyan
Lakshminrusimha
Positive Pressure Ventilation (PPV) at ≤1 s. Sustained inflation greater than 10 s can be harmful
in preterm infants and should be avoided based on the results
Most neonates breathe spontaneously after birth within from the SAIL study (Fig. 19.10) [19]. In spontaneously
30–60 s with stimulation. PPV is indicated if neonates do not breathing infants who require respiratory support, but who
breathe within the first 60 s with stimulation or are persis- have heart rates >100 bpm, continuous positive airway pres-
tently bradycardic with heart rate < 100 beats per min (bpm). sure (CPAP) should be provided.
Compared with older children and adults, neonates enter into Mask ventilation is ineffective in some infants due to a
secondary apnea before the onset of cardiac arrest (Fig. 19.4). poorly fitting facemask, inappropriate position of the head,
Hence, respiratory support should precede chest compres- obstruction by secretions, or inadequate PIP. Corrective mea-
sions during neonatal resuscitation [18]. Initial breaths with sures using the mnemonic MRSOPA focus on effective ven-
a peak inflation pressure (PIP) of 20–25 cm H2O and positive tilation of the lung (Fig. 19.9). If mask ventilation fails to
end-expiratory pressure (PEEP) of 5 cm H2O are provided at cause the chest to rise, alternative airways such as a laryngeal
a rate of 40–60/min. The inflation time should be kept brief mask or tracheal tube should be used. (Fig. 19.11).
Fig. 19.10 A graphic abstract outlining the SAIL study that evaluated of early death are listed in the inset. BPD bronchopulmonary dysplasia,
sustained inflation vs. PPV during initial resuscitation [19]. Inclusion bpm beats per minute, GI gastrointestinal, HR heart rate, IPPV intermit-
criteria, hypothesis, rationale, and results are shown. Early death (dur- tent positive pressure ventilation, IVH intraventricular hemorrhage,
ing the first 48 h after birth) occurred more frequently in premature PPHN persistent pulmonary hypertension of the neonate, SI sustained
neonates who were randomized to receive sustained inflations. Causes inflation. Copyright Satyan Lakshminrusimha
Fig. 19.11 Corrective steps

to improve efficacy of
ventilation. These steps use
the mnemonic
MRSOPA. After these
corrective measures, PPV
should be attempted as shown
and chest rise evaluated.
(Copyright Satyan
Lakshminrusimha)
Oxygen of its association with a greater mortality in term infants

[18]. A meta-analysis of studies that compared low (≤ 30%
In term infants ≥35 weeks gestation, resuscitation is initi- oxygen) vs. high (≥ 60%) inspired oxygen for initial resus-
ated with 21% oxygen and titrated up based on preductal citation of infants failed to demonstrate significant differ-
SpO2 in the right upper limb [18, 20]. In preterm infants ences in outcome [21]. A summary of current findings is
28–34 weeks gestation, most guidelines recommend the shown in Fig. 19.13.
use of 21 to 30% oxygen (Fig. 19.12). The optimal initial When depressed infants require chest compressions (see
oxygen for resuscitation of preterm infants <28 weeks is below), the inspired oxygen should be set to 100% due to
controversial. The NRP recommends 21–30% [18] but sev- compromised pulmonary, coronary, and cerebral blood
eral experts prefer to use ~30% oxygen. In extremely pre- flow [22].
term infants who require mask ventilation, the oxygen Frequent assessment of oxygenation using the pulse
gradient from inspired oxygen to alveolar gas and from oximetry chart in Fig. 19.12 and titration of inspired oxygen
alveolar gas to arterial gas (A-a gradient) might be large in is important [23]. The main goal is to achieve a heart rate of
extremely preterm infants due to their lungs being imma- >100 bpm within 2 min and a preductal SpO2 of 80–85% by
ture in the canalicular stage. In all neonates, it is not recom- 5 min. Failure to achieve these outcomes may increase mor-
mended to begin resuscitation with 100% oxygen because bidity and mortality in preterm infants [24, 25].
Fig. 19.12 Guidelines for initial titration of oxygen based on refer- pressions are needed, inspired oxygen should be immediately increased
ences [20] and modified from AHA NRP guidelines [18]. In all cases, to 100%. Goals of adjusting inspired oxygen during resuscitation are
preductal SpO2 should be monitored, and inspired oxygen should be shown on the right panel. HR: heart rate. Modified from Saugstad et al.
adjusted based on targets shown in the table. However, if chest com- [20]. Copyright Satyan Lakshminrusimha
Fig. 19.13 Current evidence on the initial oxygen concentration for showed no difference in either clinically meaningful outcomes [21] or
resuscitation of extremely preterm infants. The goal of this intervention oxidative stress markers. One trial in a post hoc analysis showed
is to achieve a preductal SpO2 of ≥80–85% and heart rate (HR) of ≥100 increased mortality with 0.21 FiO2 in extremely preterm infants [56],
beats per minute (bpm) by 5 min of birth. Systematic reviews and meta- while another trial showed better minute ventilation volumes with an
analyses of studies using low initial FiO2 ≤ 0.3 vs. high FiO2 ≥ 0.6 FiO2 of 1.0 [57]. Copyright Satyan Lakshminrusimha
Intubation the CO2 detector may change color to yellow even though the
ETT is not in the trachea. This occurs when the CO2 detector
Tracheal intubation is probably the most common procedure has been contaminated with epinephrine (and possibly gas-
for which the neonatal team is likely to seek help from the tric acid—although uncommon), if vigorous mask ventila-
anesthesiologist. Intubation is often conducted using an tion has pushed exhaled breath into the stomach, or if the
uncuffed tube. Typically, uncuffed 2.5, 3.0, 3.5, and 4.0 mm CO2 detector is defective and has changed color in the pack-
tubes are stocked in the DR. These tubes can be inserted by age before use [2].
digital (using a finger), direct laryngoscopy or using a video
laryngoscope [26]. A laryngeal mask may serve as an alter-
native to ineffective bag mask ventilation (for neonates epth of Insertion of ETT in Neonates
D
>2000 gm or 34 weeks gestation) or for any neonate whose (Fig. 19.16)
airway cannot be intubated during resuscitation [27, 28].
The trachea is very short in neonates (especially in
extremely preterm infants), 4–4.5 cm. It is important to
Indications for Tracheal Intubation in the DR place the tip of the ETT below the vocal cords but above the
carina to avoid a right mainstem intubation. Because the
(i) Improve ventilation efficacy when mask ventilation is right upper lobe bronchus may take off from the trachea (in
ineffective or inadequate. up to 2% of patients) more commonly in Down syndrome,
(ii) Prolonged PPV—ETT improves the efficacy and ease VACTERL, and others, it is important that the tube is
of ventilation. midtracheal. Gestational age is a reasonable predictor of
(iii) During chest compressions—To maximize efficacy. the correct insertion depth for orotracheal intubation. A
(iv) Diaphragmatic hernia—To minimize air entering the table based on Kempley et al. is shown in Fig. 19.16 [29].
stomach. The nasal septum-tragus length (NTL) [30], oro-helical
(v) Surfactant administration. length [31], and sternal length have also been used to calcu-
(vi) Removal of obstruction by direct suction. late the “tip-lip” depth of an orotracheal tube. The NTL
(sometimes adjusted by adding 0.5–1 cm) is most com-
monly used. The Tochen formula, also known as the 7-8-9
Size of the ETT rule, was crafted to predict the “tip to lip” length of the
tracheal tube based on the neonate’s weight (6 cm + 1 cm/
Size of the ETT is based on estimated gestational age or kg body weight) [32]. The formula is easy to remember and
weight (Table 19.1). accurate in full size neonates but more likely to predict the
tip of the tube too deep in low birth weight and extremely
premature infants. Hence, the ‘modified’ Tochen formula
Confirmation of Tube Position (5 cm + 1 cm/kg body weight), which reduced the depth of
the tube by 1 cm, positioned the tip of the tube more fre-
The two primary methods used to confirm correct placement quently mid-tracheal in low birthweight and extremely pre-
of the ETT are a rapidly increasing heart rate and SpO2 and mature infants was introduced [33]. A recent systematic
detection of exhaled CO2. Other indicators included (a) audi- review of all formulae that predict the optimal depth of the
ble and equal breath sounds over both axillae during PPV, orotracheal tube [34] and a randomized controlled trial that
symmetrical chest rise, absent air entry over the stomach, compared three formulae—the Tochen, Kempley, and
little or no air leak from the mouth during PPV, and mist in NTL—both concluded that “tip to lip” formulae equally
the ETT (Fig. 19.14). predicted malpositioned tracheal tubes in neonates [35].
In some situations where ventilation and/or perfusion of We recommend that a chest X-ray should be reviewed to
the lungs is inadequate, the CO2 detector may not show a verify the position of the tip of the tracheal tube in all neo-
color change even though the ETT is in the trachea. Possible nates notwithstanding the formulae used, to minimize the
conditions where such false negative CO2 detector color risk of complications and optimize the delivery of medica-
change might occur are shown in Fig. 19.15. Occasionally, tions via the tracheal tube.
Fig. 19.14 Methods to confirm the position of the ETT within the trachea. The primary methods are shown in red squares. Copyright Satyan
Lakshminrusimha
Deterioration after Intubation or loss of pressure in the gas source). The mnemonic
DOPE outlines these conditions [2].
Sudden deterioration after intubation can be due to dis-
placement of the ETT (too far into the right main stem or • Displaced ETT.
pulled back into pharynx or moved into the esophagus), • Obstructed ETT.
obstruction by mucus plug or blood or meconium, devel- • Pneumothorax.
opment of a pneumothorax, or other air-leak syndrome or • Equipment failure.
equipment failure (disconnections in the ventilator circuit
Fig. 19.15 Causes for

persistent purple coloration of
colorimetric CO2 detector in
neonates. The most common
reason is esophageal
intubation. The other causes
can be classified into
inadequate ventilation and
poor perfusion. Extreme
prematurity can be associated
with both hypoventilation and
low pulmonary flow. LV: left
ventricle; PIP: positive
inspiratory pressure; RV: right
ventricle. Copyright Satyan
Lakshminrusimha
Fig. 19.16 Formulas, measurements, and table to predict the depth of ETT insertion in neonates. See text for details. Copyright Satyan
Lakshminrusimha
Chest Compressions expert opinion and was made in an attempt to match the
respiratory and heart rate in the neonate. Interestingly, this
The etiology of cardiac arrest in newly born infants differs ratio provides 30 breaths and 90 compressions in 1 min,
from that of adults. Neonatal cardiac arrest in the DR arises which are significantly less than the intrinsic respiratory rate
from profound bradycardia as a result of oxygen depletion, of 40 breaths and heart rate of 120–160 beats per minute in
carbon dioxide accumulation, and increasing lactic acidosis the neonate. The optimal ventilation strategy immediately
secondary to asphyxia. Therefore, ventilation remains criti- after birth has not been determined, and different C:V ratios
cal in establishing return of spontaneous circulation (ROSC), have not improved outcomes in preclinical and neonatal
and resuscitation with exclusive chest compressions in manikin models [43–47]. A recent study in a perinatal
asphyxiated piglet models is ineffective [36, 37]. Chest asphyxiated lamb model with fluid-filled lungs and a transi-
compressions are indicated for those neonates whose heart tioning circulation, mimicking the neonate in the DR, in
rate (HR) remains <60 bpm in the presence of adequate which continuous uninterrupted chest compressions (at a
ventilation. rate of 120) were compared with asynchronous ventilation to
Severe asphyxia can lead to substrate depletion and pro- 3:1 C:V has shown greater oxygen delivery to the brain, but
found vasodilation, which can influence the effect of chest no difference in the incidence or time to ROSC [48].
compressions on hemodynamic parameters. The primary It is important to summon additional personnel if the
determinant in successful cardiopulmonary resuscitation newly born infant requires chest compressions. The inspired
(CPR) depends on adequate myocardial blood flow. oxygen should be increased to 100% [22]. If the HR after
Measuring myocardial blood flow is not currently practical. birth remains <60 bpm despite adequate PPV for at least 30 s,
Therefore, coronary perfusion pressure (CPP), the difference it is reasonable to initiate chest compressions (Fig. 19.18).
between the right atrial diastolic pressure and the diastolic Several factors other than the chest compression rate
aortic pressure, serves as a surrogate for myocardial flow impact CPR success including i) the depth of compressions,
(Fig. 19.17). Animal studies have demonstrated that a greater ii) full recoil between compressions, and iii) the method of
CPP (>20 mm Hg) improves the likelihood of achieving chest compressions and provider performance (Fig. 19.19).
ROSC and, therefore, better survival rates [38–40]. In the The depth of chest compressions should be approximately
clinical setting, patients who had a greater CPP (>25 mm one-third of the anterior-posterior chest diameter and be suf-
Hg) during CPR had a greater likelihood of ROSC [41]. ficient to generate a palpable pulse. In neonates, the two-
However, prospective clinical trials have not confirmed that thumb technique is the preferred method to provide chest
targeting CPP during CPR improves survival. Furthermore, compressions. The thumbs are placed together (side by side
the impact of CPP in predicting ROSC in neonates is or one on top of the other) on the lower third of the sternum,
unknown. Experiments on adult pigs with ventricular while the hands encircle the chest and fingers support the
fibrillation-induced cardiac arrest have shown a stepwise back. This technique delivers greater blood pressures, supe-
increase in diastolic blood pressure with each successive rior depth, and less variability with each chest compression
chest compression and an abrupt decrease in blood pressure when compared with the two-finger method (the tips of the
after interruption of chest compressions [42]. In the presence middle and either ring or index finger placed over the ster-
of a ductus arteriosus, it is not clear if this relationship is num) [49].
maintained in neonates during chest compressions in the DR Poor response to chest compressions and PPV should
(Fig. 19.17). In newly born lamb models, coronary perfusion alert the resuscitator to check the efficacy of various inter-
occurs during diastole during intrinsic beats and decompres- ventions and the presence of other factors such as pneumo-
sion phase during CPR, whereas cerebral perfusion occurs thorax, pneumopericardium, and blood loss. This checklist
during systole during intrinsic beats and compression phase goes with the mnemonic CARDIO and is shown in Table 19.2
during CPR (Fig. 19.17a–c). [2]. If HR remains <60 bpm, epinephrine should be prepared
The current recommended compression-to-ventilation to be administered through either the ETT or an umbilical
(C:V) ratio for neonatal resuscitation of 3:1 is based on venous catheter (see next section).
Fig. 19.17 Determinants of

a
cerebral and coronary blood
flow (a) during intrinsic heart
beats (b) and chest
compressions (c) at 3:1 ratio
with positive pressure
ventilation (PPV). In the
presence of a large patent
ductus arteriosus (PDA) and
variable pulmonary vascular
resistance (PVR) soon after
birth, achieving physiological
diastolic pressure during chest
compressions is difficult
during cardiac arrest (c).
Carotid flow occurs during
the systolic or compression
phase, and coronary flow
occurs during diastolic or
decompression/relaxation
phase. Copyright Satyan
Lakshminrusimha
c
Fig. 19.18 Preparation,
indications, and procedure for
chest compressions.
Copyright Satyan
Lakshminrusimha
Fig. 19.19 Procedure for

providing chest compressions.
Effective ventilation can be
provided with an endotracheal
tube (ETT) and 100%
inspired oxygen. With thumbs
placed on the lower third of
the sternum, with fingers
encircling the thorax, and
compressing one-third
anteroposterior (AP) diameter
of the thorax, adequate
pressures can be generated.
Preparation to place an
umbilical venous catheter for
administration of epinephrine
or fluids is the next step if
positive pressure ventilation
and chest compressions are
not effective. Copyright
Satyan Lakshminrusimha
Table 19.2 Questions to ask when heart rate is not improving with It can also be administered through the intraosseous route
compressions and ventilation (mnemonic CARDIO) (IO) [2].
1. Chest movement: Is the chest moving with each breath? Epinephrine is available in two concentrations
2. Auscultation: Are bilateral breath sounds audible? (1 mg/1 mL and 1 mg/10 mL), and selecting the wrong con-
3. Rate: Are three compressions plus one ventilation well-
coordinated and being delivered every 2 s? centration can result in a tenfold dosing error. The recom-
4. Depth: Is the depth of compressions adequate (one-third the AP mended tracheal (ET) dose is 0.05–0.1 mg/kg whereas the
diameter of the chest)? intravenous dose is 0.01–0.03 mg/kg [1]. Based on animal
5. Inspired oxygen: Is 100% oxygen being administered through the data, and to simplify the required calculations [50, 51], it
PPV device?
6. Other causes: Air leak, anemia. would be reasonable to administer 0.1 mg/kg (or 1 mL/kg of
1 mg/10 mL epinephrine) by the ET route in neonates in the
DR who have fluid-filled lungs. It may also be more practi-
cal to use an IV dose of 0.02 mg/kg (or 0.2 mL/kg of
Epinephrine in the DR 1 mg/10 mL epinephrine). A dose of 0.02 mg/kg enables use
of a 1 mL syringe for a wide range of birth weights from
Epinephrine is the only vasoactive drug recommended by the 500 g to 5 kg. At this dose, 0.1 mL of epinephrine can be
International Liaison Committee on Resuscitation (ILCOR) reliably prepared in a 1 mL syringe for an extremely prema-
for neonates who remain severely bradycardic (HR < 60 bpm) ture infant weighing 500 g [52].
or in cardiac arrest after effective ventilation has been estab- If the first epinephrine dose is given by the ET route, the
lished (Fig. 19.20). The preferred route of administration is IV dose can be administered as soon as intravascular access
intravascular, and access through the umbilical vein by inser- is established. Repeat doses of epinephrine should be given
tion of an umbilical vein catheter may be the best option in every 3 min. If IV access cannot be obtained, epinephrine
the poorly perfused neonate. Epinephrine may be given can also be given through an intraosseous device inserted
through the ETT while intravenous (IV) access is attempted. into the proximal tibia in term neonates.
Fig. 19.20 Indications, dose,

and routes of administration
of epinephrine. HR heart rate,
UVC umbilical venous
catheter (low – 2 to 4 cm
below skin surface), IO
intraosseous. See text for
details. Copyright Satyan
Lakshminrusimha
Volume Expansion tation (Fig. 19.20). If blood loss is suspected, type O,

Rh-negative blood administration is preferred when avail-
Neonates who cannot be successfully resuscitated despite able. The use of albumin is discouraged owing to an observed
chest compression and epinephrine administration could be association with increased mortality [53] and possible fur-
hypovolemic and may require a fluid bolus. Volume expan- ther exacerbation of transudation of fluid into the interstitial
sion should also be considered in the event of suspected space in the asphyxiated acidotic state [54].
blood loss (e.g., placental abruption, feto-maternal hemor- The recommended initial fluid bolus is 10 mL/kg and
rhage, twin anemia-polycythemia sequence). Normal saline should be given no faster than over 5 min. Additional boluses
and Ringer’s lactate are appropriate choices for fluid resusci- may be given after clinical assessment and observation of
response. The neonatal heart is less compliant and has rela- stained neonates before delivery of their shoulders: multicentre,
tive diastolic dysfunction. Administering an excess of fluids randomised controlled trial. Lancet. 2004;364(9434):597–602.
12. Fraser WD, Hofmeyr J, Lede R, Faron G, Alexander S, Goffinet F,
can have untoward hemodynamic effects. Furthermore, rapid et al. Amnioinfusion for the prevention of the meconium aspiration
infusion of volume can cause rapid changes in blood pres- syndrome. N Engl J Med. 2005;353(9):909–17.
sure, which can increase the risk of intraventricular hemor- 13. Rawat M, Nangia S, Chandrasekharan P, Lakshminrusimha
rhage in premature infants. S. Approach to infants born through meconium stained amni-
otic fluid: evolution based on evidence? Am J Perinatol.
2018;35(9):815–22.
14. Chettri S, Adhisivam B, Bhat BV. Endotracheal suction for nonvig-
Discontinuation of Resuscitation orous neonates born through meconium stained amniotic fluid: a
randomized controlled trial. J Pediatr. 2015;166:1208–13.
15. Nangia S, Sunder S, Biswas R, Saili A. Endotracheal suction in
The decision to continue or discontinue resuscitative efforts term non vigorous meconium stained neonates-A pilot study.
should be individualized and should be considered at approx- Resuscitation. 2016;105:79–84.
imately 20 min after birth if no HR is observed after effective 16. Singh SN, Saxena S, Bhriguvanshi A, Kumar M, Chandrakanta
resuscitation. S. Effect of endotracheal suctioning just after birth in non-vigorous
infants born through meconium stained amniotic fluid: A random-
ized controlled trial. Clinical Epidemiology and Global Health.
2018;
Conclusion 17. Kumar A, Kumar P, Basu S. Endotracheal suctioning for prevention
of meconium aspiration syndrome: a randomized controlled trial.
Eur J Pediatr. 2019;178(12):1825–32.
Anesthesiologists often assist in critical aspects of neonatal 18. Aziz K, Lee HC, Escobedo MB, Hoover AV, Kamath-Rayne
resuscitation. Timely help in securing airway and assistance BD, Kapadia VS, et al. Part 5: Neonatal Resuscitation: 2020
with respiratory and circulatory support are important in American Heart Association Guidelines for Cardiopulmonary
achieving good outcomes following resuscitation. Resuscitation and Emergency Cardiovascular Care. Circulation.
2020;142(16_suppl_2):S524–50.
19. Kirpalani H, Ratcliffe SJ, Keszler M, Davis PG, Foglia EE, Te Pas
A, et al. Effect of sustained inflations vs intermittent positive pres-
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Ethical and Medicolegal Considerations
20
Mariah K. Tanious and Thomas J. Mancuso
Ethical and medical-legal dilemmas frequently arise in the work is widely utilized by adult and pediatric bioethicists
perioperative care of term and preterm neonates. This when resolving difficult ethical issues in the care of patients.
requires that pediatric anesthesiologists have a working Accordingly, it behooves the practicing pediatric anesthesi-
knowledge of these ethical concerns in order to provide com- ologist to be familiar with these concepts.
prehensive care. Here we provide a concise review of com-
mon ethical challenges in the perioperative care of term and
preterm neonates utilizing a widely accepted decision- Limitations to the Four Principles Framework
making framework and then examine fundamental medical-
legal concerns in neonatal care. Autonomy, from its Greek roots, literally means self-rule and
is in many respects the foundation of the four principles frame-
work. In ethics, autonomy commonly refers to an individual’s
Reasoning About Ethical Concerns freedom from control and their unconstrained ability to make
profound life choices as they see fit. In the case of the neonate
he Four Principles Approach to Ethical
T who has not developed the capacity to reason and make inde-
Reasoning pendent decisions about life choices, there can be no literal
interpretation of this principle. Moreover, as mandated by
In their landmark text Principles of Biomedical Ethics, bio- legal regulations in nearly all US jurisdictions, and as sup-
ethicists Tom Beauchamp and James Childress advocate that ported by most pediatric ethicists, even loving parents are not
ethical dilemmas in clinical practice are most comprehen- free to autonomously make any and all medical decisions for
sively considered by utilizing a framework structured upon their children, such as the refusal of blood component therapy
four principles: autonomy, non-maleficence, beneficence, in a life-threatening situation [2, 3]. Importantly, then, the
and justice [1]. That is, when confronting a difficult ethical foundational principal of autonomy or self-determination does
dilemma in clinical practice, the four principles framework not unequivocally reside even in parental decisions for their
advocates that the clinician determines how to proceed by child. Parental autonomy is superseded, in part, by societal
assessing the net balance of the salient concerns from the norms and standards to protect the minor as established by the
perspective of each principle. Notably for pediatric practitio- Supreme Court of most countries.
ners, the conceptual foundation of this framework rests on Non-maleficence refers to the obligation of caregivers to
the perspective of the autonomous adult patient, and thus the avoid harm. In some clinical situations, agreement on what
four principles framework does not entirely transfer to all constitutes a harm would engender little debate, for example,
pediatric contexts. Nevertheless, the four principles frame- failing to provide any perioperative analgesia to an infant
suffering from significant pain after an invasive procedure
would be considered a great harm by nearly all in our society.
M. K. Tanious (*)
Department of Anesthesia and Perioperative Medicine, MUSC In other cases, such as a study requiring serial heel sticks in
Shawn Jenkins Children’s Hospital, Charleston, SC, USA otherwise healthy neonates to study glucose trends, well-
e-mail: [email protected] intended clinicians might reach opposite conclusions on
T. J. Mancuso whether such a research protocol represents, or does not rep-
Department of Critical Care, Boston Children’s Hospital, resent, a harm [4]. The principle of beneficence is a contin-
Boston, MA, USA
uum with non-maleficence but requires more of clinicians
e-mail: [email protected];
[email protected] (and others) than not causing harm. The principle of

632 M. K. Tanious and T. J. Mancuso
b eneficence requires clinicians to take active steps to ensure ric anesthesiologist, however, often meets the family only
a positive benefit to the patient. Beneficence also includes immediately before the start of the procedure. This meeting
the obligation to rescue persons from harm or harmful situa- may even take place in the holding area, not the ideal loca-
tions. This principle is interpreted from a translation of tion or timing for an in-depth discussion of the risks, bene-
Hippocrates from his Epidemics: “As to disease, make a fits, and options for anesthetic care.
habit of two things, to help but at least do no harm.” Yet, as The content of the informed permission conversation with
with “harm,” well-intentioned clinicians might not always the parents must be adapted to the context. In cases involving
agree on what constitutes a “benefit” in a particular clinical full-term neonates scheduled for relatively elective or urgent
context. For example, some clinicians in a given context may procedures such as pyloromyotomy, circumcision, or herni-
strenuously advocate for continuing life-sustaining treatment orrhaphy, it very well may be that the risk, small as it may be,
because they conclude that the benefits outweigh the harms, from the provision of anesthesia is significantly greater that
whereas others may be equally certain, after assessing the that posed by the surgical procedure itself. The parents may
same situation, that the harms of further treatment outweigh express their concern to the pediatric anesthesiologist in
any potential benefit. The fourth principle, justice, refers to these situations with statements such as: “My baby is not
the provision of fair, equitable, and appropriate treatments to likely to suffer from his hernia repair, but I am very worried
persons in light of what is owed to persons. As with the other about the anesthesia.” Discussion of the possible deleterious
principles, the concept of what constitutes justice is not free effects of various anesthetic medications on the developing
from differing interpretation by thoughtful clinicians or par- central nervous system is an important and frequently cited
ents. Furthermore, the use of justice as an ethical principle is parental concern, which is reviewed in more detail beyond
made more complex by the consideration of fairness and this chapter. In addition to a review of this issue and other
equality with respect to society, which may be especially relevant anesthetic concerns, the pediatric anesthesiologist
challenging in cases involving scarce or financially burden- should engage in a frank and understandable exchange with
some resources. In sum, while the four principles approach the parents, asking open-ended questions and providing
to reasoning about ethical dilemmas provides a framework them with time and space to weigh all of their concerns
for clinicians to think comprehensively about all of the regarding the anesthetic.
salient features, it cannot overcome variable interpretations Many surgical cases involving neonates are much more
of each of the principles that may prevent all parties to a significant and emergent in nature, however. In these cases,
given case from reaching similar conclusions on how to often involving preterm neonates, the risks from the condi-
proceed. tion afflicting the neonate and from the surgery itself may
be quite significant, reducing the anesthetic care to a resus-
citation more than the provision of analgesia, unconscious-
Perioperative Applications of the Four ness, and vital sign stability. The question of
Principles Framework cardiopulmonary resuscitation (CPR) may even be part of
the preanesthetic discussion. In such cases, the pediatric
Autonomy anesthesiologist should have a discussion with both the sur-
The biomedical principle of autonomy mandates informed geon and neonatologist in order to appreciate the gravity of
consent to medical procedures for the adult with decision- the neonate’s condition and what can be expected in the
making capacity. In the ideal process, the informed consent operating room. It may be appropriate to have a preanes-
covers the risks and benefits of the proposed procedure, the thetic discussion with the parents, surgeon, and the neona-
risks and benefits of alternatives to the procedure, and the tal intensive care unit physicians and nurses in order to
risks and benefits of doing nothing. In care of the neonate, minimize the chances in this very stressful situation that the
parental permission necessarily replaces direct informed family becomes confused and unduly anxious as a result of
consent. True informed consent requires more than a signa- hearing similar information, but with different emphasis
ture on a closely typed form. The parents who give permis- and language from different sources. In consideration of
sion to caregivers must themselves understand the difficult cases like these, Pinter has proposed classifying
information, accept the care plan, and give voluntary permis- surgical neonates according to their chances for recovery
sion without persuasion or manipulation. and the quality of life should the neonate recover [5]. The
The preanesthetic conversation, while often cursory, can details of the classification are not as important as ensuring
and should be an opportunity for the pediatric anesthesiolo- that the parents understand, as much as possible, the imme-
gist to inspire confidence and build rapport with the family as diate as well as longer-term prognosis, all before signing
well as glean any important details about the infant before the consent. Other authors, such as Caniano, reviewed neo-
the procedure. Even for urgent or emergent cases, the parents natal surgery and highlighted the important differences
have likely met and spent time with the surgeon. The pediat- between simply survival and a benefit to the neonate [6],
20 Ethical and Medicolegal Considerations 633
whereas Lorenz reviewed the important ethical consider- • In cases where survival is possible but a good outcome is
ations in the management of preterm neonates at the unlikely, the (well-informed) parental preferences should
extremes of viability and indicated the primacy of the neo- guide whether or not CPR be instituted.
nate’s best interest in these difficult choices [7]. Parents are • In cases where a good outcome is considered more likely,
considered by all of these commentators to be the persons CPR should be undertaken and continual reevaluation of
best suited to determine and advocate for the best interests the utility of continued intensive care be undertaken [10].
of their neonate, once again underscoring the importance of
the preanesthetic discussions. Beneficence
There are two aspects of beneficence: Positive beneficence
Non-maleficence requires that clinicians act to increase the welfare of patients,
The principle of non-maleficence comes into importance while utility requires clinicians to balance the benefits and
especially in the care of neonates at the extremes of viability burdens of an action and choose the action leading to the best
and/or with such serious surgical conditions that survival is overall result [1]. The utility aspect of beneficence becomes
in doubt and prognosis grim. Harm, as defined by Beauchamp relevant to pediatric anesthesiologists in terms of assessment
and Childress, means an unjustifiable setback or defeat of a of the risks and benefits of appropriate anesthetic care for an
person’s interests [1]. They also limit their definition to phys- operation or procedure and in the management of pain in the
ical harms. As mentioned, parents are generally, but not neonate in both intraoperative and postoperative periods
unequivocally, considered the prima facie authority to deter- [11]. The principle of utility serves as a useful decision-
mine the best interests for the neonate. Yet, some have argued making framework in these situations since anesthetic agents
that the best interest standard is insufficient for severely have immediate deleterious cardiovascular effects as well as
impaired infants and instead advocate for additional view- possibly longer-term effects on the developing central ner-
points in the evaluation of care provided to these unfortunate vous system of the neonate. In the postoperative period,
neonates [8]. Proponents of this view argue that the suffering assessing the adequacy of analgesia can also be quite prob-
of infants is not given sufficient weight and propose that lematic. There are a variety of pain assessment tools avail-
severely impaired infants have the right to a dignified death able for the neonate for evaluation of acute, procedural, and
and support palliative as opposed to intensive care for these chronic pain [12]. These tools include both physiologic and
unfortunate patients. behavioral components and will be most effective only if all
The Committee of the Fetus and Newborn (COFN) of the caregivers have ongoing training in their use. Yet even in the
American Academy of Pediatrics (AAP) addressed the issue case of clearly suboptimal pain control, analgesics present
of determining an infant’s best interests. In a policy state- both benefits and potential harms to the neonate. Careless
ment on high-risk neonates, the Committee notes, “…inten- use of analgesics in any neonate can lead to significant car-
sive treatment of all severely ill infants may result in the diopulmonary derangements. A proper balance of the bene-
prolongation of dying accompanied by significant discom- fits and harms of such essential treatment as adequate pain
fort for the infant or survival with unacceptable quality of relief begins with clinically competent assessment of the
life…non-intensive treatment may result in increased mor- patient and appropriate dosing of any medication.
tality and morbidity….either approach risks undesired and In sum, ethical considerations of benefit and harm are
unpredictable results” [9]. The COFN also notes the impor- inextricably linked to competent clinical care. This is par-
tance of the parents’ role in decision-making regarding the ticularly relevant to the provision of palliative care to
care of these critically ill neonates but also reemphasizes that infants with a life-threatening and/or terminal condition in
the physician’s first responsibility is to the patient. The which the unique training and expertise of the pediatric
Committee further states that physicians are not required to anesthesiologist can guide the development and implemen-
provide treatment that they consider to be inappropriate or to tation of effective treatment regimens with minimal untow-
withhold beneficial treatments [10]. In cases of honest dis- ard effects [13].
agreement, the COFN recommends that the hospital bioeth-
ics committee become involved to resolve the issues. In Justice
practice, there may be insufficient time for this to occur, and The concept of what constitutes justice in the context of
the pediatric anesthesiologist must personally decide if their healthcare is more problematic as there are widely differing
personal morals allow them to participate in the care of a views in our plural society. Barnum describes what she calls
particular neonate. Last, the Committee’s policy statement “benevolent injustice,” an outcome in which an infant sur-
notes the following: vives a difficult neonatal course but with significant morbid-
ity such that they depend on significant technological
• In cases where there is little or no chance for survival, support. She quotes Norman Daniel’s definition of justice as
CPR should not be begun. it applies to healthcare as the maintenance of normal function
and then describes it as an injustice when healthcare fails in the resuscitation were successful. DNR orders are most often
its primary function to maintain normal functioning of the established when the parents have already decided to limit
individual neonate. Barnum elaborates that a benevolent care or when a cardiac or respiratory arrest has previously
injustice occurs when well-intentioned treatment leaves a occurred; these orders precede death by a matter of days on
neonate with significant morbidity and disabilities [14]. average [16]. Accordingly, resuscitation in this context is not
Recently, outcomes of perinatal care in the United States warranted. Yet, this premise does not hold in the periopera-
were compared with that in several other countries, including tive setting because anesthetic medications inherently induce
Australia, Canada, and the United Kingdom. Care in the some degree of cardiorespiratory instability, which anesthe-
United States differed from these other countries in provid- siologists expect and are present to ameliorate, if not reverse.
ing proportionally less prenatal care but having proportion- The American Society of Anesthesiologists (ASA) has
ally more intensive care nursery capacity and expended promulgated recommendations for the care of patients with a
significantly more resources on neonatal intensive care. Low DNR order who undergo anesthesia [17]. These recommen-
birth weights were seen more often in the United States dations strongly disagree with routine suspension of the
though the relative risk for overall neonatal mortality did not DNR order for patients undergoing anesthesia for procedures
differ significantly among the four countries [15]. and instead endorse a discussion among the caregivers and
Case Example: In the case of the neonate born to a family family members before the procedure on the overall goals of
of the Jehovah’s Witnesses faith, the Supreme Court in both care and the extent to which resuscitation measures will be
the United States and Canada have ruled that blood products applied.
cannot be withheld if the neonate’s life is believed to be in More recently, the American Academy of Pediatrics has
jeopardy. The tacit assumption is that the child would follow also put forth a statement advocating a similar approach [18].
the parent’s religion and hence would refuse blood even in This report describes three approaches to DNR orders for
the face of death. However, the Supreme Court have ruled children who come to the OR for anesthesia and surgery: full
that this assumption may not hold true and until the neonate resuscitation, a goal-directed approach, or a procedure-
reaches the age of maturity to make such a decision, society directed approach. The informed consent process assumes
must protect the child and provide the lifesaving treatment. particular importance in these cases as it is likely that neither
It has been the editors’ experience through encounters the surgeon nor the anesthesiologist was involved in the deci-
with the Medical Liaison Committee of the Jehovah’s sion to invoke the DNR order. During the preanesthetic visit,
Witnesses that when a face-to-face discussion takes place the presence of the child’s primary neonatal physician as
between the members of the Committee, the parents and the well as the surgeon would ensure that all members of the
medical team, and the care team describes all efforts will be medical team participate in a discussion with the family to
made to optimize the neonate before surgery, to implement reach a congruous approach to the DNR order in the operat-
all blood-saving measures and to minimize all blood loss ing room.
during surgery, it becomes unnecessary to proceed to court to With the procedure-directed approach to anesthetic care
make the neonate a ward of the state for the period of the of these neonates, the details of intraoperative care must be
surgery. It has likewise been the editors’ experience that fol- carefully reviewed with the family. If the trachea is not intu-
lowing such discussions, although the parents may remain bated, but the procedure would generally be done with an
steadfast and refuse to consent to a blood transfusion for anesthetic technique that would include tracheal intubation,
their neonate, they do understand and respect the efforts this must be discussed in detail with the family. In addition,
expended by the medical team to respect their beliefs and, in other possible eventualities that would be routinely managed
most circumstances, will consent to the anesthesia and in the provision of an anesthetic and that would otherwise be
surgery. considered resuscitation such as stabilizing abnormal vital
signs and rapid administration of intravenous fluids, blood,
or blood products must be reviewed.
Perioperative Do-Not-Resuscitate Orders Others have advocated for a goal-directed approach to the
anesthetic care of children with a DNR order in place [19]. In
Neonates with existing do-not-resuscitate (DNR) orders may this approach, the medical details of perioperative care are
require anesthesia for palliation or for placement of devices less important than understanding and respecting the goal of
that simplify care such as a gastrostomy tube, tracheostomy, the family vis-à-vis the procedure. This approach does not
or central line. Underlying the decision to invoke a DNR specify the details of anesthetic care as they are specified in
order is typically the premise that the neonate has a terminal the procedure-directed approach. Rather, the concept here is
or irreversible condition and that a cardiac arrest, if it were to to utilize any techniques that are consistent with the overall
occur, will leave the patient in yet a worse condition, even if goal of care that is established in the preanesthetic meeting
with the family. An additional concept of great importance in Final Rule legislation: “The term ‘withholding of medically
this context is that whenever a DNR order is transiently indicated treatment’ means the failure to respond to the
altered in order to perform a procedure, whether suspended, infant’s life threatening conditions by providing treatment
or a procedure-directed or goal-directed approach is adopted, (including appropriate nutrition, hydration, and medication)
it is essential to clearly define a priori when these changes which, in the treating physician’s reasonable medical judg-
will commence and when they will cease. Advanced agreement, will be most likely to be effective in ameliorating or
ment among the parents and caregivers on the timing for correcting all such conditions, except that the term does not
resumption of the DNR order must be respected unless all include the failure to provide treatment (other than appropri-
parties agree that circumstances warrant revision of the pre- ate nutrition, hydration, or medication) to an infant when, in
anesthetic treatment plan. Failure to do so is a certain recipe the treating physician’s reasonable medical judgment any of
for ethical conflict. the following circumstances apply:
In addition to specific approaches to discuss periopera-
tive DNR orders, pediatric anesthesiologists, along with (i) The infant is chronically and irreversibly comatose;
neonatologists and pediatric surgeons, benefit from use of a (ii) The provision of such treatment would merely prolong
shared decision-making (SDM) model [20, 21]. This meth- dying, and not be effective in ameliorating or correcting
odology has been widely published and is a helpful model the infant’s life-threatening conditions, or otherwise be
for the perioperative care of critically ill neonates. There are futile in terms of survival of the infant; or.
challenges to its use, however, in situations when the paren- (iii) The provision of such treatment would be virtually
tal values and the neonate prognosis are uncertain. These futile in terms of survival of the infant and the treat-
choices are often made in very emotionally stressful ment itself under such circumstances would be inhu-
moments further complicated by, in many cases, the pres- mane.” [26].
sures of time [22]. Leaders in the field describe utilization of
the “best interests of the child” standard or the more com- Many argue that the Baby Doe regulations are not helpful
prehensive biopsychosocial framework to guide discussions in decision-making for infants because of ambiguity regard-
with parents and to weigh benefits/risks of different inter- ing the term “appropriate.” Regardless of how one interprets
ventions [23]. the intentions of the Final Rule legislation, this is not a com-
monly recommended framework for ethical decision-making
at the end-of-life in the child. The American Academy of
Regulatory Concerns in Perinatal Care Pediatrics (AAP) Committee on Fetus and Newborn (COFN)
describes the foundations upon which difficult decisions
The Baby Doe Regulation Controversy about resuscitation rest: clear, open communication between
the healthcare team and the family, active involvement of the
Few regulations have generated as much confusion and con- family in decision-making, continued care when ICU care is
troversy as the so-called “Baby Doe” regulations [24]. Baby stopped, and finally, that treatment be guided by the best
Doe was an infant with Down syndrome and tracheoesopha- interests of the child [9]. In a more recent clinical report,
geal fistula born in Bloomington, Indiana, in 1982. His par- COFN again emphasized the importance of individualized
ents declined corrective surgery on the grounds that he would consideration of all factors by the care team and the parents
never achieve a “minimally acceptable quality of life,” and before reaching a decision about resuscitation [10]. Other
the child subsequently died. The case generated public con- commentators have noted that the literal interpretation of the
troversy. After a number of appeals, the final Baby Doe regu- regulation mandates the treatment of all critically ill neo-
lations, often referred to as the “Final Rule,” were passed by nates under all circumstances, and even possibly against the
the Congress as the 1984 Amendments to the Child Abuse wishes of loving and informed parents, and the professional
Prevention and Treatment Act [25]. This legislation required opinion of the clinicians, leading to permanent care of all
all states to create a regulatory system to investigate cases infants, no matter how devastated and compromised. Few
where medically indicated treatment is withheld from handi- would agree that such an inflexible approach to every infant’s
capped infants or states would risk the withholding of federal care is wise [27].
funding for children’s services. It also stipulated that “the
withholding of medically indicated treatment from a dis-
abled infant with a life-threatening condition” by parents or Born Alive Infant Protection Act
providers was considered medical neglect. The legislation
then outlined three medical conditions that would justify Subsequent to the Baby Doe regulations, the Born Alive
withholding otherwise required treatment. According to the Infant Protection Act (BAIPA) was passed in 2002. This law
extends the definitions of “person” or “child” to include References

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Index
A Adverse events, 553–555

Abdominal surgery addressing risks and, 568–570
anorectal anomalies (see Anorectal anomalies) prevention of
biliary atresia, 329–331 equipment-related incidents, 567
bladder exstrophy, 326, 327 human factors, 564, 565
cloacal exstrophy, 326, 327 medication errors, 565–567
exomphalos, 325, 326 Agency for Healthcare Research and Quality (AHRQ), 555
gastroschisis, 323–325 Agitation and Sedation Scale, 110
Hirschsprung’s disease Airtraq optical laryngoscope, 202, 203
anesthetic considerations, 321 Airway events, risk factors for, 476
diagnosis, 320 Airway management
embryology, 319 difficult airway, 198
genetics, 320 adjuncts, 200, 201
management, 320 Airtraq optical laryngoscope, 202, 203
outcomes, 320, 321 awake intubation, 200
surgical considerations, 321 challenges, 198
surgical procedure, 320 channelled video laryngoscopes, 201
inguinal hernia (see Inguinal hernia) clinical scenarios, 205
intestinal atresia (see Intestinal atresia) cricothyroid membrane, 205
malrotation epidemiology, 198
anesthetic considerations, 319 ETT, 202
diagnosis, 318 fiber-optic bronchoscope, 204
embryology, 318 general anesthesia, 200
management, 318 GlideScope video laryngoscope, 201, 202
outcomes, 318 Goldenhar’s syndrome, 199, 200
overview, 317, 318 laryngeal cleft, 201
surgical approach, 318, 319 lighted stylet, 204
meconium ileus, 317 mask ventilation, 200
NEC (see Necrotizing enterocolitis) operating room and airway equipment, 200
PUV, 327 optical stylets, 204
pyloric stenosis Pierre Robin sequence, 199
anesthetic considerations, 313, 314 Quicktrach babyTM, 205
diagnosis, 312 Storz Video laryngoscope, 201
medical management, 312 topical anesthesia, 200
overview, 312 Treacher Collins syndrome, 199
surgical management, 312, 313 EXIT, 205, 206
sacrococcygeal teratoma (see Sacrococcygeal teratomas (SCT)) face mask ventilation, 190, 191
Abdominal wall defects, 10 laryngoscopy and orotracheal intubation, 192–194
Acetaminophen (paracetamol), 510, 511, 518, 519 LMAs and supraglottic devices, 191, 192
adverse effects, 130 nasotracheal intubation, 194
mechanism of action, 129, 130 preanesthetic assessment, 190
pharmacodynamics, 129 preoperative preparation, 190
pharmacokinetics, 129, 130 RSI, 197, 198
Acquired subglottic stenosis, 558 tracheal tube
Activated clotting time (ACT), 445 positioning, 197
Acute bilirubin encephalopathy (ABE), 71 selection, 194, 195
Acute pain, 530 size, 196, 197
Acute respiratory distress syndrome (ARDS), 468 uncuffed vs. cuffed, 195, 196
Adjustable pressure-limiting (APL), 196 upper airway anatomy, 189
Adrenergic function, 28 upper airway reflexes, 189, 190
Adult hemoglobin (HbA), 228 Airway obstruction, 556

J. Lerman (ed.), Neonatal Anesthesia, https://doi.org/10.1007/978-3-031-25358-4
640 Index
Airway pressure release ventilation (APRV), 215 future studies, 598

Alagille syndrome, 65 human outcome measures, population migration, and sample
Alanine aminotransferase (ALT), 487 sizes, 596, 597
Albumin, 279, 280 issues, 599, 600
Alfentanil, 135–136, 173, 180, 181, 513 large databases, 594, 595
Allometry, 99, 100 prospective human trials, 595, 596
Alpha-2 adrenoreceptor agonist retrospective cohort studies, 591, 594
clonidine, 140 sex, parenting, and low birth weight, 597, 598
dexmedetomidine, 140, 141 on rodents and nonhuman primates, 590
Ambu Aura Gain, 192 Anesthetic technique, 476, 477
Amethocaine gel, 517 Angiocrine signaling, 44
Amplitude–integrated EEG (aEEG), 110, 243, 244 Anorectal anomalies
Analgesic drugs abnormalities, 321
acetaminophen (paracetamol) anesthetic considerations, 322
adverse effects, 130 classification, 321, 322
mechanism of action, 129, 130 cloaca, 322, 323
pharmacodynamics, 129 diagnosis, 321
pharmacokinetics, 129, 130 embryology, 321
non-steroidal anti-inflammatory drugs management, 322
adverse effects, 132 outcomes, 321, 322
drug interactions, 131 surgical considerations, 322
mechanism of action, 130, 131 Anticholinergic drugs
pharmacodynamics, 131 adverse effects, 148
pharmacokinetics, 131 atropine, 121, 123, 124, 147, 148
opioid analgesic drugs glycopyrrolate, 148
alfentanil, 135, 136 scopolamine, 148
codeine, 136, 137 Anticoagulation
fentanyl, 133–135 ACT, 445
meperidine, 137 clinical status, 445
methadone, 137, 138 DTIs, 445
morphine, 132–134 TEG, 445
remifentanil, 135 Antidiuretic hormone (ADH), 261, 262
sufentanil, 136 Anti-hypotensive therapy, 38
Analgesics, 167, 172, 180, 181 Antipyretic plasma levels, 511
effects of, 508 Aortopulmonary (AP) window, 390, 391
Anemia, 493 Apnea, 31, 51, 53, 55, 59–64, 72
Anesthesia-induced apoptosis, 600 Apnea monitors
Anesthesia, maintenance of acoustical monitoring, 235
analgesia, 180, 181 capnography, 235
hypnosis, 179, 180 classification, 235
muscle relaxants, 181 proboscis modification, 235
Anesthesia-related neurotoxicity, 583 pulmonary mechanics, 236
Anesthetic complications RVM, 235, 236
adverse events Apnea of prematurity (AOP), 62, 63
addressing risks and, 568–570 Apoptosis, 582–584
peri-anesthetic mortality and, 553–555 Aquaporin peptides (AQPs), 262, 263
adverse events, prevention of Arnold-Chiari malformation, 31
equipment-related incidents, 567 Arterial hemoglobin oxygen saturation, see Pulse oximetry
human factors, 564, 565 Aspartate aminotransferase (AST), 487
medication errors, 565–567 Asphyxia, 610, 623
cardiac arrest during pediatric anesthesia, 555, 556 Atrial natriuretic peptides (ANPs), 260
location of operative procedure, 559–561 Atropine, 147–148
oxygen toxicity, 563, 564 Attention-deficit hyperactivity disorder (ADHD), 596
peri-anesthetic mortality, 553–555 Auditory brainstem responses (ABRs), 247, 248
respiratory and airway complications, 556–559 Autoregulation, 39
transfusions of blood products, 561–563 Axillary blocks, 542
Anesthetic-induced apoptosis, 584
Anesthetics
animal and preclinical data for, 582–584 B
animal age, safe from neurocognitive effects, 584 Baby Doe regulations, 635
duration of exposure impact long-term effects, 585 Balanced analgesia, 167, 510, 518
neurocognitive dysfunction, anesthetic agents cause Base disturbances, 468
(see Neurocognitive dysfunction, anesthetic Beckwith-Wiedemann syndrome, 266
agents cause) Benefits of Oxygen Saturation Targeting (BOOST)–II trials
human studies, 591, 598, 599 (BOOST-II), 563
age at exposure, duration of surgery/number of exposures, and Benylisoquinolones, 174
impact of surgery, 597 Benzodiazepines, 138–140, 586
Index 641
Betamethasone, 496 systemic to pulmonary artery shunt placement, 417, 418

Biliary atresia (BA), 329–331 temperature, 398
Bilirubin induced neurologic damage (BIND), 71 transesophageal echocardiography, 402, 403
Biophysical profile, 60 transport to operating room, 396, 397
Biotransformation reactions, 101 transthoracic pressure-monitoring catheters, 402
Bispectral Index, 110 ultrasound guidance, 400, 401
Bladder exstrophy, 326, 327 urinary output measurements, 402
Blood-brain barrier (BBB), 71, 105, 106 vascular rings, 418, 420
Blood flow distribution, 361 ventricular pressure overload, 424
Blood loss, 475 ventricular volume overload, 424
Blood transfusions, 561 Cardiopulmonary arrest, 556
Bonfils fiber-optic laryngoscope, 204 Cardiopulmonary bypass (CPB), 440, 443
Born Alive Infant Protection Act (BAIPA), 635, 636 anticoagulation, 409
Brachiocephalic vein (BCV), 243 aortic cross-clamping, 410
Brain functions, 168 bleeding and coagulation, 413–415
Brain tumors, 352, 353 cannulation and initiation of, 409
Breast milk jaundice, 69 cooling and temperature management, 409, 410
Bronchopulmonary dysplasia (BPD), 47, 48, 56, 57, 62–64, 78, 556 DHCA, 411, 412
Brown adipose tissue (BAT), 283, 284 intensive care unit, 411
Budin, Pierre, 2 myocardial effects, 416
Bupivacaine, 516, 517, 536 myocardial protection, 410
Buprenorphine, 587 myocardial reperfusion, 410
neonate vs. adult, 412, 413
neurologic effects, 415, 416
C perfusion equipment, 407–409
Calcium-induced calcium release (CICR), 26 pre-bypass period, 406, 407
Canadian Pediatric Adverse Events Study, 554 pulmonary effects, 416
Cannulation methods, 443, 444 removal of cannulas, 410
Capnography, 458, 465 renal and gastrointestinal effects, 416
end-tidal CO2 monitoring (ETCO2), 460 reversal of anticoagulation, 410
Cardiac arrest during pediatric anesthesia, 555, 556 SACP, 411, 412
Cardiac arrhythmias, 475 SIRS, 413
Cardiac catheterization laboratory, 473–475 tubing, circuits, and bypass prime, 407–409
Cardiac monitoring, 607 Cardiopulmonary resuscitation (CPR), 623
Cardiac MRI, 473 Cardio-respiratory monitoring
Cardiac opioid system, 28 advanced pulse CO-oximetry, 231, 232
Cardiac output, 361 apnea monitors
Cardiac surgery, 282 acoustical monitoring, 235
altered respiratory mechanics, 424 capnography, 235
arterial cannulation, 399 classification, 235
capnography, 397, 398 proboscis modifcation, 235
central venous access, 400–402 pulmonary mechanics, 236
central venous pressure monitoring, 399, 400 RVM, 235, 236
CoA, 418, 419 central venous pressure monitoring
conduction disturbances and arrhythmias, 424 BCV, 243
congestive heart failure, 423 IJV, 242, 243
cyanosis, 423 parenteral nutrition fluids, 240
drugs for emergency situations, 397 principles, 243
electrocardiography, 397 USG, 240
induction of anesthesia, 405, 406 electrocardiography, 230
indwelling arterial monitoring, 398 inspired and expired gas analysis, 234
intravenous access, 397 mainstream capnography, 234, 235
invasive monitoring, sites for, 398, 399 ORI, 232, 234
maintenance of anesthesia, 406 precordial stethoscope, 227
mechanical circulatory support, 420–422 pulse oximetry
myocardial ischemia, 424 Blue Sensor, 228
neurologic monitoring, 403–405 clinical application, 230
non-invasive monitoring, 398 clinical practice, 228–230
perioperative stress response, 424, 425 R and arterial saturation, 228
post-cardiac transplant recipients, 425 wavelengths, 228
premedication, 397 sidestream capnography, 234
pulmonary artery banding, 417 systemic blood pressure monitoring
pulmonary hypertension, 422, 423 hypotension, 239, 240
pulse oximetry, 397 invasive blood pressure, 237–239
short- and long-term outcomes, 396 NIBP, 237
systemic air embolization, 424 tcpCO2, 235
systemic hypotension, 423 Cardiovascular depression, 120
642 Index
Cardiovascular function pathophysiology, 368

adrenergic function, 28 surgical considerations, 369
clinical significance, 30 Codeine, 136–137, 514
fetal circulation, 20–23 Cole, 4
myocardial compliance, 27 Colloids
myocardial development albumin, 279, 280
myocytes, 25, 26 meta-analysis, 279
subcellular components, 26, 27 nonprotein, 280
placenta, 24, 25 transfusion triggers, 280
preterm infant, 28, 29 Colonic atresia, 316, 317
Cardiovascular surgery, 10 Combined spinal-epidural anesthesia (CSEA), 558
Cardiovascular system, 122–124 Combined ventricular output (CVO), 20–22, 24, 361
Caudal analgesia, 534–536 COMFORTneo, 510
Caudal block, 534–536 Committee of the Fetus and Newborn (COFN), 633
Caudal catheter techniques, 536–538 Common bile duct, 65
Central chemoreceptors, 59, 61, 62 Complications from cardiac catheter procedures, 477, 478
Central nervous system (CNS), 121, 122 Compression-to-ventilation (C:V) ratio, 623
age-related patterns of injury, 32, 33 Congenital anomalies
anatomy, 348, 349 anesthetic management
cerebrovascular physiology, 347, 348 intra-operative management, 350, 351
circulatory immaturity, 30 post-operative management, 351
congenital heart disease, 36, 37 preanesthetic evaluation, 350
embryology, 347 cranial dysraphisms, 349, 350
normal development, 31, 32 spinal dysraphisms, 350
vulnerable cell populations Congenital cystic adenomatoid malformation (CCAM)
preterm infant, 33, 34 classification, 298
term infant, 34–36 diagnosis, 298, 299
Central neuroexcitation, 126 overview, 297, 298
Central pattern generator, 59 postnatal management, 299
Central venous access, 563 surgery, 299
Central venous catheterization, 463, 464 Congenital diaphragmatic hernia (CDH), 9, 10, 45–47, 451, 460, 471,
Central venous pressure (CVP), 449 472, 495, 496, 554
Cerebellar injury, 43 anesthetic considerations, 310
Cerebral angiography, 478 antenatal treatment, 308
Cerebral autoregulation, 37, 169 Bochdalek defect, 306, 307
Cerebral blood flow (CBF), 28, 29, 35–40, 42, 169 diagnosis, 308
auto-regulation, 37–39 embryology, 306, 308
cerebellar injury, 43 medical management, 308, 309
GM-IVH, 41, 42 Morgagni defect, 306, 307
white matter injury, 39, 40 outcomes, 308
Cerebral damage, 169–170 surgery, 309, 310
Cerebral perfusion pressure, 169 Congenital heart defects, 494
Cerebrovascular critical closing pressure, 38 Congenital heart disease (CHD), 21, 26, 36, 37, 44, 45
Cerebrovascular injury, 30 AP window, 390, 391
Cervical teratoma, 205 cardiac surgery
Cesarean section, 493 altered respiratory mechanics, 424
Chest compressions, 623, 625, 626 arterial cannulation, 399
Chest wall, 49–51, 54, 59, 61–63 capnography, 397, 398
Chloroprocaine, 516, 517, 533 central venous access, 400–402
Cholangiocytes, 65 central venous pressure monitoring, 399, 400
Cholestasis, 65, 70 CoA, 418, 419
Chronic bilirubin encephalopathy (classic kernicterus), 71, 72 conduction disturbances and arrhythmias, 424
Chronic lung disease, 556 congestive heart failure, 423
Circulatory immaturity, 30 cyanosis, 423
Circumcision, 518 drugs for emergency situations, 397
Cisatracurium, 175 electrocardiography, 397
Citrate, 561 induction of anesthesia, 405, 406
Clearance (CL), 446 indwelling arterial monitoring, 398
Cloacal exstrophy, 326, 327 intravenous access, 397
Clonidine, 126, 140, 515, 516, 536, 540 invasive monitoring, sites for, 398, 399
Coarctation of the aorta (CoA), 418, 419 maintenance of anesthesia, 406
anatomic features, 367, 368 mechanical circulatory support, 420–422
anesthesia, 368 myocardial ischemia, 424
arterial pressure monitoring, 368 neurologic monitoring, 403–405
cerebral oximetry monitoring, 369 noninvasive monitoring, 398
management, 368 perioperative stress response, 424, 425
Index 643
post-cardiac transplant recipients, 425 management, 389, 390

premedication, 397 pathophysiology, 389
pulmonary artery banding, 417 rationale, 365
pulmonary hypertension, 422, 423 TAPVR
pulse oximetry, 397 anatomic features, 375, 376
short- and long-term outcomes, 396 anesthesia, 377
systemic air embolization, 424 issues, 377
systemic hypotension, 423 management, 377
systemic to pulmonary artery shunt placement, 417, 418 pathophysiology, 375
temperature, 398 TOF
transesophageal echocardiography, 402, 403 anatomic features, 372
transport to operating room, 396, 397 anesthesia, 373, 374
transthoracic pressure-monitoring catheters, 402 arch sidedness, 374
ultrasound guidance, 400, 401 arterial blood pressure monitoring, 374
urinary output measurements, 402 coronary artery anomalies, 374
vascular rings, 418, 420 JET, 375
ventricular pressure overload, 424 management, 373
ventricular volume overload, 424 pathophysiology, 372, 373
classification, 363, 364 pulmonary vascular resistance, 374
clinical presentation, 363 restrictive physiology, 375
coarctation of the aorta surgical intervention, 374, 375
anatomic features, 367, 368 truncus arteriosus
anesthesia, 368 anatomic features, 377, 378
arterial pressure monitoring, 368 anesthesia, 379
cerebral oximetry monitoring, 369 issues, 379
management, 368 management, 379
pathophysiology, 368 pathophysiology, 378
surgical considerations, 369 Congenital lobar emphysema (CLE)
CPB (see Cardiopulmonary bypass) diagnosis, 300
critical aortic stenosis management, 300
anatomic features, 379, 380 overview, 300
anesthesia, 381 Congenital ophthalmologic lesions, 355
management, 380, 381 Congenital pulmonary airway malformations (CPAM), 496
pathophysiology, 380 Congenital pulmonary lesions, 496
post-bypass period, 381 Congenital thoracic malformations, 297
transcatheter procedures, 381 Congestive heart failure, 423
diagnosis, 363 Conjoined twins
d-Transposition of great arteries anaesthesia issues
anatomic features, 369, 370 airway, 336, 337
anesthesia, 370, 371 antibiotics, 337
left ventricular compliance, 372 assessment, 336
management, 369–371 conduct of anaesthesia, 337
myocardial ischemia, 372 fluid loss and blood loss, 337
pathophysiology, 369 induction, 337
pulmonary hypertension, 372 inotropes and resuscitation, 337, 338
Ebstein anomaly, 391–394 lines, 337
epidemiology, 362, 363 logistics, 336
HLHS (see Hypoplastic left heart syndrome) monitoring, 337
IAA, 387, 388 post-operative care, 338
patent ductus arteriosus surgical principles, 338
anatomic features, 365 theatre set-up, 336, 337
anesthesia, 366 vascular access and blood loss, 336
issues, 366, 367 clinical presentation, 334–336
management, 366 epidemiology, 334
pathophysiology, 365, 366 management, 334, 336
preoperative assessment Continuous epidural infusions, 539, 540
ancillary studies, 394–396 Continuous positive airway pressure (CPAP), 217, 218, 446, 616
fasting guidelines, 396 Conventional mechanical ventilation (CMV), 445
history, 394 Coronary perfusion pressure (CPP), 623
informed consent, 395, 396 Corpus callosum, 31, 33
laboratory data, 394–396 Corticospinal tract (CST), 248
physical examination, 394 Corticotropin releasing hormone (CRH), 259
pulmonary stenosis Couney, Martin, 2
anatomic features, 388, 389 COVID-19 pandemic, 460
anesthesia, 390 Creatinine clearance, 75
issues, 390 Cricoid pressure, 177
644 Index
Crigler-Najjar syndrome, 72 Elective surgery, general anesthesia for

Critical aortic stenosis inhalational induction, 172
anatomic features, 379, 380 alfentanil, 173
anesthesia, 381 fentanyl, 172
management, 380, 381 remifentanil, 173
pathophysiology, 380 sufentanil, 173
post-bypass period, 381 intravenous induction, 173, 174
transcatheter procedures, 381 Electrolyte and acid, 468
Cuffed tracheal tube, 457 Electrophysiology (EP), 477
Cyanosis, 423 Elsberg, C., 3
Cystatin C (CysC), 75, 76 Embryogenesis, 31
Cytochrome P450 system, 68 Emergence delirium, 127, 140
Emergence/recovery, 126
Emergency Medical Treatment and Active Labor Act (EMTALA), 636
D EMLA, see Eutectic Mixture of Local Anesthetics (EMLA)
Decannulation, 446, 447 Encephalopathy of prematurity, 30
Deep hypothermic circulatory arrest (DHCA), 411, 412 Endogenous pulmonary surface-active agent, 53–55
Deferring cord clamping (DCC), 609 Endothelial nitric oxide synthetase activity (eNOS), 23, 32
Delaying cord clamping, 24, 25 Endothelin-1 (ET-1), 24
Desflurane, 103, 107, 114–117, 119–128, 589 Endotracheal intubation of neonates, 3–5
Developmental plasticity theory, 20 Endotracheal tube (ETT), 202, 620, 622, 626
Dexmedetomidine, 107, 140–142, 174, 446, 477, 515, 516 in neonates, depth of insertion of, 620
Diaphragmatic fatigue, 50 position, within trachea, 621
Diethyl ether, 1 size, 613, 620
Direct thrombin inhibitors (DTIs), 445 End-tidal carbon dioxide (ETCO2), 398
Do-not-resuscitate (DNR) order, 634, 635 Enhanced placental transfusion, 25
Dorsal root ganglion (DRG), 505 Enteral nutrition
Drip and tube method, 538 feeding, 268
d-Transposition of the great arteries (d-TGA) metabolic requirements, 267
anatomic features, 369, 370 minimal/small volume enteral nutrition, 268
anesthesia, 370, 371 total parenteral nutrition, 268
left ventricular compliance, 372 Epidural adjuvants, 540
management, 369–371 Epidural analgesia, 531
myocardial ischemia, 372 Epidural fat, 532
pathophysiology, 369 Epileptiform EEG activity, 172
pulmonary hypertension, 372 Epinephrine, 610
d-tubocurarine (dTc), 5 in DR, 626
Duodenal atresia Episodic events, 168
anesthetic considerations, 315 Erector spinae plane block (ESPB), 543
classification, 314 Esophageal atresia (EA), 8, 9
diagnosis, 315 anesthetic considerations, 305, 306
embryology, 314 classification, 301–303
management, 315 diagnosis, 303
outcomes, 315 medical management, 304
surgical considerations, 315 overview, 301
risk stratification, 303, 304
surgery, 304, 305
E and tracheoesophageal fistula (TEF), 301–306
Early postnatal hepatic function Ethical reasoning
acute bilirubin encephalopathy, 71 DNR order, 634, 635
anatomy, 66 four principles framework, 631
BIND, 71 autonomy, 631–633
chronic bilirubin encephalopathy, 71 beneficence, 633
common neonatal hepatic disorders, 68 justice, 633, 634
hemorrhagic disease of the newborn, 68 non-maleficence, 631–633
hyperbilirubinemia, 69–73 perinatal care regulations
jaundice, 69 Baby Doe regulations, 635
Kernicterus Spectrum Disorders, 71 BAIPA, 635, 636
metabolism, 67, 68 Ethyl chloride, 2
phototherapy, 72, 73 Eutectic Mixture of Local Anesthetics (EMLA), 516, 517
synthesis, 66, 67 Exomphalos, 325, 326
Ebstein anomaly, 391–394 Explicit memory, 168, 169
Edema, 487 Extracellular matrix/cytoskeleton, 27
EDIN scale, 510 Extracorporeal life support (ECLS), see Extracorporeal membrane
Effective cerebral perfusion, 38 oxygenation (ECMO)
Effects of Transfusion Thresholds on Neurocognitive Outcome of Extracorporeal membrane oxygenation (ECMO), 559
extremely low-birth-weight infants (ETTNO) trial, 562 anesthesia
Index 645
intraoperative conduct, 448 Functional echocardiography, 29

preparation, 447, 448 Functional residual capacity (FRC), 51–53, 55, 62, 63, 102, 107, 115,
anticoagulation and homeostatic system, 444, 445 116, 118, 214, 556
cannulation and initiation, 443, 444
complications, 447
components, 440–441 G
definition, 439 Gamma-aminobutyric acid (GABAA) receptors, 581–584
fluid management, 446, 447 Gasping syndrome, 99
gas exchange, 441–443 Gastric decompression, 470
history, 439 Gastric emptying, 177, 270–272
indications and contraindications, 439, 440 Gastrointestinal ontogeny, 269
mechanical ventilation, 445, 446 Gastroschisis, 323–325, 469, 470
modes of, 443 General anesthesia, 492, 498, 558
operation theatre General tracheal intravenous anesthesia, 469
Bulky equipment, 448 Germinal matrix-intraventricular hemorrhage (GM-IVH), 37, 41–43
CDH, 451 Gillespie, N.A., 3, 4
challenges, 448 GlideScope video laryngoscope, 201, 202
evidence-based approach, 452 Glomerular filtration rate (GFR), 74–78, 108, 262, 457
surgical procedure, 448–450 Glutamate, 32
patient selection, 439, 440 Glycopyrrolate, 147, 148
sedation and analgesia, 446 Goldenhar’s syndrome, 200
survival and outcome, 447 Gray baby syndrome, 99
Extrahepatic routes of metabolic clearance, 107
Extralobar sequestration (ELS), 299
Extremely low birth weight (ELBW) infants, 19, 20, 28–30, 39–41, H
43, 47, 48, 52, 56, 57, 59, 74, 75, 77, 79, 457, 562 Halothane, 107, 123–125
Ex-utero intrapartum therapy (EXIT) procedure, 12, 451, 485, Hematologic disturbances, 469
496–498 Hemodynamic instability, 30
airway management, 205 Hepatic drug metabolism activity, 101
Hepatic effects, 125, 126
Hepatic function
F anatomy, 64, 65
Face mask ventilation, 190, 191 early postnatal
Femoral nerve blocks, 542 acute bilirubin encephalopathy, 71
Fentanyl, 106, 126, 133–135, 172, 173, 446, 513, 518 anatomy, 66
Fetal accretion rates for calcium and phosphorus, 457 BIND, 71
Fetal alcohol syndrome, 583 chronic bilirubin encephalopathy, 71
Fetal circulation, 20–23, 37, 359, 360, 489, 609 common neonatal hepatic disorders, 68
Fetal/early postnatal development, 20 hemorrhagic disease of the newborn, 68
Fetal hemoglobin (HbF), 228 hyperbilirubinemia, 69–73
Fetal neonatal postjunctional acetylcholine receptors, 144 jaundice, 69
Fetal pain perception, 490 Kernicterus Spectrum Disorders, 71
Fetal surgery, 485 metabolism, 67, 68
anesthetic management phototherapy, 72, 73
for minimally invasive fetal procedures, 490, 491 synthesis, 66, 67
for open fetal surgery, 491, 492 in utero development, 65, 66
anesthetic neurotoxicity, 490 Hepatic metabolic clearance, 106–109
fetal conditions amenable to fetal treatment Hering–Breuer inflation reflex, 61
anemia, 493 Hering–Breuer reflex, 61
congenital diaphragmatic hernia (CDH), 495, 496 Heterogeneous liver parenchyma, 65
congenital heart defects, 494 High-flow nasal oxygen therapy, 177
congenital pulmonary lesions, 496 High-frequency flow interruption (HFFI), 217
myelomeningocele (MMC), 497 High-frequency jet ventilator (HFJV), 458, 466
obstructive uropathy, 494, 495 High-frequency oscillatory ventilation (HFOV), 217, 446, 458, 466
sacrococcygeal teratomas (SCT), 496, 497 High-frequency ventilation (HFV), 217, 466
Twin Reversed Arterial Perfusion (TRAP) Sequence, 493 Hirschsprung’s disease
Twin to twin transfusion syndrome (TTTS), 493, 494 anesthetic considerations, 321
fetal pain perception, 490 diagnosis, 320
fetal physiology, 487–489 embryology, 319
maternal physiology, 486, 487 genetics, 320
postoperative considerations, 492, 493 management, 320
preoperative evaluation of patient, 485, 486 outcomes, 320, 321
uterine and placental physiology, 487 surgical considerations, 321
Flow-volume loop, 223 surgical procedure, 320
Fractal geometry, 100 Homeostasis, 167, 179
Fresh frozen plasma (FFP), 562 Homeostatic system, 444, 445
Full-Scale Intelligence Quotient standard score, 596 Human breast milk (HBM), 268, 270, 272
646 Index
Hyaline membrane disease, see Respiratory distress syndrome (RDS) induction techniques, 126
Hydrocephalus, 351, 352 malignant hyperthermia, 127, 178
Hydromorphone, 514 stability, 127, 128
Hydroxyethyl starches (HES), 280 metabolism
Hyperbilirubinemia, 69–73, 77 cardiovascular system, 121–124
Hypercarbia, 39 emergence, 120
Hyperglycemia, 267 hepatic effects, 125, 126
Hyperkalemia, 561 pharmacodynamics, 120, 121
Hyperthermia, 459 renal dysfunction, 124, 125
Hypnosis, 179, 180 respiratory system, 124
Hypnotics, 167, 172 pharmacokinetics, 114–117
Hypoalbuminemia, 72 physicochemical and pharmacological properties, 114
Hypocarbia, 39, 42 physicochemical properties, 114
Hypoglycemia, 266, 267 ventilation, 117, 118
Hyponatremia, 272, 273 Inhalational induction, 172, 175, 179
Hypoplastic left heart syndrome (HLHS) Intercostal blocks, 543
anatomic features, 381, 382 Intermittent positive pressure ventilation (IPPV), 5
anesthesia, 385 Internal jugular vein (IJV), 242, 243
circulation balancing, 386 Interrupted aortic arch (IAA), 387, 388
hybrid procedure, 386 Interventional radiology for neuroimaging, 478
management, 382–385 Intestinal atresia
mixed venous oxygen saturation monitoring, 386 colonic atresia, 316, 317
pathophysiology, 381, 382 duodenal atresia
postoperative issues, 386 anesthetic considerations, 315
right ventricular optimization, 386 classification, 314
surgical approach, 385, 386 diagnosis, 315
Hypotension, 28, 29, 32, 38, 40, 42, 279, 468, 469 embryology, 314
Hypothalamic-pituitary-adrenal (HPA) axis, 259, 260 management, 315
Hypothermia, 284, 458, 465 outcomes, 315
Hypoxia, 169–170 surgical considerations, 315
Hypoxic-ischemic encephalopathy (HIE), 27 jejunal/ileal atresia, 315, 316
Hypoxic-ischemic injury, 32 pyloric atresia, 314
Hypoxic ventilatory depression (HVD), 61 Intracellular calcium, 23, 32, 42
Intracranial hemorrhage (ICH), 40, 68, 447
Intracranial pressure, 169
I Intrahospital transports, 467
Ilio-inguinal nerve block, 543 Intralobar sequestration (ILS), 299
Implicit memory, 168, 169, 180 Intraoperative temperature control, 7, 8
Induction techniques, 126 Intratracheal insufflation technique, 3
Infant death, 19 Intrauterine transfusion (IUT), 493
Infantile amnesia, 168 Intravenous anesthetics, 585
Informed consent, 395, 396 α2 agonists, 586, 587
Infra-orbital nerve block, 542 benzodiazepines, 586
Inguinal hernia ketamine, 585
anesthetic management, 311, 312 opioids, 587
diagnosis, 311 propofol, 586
pathophysiology, 311 Intravenous hypnotics, 177
surgical management, 311 Intravenous induction agents
Inguinal hernia repair, 518 ketamine
Inhalation agents, 530, 587, 588 adverse effects, 113, 114
in infants, 115 mechanism of action, 113
in vivo metabolism, 124 pharmacodynamics, 113
nitrous oxide, 589 pharmacokinetics, 113
pairwise comparisons, 589 propofol
pharmacology of, 114 adverse effects, 112
single, 588, 589 mechanism, 111
xenon, 589 phamacokinetics, 112
Inhalational anesthetics, 102 pharmacodynamics, 111, 112
cardiac output, 118 thiopentone
control of anesthetic depth, 118 adverse effects, 113
induction, 118 mechanism, 112
shunts, 119, 120 pharmacodynamics, 112
clinical effects pharmacokinetics, 113
central neuroexcitation, 126 Intravenous vs. inhaled anesthetic neurocognitive effects, 587
emergence delirium, 127 Intraventricular hemorrhage (IVH), 457
emergence or recovery, 126 Ionotropic (ligand-gated ion channels) receptors, 582
Index 647
Ischaemia, 169–170 Major gastrointestinal/genitourinary surgery, 518, 519

Isoflurane, 107, 110, 114–117, 120–128, 141 Maladaptation, 22
Item Response Theory, 508 Maldevelopment, 22
Malignant hyperthermia (MH), 127, 178
Mask ventilation, 177, 616
J Maternal airway and pulmonary systems, 487
Jaundice, 69–73 Maternal circulatory system, 486, 487
Jejunal/ileal atresia, 315, 316 Maturation, 100, 101
Junctional ectopic tachycardia (JET), 375 Mayo Anesthesia Safety in Kids (MASK) study, 596
McGrath video laryngoscope, 202
Mean arterial pressure (MAP), 169, 170, 448
K Mechanical ventilation, 445, 446
Kasai procedure, 70 Mechanoreceptors, 59
Kernicterus, 71 Meconium ileus, 317
Kernicterus Spectrum Disorders, 71 Meconium stained amniotic fluid (MSAF), 616
Ketamine, 178, 516, 585 infant born through, 615
adverse effects, 113, 114 Medical management, 312
mechanism of action, 113 Memory processes, 168
pharmacodynamics, 113 Meperidine, 137
pharmacokinetics, 113 Metabotropic (G protein-coupled) receptors, 582
Ketogenesis, 267 Methadone, 137–138, 587
Ketorolac, 131 Methylxanthines, 558
Microcuff® tube, 195–197
Microglia, 34
L Microsomal enzyme activity, 101
Large databases, 594, 595 Midazolam, 446, 464, 519
Large macrocystic lesions, 496 Mild hypercapnia, 222
Large pleural effusions, 496 Milking of the cord, 25
Laryngeal mask airways (LMAs), 191, 192, 293 Minimally invasive fetal procedures, 490, 491
Laryngeal tube suction II (LTS II), 192 Minimally invasive neonatal surgery, 12
Laryngoscopy, 192–194 Minimum alveolar concentration (MAC), 110, 116, 118, 120–125,
Late-moderate preterm infants, 19 127, 128, 487
Late preterm infants, 19, 34, 72 Mirror syndrome, 497
Levobupivacaine, 516, 517 Mivacurium, 175
Lidocaine, 516, 517 MK-801, 583
Liver, fetal metabolism, 64 Modified myocardial performance index, 26
Liver function tests, 70 Morphine, 106–109, 132–137, 140, 148, 446, 512, 513
Liverpool technique, 5 Morton, William G., 1
Local anaesthetic toxicity, management of, 545 Multi-modal/balanced analgesia, 510
Local anesthesia (LA), 516–518, 532 Muscle relaxants, 172, 175, 178, 181
Local anesthetics agents Myasthenic response, 249
adverse effects, 144 Myelomeningocele (MMC), 497
mechanism of action, 142 Myocardial compliance, 27
pharmacodynamics, 142 Myocardial contraction, 26
pharmacokinetics, 142, 143 Myocardial development
Local anesthetics toxicity, 171 myocytes, 25, 26
Local anesthetic systemic toxicity (LAST), 545 subcellular components, 26, 27
Long, Crawford, 1 Myocardial ischemia, 424
Low arterial oxygen saturation, 169 Myocardium, developmental aspects, 361, 362
Low birth weight, 598 Myocytes, 25, 26
Lower urinary tract obstruction (LUTO), 494
Lumbar epidurals, 538, 539
Lung injury N
ventilator-induced lung injury (VILI), 214 Na+–Ca+ exchanger (NCX), 26
Lung, postnatal development of, 47, 48 Nasal high-flow oxygenation (NHFO), 218, 219
Lung protective ventilation, 219 Nasal septum-tragus length (NTL), 620
Nasotracheal intubation, 194
National Surgical Quality Improvement Program, 555
M Near infrared spectroscopy (NIRS), 38, 244–246, 599
MacEwen, W., 3 Necrotizing enterocolitis (NEC), 468, 469, 554
Magill, I., 3 anesthetic considerations, 333, 334
Mainstream capnography, 234, 235 diagnosis, 331, 332
Maintenance fluid therapy management, 332
glucose, 265 outcomes, 331, 332
sodium and electrolyte requirements, 264, 265 pathogenesis, 331
water requirement, 263, 264 surgical approach, 332, 333
648 Index
Neonatal anesthesia significance of, 507, 508

ethical considerations, 13 effects of analgesics, 508
history Neonatal pain, 110
anesthesia circuit, 6 Neonatal pharmacodynamic differences, 110, 111
controlled ventilation, 6 Neonatal pharmacokinetic differences
early times, 1, 2 absorption, 102, 103
endotracheal intubation of neonates, 3–5 distribution
neuromuscular blocking drugs, 5 blood-brain barrier, 105, 106
twentieth century, 2, 3 body composition, 103, 104
intraoperative temperature control, 7, 8 plasma proteins, 104
monitoring, 6, 7 regional blood flow, 104, 105
procedure and development elimination
abdominal wall defects, 10 extrahepatic routes of metabolic clearance, 107
congenital diaphragmatic hernia, 9, 10 hepatic metabolic clearance, 106–109
endotracheal intubation of neonates, 3 pulmonary elimination, 107
esophageal atresia, 8, 9 renal elimination, 108, 109
Exit procedure, 12 Neonatal physiology, 144
minimally invasive neonatal surgery, 12 Neonatal resuscitation, 58
neonatal cardiovascular surgery, 10 Neonatal resuscitation for anesthesiologists, 608
open heart surgery, 11 asphyxia, 610
regional analgesia, 11 chest compressions, 623, 626
tracheoesophageal fistula, 8, 9 discontinuation of, 628
regionalization of neonatal services, 12, 13 epinephrine in DR, 626
research, 13 equipment, 608
Neonatal circulation, 609 evaluated sustained inflation vs. PPV, 617
Neonatal death, 19 heart rate assessments, 615
Neonatal intensive care unit (NICU), 559 improve efficacy of ventilation, 618
anesthesia requirements, 464, 465 infant born through meconium stained amniotic fluid (MSAF), 615
benefits of performing surgery in, 458, 459 initial titration of oxygen, 619
cardiac catheterization laboratory, 473–475 mechanisms of heat loss, 614
cardiac MRI, 473 monitoring, 614
high-frequency ventilation, 466 oxygen, 618, 619
logistics of surgery in, 459–461 patient positioning, 613
patient indications for surgery in, 459 persistent purple coloration of colorimetric CO2 detector, 622
preanesthetic assessment of neonate in cath lab, 475, 476 physiology of, 609, 611
sedation and analgesia for procedure in, 465, 466 physiology of transition at birth
sedation for imaging procedures (MRI/CT), 472, 473 and deferred cord clamping (DCC), 609
specific conditions requiring surgery in fetal circulation, 609
congenital diaphragmatic hernia, 471, 472 positive pressure ventilation, 616
gastroschisis, 469, 470 preparation for delivery, 611
necrotizing enterocolitis (NEC), 468, 469 stimulation, 614
patent ductus arteriosus (PDA), closure of, 467, 468 temperature management, 613
retinopathy of prematurity, 470 tracheal intubation, 613, 620, 621
spontaneous intestinal perforation, 469 volume expansion, 627, 628
transport, 466, 467 Neonatal resuscitation program (NRP), 608
Neonatal life support in delivery room, 607 Neonates, 348, 455–458
Neonatal Oxygenation Prospective Meta-analysis (NeOProM), 58, 563 oxygen toxicity in, 455
Neonatal pain respiratory control in, 456
analgesia for neonates in ICU, 519 Neurally adjusted ventilator assist (NAVA), 215, 216
assessment of, 508 Neuraxial anesthesia, 531
measurement tool, 508–510 Neuraxial blockade
management caudal analgesia for, 534–536
information and protocols, 510 caudal catheter techniques, 536–538
multi-modal or balanced analgesia, 510 continuous epidural infusions, 539, 540
pharmacological methods, 510, 511 epidural adjuvants, 540
local anesthesia, 516, 517 lumbar and thoracic epidurals, 538, 539
non-opioid analgesics, 515, 516 sacral epidural block, 539
NSAIDS, 511, 512 spinal anesthesia for, 533, 534
opioid, 512–515 Neuroapoptosis, 121
sucrose, 517, 518 Neurocognitive dysfunction, anesthetic agents cause, 585
pharmacological Methods, 510 inhalation agents, 587, 588
mechanisms, 505–507 nitrous oxide, 589
postoperative pain management, 518 pairwise comparisons, 589
cardiothoracic surgery or complex gastrointestinal/ single, 588, 589
genitourinary surgery, 519 xenon, 589
inguinal hernia repair, circumcision, pyloromyotomy, 518 intravenous anesthetics, 585
major gastrointestinal or genitourinary surgery, 518, 519 α2 agonists, 586, 587
procedural pain, 519, 520 benzodiazepines, 586
Index 649
ketamine, 585 Opioid analgesic drugs

opioids, 587 alfentanil, 135, 136
propofol, 586 codeine, 136, 137
intravenous vs. inhaled anesthetic neurocognitive effects, 587 fentanyl, 133–135
preventative measures or treatments, 590 meperidine, 137
single and multiple exposures/duration of exposure on apoptosis, methadone, 137, 138
589, 590 morphine, 132–134
translation and effects of surgery, 590, 591 remifentanil, 135
Neurocognitive function, 581 sufentanil, 136
Neuroimaging, interventional radiology for, 478 Opioid induced hyperalgesia (OIH), 514
Neuromuscular blocking drugs (NMBDs), 5, 248, 249, 585 Opioid withdrawal syndromes, 513
adverse effects, 147 Optimal mean arterial blood pressure, 38
antagonism, 146, 147 Oral/airway stimulation, 558
neonatal physiology, 144 Organ function, 102
pharmacodynamics, 144, 145 Orotracheal intubation, 192–194
pharmacokinetics, 145, 146 Oscillometry, 7
Neuromuscular junction, 127 Oxygen content (CaO2), 449
Neuromuscular transmission, 144 Oxygen delivery, 442, 449
Neuronal injury, 583 Oxygen fraction (FiO2), 222
Neuroplasticity, 180 Oxygen partial pressure in blood (PaO2), 232
Neurosurgery Oxygen reserve index (ORI), 232, 234
brain tumors, 352, 353 Oxygen saturation of venous blood (SvO2), 232
congenital anomalies Oxygen toxicity, 57–59, 455, 563, 564
anesthetic management, 350, 351 Oxygenation, assessment of, 618
cranial dysraphisms, 349, 350
spinal dysraphisms, 350
hydrocephalus, 351, 352 P
vascular anomalies Panencephalopathy, 30, 40
clinical manifestation, 353 Paracetamol, 510, 511
perinatal stroke, 353 Paradoxical reflex of head, 62
VOGM, 354 Paravertebral block, 543
Neurotoxicity, 171, 175, 180, 181 Parks Doppler Flowmeter, 7
Neurotrophins, 585 Partial thromboplastin time (PTT), 487
Neutral thermal environment, 8 Patent ductus arteriosus (PDA), 457, 460, 467, 468
Nitric oxide (NO), 23, 24, 589 anatomic features, 365
Nitrous oxide (N2O), 175 anesthesia, 366
N-Methyl-D-Aspartate (NMDA), 516, 581–585 issues, 366, 367
Nociception, 167 management, 366
Nociceptive stress, 167 pathophysiology, 365, 366
Nociceptors, 505 Peak inspiratory pressure (PIP), 215
Non-depolarizing muscle relaxants, 127 Pediatric Anesthesia Neurodevelopment Assessment (PANDA) trial, 596
Non-depolarizing neuromuscular blocking drugs, 5 Pediatric Difficult Intubation Registry (PeDI-R), 558
Non-hemorrhagic ventriculomegaly, 41 Pediatric Participant Use Data File (PUF), 554
Non-invasive blood pressure (NIBP), 237 Pediatric Risk Assessment (PRAm) score, 555
Non-invasive ventilation (NIV), 217, 218 Percutaneous Fetal Aortic Balloon Valvuloplasty, 495
Non-opioid analgesics, 515, 516 Perfluorocarbons (PFC), 451
Non-steroidal anti-inflammatory drugs (NSAIDs), 511, 512 Perfusion index (PI), 231, 232
adverse effects, 132 Peri-anesthetic mortality, 553–555
drug interactions, 131 Perinatal care regulations
mechanism of action, 130, 131 Baby Doe regulations, 635
pharmacodynamics, 131 BAIPA, 635, 636
pharmacokinetics, 131 Perinatal stroke, 353
Normal breathing, 556 Peri-operative monitoring
Normothermia, 284 cardio-respiratory monitoring (see Cardio-respiratory monitoring)
N-PASS tools, 510 factors, 227
Nurse-controlled analgesia (NCA) regimen, 512, 513 monitoring blood glucose, 250
nervous system
aEEG, 243, 244
O EEG, 243
Oberant Test Battery (OTB), 596 neuromuscular junction monitoring, 248, 249
Obligate nasal breathers, 48 neurophysiological monitors, 246–248
Obstructive uropathy, 494, 495 NIRS, 244–246
Open fetal surgery, 491, 492 transcranial Doppler, 246
Open heart surgery, 11 renal function, 250
Ophthalmic drugs, 354 temperature monitoring, 249, 250
Ophthalmologic trauma, 355 Peripheral arterial cannulation, 463
Opioid, 490, 512–515, 518, 585, 587 Peripheral chemoreceptors, 59, 61
Opioid analgesia, 518 Peripheral nerve block, 532, 542, 543
650 Index
Peripheral sensory nociceptors, 490 GFR, 262

Peripherally inserted central catheters (PICC), 563 HPA axis, 259, 260
Periventricular leukomalacia (PVL), 37 RAA, 260
Persistent pulmonary hypertension, 439 RBF, 261, 262
Persistent pulmonary hypertension of the newborn (PPHN), 22–24 renal function, 261
Pethidine, 137 tubular function, 263
Pharmacodynamic measures, 111 intraoperative maintenance fluid
Pharmacogenetic (PG) effects, 513 estimation, 272
Pharmacokinetic covariates glucose-containing solutions, 274, 275
maturation, 100, 101 hyponatremia, 272, 273
organ function, 102 intravenous solutions, 273, 274
size, 99–101 maintenance fluid therapy
Pharmacokinetic parameters (P), 102 glucose, 265
Pharmacological methods, 510, 511 sodium and electrolyte requirements, 264, 265
local anesthesia, 516, 517 water requirement, 263, 264
non-opioid analgesics, 515, 516 neonatal body water distribution and metabolism, 257–259
NSAIDS, 511, 512 perioperative fluid management
opioid, 512–515 colloids, 279, 280
sucrose, 517, 518 emergency surgery, 276
Phenobarbitone, 102 hypotension, 279
Phototherapy, 72, 73 maintenance fluids, 273, 276, 278
Physiologic positive feedback mechanism, 61 perioperative steroids, 276
Physiological cell death, 582 principles, 275–277
PICC lines (peripherally inserted central catheters), 461 replacement, 276, 279
Pierre Robin sequence, 199 third space, 276
Pierson, Abel, 1 post-operative fluid maintenance, 280, 281
Placenta, 20–22, 24, 28, 36, 44, 64–66, 69, 73, 75 postoperative metabolic needs, 281, 282
Placental transfusion, 613 temperature homeostasis
Plasticity of the CNS, 505 anesthesia, 284, 285
Plethysmograph variability index (PVI), 231, 232 BAT, 283, 284
Polymethylpentene (PMP), 441 heat loss, 282
Polymorphisms, 558 hypothalamus, 282
Positive end-expiratory pressure (PEEP), 616 normothermia and hypothermia, 284
Positive pressure ventilation (PPV), 610, 616, 623 thermoneutral zone, 282
Post-conceptional age (PCA), 170, 171 Preterm infants, 19, 20, 23–25, 27–30, 32–41, 43, 44, 46–54, 56, 57,
Posterior urethral valves (PUV), 327 59–64, 66, 67, 71–75, 77, 78
Postnatal circulation, 361 Profoundly hypothermic circulatory arrest (PHCA), 11
Preanesthetic assessment of neonate in cath lab, 475, 476 Programmed cell death, 582
Preferential nasal breathers, 48 Prolonged endotracheal intubation, 4
Premature and full-term neonates, 456 Prolonged tracheal intubation, 558
Premature and term infants, 457 Propofol, 172–175, 177–181, 476, 586
Preoxygenation, 176–177 adverse effects, 112
Pressure-controlled ventilation, 215, 216 mechanism, 111
Pressure-regulated volume control (PRVC) mode, 216 phamacokinetics, 112
Pressure support ventilation (PSV), 215 pharmacodynamics, 111, 112
Preterm and term infant Proportional assist ventilation (PAV), 215
cardiac surgery, 282 ProSeal LMA, 192
definitions, 257 Prospective human trials, 595, 596
endocrine response at birth Prostacyclin-cyclic adenosine monophosphate pathway, 23
blood glucose concentrations, 265 Prostaglandin H2 synthetase (PGHS), 129, 130
hepatic synthesis, 265 Prostaglandins, 78
hyperglycemia, 267 Pseudohypoaldosteronism, 78
hypoglycemia, 265–267 Pulmonary arterial hypertension (PAH), 477
enteral nutrition Pulmonary artery banding, 417
feeding, 268 Pulmonary aspiration of gastric contents, 559
metabolic requirements, 267 Pulmonary blood flow, 20, 22, 24, 25, 74
minimal/small volume enteral nutrition, 268 Pulmonary circulation, 22, 23
total parenteral nutrition, 268 Pulmonary edema, 468
fasting and preoperative oral fluids Pulmonary elimination, 107
electrolyte management, 268 Pulmonary function testing (PFT), 52, 53
gastric emptying, 270–272 Pulmonary hypertension, 422, 423, 476
gastric fluid pH and volume, 269, 270 Pulmonary hypoplasia, 451
gastrointestinal ontogeny, 269 Pulmonary mechanics, 236
hypothalamic, endocrine, and renal physiology Pulmonary stenosis
ANPs, 260 anatomic features, 388, 389
antidiuretic hormone, 261, 262 anesthesia, 390
AQPs, 263 issues, 390
Index 651
management, 389, 390 caudal catheter techniques, 536–538

pathophysiology, 389 continuous epidural infusions, 539, 540
Pulmonary surfactant, 53–55 epidural adjuvants, 540
Pulmonary system lumbar and thoracic epidurals, 538, 539
alveolar phase (36 weeks gestation until ~2–3 years), 46, 47 sacral epidural block, 539
anatomy spinal, 533, 534
chest wall, 49–51 peripheral nerve block, 542, 543
neonatal airway, 48, 49 pharmacological differences, 533
apnea of newborn, 62–64 risks, 530, 531
canalicular stage (17–27 weeks), 46 ultrasound imaging of spinal cord, 540, 542
control of ventilation, 59–61 Regional blood flow, 104, 105
embryology, 44 Regionalization of neonatal services, 12, 13
embryonic stage (0–7 weeks gestational age), 45 Remifentanil, 107, 135, 173, 181, 476, 513, 514, 587
endogenous pulmonary surface-active agent/pulmonary Renal blood flow (RBF), 74–76, 78, 261, 262
surfactant, 53–55 Renal dysfunction, 124, 125, 128
FRC, 51, 52 Renal elimination, 108, 109
oxygen toxicity, 57–59 Renal function
postnatal development of lung, 47, 48 GFR, 74–76
pseudoglandular stage (7–17 weeks gestational age), 45 renal blood flow, 74, 75
pulmonary function testing, 52, 53 renal tubular function, 76
respiratory distress syndrome, 55–57 renin-angiotensin-aldosterone system, 78
saccular phase (28–36 weeks gestation), 46 sodium-driven transport function, 76, 77
spontaneous breathing, 51 total body water, 74
Pulmonary vascular resistance (PVR), 609 Renal tubular function, 76
Pulmonary vasoactivity, 23, 24 Renin-angiotensin-aldosterone (RAA) system, 78, 260
Pulmonary vasodilatation, 23 Residual muscle weakness, 559
Pulse oximetry Respiratory and airway complications, 556–559
Blue Sensor, 228 Respiratory control, 54, 61–63
clinical application, 230 Respiratory distress syndrome (RDS), 54–57, 469
clinical practice, 228–230 Respiratory failure, 468
R and arterial saturation, 228 Respiratory volume monitor (RVM), 235, 236
wavelengths, 228 Respiratory system, 124
Pyloric atresia, 314 Retinopathy of prematurity (ROP), 7, 57–59, 63, 355, 470, 559
Pyloric stenosis, 3 Retrospective cohort studies, 591, 594
diagnosis, 312 twin and sibling studies, 594
overview, 312 Return of spontaneous circulation (ROSC), 623
Pyloromyotomy, 518, 597 Right internal jugular vein (RIJV), 441
Risks of transporting neonate, 458
Rocuronium, 174, 175, 178, 181
Q Ropivacaine, 516, 517
Quintero staging system, 493
S
R Sacral epidural block, 539
Ramstedt’s extramucosal pyloromyotomy, 3 Sacral hiatus, 535
Rapid metabolizers, 514 Sacral inter-vertebral block, 539
Rapid sequence induction (RSI), 197, 198, 455 Sacrococcygeal teratomas (SCT), 496, 497
anesthetic agents anesthetic considerations, 329
ketamine, 178 Currarino triad, 328
propofol, 178 diagnosis, 328
rocuronium, 178 malignancy rate, 328
thiopental, 178 management, 328
cricoid pressure, 177 outcomes, 328, 329
gastric emptying, 177 overview, 327, 328
mask ventilation, 177 perinatal mortality, 327
reoxygenation, 176 surgical considerations, 329
Rapidly adapting stretch receptors (RARs), 61 Scopolamine, 147, 148
Reactive oxygen species (ROS), 57 Score for neonatal acute physiology (SNAP), 465
Receptor activity of anesthetic agents, 581 Sedation techniques, 476
Regeneration, 44 Sedatives, 556
Regional analgesia, 11 alpha-2 adrenoreceptor agonist
Regional anesthesia for neonates, 529 clonidine, 140
anatomical considerations, 532 dexmedetomidine, 140, 141
benefits, 530, 531 benzodiazepines, 138–140
management of local anaesthetic toxicity, 545 Selective antegrade cerebral perfusion (SACP), 411, 412
neuraxial blockade Selective fetoscopic laser photocoagulation (SFLP), 494
caudal analgesia, 534–536 Septic/aseptic meningitis, 171
652 Index
Septum pellucidum, 31 management, 373

Sevoflurane, 103, 107, 110, 111, 114–128, 172, 179, 477, 588, 589 pathophysiology, 372, 373
Shadwell laryngoscope, 4 pulmonary vascular resistance, 374
Shikani optical stylet (SOS), 204 restrictive physiology, 375
Shunts, 119, 120 surgical intervention, 374, 375
Sidestream capnography, 234 Therapeutic hypothermia, 34, 35
Sigmoid hyperbolic/Hill model, 100 Thermoregulation, 465
Single-center quality improvement study, 554 transcutaneous CO2 (TCCO2), 459, 460
Single inhalational agents, 588, 589 Thiopental, 170, 173, 175, 177, 178
Slowly adapting pulmonary stretch receptors (SARs), 61 Thiopentone
Sniffing position, 192 adverse effects, 113
Snow, John, 2 mechanism, 112
Sodium-driven transport function, 76, 77 pharmacodynamics, 112
SPA Critical Event Checklists (SPA-CECs), 569 pharmacokinetics, 113
Spina bifida, 31 Thoracic epidurals, 538, 539
Spinal anesthesia, 170, 171, 531, 533, 534 Thoracic surgery
complications, 534 anaesthesia complications, 291
dose guidelines, 534 anaesthetic implications, 300, 301
techniques, 534 CCAM (see Congenital cystic adenomatoid malformation)
Spinal versus general anesthesia, 170 CDH (see Congenital diaphragmatic hernia)
SpO2 monitoring, 607 CLE
Spontaneous breathing (SBT), 51 diagnosis, 300
Spontaneous intestinal perforation (SIP), 469, 470 management, 300
Stellate ganglion block, 542 overview, 300
Storz Video laryngoscope, 201 conduct of anaesthesia
Succinylcholine, 174, 178 fluid management, 295, 296
Sucrose, 517, 518 induction, 293, 294
Sudden infant death syndrome (SIDS), 190 monitoring, 293
Sufentanil, 135, 136, 173, 180, 181, 513 point of care testing, 296
Sugammadex, 181, 559 positioning, 295
Supine hypotension, 486 temperature monitoring and warming, 294, 295
Supraglottic devices, 191, 192 vascular access, 294
Surface tension, 54 congenital thoracic malformations, 297
Surfactant, 53 EA/TEF (see Esophageal atresia (EA))
Swallowing, 270 logistical issues
Synaptic plasticity, 57 emergency status, 292
Synaptogenesis, 584 NICU, 292, 293
Synchronized intermittent mandatory ventilation (SIMV), 215 team brief, 293
Systemic blood pressure monitoring theatre preparation, 293
hypotension, 239, 240 lung sequestration
invasive blood pressure, 237–239 classification, 299
NIBP, 237 diagnosis, 299
Systemic hypotension, 423 management, 299
Systemic inflammatory response syndrome (SIRS), 413 surgical considerations, 299, 300
Systemic vascular resistance (SVR), 609 minimally invasive surgery
Systolic cerebral blood flow velocity, 38 benefits, 296
laparoscopic techniques, 296
one lung ventilation, 297
T physiological effects, 297
Tarnier, Stephane, 2 postoperative care, 297
Temperature homeostasis neonatal anaesthesia, 291, 292
anesthesia, 284, 285 preoperative assessment
BAT, 283, 284 history and examination, 292
heat loss, 282 investigations, 292
hypothalamus, 282 Thrifty phenotype hypothesis, 20
normothermia and hypothermia, 284 Thrombocytopenia, 469
thermoneutral zone, 282 Thromboelastography (TEG), 445, 562
Temperature monitoring, 249, 250 Thromboelastometry (TEM), 562
Term infant, 22, 32, 34, 36–38, 40, 62, 74, 75, 78 Tochen formula, 620
Tetralogy of Fallot (TOF) Topical anesthesia, 543
anatomic features, 372 Topical LA preparations, 517
anesthesia, 373, 374 Total anomalous pulmonary venous return (TAPVR)
arch sidedness, 374 anatomic features, 375, 376
arterial blood pressure monitoring, 374 anesthesia, 377
coronary artery anomalies, 374 issues, 377
JET, 375 management, 377
Index 653
pathophysiology, 375 V
Total parenteral nutrition (TPN), 268 Vaginal squeeze, 52
T-piece system, 6 Vascular access, 461, 469, 562, 563
Tracheal balloon occlusion, 496 central venous catheterization, 463, 464
Tracheal intubation, 173, 620 peripheral arterial cannulation, 463
conformation of tube position, 620 umbilical arterial catheter, 462, 463
depth of insertion of ETT in neonates, 620 umbilical venous catheter, 461
deterioration after, 621 Vascular anomalies
indication, 620 clinical manifestation, 353
muscle relaxants, 174, 175 perinatal stroke, 353
nitrous oxide, 175 VOGM, 354
oral or nasal route, 175, 176 Vasomotor control, 22
size of ETT, 613, 620 Vein of Galen Malformations (VOGM), 354
Tracheal tube (TT) Ventilation strategies
positioning, 197 modes
selection, 194, 195 CPAP and NIV, 217, 218
size, 196, 197 HFV, 217
uncuffed vs. cuffed, 195–196 NHFO, 218, 219
Tracheoesophageal fistula (TEF), 8, 9 in operating theatre, 219–221
Tramadol, 514, 515 pressure-controlled ventilation, 215, 216
Trans-abdominal plane (TAP) block, 543 randomized trials, 214
Transcutaneous carbon dioxide monitoring, 235 VCV, 216
Transcutaneous oxygen tension, 7 volume-targeted ventilation, 216
Transfusion-associated circulatory overload (TACO), 562 monitoring, 222, 223
Transfusion-associated hyperkalemic cardiac arrest, 556 in operating theatre
Transfusion-related acute lung injury (TRALI), 562 CPAP, 221
Transfusions of blood products, 561–563 inspired oxygen fraction, 222
Transitional circulation, 360, 361, 609 mild hypercapnia, 222
Translating time, 584 open-lung strategy, 221
Treacher Collins syndrome, 199 pressure-regulated volume control mode, 222
Trial Remifentanil and dEXmedetomidine (TREX) pilot study, 596 T-piece breathing system, 221
Truncus arteriosus (TA) respiratory system, 213, 214
anatomic features, 377, 378 Ventilation–perfusion (V–Q) mismatch, 53
anesthesia, 379 Very low birth weight (VLBW), 455
issues, 379 Vesicoamniotic shunting, 495
management, 379 Visual system
pathophysiology, 378 anatomy, 348, 349
Tubular function, 263 cerebrovascular physiology, 347, 348
Twin and sibling studies, 594 embryology, 347
Twin Reversed Arterial Perfusion (TRAP) Sequence, 493 Volume-controlled ventilation (VCV), 216
Twin to twin transfusion syndrome (TTTS), 493, 494 Volume expansion, 627, 628
Twin-twin transfusion syndrome, 494 Von Willebrand Factor (VWF), 444
U W
Ultrasound guidance (USG), 240 Wake Up Safe (WUS), 555, 565, 569
Ultrasound imaging of spinal cord, 540, 542 Wechsler Abbreviated Score of Intelligence, 596
Umbilical arterial catheter, 462, 463 White matter injury (WMI), 32–34, 36, 37, 39–43
Umbilical cord clamping, 24, 25 Work of breathing (WOB), 215, 217
Umbilical cord management, 607
Umbilical venous catheter, 461, 462
Uncuffed tracheal tubes (TTs), 457 X
Underdevelopment, 23, 43 Xenon, 585, 589
Unfractionated heparin (UFH), 443, 445
Unilateral spinal blockade, 534

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ISBN 978-3-031-25357-7 ISBN 978-3-031-25358-4 (eBook)

© Springer Nature Switzerland AG 2023

Department of Anaesthesia, Pharmacology and Therapeutics David J. Steward

16 Regional Anesthesia for Neonates����������������������������������������������������������������������������� 529

Omar Alibrahim, MD Division of Pediatric Critical Care Medicine, Duke University

David Robinowitz, MD Department of Anesthesia and Perioperative Care, UCSF School of

Prelude Early Times

© Springer Nature Switzerland AG 2023 1

 nesthesia Circuits and Controlled

and by thoracoscopic clipping of the ductus in a preterm

 x Utero Intrapartum Treatment: “The EXIT

The “EXIT Procedure” was described in 1997 as a means to

© Springer Nature Switzerland AG 2023 19

However, the distribution of the combined ventricular output

600 A wide range of therapies and agents (ventilation, vasoac-

vide short-term benefits (e.g., decreased need for ECMO), it

Mean blood pressure (mm Hg)

[155, 156], and this constitutes a definition of hypotension. A

Clinical Significance and Summary Central Nervous System Function

the meningomyelocele is closed because cerebrospinal 50

95th% uniquely vulnerable to injury in the preterm infant [199, 201,

terns of defective “connectivity” in brain development that

75 develop after the injury and, second, to correlate these pat-

Cerebral White Matter Injury

attentional, behavioral, or socialization problems. Thus,

Cerebellar Injury tiple remote tropic transneuronal interactions” [195]. For

Fig. 2.11 Stages of normal

P seudoglandular Bronchioli 12-16 weeks

Terminal Bronchiolus 16-17 weeks

Alveolar ducts 25 wk-1yr

 he Embryonic Stage (0–7 Weeks’

Ribs pally the diaphragm, can be characterized in terms of pre-

to debate the optimal approach to analyze these data [643].

exchange for survival. The exact mechanism by which these

Fig. 2.16 Nomogram used to 25 428

age and birth weight of

values. Note that this I k Zo

Extracellular fluid volume, water balance, and sodium and

Introduction its effects in the neonate have increased considerably in the

Allometry is a term used to describe the nonlinear relation-

© Springer Nature Switzerland AG 2023 99

Fig. 3.2 Weight-predicted 1000

Fig. 3.3 Size and maturation ¾ Allometry alone ¾ Allometry + maturation

Fig. 3.4 Change in 100%

Maturation is slower than

asphyxia, organ damage, and illness. Postnatal changes in 40

Organ function is typically depressed in the presence

alveolar ventilation. Consequently, the alveolar to inspired Distribution

Fig. 3.6 Body water 100

Total body water

Fig. 3.7 Alpha-1 acid 25

Fig. 3.8 The increase in %

Fig. 3.11 Time-­ 0.4 0.05

M1 metabolite concentration (mg/L)

Tramadol concentration (mg/L)

Fig. 3.12 Clearance 100

major role. These profiles are

1.6 this age group than in older children or adults. Conversely,

In general, outcome measures are more difficult to assess in

Department of Anaesthesia, Pharmacology and Therapeutics David J. Steward

16 Regional Anesthesia for Neonates�� 529

Prelude Early Times

nesthesia Circuits and Controlled

x Utero Intrapartum Treatment: “The EXIT

Clinical Significance and Summary Central Nervous System Function

Cerebral White Matter Injury

Cerebellar Injury tiple remote tropic transneuronal interactions” [195]. For

he Embryonic Stage (0–7 Weeks’

Introduction its effects in the neonate have increased considerably in the

alveolar ventilation. Consequently, the alveolar to inspired Distribution

Fig. 3.11 Time- 0.4 0.05

The use of ketamine in neonates is limited because of Pharmacokinetics

Physicochemical Properties 0.7

Volume of the brain mL Brain / blood solubility

4 ETHER Control of Anesthetic Depth

Analgesic Drugs Analgesic Pharmacodynamics

Adverse Effects major metabolite of clonidine is p-hydroxyclonidine,

electrophysiology laboratory. Heart rate decreased while Pharmacodynamics

art 1. General Principles and Aims

econd Objective: To Avoid the Storage

Gastric Emptying Mask Ventilation

ncuffed Versus Cuffed Tracheal Tubes

Pressure-Controlled Ventilation fore routinely used in clinical practice. Synchronized inter-

Introduction This chapter describes and discusses methods for periop-

rterial Hemoglobin Oxygen Saturation—

linical Application of Pulse Oximetry

dvanced Pulse CO-Oximetry and Oxygen

COOK MEDICAL INC., P.O. Box 4195, Bloomington, IN 47402-

trolled infusion device (e.g., intraflo or squeezeflo2 system) Definition of Hypotension

annulating the Brachiocephalic Vein (BCV)

60 ostnatal Changes in Hypothalamic,

Antidiuretic Hormone Neonatal Renal Function

Tubular Function Aquaporin Peptides