The Newborn

The newborn's cardiac output per unit of weight is the highest of any age group
(≈200 mL/kg/min). Teitel and colleagues (1985) hypothesized that the greater

increase in myocardial performance in response to adrenergic stimulation in older
lambs is due to a “lesser resting β-adrenergic tone.” The baseline state of the
newborn's myocardium consists of a higher β-adrenergic tone and a high resting
cardiac output. This limits the ability to increase the cardiac output further in
response to an increased demand or to wide variations in preload or afterload.
In summary, impaired ventricular function of the fetus, preterm baby, and term
newborn correlates with the presence of fewer myofibrils; decreased sympathetic
innervation; decreased β-adrenoreceptor concentrations; immaturity of the structure
and function of the sarcoplasmic reticulum; immature mechanisms for calcium
uptake, release, and storage; and a specific spectrum of expression of various
isoforms of contractile and noncontractile proteins, channels, exchangers, and
enzymes. Over the first months of life, myocardial contractility gradually increases,
so the cardiac output can be maintained over a wider range of preloads and
afterloads. This improved function correlates with quantitative and qualitative
changes in contractile proteins (e.g., expression of age-specific isoforms), the
development of the sarcoplasmic reticulum and T-tubules, and improved calcium
recruitment and transport. The overall myocardial response to stress or increased
demands improves with these complex maturation-specific changes in force
development.
Preoperative Cardiovascular Evaluation

Preoperative evaluation of the newborn is facilitated by understanding what is
“normal” for each infant. Infants of different gestational ages have significant
variance in baseline heart rates and blood pressure levels ( Fig. 23-8 ). Infants of each
specific gestational age also have a wide range of “normal” physiologic
characteristics. These physiological parameters are also affected by postnatal
development. ELBW infants (born at 23 to 27 weeks' gestational age) are a
particularly challenging subgroup, as shown by a cohort from the National Institute
of Child Health and Human Development (NICHD). Their systolic, diastolic, and
mean blood pressures decreased for the first 4 hours after birth, reached a nadir at 4
to 5 hours, and then increased until 24 hours. Like more mature infants, their values
for blood pressure varied widely. They generally increased with increasing
gestational age, but this too was unpredictable ( Batton et al. 2014 ).
Open full size image

FIG 23-8
A, Linear regression between birth weight mean systolic (top) and diastolic (bottom) blood
pressure, along with upper and lower 95% confidence limits, which approximate mean ±2
standard deviations. B, SBP and DBP are plotted for first five days of life, with each day
subdivided into 8-hour periods. Infants are categorized by gestational age into the following four
groups: ≤28 weeks ( n = 33); 29 to 32 weeks ( n = 73); 33 to 36 weeks ( n = 100); and ≥37
weeks ( n = 110). C, Linear regression between gestational age and mean systolic (top) and
diastolic (bottom) blood pressure, along with upper and lower 95% confidence limits, which
approximate mean ±2 standard deviations. D, Linear regression between postconceptual age
and mean systolic (top) and diastolic (bottom) blood pressure, along with upper and lower 95%
confidence limits, which approximate mean ±2 standard deviations.
(From Zubrow AB, Hulman S, Kushner H, et al. Determinants of blood pressure in infants
admitted to neonatal intensive care units: A prospective multicenter study. Philadelphia Neonatal
Blood Pressure Study Group. J Perinatol. 1995;15:470.)
Acid-base status (electrolytes, pH, Pa co 2 ), urine output, and rates of fluid
administration must be interpreted in the context of a “normal” blood pressure level
and heart rate, and whether interventions are required to maintain stability. Trends
in these data over 1 hour, 6 hours, and 12 to 48 hours prior to examination help to
clarify the cardiorespiratory and acid base status, as well as to direct perioperative
care. For example, the blood pressure and heart rate must be interpreted by noting
the rates of fluid and blood products delivered (including boluses). If the pH has
improved over the prior 4 hours, the relationship of this change to delivery of colloid
or crystalloid and/or initiation of vasopressor support should be evaluated. Thus
appreciating the responses to fluid boluses and vasopressor support will establish the
framework for designing anesthetic management, including intraoperative
administration of fluids and vasopressor to maintain cardiovascular stability during
surgery. Evaluation of the current level of sedation and the response to drugs
administered in the NICU allows anesthesiologists to determine if these agents (e.g.,
morphine, fentanyl) were associated with unacceptable side effects (e.g.,
hypotension).
The Central Nervous System

Embryologic Development and Abnormalities of the Central
Nervous System
Derangements of early brain development correlate with abnormalities in the two
major structures of embryogenesis: the neural tube (future brain and spinal cord)
and the prosencephalon (future forebrain) ( Volpe 2008 ). Primary development of
the neural tube (at 3 to 4 weeks' gestation) and prosencephalon (at 2 to 3 months'
gestation) is complete early in gestation. The primary neural tube encompasses
embryogenesis of both the brain and spinal cord. The prosencephalon develops
shortly after the anterior neural tube closes and is related to both the telencephalon
(future cerebral hemispheres) and diencephalon (future thalamus and
hypothalamus). Severe anomalies of the neural tube or prosencephalon are often
fatal. Neural tube anomalies, such as anencephaly, craniorachischisis totalis,
myeloschisis, and encephalocele, are associated with these early events and are often
fatal. Severe prosencephalic anomalies (holoprosencephalies) are also often fatal,
especially when they are associated with chromosomal abnormalities (e.g., trisomy
13 to 15 or trisomy/ring/deletion 18).
Spina bifida (incidence of 3 to 7 per 10,000 births), a less severe form of abnormal
neural tube closure, is clinically important because affected infants often survive with
lifelong problems. The following are the four primary types of spina bifida, in order
of severity of the defect:
 1.
Spina bifida occulta, in which the divided vertebral arch, spinal cord, and meninges
are covered with skin; hair is often growing from the skin overlying the defect; and a
sacral dimple is often present (the presence of hair or a dimple suggests caution for
performing a caudal block without additional information, e.g., MRI studies).
 2.
Spina bifida cystica, in which neural tissue and its coverings protrude through the
incompletely formed vertebral arch as a cystlike structure.
 3.
Meningocele, in which the neural tube lies in its normal position, but the meninges
protrude through the defect; skin usually covers this lesion.
 4.
Meningomyelocele, in which both the spinal cord and the meninges protrude, often
without skin.
These lesions occur at any spinal level. Hydrocephalus commonly accompanies

meningomyelocele; it is present in about 60% of occipital, cervical, thoracic, or sacral
lesions and about 90% of thoracolumbar, lumbar, or lumbosacral lesions ( Lorber
1961 ). In most infants, hydrocephalus is not evident before the meningomyelocele is
closed, because cerebrospinal fluid leaks through the open lesion and decompresses
the ventricles.
An Arnold-Chiari malformation is a hindbrain defect that occurs in most patients
with meningomyeloceles ( Fig. 23-9 ). The medulla oblongata is flattened and
elongated, and it protrudes through the foramen magnum into the spinal canal, as
does the fourth ventricle. Downward positioning of the medulla elongates the lower
pons and upper medulla, which may compress brainstem nuclei and cranial nerves.
Displacement of the cerebellar tonsils through the foramen magnum can lead to
aqueductal stenosis and hydrocephalus. Whether decompression of the posterior
fossa is necessary depends on the severity of the anatomic abnormalities and the
patient's symptoms. Early correction of an Arnold-Chiari malformation often is
necessary in patients who have apnea, vocal cord paralysis, or central and obstructive
ventilatory disturbances ( Kirk, Morielli, and Brouillette 1999 ). Up to 20% of infants
with a meningomyelocele have sleep-disordered breathing. Despite surgical
intervention, the symptoms may persist; some patients require a tracheostomy ( Kirk
et al. 2000 ). Patients with meningomyeloceles typically have abnormalities that
persist beyond infancy (dependence on ventriculoperitoneal shunts; urologic and/or
orthopedic dysfunction) (see Chapter 28 , “Anesthesia for Neurosurgery”).

FIG 23-9
This MRI of Chiari's Malformation Shows the Brainstem Displaced Through the Foramen
Magnum.
(Courtesy Jim Barkovich, MD, University of California, San Francisco.)
In-utero open repair of meningomyelocele at midgestation was shown to decrease
the incidence of hydrocephalous and the need for a ventriculoperitoneal shunt after
birth. Less mental and motor disability was identified at 30 months of age ( Adzick
et al. 2011 ). However, a recent Cochrane analysis suggested that evidence is
insufficient to draw conclusions about such interventions because of the small
number of fetuses treated and the importance of weighing improved fetal neurologic
outcomes against the risks to both mother (surgery, general anesthesia, and
premature rupture of membranes) and fetus (prematurity) ( Grivell et al. 2014 )
(see Chapter 25 , “Anesthesia for Fetal Surgery”).
Other disorders, such as agenesis of the corpus callosum and septum pellucidum, are
less commonly fatal but are frequently associated with abnormal neuronal migration
and significant clinical abnormalities. In many instances, agenesis of the corpus
callosum is part of a syndrome (e.g., Aicardi syndrome or Andermann syndrome) or
is associated with a chromosomal abnormality (e.g., chromosome 8, 11, 13, 15, or 18).
Up to 80% of patients in whom the corpus callosum is absent have other brain
anomalies and/or non-CNS malformations ( Parrish, Roessmann, and Levinsohn
1979 ; Jeret et al. 1987 ). Partial agenesis of the brain is thought to occur later in
development and often accompanies syndromes associated with migrational and
structural abnormalities. Agenesis of the septum pellucidum is never an isolated
lesion and is often found in conjunction with optic nerve hypoplasia (septooptic
dysplasia).
Following completion of neural tube and prosencephelon development at 2 to 3

months' gestation, proliferation and migration of neurons and glial cells account for
most CNS development. Neurons proliferate from ventricular and subventricular
regions at every level of the developing nervous system. Some glial cells are formed
during the second to fourth months, but neurons account for most proliferating cells
during this time. From the fifth month of gestation into adulthood, glial
multiplication is the primary developmental process.
Growth of the Fetal Brain

During the third trimester of pregnancy, cortical gray and white matter volumes
increase fourfold to fivefold, a process that is characterized by growth and
differentiation of dendrites and axons, proliferation of glia, synaptogenesis, and
myelination. Cerebellar proliferation, which is characterized by intense migration of
various cell populations, is even more rapid than cerebral cortex growth ( Allin et al.
2001 ; Limperopoulos, Soul, and Haidar 2005 ; Limperopoulos and du Plessis
2006 ; Volpe 2009a ).
The brain's vascular network develops rapidly during late gestation. During the last
16 weeks, the long and short penetrating vessels lengthen and arborize, increasing
flow to end zones and border zones. Despite the rapid growth of cerebral vessels,
cerebral blood flow is remarkably low during late fetal life (8 to 15 mL/100 g/min)
compared with that of adults. Blood flow to white matter is even lower (1.6 to
3 mL/100 g/min), only 25% of the flow to the cerebral cortex ( Khwaja and Volpe
2008 ).
Autoregulation of Cerebral Blood Flow in Newborn Infants

Because of intermittent and recurrent pressure-passive cerebral blood flow,
newborns, especially premature infants, are predisposed to ischemic CNS injury
( Greisen 20052009 ). Various vasoactive factors (e.g., hydrogen ions, potassium,
adenosine, prostaglandins, calcium, and osmolarity) are known to affect regulation
of local cerebral blood flow ( Volpe, 2008 ). When “pressure-passive,” cerebral blood
flow responds to changes in arterial blood pressure. Autoregulation is often intact in
fetal and newborn brains, but the range over which regulation of flow occurs (40 to
120 mm Hg) is narrower than in mature brains (60 to 150 mm Hg) ( Paulson et al.
1990 ). Although normal fetal blood pressure increases during the third trimester,
the upper limit of autoregulation remains relatively constant. With decreasing
gestational age, normal mean arterial blood pressures are closer to or below stated
lower autoregulatory limits ( Lou et al. 1979 , Versmold et al. 1981 ; Lou 1998 ). The
concern is that a rapid increase in arterial blood pressure may rupture the fragile
vessels of the immature brain and that hypotension and low perfusion pressures may
cause cerebral ischemia.
Greisen (2009) emphasized that the cerebrovascular autoregulation of critically ill

newborns should be presumed “imperfect,” not simply present or absent, because the
usually flat portion of the autoregulatory plateau is tilted. The amount of “tilt”
defines the magnitude of disturbance in autoregulation ( Fig. 23-10 ). Although the
limits of the autoregulatory plateau have not been defined with certainty, the
estimated range is 25 to 50 mm Hg (mean arterial pressures) in term infants, and
undoubtedly the range is lower and narrower in preterm infants. Postnatal age and
other factors likely affect the range and the lower and upper limits of autoregulation
( Volpe 2008 ). To complicate matters, common neonatal metabolic abnormalities
(e.g., hypoxia, hypercarbia) disturb autoregulation ( Lou et al. 19771979 , Tweed et al.
1983 ; Kaiser et al. 2005 ). Lou documented cerebral blood flow of only
20 mL/100 g/min in the newborn ( Lou et al. 1979 ).

FIG 23-10
Theoretical Concept of Autoregulation in the Newborn.
The flat section of the heavy line represents intact autoregulation, where minimal change in
cerebral blood flow occurs over a range of arterial blood pressure. Below the knee of this curve,
cerebral blood flow decreases as blood pressure decreases. Above the flat part of the curve,
cerebral blood flow increases as blood pressure increases. Greisen suggests that the flat part of
the autoregulatory plateau may never be horizontal, and the shape of the curve may change in
various clinical scenarios. The degree of the tilt may be the critical clinical factor. Autoregulation
should not be simply considered “present” or “absent.”
(From Greisen G. To autoregulate or not to autoregulate—That is no longer the question. Semin
Pediatr Neurol. 2009;16:207-215.)
In infants with intact cerebrovascular autoregulation who are breathing
spontaneously (and in infants after 48 hours of age who are mechanically ventilated),
every change in PaCO 2 of 1 mm Hg is associated with a 4% change in cerebral blood
flow. This change is much more robust than the 1% change in flow associated with
each change of 1 mm Hg in mean arterial blood pressure ( Greisen 2005 ; Noori et al.
2009 ). However, when autoregulation is impaired, responses to PaCO 2 are
unpredictable. For example, in severely asphyxiated infants ( Pryds et al. 1990 ),
following seizures ( Boylan et al. 2000 ), and, to a lesser degree, in mechanically
ventilated preterm infants, especially during the first day of life ( Pryds et al.
1990 ; Pryds 1991 ), cerebral blood flow responses to changes in ventilation are
variable.
In summary, accurately predicting the response of cerebral blood flow to changes in

PaCO 2 is impossible in the newborn, because the relationship varies with gestational
and postnatal age and the presence of neurologic injury, systemic illness, and
metabolic derangement. Both hypocarbia and hypercarbia may dramatically affect
cerebral blood flow ( Wyatt et al. 1991 ) and, therefore, may be associated with severe
neurologic insults ( Fujimoto et al. 1994 ; Kaiser et al. 2006 ). Hypercarbia has been
shown to directly inhibit cerebral autoregulation in preterm infants weighing 500 to
1500 g ( Kaiser et al. 2006 ), and, within various developmentally distinct ranges,
both hypoxemia and hypoglycemia directly increase cerebral blood flow ( Liem and
Greisen 2010 ). Common therapeutic maneuvers (mechanical ventilation, airway
suctioning), metabolic derangements (hypoglycemia, hypercarbia, hypocarbia,
hypoxia, hyponatremia, hypernatremia, and hypocalcemia), the presence of a PDA,
and other insults (seizures, sepsis) may dramatically affect the newborn's ability to
compensate for derangements in either hemodynamic or cerebrovascular status.
Those who anesthetize neonates must be aware of this deranged physiologic status.
Unique and Vulnerable Cell Populations in the Brain of the Fetus

and Premature Infant
The vulnerability of the premature brain is affected by unique time-specific
populations of cells, including preoligodendrocytes, microglia, and subplate neurons.
 •
Microglia: Microglia are macrophages that are mainly found in cortical white matter
during the late second and third trimesters of pregnancy. Their number decreases
rapidly after 37 weeks ( Billiards et al. 2006 ). Although microglia are important for
apoptosis, axonal development, and vascular development during normal brain
development, activation of these cells by infection or inflammation generates reactive
oxygen and nitrogen species, glutamate, and cytokines that can injure the brain
( Khwaja and Volpe 2008 ).
 •
Preoligodendrocytes: Before myelination and during the time of peak vulnerability

to periventricular leukomalacia (PVL) (23 to 32 weeks of gestation), late
oligodendrocyte progenitors (preoligodendrocytes) are the predominant cells in the
subcortical white matter. Although mature oligodendrocytes are relatively resistant
to injury by oxidative and excitotoxic stress, preoligodendrocytes are not; when
injured, preoligodendrocytes fail to fully mature, resulting in diffuse
hypomyelination, axonal disruption, and persistence of a population of cells that are
highly susceptible to excitotoxicity. Injury to preoligodendrocytes inhibits production
of mature oligodendrocytes capable of myelination ( Volpe 2009b ).
 •
Subplate neurons: Subplate neurons are present in subcortical white matter by

approximately 10 weeks' gestation and peak in number at 24 to 32 weeks ( McQuillen
and Ferriero 2005 ; Kostovic and Jovanov-Milosević 2006 ). At this time, the
subplate zone is four to five times thicker than the cortical plate. The subplate is a
“waiting zone” for cells and thalamocortical axons until their ultimate locations in
the cortex are defined ( Leviton and Gressens 2007 ). By expressing various
neurotransmitters and growth factors, this zone orchestrates the migration of cells
from the germinal neuroepithelium to distant sites (e.g., corpus callosum, basal
ganglia, thalamus) and initiates synapse formation. Subplate neurons have abundant
receptors for excitatory amino acids (e.g., glutamate) that modulate normal
development. Hypoxia/ischemia may initiate excessive mediator release,
excitotoxicity, and white matter injury. Subplate neurons are more sensitive to
glutamate injury than other cortical cells ( Nguyen and McQuillen 2010 ). Damage to
the subplate disrupts development of integrative processes, such as thalamocortical
connections. Failure to establish connectivity among various distant structures
(especially between the thalamus and cortex) during brain development has been
associated with deficits in behavior, cognition, and other complicated higher cortical
functions (e.g., executive function) commonly identified in the ex-ELBW premature
infant ( Limperopoulos, Soul, and Haidar 2005 ; Boardman et al. 2006 ; Kapellou
et al. 2006 ; Counsell et al. 2007 ; Dudink et al. 2008 ). The subplate gradually
involutes in human fetuses during the third trimester and disappears by 6 months of
age.
Germinal Matrix–Intraventricular Hemorrhage and Periventricular

Hemorrhagic Infarction
The pathophysiology of germinal matrix–intraventricular hemorrhage (GM-IVH) is
related to the structure of the immature brain ( Fig. 23-11 ) ( Volpe 2008 ). During the
second and early third trimesters, the proliferating germinal matrix and the
ventricular germinal zone produce neuroblasts (precursors for gray and white
matter) and glioblasts. The highly gelatinous germinal matrix existing at
midgestation gradually decreases during the third trimester and is barely present in
full-term infants. At 24 to 28 weeks, the germinal matrix is most prominent at the
body of the caudate nucleus. By 28 to 32 weeks, it is most prominent at the head of
the caudate. The germinal matrix is the most common site of GM-IVH.

FIG 23-11
MRI of IVH in a 980-g Infant.
The ventricles are filled with blood; blood is in the interstitium of the brain.
The richly cellular subependymal germinal matrix is highly vascularized, with a
dense, well-developed network of vessels that arises from the anterior and middle
cerebral arteries and anterior choroidal artery. These arteries supply a network of
thin-walled capillaries that connect to the deep venous system. The deep venous
system receives blood from the entire brain that enters a “terminal vein,” which
courses through the germinal matrix before making a “U-turn” near the head of the
caudate to join the vein of Galen. A large GM-IVH often obstructs the terminal vein,
causing venous engorgement and ischemia. A periventricular hemorrhagic infarction
(PVHI) results from rupture of this engorged system (see below) ( Volpe 2008 ).
PVHI accompanies or follows, but does not precede, GM-IVH. In the premature
brain, bleeding primarily occurs where capillaries connect with veins, not where
capillaries connect with arteries or arterioles.
Papile and associates proposed a system for categorizing GM-IVHs according to the
severity and extent of the initial injury ( Papile et al. 1978 ):
 1.
Grade I: A subependymal hemorrhage with minimal or no IVH
 2.
Grade II: IVH without distended ventricles
 3.
Grade III: IVH plus ventricles that are enlarged with blood
 4.
Grade IV: IVH, ventricular dilation with blood, and bleeding into the parenchyma of
the brain
Volpe (2008) revised the grading system as follows:
 1.
Grade I: Germinal matrix hemorrhage; ventricular enlargement is less than 10% of

the ventricle's volume.
 2.
Grade II: Blood fills 10% to 50% of the ventricle.
 3.
Grade III: More than 50% of the ventricle is filled with blood; the lateral ventricles
are usually enlarged.
Grade IV was eliminated. The presence of an echo density in the periventricular

parenchyma (PVHI) provides criteria for a separate process: a hemorrhagic
infarction. This lesion is not a direct extension of an IVH into the parenchyma of the
brain. PVHI is most often unilateral; bilateral lesions are found in less than 30% of
cases.
Fifty percent of GM-IVHs occur on day 1 and 90% before day 4 of life ( Ment and
Schneider 1993 ). Although one estimate suggests an overall incidence of 7% to 23%
( Adams-Chapman et al. 2008 ), the incidence and severity of IVHs increase with
decreasing gestational age. Since the early 2000s, several studies have reported
lower rates of IVH than rates reported earlier, when the incidence in ELBW infants
was as high as 40% to 50%. Reporting the incidence of GM-IVH in ELBW infants (22
to 28 weeks) born between 2003 and 2007, Stoll and colleagues (2010) noted slight
to moderate differences in the incidence of grade I to III lesions across a range of
gestational ages (grade I, 9% to 13%; grade II, 4% to 13%; and grade III, 4% to 15%).
The incidence of PVHI varied significantly as a function of gestational age (30% at 22
weeks; 21% at 23 weeks; 14% at 24 weeks; 13% at 25 weeks; 7% at 26 weeks; 5% at 27
weeks; and 3% at 28 weeks) (Stoll et al. 2010) . Fanaroff and colleagues
(2007) reported similar incidences of severe GM-PVHI in 500- to 750-g and 750- to
1000-g infants born between 1997 and 2002. Twelve percent and 9% had Grade III,
and 12% and 5% had PVHI in the two weight groups, respectively. Although the
overall incidence has decreased dramatically over the last one to two decades, severe
IVH continues to be a significant problem in infants of 22 to 24 weeks' gestational
age.
Survivors of grade III IVH and PVHI are often left with severe neurologic sequelae.
Thirty-five percent of survivors with grade III IVH and 90% of survivors with grade
IV IVH had poor neurodevelopmental outcomes ( Whitelaw 2001 ). Those with
posthemorrhagic hydrocephalus requiring ventriculoperitoneal shunts had the
highest incidence of severe neurocognitive impairment in early childhood (78% with
grade III IVH and 92% with grade IV IVH) ( Adams-Chapman et al. 2008 ). Although
neurodevelopmental delays are usually less severe following grade I and II IVHs,
outcomes vary from study to study. Near-term infants with uncomplicated grade I or
II IVH are reported to have lower developmental functioning and gray matter
volumes (≈16% smaller by MRI findings) than predicted (Vasileiadias et al. 2004).
Reported outcomes in ELBW infants are inconsistent. Patra and colleagues
(2006) noted more adverse neurodevelopmental outcomes at 20 months in ELBW
infants born between 1992 and 2000 who had had grade I and II IVHs than a similar
group without hemorrhage. Adverse neurodevelopmental outcomes were also noted
at 2 to 3 years of age in a different cohort of ELBW infants born between 1998 and
2004 ( Bolisetty et al. 2014 ). Infants with isolated grade I or II IVHs and no PVL,
late ventricular dilatation, or porencephalic cysts were still at significant risk for
neurosensory impairment, developmental delay, cerebral palsy, and deafness
( Bolisetty et al. 2014 ). Adverse outcomes were also noted in school-age and older
children. On the other hand, Payne and colleagues (2013) reported
neurodevelopmental outcomes of a large cohort of ex-ELBW infants who had low-
grade IVH and found that neurodevelopmental outcomes did not differ from those
without IVH when tested at 18 to 22 months of age.
Although the results from studies of neurodevelopmental outcome are inconsistent,

brain injury following even low-grade IVH is not surprising. Any insult to the
migration and proliferation of neuronal and glial precursor cells in the germinal
matrix (primarily after 20 weeks) is likely to increase the risk for deleterious effects
on cortical development. The degree and extent of injury vary enormously from one
infant to the next, depending in part on the degree of associated inflammation;
coexisting hypotension, acidosis, or disturbed autoregulation of cerebral blood flow;
excitotoxicity; and a host of other factors. Simultaneous injury to the cerebellum or
other areas of the brain magnifies the insult. Although some infants with grade III
IVH have minimal long-term impairment, some with low-grade IVH have moderate
to severe injury. Coexisting seizures increase the complications.
Periventricular Leukomalacia
Periventricular leukomalacia (PVL) is a bilaterally symmetric, nonhemorrhagic
lesion due to white matter necrosis dorsal and lateral to the external angles of the
lateral ventricles of ELBW infants ( Fig. 23-12 ). In the past, lesions were macrocystic
and easily identified by ultrasound. More recently, the most common form of PVL is
a diffuse cerebral white matter injury without any cystic lesions or with microcyst
formation that are identified by MRI but often not visible by routine screening with
ultrasound.

FIG 23-12
MRI of Cystic PVL.
Apgar Score
The Apgar score was initially proposed as a means of rapidly assessing the status of
newborns 1 minute after birth to determine if they required respiratory support
( Apgar 1953 , American Academy of Pediatrics Committee on Fetus and Newborn
2006 ) ( Table 23-3 ). As Casey and colleagues (2001) noted, “Every baby born in a
modern hospital in the world is looked at first through the eyes of Virginia Apgar.”
Five variables (heart rate, respiratory effort, muscle tone, reflex irritability, and
color) are assessed and scored between 0 to 2; the healthiest infants have a score of
10. Scoring is performed at 1 and 5 minutes. If continued resuscitative efforts are
required, scoring continues for as long as 20 minutes.
TABLE 23-3
Apgar Score
Sign 0 1 2
Heart rate Absent <100 beats per minute >100 beats per m
Respiratory effort Absent Slow, irregular Good, crying
Muscle tone Flaccid Some flexion of extremities Active motion
Reflex irritability No response Grimace Vigorous cry
Color Pale Cyanotic Completely pink
View full size
Apgar scoring may predict the risk of death, although this function was not included
in its original purpose. Casey and colleagues (2001) reported a mortality rate of
24.4% in full-term infants whose 5-minute Apgar scores were 1 to 3 and 0.02% when
scores were 7 to 10. The mortality rate of preterm infants of 26 to 36 weeks' gestation
was 31.5% when the 5-minute Apgar score was 0 to 3 but 0.5% with a score of 7 to 10.
Thus the neonatal death rate was highest when the 5-minute Apgar score was 3 or
lower, independent of gestational age. Death most commonly occurred during the
first day of life; the majority of infants died before 3 days of age.
The Apgar score better predicts outcomes than an umbilical artery blood pH of 7.0 or
less. Combining a 5-minute Apgar of 0 to 3 with an umbilical artery blood pH of 7.0
or less provides a more accurate prediction of death in both preterm and full-term
infants. An Apgar score of 0 for more than 10 minutes suggests that resuscitative
efforts should be suspended ( Jain et al. 1991 ). In 2001, Papile said, “At present,
there is no single measure of the fetal or neonatal condition that accurately predicts
later neurodevelopmental disability, … but few will deny the Apgar score's
application at 1 minute of age accomplishes Dr. Apgar's goal of focusing attention on
the condition of the infant immediately after birth.” Although outcomes vary with
gestational age, the cause of neonatal depression, and other factors, providing
effective resuscitation for infants with low Apgar scores resulted in survival of 40% to
60% of infants. Approximately two-thirds of the survivors had normal neurologic
function ( Leuthner and Das 2004 ).
In 1964, the Collaborative Study on Cerebral Palsy reported a stronger relationship

between the 5-minute Apgar score and neonatal death than the 1-minute score
( Drage, Kennedy, and Schwarz 1964 ). Apgar scores, however, do not accurately
predict neurologic outcomes. The score was not intended to establish the diagnosis of
asphyxia, to measure the severity of perinatal asphyxia, or to predict long-term
neurologic outcomes. In fact, 75% of children with cerebral palsy had a normal 5-
minute Apgar score ( Nelson and Ellenberg 1981 ).
Hypoxic-Ischemic Injury
Asphyxia-related insults follow a pattern of early energy depletion and failure of the
Na + , K + -ATPase pump, which disrupts normal transmembrane ion gradients. Loss
of these gradients elicits release of excitatory neurotransmitters, such as glutamate,
dopamine, serotonin, and aspartate. Although glutamate is important for normal
brain development, excessive excitation of glutamate receptors (e.g., N -methyl- d -
aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA],
and kainite) produces excessive intracellular calcium concentrations and activates a
variety of phospholipases and proteases that release arachidonic acid and other
mediators. Downstream production of xanthine and prostaglandins generates free
radicals, in part via the NOS system. In response to these insults, the developing
brain releases inhibitory amino acids (e.g., γ-aminobutyric acid) and adenosine.
These inhibitory molecules seem to delay the onset and severity of energy failure
during asphyxia ( Drury et al. 2014 ).
Although neurons die during the “primary phase” of an asphyxial event, cellular
function can at least partially recover during the “latent phase” (early recovery
phase). Some recovery of oxidative metabolism can occur, even when activity on an
electroencephalogram is suppressed. However, 6 to 15 hours later, secondary
deterioration may develop, characterized by seizures, edema, release of excitatory
amino acids, and failure of mitochondrial oxidative function, and, eventually, cell
death may occur ( Drury et al. 2014 ). In general, more severe injuries during the
“primary phase” imply more severe initial damage and increased risk for delayed cell
death during the “secondary” deterioration. This probably represents an irreversible
stage of injury, a time of “secondary energy failure.”
Although this is a condensed, simplified description of some of the pathways of

cellular injury, the basic pattern of hypoxic-ischemic injury is clearly disruption of
membrane and intracellular function ( Volpe 2008 ). The clinical correlates of this
intense cellular injury include seizures, abnormal mental status, eventual cell death,
and long-term CNS deficits.
Perinatal Stroke
With improvement in neuroimaging over the last decade, perinatal stroke has been
increasingly recognized, occurring in 1 : 2300 to 1 : 5000 term infants and 7 : 1000
premature infants ( Raju et al. 2007 ; Benders et al. 2008 ). The incidence of
ischemic perinatal strokes is higher in infants with congenital heart disease than in
those without heart disease ( Sherlock, McQuillen, and Miller 2009 ), with
approximately 40% of newborns with aortopulmonary transposition showing
evidence of preoperative stroke on MRI. The risk for preoperative stroke is especially
high when balloon septostomy is performed to increase “mixing” between the right
and left atria to improve systemic oxygen delivery in aortopulmonary transposition
( McQuillen et al. 2006 ). After cardiac surgery, an additional 30% of infants show
evidence of a new stroke.
Neonatal strokes typically occur during the first few days of life or after 28 days of
age. Strokes identified early are often associated with seizures; the seizures often
prompt imaging that detects the lesion. For example, strokes are commonly
identified in patients who have seizures associated with a cerebral venous thrombosis
( Wu et al. 2003a ). In most cases, perinatal strokes are located within the area
perfused by the middle cerebral artery (often on the left side of the brain) ( Schulzke
et al. 2005 ). Many newborns have no signs of neurologic dysfunction after their
seizures are adequately controlled ( Miller 2000 ).
Infants who have perinatal strokes after 28 days show no evidence of injury in the
neonatal period. The diagnosis is usually suspected by 4 to 8 months of age, with
onset of hemiplegia, seizures, or difficulty with locomotion or handedness. Most of
these injuries are the result of middle cerebral artery occlusion.
Often, the specific cause of a neonatal stroke is never identified. Possible maternal
factors include chorioamnionitis, prolonged rupture of the membranes,
preeclampsia, and intrauterine growth retardation ( Wu et al. 2004 ). In addition,
20% to 68% of infants with arterial ischemic stroke have a predisposing
prothrombotic state ( Golomb et al. 2001 ). Polycythemia, infection, inflammation,
and hypoglycemia are also associated with an increased risk for neonatal stroke
( Günther et al. 2000 ; Benders et al. 2007 ).
Preoperative Neurologic Evaluation

Some neurologically injured newborns require surgery for treatment of CNS
abnormalities (e.g., insertion of a ventriculoperitoneal shunt), to provide supportive
care (e.g., insertion of a gastrostomy tube or central venous catheter for intravenous
alimentation), or to treat associated anomalies and problems (e.g., congenital
diaphragmatic hernia, laparotomy, meningomyelocele).
Preoperative evaluation of the nervous system must include assessment of

cardiorespiratory status, including trends in respiratory and heart rates. Examining
the fontanelle provides important data about intravascular status as well as
intracranial pressure. The skin over the fontanelle is normally even with the outer
table of the skull. A bulging fontanelle suggests increased intracranial pressure, and a
sunken fontanelle indicates dehydration, volume depletion, or major malformations
of the brain. A difference in muscle tone between the upper and lower extremities or
between one side of the body and the other suggests a neonatal stroke ( Ibrahim,
Hamid, and Mueed 2008 ). The newborn's reflexes, including the Moro (startle)
reflex, should be the same bilaterally. The infant should have a normal Babinski
reflex (the infant curls the toes in a grasping motion when a finger is placed on the
anterior sole of the foot) and a normal grasp reflex (the infant grasps the examiner's
finger when it is placed in the infant's hand). Finally, eye movements, the response of
the pupils to light, and evidence of a gag reflex and a strong suck should be
evaluated.
Infants with neurologic injury are usually divided into three categories:
 1.
Stable infants with a well-defined neurologic status who are scheduled for elective
procedures
 2.
Stable infants with evolving neurologic injuries
 3.
Acutely ill infants who require urgent surgery
Preoperative evaluation of neurologically stable infants who require an elective

surgical or diagnostic procedure and have no evidence of acute cardiorespiratory,
hepatic, or renal problems should focus on determining the range of “normal” for
that patient. The blood pressure, heart rate, respiratory rate, oxygen saturation (and
Fi o 2 ), urine output, and nutritional status must be evaluated according to normal
limits for gestational age. Because of enormous variability among infants of the same
gestational age, the trends over 24 to 48 hours (or longer) prior to surgery must be
analyzed for each patient. Determining the presence of gastroesophageal reflux and
current treatment, as well as the incidence of seizures (if any) and treatment, may
influence the induction of, emergence from, and other aspects of general anesthesia.
If available, electrolyte and calcium concentrations (especially, ionized calcium), and
liver function studies should be reviewed. If the neonate's course is stable and the
proposed procedure is noninvasive, the most relevant laboratory value is the
hematocrit.
Infants whose condition is stable except for ongoing neurologic problems (e.g.,
encephalopathy or seizures) require review of vital signs, laboratory values, and
medications, as well as a physical examination. The hemodynamic responses to
sedatives and analgesics and to painful procedures should be reviewed so the
anesthesiologist can develop a plan that minimizes wide variations in arterial blood
pressure and heart rate. An adequate intravascular volume should be documented to
minimize the need to rapidly administer intravenous fluid during the induction of
anesthesia. In some premature infants who have abnormal cerebrovascular
autoregulation, either hypertension or hypotension can exacerbate existing
neurologic injury secondary to effects on cerebral blood flow. For some infants with
neonatal injury, data from near-infrared spectroscopy and/or
electroencephalography may be available for review. Understanding the effects of
feeding, tracheal suctioning, medications (e.g., sedation), and fluid therapy on
cerebral oxygenation ( Baserga, Gregory, and Sola 2003 ) may suggest that a patient
is particularly fragile. If the patient is mechanically ventilated, understanding how
oxygenation and ventilation are affected by various changes in ventilator settings and
the FiO 2 provides clues about the most appropriate intraoperative ventilatory
strategy.
If the surgery is urgent or emergent, the above factors must be evaluated as quickly
as possible. Understanding trends in the patient's cardiorespiratory and metabolic
status helps the anesthesiologist to develop an intraoperative plan that will
minimally affect the arterial blood pressure and cerebral perfusion to decrease the
risk for CNS injury.
Postanesthetic Apnea
Preterm and ex-premature infants undergoing elective surgery are prone to
postoperative apnea ( Steward 1982 ; Gregory and Steward 1983 ), which is usually
defined as cessation of breathing for 20 seconds or more. The likelihood of
postoperative life-threatening apnea increases in patients with a history of apnea in
the NICU ( Liu et al. 1983 ). During the first month of life, apnea with cyanosis and
bradycardia occurs in at least 20% to 30% of preterm infants. Steward
(1982) reported that 18% of infants who were born before 38 weeks and had reached
a postnatal age of 3 to 28 weeks had apnea during the first 12 hours after surgery.
Other studies have also addressed postconceptual age and risk of apnea ( Liu et al.
1983 ; Welborn et al. 1986 ; Kurth and LeBard 1991 ; Malviya, Swartz, and Lerman
1993 ; Coté et al. 1995 ).
A prospective study by Liu and colleagues (1983) suggested that a history of apnea

and a postconceptual age of less than 44 weeks increased the risk for postoperative
apnea. Kurth and LeBard (1991) reported that postanesthetic apnea (defined as
cessation of breathing for more than 15 seconds) occurred commonly in ex-
premature infants of postconceptual age 32 to 55 weeks. The initial episode of apnea
occurred as late as 12 hours after the end of anesthesia. They recommended that
infants with a postconceptual age of less than 60 weeks who had apnea after surgery
be continuously monitored in the hospital until apnea had not occurred for at least 12
hours.
Welborn and colleagues (1986) found no evidence of apnea in a group of healthy

premature infants whose postconceptual ages were 44 weeks or older at the time of
surgery and who received general anesthesia for herniorrhaphy. Although many of
these patients had no apnea, 63.6% had periodic breathing, which is characterized by
repetitive pauses in breathing that last less than 5 to 10 seconds without oxygen
desaturation or cyanosis. Periodic breathing is common in preterm infants and is
considered “harmless.” Malviya and colleagues (1993) noted that ex-premature
infants younger than postconceptual age 44 weeks had significantly more apnea than
those older than postconceptual age 44 weeks. The two (total number, 63)
anesthetics associated with apnea at more than 44 weeks' gestation occurred in one
patient with severe neurologic injury. After analyzing data from 255 patients
garnered from previously published studies, Coté and colleagues (1995) reported a
1% incidence of apnea in infants whose postconceptual age ranged between 55 and
56 weeks and also found an inverse relationship between postconceptional age and
the incidence of apnea. Infants younger than 56 weeks' postconceptual age had the
greatest risk for apnea. Anemia (hematocrit <30%) was an important risk factor for
apnea ( Fig. 23-13 ).

FIG 23-13
Predicted Probability of Apnea for All Patients by Gestational Age and Weeks of Postconceptual
Age.
Patients with anemia are shown as the horizontal line. The bottom marks indicate the number of
data points by postconceptual age. The shaded boxes represent the overall rates of apnea for
infants within that range of gestational ages. The probability of apnea was the same regardless
of postconceptual age or gestational age for infants with anemia.
(Redrawn from Coté CJ, et al. Postoperative apnea in former preterm infants after inguinal
herniorrhaphy: A combined analysis. Anesthesiology. 1985;82:807.)
In these studies, most premature infants were anesthetized with halothane or
isoflurane, drugs with higher blood-gas solubility coefficients than newer inhaled
anesthetics such as sevoflurane. Residual effects of highly soluble anesthetics on
pharyngeal muscles in preterm infants with a cartilaginous upper airway may also
increase the risk for upper airway obstruction and apnea ( Dransfield, Spitzer, and
Fox 1983 ). The incidence of apnea may be lower when less soluble agents are used
for patients with no history of preoperative apnea ( William et al. 2001 ).
Other factors predispose infants, especially premature infants, to apnea, including

hypoglycemia, hypoxia, hyperoxia, sepsis, anemia, hypocalcemia, and changes in the
environmental temperature ( Schulte 1977 ). Interactions between general anesthesia
and an immature CNS (e.g., the respiratory center) may also increase the risk for
apnea. Low concentrations of halothane depress chemoreceptor responses to hypoxia
( Knill and Gelb 1978 ). Furthermore, inhaled anesthetics decrease intercostal muscle
function, reduce the FRC, and increase the risk for hypoxemia ( Tusiewicz, Bryan,
and Froese 1977 ). These differences coupled with an immature response to hypoxia
and hypercarbia predispose premature infants to erratic respiratory responses in the
perioperative period ( Rigatto et al. 1982 ).
If possible, elective surgery should be delayed until preterm infants are older than 44
weeks' postconceptual age ( Gregory and Steward 1983 ; Malviya et al. 1993 ). Infants
younger than 44 weeks who require surgery must be individually evaluated. The type
of surgery, the gestational and postconceptual ages, the hematocrit, and the current
cardiorespiratory function (i.e., oxygen or diuretic dependence, presence of BPD,
neurologic status) must be considered when developing perioperative plans for ex-
premature infants. In general, patients younger than 44 weeks should be admitted to
the hospital for 24 to 48 hours for postoperative monitoring. Although most episodes
of apnea occur within 12 hours following surgery, some have recurred 48 hours later
( Malviya et al. 1993 ). Infants older than 44 weeks should be evaluated individually
to define the need for postoperative monitoring.
Thermoregulation
Newborns are abruptly born into an environment that is approximately 20° C cooler
than the uterine environment. Neonates are homeotherms. Compared to adults,
neonates can maintain their body temperature within a narrower range of
environmental temperatures. For example, exposure to an environment outside of
this range markedly increases the caloric expenditure required to regulate body
temperature. If the newborn's ability to compensate is exceeded, hypothermia or
hyperthermia develop, along with significant physiological consequences (e.g., apnea
and cardiovascular instability). Neonates lose heat by evaporation, convection,
conduction, and radiation. Extremely preterm infants lose about 15 times more heat
by transdermal water loss than full-term babies ( Hammarlund et al. 1979 ). To
compensate for increased heat losses, the sympathetic nervous system constricts skin
blood vessels to centralize blood flow and conserve body heat ( Asakura 2004 )
(see Chapter 6 , “Thermoregulation: Physiology and Perioperative Disturbances”).
Other factors also contribute to heat loss, including a high ratio of surface area to
body weight, reduced subcutaneous fat, and an underdeveloped or absent ability to
shiver in response to cold. In part, shivering is limited by the neonate's smaller
muscle mass (25% vs. 45% in the adult). As a result, nonshivering thermogenesis is
the major compensatory mechanism for cold stress. Norepinephrine and thyroid
hormone stimulate triglyceride and fatty acid metabolism of energy-rich brown fat
( Stern, Lees, and Leduc 1965 ). Brown fat, which is mostly deposited during the third
trimester, is stored between the scapulae and around major abdominal organs.
Infants born before the third trimester are less able to generate heat by nonshivering
thermogenesis and are therefore more prone to hypothermia. SGA neonates also
have limited nonshivering thermogenesis compared with AGA term infants.
Hypothermia (body temperature <36° C) increases oxygen consumption and

predisposes to metabolic acidosis, increased pulmonary and peripheral vascular
resistance, and reduced cardiac output ( Brady and Ceruti 1966 ). Infants admitted to
the NICU with a temperature of 35.5° C had a Pa o 2 approximately 18 mm Hg lower
than the PaO 2 of newborns with a body temperature of 36.5° C; warming cold infants
to 36.5° C or higher increased the Pa o 2 ( Stephenson, Du, and Oliver 1970 ). A
neutral thermal environment (i.e., the environmental temperature associated with
minimal oxygen consumption) normally corresponds to a skin temperature of 36° C
and an environmental temperature of 32° to 34° C ( Adamson and Towell 1965 ).
Prematurity, hypoglycemia, and general anesthesia exaggerate the newborn's
metabolic response to hypothermia ( Swyer 1975 ). Because preterm and asphyxiated
or neurologically injured full-term newborns have limited ability to maintain a
normal body temperature, the environmental temperature must be carefully
controlled with overhead heaters, isolettes, and warm operating rooms.
If the staff in the NICU must adjust the environmental temperature to maintain a
normal body temperature, the infant has temperature instability. Preterm infants
usually require servocontrolled devices to maintain normal body temperatures.
Neurologically intact term infants usually require minimal assistance to maintain
stable body temperatures (e.g., clothing and a blanket). AGA infants who have
difficulty maintaining the body temperature are commonly septic or have neurologic
injury. Avoiding hypothermia is crucial to prevent increased PVR, decreased
pulmonary blood flow, and right-to-left shunting of blood through the foramen ovale
or PDA ( Brady and Ceruti 1966 ; Stephenson, Du, and Oliver 1970 ). Infants with
hypothermia for prolonged periods of time may develop hypoventilation, inadequate
oxygen delivery, acidosis, and cardiovascular collapse ( Adamsons, Gandy, and
James 1965 ).
Wrapping the trunk and extremities with plastic wrap, using stockinette caps, and
caring for the infant in an incubator or with an overhead heater help maintain a
normal body temperature during surgery ( Roberts 1981 ; Vora et al. 1999 ).
Overhead heaters may be used in the operating room before surgical drapes are
applied but cannot be used intraoperatively. Compared with incubators, overhead
warmers increase insensible water loss by approximately 0.94 mL/kg/hour or
22.6 mL/kg/day ( Flenady and Woodgate 2003 ). As a result, patients maintained
with overhead warmers may have an increased fluid requirement. The oxygen and
energy consumption and incidence of bradycardia are increased in neonates cared
for with overhead warmers ( Long, Phillip, and Lucy 1980 ; Gorski, Huntington, and
Lewkowicz 1990 ; Hutchison 1994 ).
Although infants cared for in incubators have less insensible fluid loss (and therefore
require less fluid intake) and lower body temperatures on the first 2 days of life, no
differences in weight gain, maximum serum sodium levels, or serious complications
(e.g., NEC, IVH, PVL, or ROP) were noted compared with infants treated with
overhead warmers ( Meyer et al. 2001 ). When evaluating neonates for surgery,
anesthesiologists must be aware that patients cared for under overhead warmers are
predisposed to hypovolemia.
Hepatic Function
During the third to fourth week of gestation, epithelium of the posterior foregut
forms an outpouching (liver bud) that invades the mesenchymal cells of the septum
transversum of the diaphragm. Cells from both structures form hepatocellular tissue
that is separated by sinusoids. The blood supply of the developing liver originates
from the yolk sac, and these vessels eventually become the hepatic and portal venous
systems ( Mitchell and Sharma 2009 ). A connection between the hepatic bud and
the duodenum forms the common bile duct, and an outgrowth from the common bile
duct forms the gallbladder and the cystic duct. Endodermal cells occlude the
extrahepatic bile ducts for the first 3 months of gestation. Failure of recannulation of
the ducts around this time results in extrahepatic biliary obstruction (i.e., biliary
atresia), a common cause of liver failure during the first year of life. By the fourth
week of gestation, hepatocytes produce and secrete various proteins, including α-
fetoprotein and α 1 -antitrypsin ( Diehl-Jones and Askin 2002 ). By the fifth week,
hematopoietic stem cells are present; they are the primary source of hematopoiesis
during the first and second trimesters; the bone marrow assumes this role during the
third trimester. To accomplish hematopoiesis, the liver mass increases 40-fold; in
early gestation, hematopoietic cells outnumber hepatocytes. Early in gestation,
hepatic cells differentiate into type II hepatocytes and intrahepatic bile ducts; failure
of this process is another major cause of liver failure during infancy. Formation of
the Golgi apparatus permits synthesis and secretion of albumin and other proteins.
By the second month of gestation, bile is secreted; glycogen synthesis occurs by the
10th week; and acini are present by the third month. The umbilical vein, not the
portal vein, supplies 90% of the blood flow to the left lobe of the liver and 60% to the
right lobe in utero ( Bloom and Fawcett 1975 ).
The liver is an important site for carbohydrate, protein, and lipid metabolism, as well
as for synthesis of a wide array of compounds essential for coagulation. At the same
time, the liver stores iron (ferritin) and biotransforms many endogenous substances
(e.g., thyroxine and steroid hormones) and exogenous substances (e.g., drugs and
toxins).
The following discussion focuses on the aspects of liver function most relevant to the
anesthetic care of the newborn: glucose metabolism, coagulation, and
biotransformation of drugs. Because of its high incidence, hyperbilirubinemia is also
discussed.
Glucose Metabolism
Hypoglycemia
A wide range of reports based on a diversity of populations has resulted in confusing
definitions of hypoglycemia over the last eight decades ( Rozance and Hay 2012 ; Tin
2014 ). In 1988, Lucas and colleagues hypothesized that motor and cognitive
development were impaired after “asymptomatic hypoglycemia.” Based on a detailed
mathematical analysis, a glucose level of less than 47 mg/dL was suggested as the
level associated with an adverse neurologic outcome. In spite of their emphasis that
confounding factors prohibited establishing a definite causal relationship, this
number (<47 mg/dL) is the commonly quoted definition of neonatal hypoglycemia
( Tin 2014 ). After systematically reviewing 18 studies, Boluyt and colleagues
(2006) concluded that none of these studies provided sufficiently robust data to
accurately correlate the degree of hypoglycemia with neurodevelopmental outcome.
Consistent with this, Houin and Rozance (2014) commented: “We are not much
closer today to understanding the long-term neurodevelopmental consequence of
hypoglycemia for these patients, and at what glucose concentrations to become
concerned.” Some investigators have suggested that “it is not possible to identify a
‘single cutoff’ value of blood glucose that can be applied to define ‘significant
neonatal hypoglycemia’ for all newborn infants with different conditions” ( Tin
2014 ).
Although neurologic injury has been linked to “hypoglycemia” for decades, most
experts recognize that the degree, duration, and frequency of hypoglycemic events, as
well as the presence of complex metabolic disorders (e.g., hyperinsulinemia), also
contribute to the risk for eventual poor neurodevelopmental outcomes. Signs
associated with hypoglycemia (lethargy, hypotonia, tremulousness, irritability,
tachypnea, poor feeding, and, with increasing severity and/or duration of
hypoglycemia, seizures, apnea, or coma) are nonspecific and commonly encountered
in sick newborns who do not have hypoglycemia. Clearly, symptoms with profound
hypoglycemia (<20 mg/dL) and/or prolonged or recurrent hypoglycemia, especially
if associated with seizures or coma, predict a poor prognosis. However, the prognosis
for most neonates who develop hypoglycemia, especially when asymptomatic, is less
certain. One group of investigators found that the incidence of a low plasma glucose
concentration did not correlate with adverse neurodevelopmental outcomes at 2 and
15 years of age ( Tin et al. 2012 ). Another group reported significant variability in
both the type of seizures and, most important, the course of seizures associated with
hypoglycemia (glucose <47 mg/dL) ( Fong and Harvey 2014 ).
The specific pattern of predominantly posterior brain injury that has been recognized
after isolated neonatal hypoglycemia ( Barkovich et al. 1998 ) is associated with
visual loss, epilepsy, and cognitive impairment. However, hypoglycemia frequently
coexists with hypoxic-ischemic encephalopathy (e.g., after-birth asphyxia), and the
effects of each are difficult to identify separately. Both hypoglycemia and hypoxic-
ischemic insults are associated with seizures and a depressed mental status, so
patterns of injury overlap. In one MRI study, neonatal hypoglycemia with perinatal
hypoxia-ischemia was associated with injury to the sensorimotor cortex and
corticospinal tracts, but parietooccipital areas were spared. At 12 months of age, the
combination of early hypoglycemia and hypoxic-ischemic injury was associated with
worse outcomes (motor and cognitive) ( Tam et al. 2012 ). Others have described
specific patterns for hypoglycemia versus hypoxic-ischemic injury ( Wong et al.
2013 ).
In view of the uncertainty about the definition and implications of hypoglycemia,

experts have suggested that an “operational threshold” (i.e., concentration at which
organ damage is highly likely to occur, which can be used to define timing for
intervention) should serve as the basis for protocols for diagnosing and treating
glucose disturbances postnatally, especially in high-risk populations (e.g., SGA or
LGA infant, infant with intrauterine growth retardation, infant of a diabetic mother)
( Cornblath et al. 2000 ; Hawdon 2013 ). This view embraces the concept that
intervention requires persistently low glucose levels in an asymptomatic infant or a
single low value in a symptomatic infant who is at high risk for impaired metabolic
responses rather than a single numerical cutoff point. The following have been
suggested as a basis for intervention ( Tin 2014 ):
 •
A single glucose measurement of 18 mg/dL
 •
A level of 36 mg/dL and a lower value on the next measurement
 •
A single glucose measurement of 45 mg/dL in a newborn with symptoms of

hypoglycemia
In contrast to an “operational threshold,” the guidelines of the American Academy of

Pediatrics emphasize a “target concentration,” considering symptomatic and
nonsymptomatic patients separately ( Committee on Fetus and Newborn, Adamkin
2011 ). The screening and interventions described in these guidelines focused on
high-risk infants (term and late preterm SGA and LGA infants and infants of diabetic
mothers):
 Symptomatic with glucose level lower than 40 mg/dL→ Intravenous glucose
 Asymptomatic: birth to 4 hours
o •
Initial feed within 1 hour of birth; screen 0.5 hour later
o •
If glucose is then less than 25 mg/dL→ Feed, recheck glucose in 1 hour
o •
1 hour: glucose 25 to 40 mg/dL→ Refeed, consider intravenous glucose
o •
1 hour: glucose less than 25 mg/dL→ Intravenous glucose
 Asymptomatic: 4 to 24 hours
o •
Feed every 2 to 3 hours; measure serum glucose before each feed
o •
If plasma glucose is less than 35 mg/dL→ Intravenous glucose
o •
If plasma glucose is 35 to 45 mg/dL→ Refeed, consider intravenous glucose
The authors of this practical guide on postnatal glucose homeostasis described the
document (endorsed by the American Academy of Pediatrics) as a “pragmatic
approach to a controversial issue for which evidence is lacking but guidance is
needed” ( Committee on Fetus and Newborn, Adamkin 2011 ). Because blood glucose
concentrations as low as 30 mg/dL are common in normal newborns at 1 to 2 hours,
are usually transient, and are generally considered characteristic of mammalian
adaptation from intrauterine to extrauterine life, some authors recommend
classifying this as “physiologic glucose homeostasis” ( Heck and Erenberg 1987 ).
Consistent with the marked variability in blood glucose levels over the first 3 days,
another group of investigators identified the range of glucose levels in normal-term
infants using a population metaanalysis of published studies of neonatal
hypoglycemia. At 1 to 2, 3 to 23, 24 to 47, and 48 to 72 hours of age, the lower
threshold (<5th percentile) was reported as 28, 40, 41, and 48 mg/dL, respectively
( Alkalay et al. 2006 ). These data are consistent with the advice from the American
Academy of Pediatrics ( Adamkin 2011 ).
In summary:
 1.
Serum glucose should only be measured in newborns who have symptoms or who are
at high risk for hypoglycemia (e.g., SGA or LGA infant, infant of a diabetic mother).
 2.
If the infant is symptomatic and the serum glucose is lower than 40 mg/dL,
administer intravenous glucose.
 3.
In addition to glucose levels, treatment of asymptomatic infants depends on their age

and ability to feed.
 4.
Critically ill infants usually have NPO status and require intravenous glucose. To
ensure a “margin of safety,” a level of 45 to 60 mg/dL may be appropriate.
Glucose Metabolism in the Fetus and Newborn

Because of the steady supply of glucose and other substrates (ketones, free fatty
acids, amino acids) via the placenta, the fetus normally produces minimal amounts
of glucose, although the enzymes for gluconeogenesis are present by the third month
of gestation. During either hyperglycemia (e.g., infant of a diabetic mother) or
hypoglycemia (e.g., intrauterine growth restriction), the fetus is capable of inducing
or decreasing hepatic glucose and/or insulin production. Throughout gestation, the
normal lower limit of glucose concentration is approximately 54 mg/dL ( Tin 2014 ).
Although gluconeogenesis is not active in the normal fetal liver, a variety of hepatic
enzymes important for gluconeogenesis (e.g., glucose-6-phosphatase) develop
rapidly after birth ( Kalhan and Parimi 2000 ; Kalhan et al. 2001 ). In part, these
normal events after birth are secondary to the perinatal surge in concentrations of
catecholamine and glucagon (e.g., activated glycogen phosphorylase, increased
cofactors such as NADPH for glycogenolysis) and to cortisol secretion (e.g.,
stimulates glucose-6-phosphatase and release of hepatic glucose).
When the placental supply is abruptly interrupted at birth, the concentration of

glucose decreases in the newborn, with the nadir as low as 30 mg/dL 1 to 2 hours
after birth. By 12 hours, the concentration increases to approximately 45 mg/dL
( Committee on Fetus and Newborn, Adamkin 2011 ). The decreased concentration of
glucose immediately after birth is considered to be a normal physiologic process
essential for activation of glucose production ( Rozance and Hay 20102012 ).
Newborns use a variety of mechanisms to maintain glucose homeostasis, including
intake from exogenous sources, converting glycogen (which is stored in the liver and
heart during the third trimester) to glucose via glycogenolytic enzymes, and/or
initiating gluconeogenesis using a variety of substrates (e.g., amino acids, lactate,
glycerol). Hormones that regulate glucose metabolism (insulin, glucagon) are
functional. Term newborns use glucose at a rate of 4 to 6 mg/kg/min, compared with
a much higher rate (8 to 9 mg/kg/min) in fetuses and preterm infants ( Rozance and
Hay 2010 ). The brain of the newborn is capable of using alternative substrates such
as ketone bodies and lactate in place of glucose to maintain oxidative metabolism,
which contributes to avoiding neurologic injury when glucose levels normally
decrease during the transition from intrauterine to extrauterine life ( Tin 2014 ).
Because the liver of a term infant has greater stores of glycogen than the adult liver
( Kalhan and Parimi 2000 ), glycogenolysis is a major mechanism used by term
newborns to maintain adequate serum glucose concentrations during a 10- to 12-
hour fast. On the other hand, preterm, SGA, and LGA infants are predisposed to
hypoglycemia secondary to decreased glycogen stores and/or unreliable glucose
metabolism (e.g., chronic exposure to an abnormal intrauterine environment). In a
recent study that attempted to define the incidence of hypoglycemia (<47 mg/dL) in
the first 48 hours of life, Harris and colleagues (2012) noted that 51% of high-risk
infants (SGA or LGA infant, infant of a diabetic mother, late preterm infant) had at
least one episode of hypoglycemia, and 19% had a severe episode (<36 mg/dL) or
more than one episode of hypoglycemia; 81% of episodes occurred in the first 24
hours after birth ( Harris et al. 2012 ).
Perioperative Management of Hepatic Function

Preoperatively, most newborns with NPO status are receiving an intravenous
infusion that contains 5% to 10% dextrose and, after day 1 of life, electrolytes. In both
full-term and preterm infants, normoglycemia is usually maintained by infusing 4 to
7 mg/kg/min of dextrose (e.g., 10% dextrose at 4 mL/kg/hour provides
6.6 mg/kg/min of dextrose).
During a preoperative visit, noting the concentration and rate of delivery of

intravenous glucose needed to maintain a plasma glucose concentration greater than
45 to 50 mg/dL allows the anesthesiologist to plan for intraoperative delivery.
Although the specific level of glucose that provides the safe “lower limit of
normoglycemia” to prevent neurologic injury has not been defined, during general
anesthesia and surgery, a greater margin of safety (e.g., maintaining glucose
>50 mg/dL) may be appropriate, as would be the practice during a major systemic
illness. If the serum glucose has varied widely in the NICU and especially if levels
have been less than 40 mg/dL, the rate of intraoperative delivery should aim for a
high-normal concentration (e.g., serum glucose ≈60 to 70 mg/dL). Occasionally,
administering glucose at preoperative infusion rates produces hyperglycemia.
Ideally, glucose levels can be monitored intraoperatively, but access to sampling is

sometimes challenging. Unfortunately, the accuracy of point-of-care devices
decreases at lower glucose levels ( Committee on Fetus and Newborn, Adamkin
2011 ). If a glucose level below 45 to 50 mg/dL is noted, a blood sample should be
sent to the laboratory to ensure an accurate and reliable concentration of glucose.
Biotransformation
The liver is the primary site for metabolism of drugs and other xenobiotics, as well as
for detoxification of nontherapeutic and environmental compounds. At times the
liver is vulnerable to the toxic effects of these compounds. Because degradation
pathways are immature, infants (especially newborns) often metabolize drugs and
toxins less efficiently, increasing their susceptibility to the toxic effects of these
compounds compared with older infants and children. The three main categories of
hepatic-drug metabolizing systems include nonsynthetic phase I reactions
(oxidation-reduction and hydrolysis), phase II synthetic reactions (glucuronidation,
sulfation, methylation, acetylation), and phase III (transport from liver) reactions. In
general, deficiencies in the activity or capacity of many of the enzymes involved in
oxidation, reduction, hydrolysis, and conjugation decrease the capacity of the
neonatal liver to metabolize and excrete drugs.
An age-dependent ability to metabolize compounds matures in an isoenzyme-specific

pattern for both phase I and phase II reactions. However, other factors contribute to
the newborn's ability to metabolize drugs, including the coexisting medical status
(hypothermia, cardiac function, hypothyroidism), genetic factors (polymorphisms of
enzymes), and environmental factors (other medications, maternal smoking)
( Allegaert et al. 2009 ). Finally, newborns clear drugs less efficiently and less
predictably than older patients owing to immature renal function (decreased
glomerular filtration rate [GFR] and tubular function) (see Renal Function ).
Phase I: CYP450
In humans, phase I processes are primarily the function of the cytochrome P450
(CYP) superfamily, which is subdivided into 18 families and 44 subfamilies. At least
57 genes that encode 57 monooxygenases are involved. These 57 genes are
responsible for metabolism of xenobiotics (e.g., environmental pollutants,
carcinogens), most commonly used drugs, and endogenous compounds (e.g., growth
factors, cholesterol, vitamin D, prostaglandins) ( Fanni et al. 2014a ). Of particular
relevance to the anesthesiologist are the drug-metabolizing CYPs (CYP1, A1/A2;
CYP2, A6/B6/C8/C9/C19/D6/E1/J2; CYP3, A4/A5) that account for over 95% of the
processes for drug metabolism in adults ( Zanger et al. 2014 ). Although hepatic
CYP450 isoenzymes account for most drug metabolism processes, these proteins are
also active in the kidneys, lungs, brain, breast, prostate, and gastrointestinal mucosa.
Depending on the isoform and tissue, activity of these proteins can vary up to 100-
fold among individuals. This accounts for variable rates of drug disposition and a
wide range of pharmacologic effects, toxicities, and drug-drug interactions ( Blake
et al. 2005 ).
Enormous variability in genetic and developmental regulation of the expression of
these isoenzymes during fetal and postnatal life contributes to the age-associated
differences in metabolism and, therefore, to the pharmacokinetics and
pharmacodynamics of drugs essential to newborn care. In addition, the huge variety
of genetic factors (e.g., gender, polymorphisms) and nongenetic host (e.g., age,
disease) and environmental factors (e.g., drug exposure) implies that “every
individual possesses his or her own unique CYP profile with important implication
for drug treatment” (Zanger 2014).
The CYP3A gene family ( CYP3A4, CYP3A5, CYP3A7, CYP3A43 ) produces the largest

portion of CYP450 proteins and is linked to metabolism of steroid hormones, toxins,
and at least 50% of clinically relevant drugs ( Blake et al. 2005 ; Fanni 2014a ).
Developmental expression of the protein products of these genes has been reported,
but those identified for CYP3A4 and CYP3A7 seem especially noteworthy ( Fig. 23-
14 and Table 23-4 ) . Recently, the generally held view that expression of the dominant
isoform for hepatic oxidative metabolism abruptly transitions from CYP3A7 to
CYP3A4 at birth has been updated. By examining human livers (gestational age <24
to 41 weeks), Fanni and colleagues (2014b) documented that CYP3A4 is also
expressed before birth and that interindividual variability in the expression of both
isoforms was significant throughout this range of gestations. Many investigators also
have reported enormous functional variability of these two isoforms. In general, the
activity of CYP4A gradually increases from fetal levels to 50% and 100% of adult
levels by 6 months and 1 to 2 years of age (Blake 2005; Hines 20082013 ). On the
other hand, although highly expressed in utero, the activity of CYP3A7 is negligible
within 1 week after birth.

FIG 23-14
Ontogeny of Cytochrome P450 (CYP) 3A4 and 3A7 Activity Expressed as Activity Measured
Using Isoform-Specific Probes in Human Liver Microsomes.
(From de Wildt SN, et al.: Cytochrome P450 3A: Ontogeny and drug disposition, Clin
Pharmacokinet 37:485, 1999.)
TABLE 23-4
Ontogeny of Human Phase I and Phase II Metabolizing Enzymes
From Chetomb S. Basic pharmacologic principles. In Polin RA, Fox WW, Abman SH. Fetal and
neonatal physiology, 4th ed. Philadelphia: Saunders; 2011. Modified from Morselli PL, Franco-
Morselli R, Bossi L. Clinical pharmacokinetics in newborns and infants: Age-related differences
and therapeutic implications. Clin Pharmacokinet. 1980;5:485; and Lang D, Hofstetter R, von
Bernuth G. Postmortem tissue and plasma concentrations of digoxin in newborns and
infants. Eur J Pediatr. 1978;128:151.
Enzyme Fetus Newborn Infancy A
Phase I
CYP1A1 + − −
CYP1A2 − − +
CYP2C − + +
CYP2D6 ± + +
CYP2E1 ± + +
Enzyme Fetus Newborn Infancy A
CYP3A7 + + −
CYP3A4/5 − + +
Phase II
UGT1A1 − + +
UGT1A3 ± ± +
UGT2B7 ± ± +
GSTA ± ± +
SULT1A1 ± ± +
SULT1A3 + + +
View full size
GST, Glutathione; S -transferase; MGT, UDP-glucuronosyltransferase; SULT, sulfotransferase.
At birth, the total CYP450 content is estimated to be approximately 30% to 60% of
adult levels. The various isoenzymes seem to mature according to unique timetables.
Some of the developmental characteristics documented for the CYP450 superfamily
( Blake et al. 2005 ; Hines 2008 ; Fanni et al. 2014b ) include:
 •
CYP3A4
o The dramatic increase in postnatal expression of this isoenzyme during

the first month after birth implies that the newborn's capacity for drug metabolism
changes from day to day. Of particular relevance to the anesthesiologist, this
isoenzyme is important for metabolism of midazolam, fentanyl, and acetaminophen,
as well as antibiotics, proton pump inhibitors, steroids, and sildenafil. Preterm
infants clear midazolam less well than term infants, leading to a prolonged duration
of action ( Burtin et al. 1994 ).
 •
CYP3A7
o Playing a key role in biosynthesis of estriol (critical for fetal growth and
development), this isoform has been identified in early gestation; levels increase
during pregnancy and decline late in gestation, and levels are negligible postnatally.
 •
CYP2D6
o Although it is only a small fraction of all CYPs in humans, CYP2D6

contributes to the metabolism of as many as 25% of clinically important drugs,
including antiemetics, β-blockers, and opioids. Because CYP2D6 activity varies
within populations, patients are classified as ultrarapid metabolizers (UM), extensive
metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM).
Because of variability in the distribution of the CYP2D6 allele among ethnic groups,
percentages of UMs, EMs, IMs, and PMs in a given population must be specifically
defined to understand relevant drug responses (e.g., tramadol, morphine) ( Zhou
2009 ).
 •
CYP2C
o Although levels are negligible in the fetal liver, expression of CYP2C9

rises during day 1 of postnatal life and reaches 40% and 100% of adult levels by week
2 and 1 to 6 months of life, respectively. Polymorphisms of CYP2C9 result in patients
who are “poor metabolizers” of ibuprofen and indomethacin (e.g., for closure of a
PDA). Low activity of an isoenzyme, CYP2C19, probably accounts for the low
metabolism of diazepam for the first 1 to 2 days of life. Adult levels of CYP2C9 are
present by 2 years of life ( Blake et al. 2005 ).
 •
CYP1A2
o This isoenzyme accounts for approximately 13% of total CYP activity

and contributes to metabolism of several drugs (e.g., theophylline, caffeine,
lidocaine) commonly included in anesthetic care of newborns. Based on studies of
the metabolism of caffeine, CYP1A2 was noted to be nonfunctional in the fetal liver.
Although activity is low in the newborn, levels increase by 1 to 3 months, reaching
50% of the adult values at 1 year of age ( Sonnier and Cresteil 1998 ).
The enormous age-dependent variability of activity and the multitude of

polymorphisms among the CYP superfamily are associated with varied responses to
some sedatives and anesthetics. In addition, although a single enzyme metabolizes
some drugs/molecules, others are substrates of several. For example, both CYP2A6
and CYP2B6 contribute to propofol's metabolism. As more information becomes
available on the ontogeny of metabolizing enzymes and transporters, individualized
dosing of drugs may become a reality and allow anesthesiologists to minimize age-
related therapeutic misadventures and toxicity while improving predictable clinical
effectiveness.
Phase II: UGT, SULT, NAT

Fewer data are available concerning the ontogeny of phase II reactions that
deactivate both endogenous (e.g., bilirubin, bile acids, steroids) and exogenous (e.g.,
morphine, acetaminophen, nonsteroidal antiinflammatory drugs [NSAIDs], toxic
xenobiotics) substances by conjugation with molecules such as uridine
glucuronosyltransferases (UGTs). In general, UGT activity is both isoform and sub-
strate specific, and function is reduced in neonates compared with adults. Other
phase II enzymes include sulfotransferases (SULTs) and N -acetyltransferase (NAT).
Morphine is conjugated by UGT2B7, producing morphine-3 and morphine-6-

glucuronide ( Stone et al. 2003 ). Microsomes from fetuses of 15 to 27 weeks'
gestation metabolized morphine at only 10% to 20% of the rate achieved in adult
preparations ( Pacifici et al. 1982 ). In vivo morphine clearance correlates with these
in vitro data. Premature infants clear morphine five times more slowly than children
1 to 16 years old. Clearance of morphine often matures by 2 months, but it may be
delayed until 30 months of age ( Choonara et al. 1992 ; de Wildt et al. 1999 ). Other
investigators documented that morphine clearance is correlated with postnatal age;
clearance reaches 80% of adult values by 6 months ( Bouwmeester et al. 2004 ).
Although metabolized (sulfation or glucuronidation) by different isoforms (primarily
UGT1A6, but also UGT1A9), acetaminophen metabolism follows a similar pattern:
lower in preterm infants and increased by several postnatal months of age (van
der Marel et al. 2003 ). The age-dependent clearance of propofol correlated with
glucuronidation (GT1A9) activity. Clearance of propofol (a lipophilic compound) is
highly correlated with hepatic processing, which is necessary for renal elimination of
its conjugated metabolites. In adults, although hydroxylation by cytochrome
isoforms of CYP2B6 accounts for 22% of the drug's metabolism, glucuronidation
accounts for more (77%) following a single intravenous bolus of the drug. Newborns,
on the other hand, primarily metabolize propofol by hydroxylation (65%) and to a
lesser extent by glucuronidation (34%) ( Allegaert et al. 2007 , 2008 ; Smits et al.
2013 ). Thus propofol's physiologic effects are more likely to be prolonged and/or
exaggerated in both preterm and term infants due to both the limited
glucuronidation and, therefore, accumulation of propofol.
The SULTs include a variety of isoforms that modulate activity of various

endogenous compounds during fetal life (steroids, catecholamines, thyroid
hormone). For example, the level and activity of SULT2A1, which is involved in
metabolism of steroids, are low at 25 weeks' gestation, increase during the latter half
of gestation, and achieve adult levels in the neonatal period ( Barker et al. 1994 ). Of
more relevance to the anesthesiologist, the pattern of expression and activity of
SULT1A3 during fetal and neonatal life can dramatically affect metabolism of
catecholamines and protect the fetus from possible adverse effects of these
mediators. In contrast, during the transition to extrauterine life, the lower activity of
SULT1A3 plays a role in maintaining the higher levels of catecholamines, which may
regulate the unique cardiovascular function of the newborn. The highly variable
levels of this enzyme are consistent with the rapid development and variable
physiology of the heart and peripheral vascular beds over the first few months of
extrauterine life ( Blake et al. 2005 ).
Polymorphisms of N -acetyltransferase (NAT2) have been associated with protein

products that have impaired enzyme activity (slow acetylators, SS), high activity (fast
acetylators, FF), or intermediate activity (FS). Compared with the CYP enzymes,
much less is known about the developmental aspects of NAT activity, except for
several studies about the pharmacokinetics of isoniazid in infants. Earlier studies
reported that clearance increased with age, but few patients less than 3 months of
age were included. The authors suggested that NAT activity matures during the first
4 years of life, implying that the fast- versus slow-acetylator status cannot be reliably
assigned to newborn or young infants ( Pariente-Khayat et al. 1997 ; Rey et al. 2001 ).
More recently, a prospective, randomized trial of isoniazid for prevention of
tuberculosis in infants (3 to 24 months of age) who had perinatal human
immunodeficiency virus (HIV) exposure provided more insight into the age-related
function of NAT2. Clearance consistently increased with postnatal age but only for
the FF and FS acetylators; the effect of age was most dramatic for the FF group.
Activity approached adult levels over the first 2 years of life ( Zhu et al. 2012 ). In a
group of low-birth-weight (LBW) and/or premature infants (34 to 38 weeks'
gestation), prolonged half-lives and reduced elimination of isoniazid were reported,
especially for slow acetylators. The half-life of the drug was highly variable and
clearance was markedly reduced, especially in smaller and more immature infants.
The clearance and half-life clearly correlated with three distinct groups (SS, FS, SS)
( Bekker et al. 2014 ).
In summary, data defining age-related maturation of the NAT family are limited and
incomplete. However, studies of isoniazid pharmacokinetics suggest that
developmental aspects of this system are highly important to both term and preterm
infants.
The preoperative evaluation of a newborn should include a review of current

medications and determination of unexpected durations of action, toxicity, or side
effects. Prolonged effects of many drugs can be expected in neonates because the
enzymes of metabolism and elimination are immature.
Coagulation
Although the overall process of hemostasis and coagulation remains unchanged
throughout life, many aspects differ in term and preterm infants compared with
adults. The lifelong complex process of hemostasis includes primary hemostasis,
which refers to the response of platelets (adhesion, aggregation) to an injured vessel
wall. Secondary hemostasis (cross-linked fibrin reinforcement and stabilization of
the platelet aggregate) results from coagulation factors interacting with endothelium
and other cells. Developmental hemostasis refers to the age-related changes in this
system over the weeks, months, and years after birth.
Normal hemostasis results from a balance between procoagulation and

anticoagulation rather than specific levels of factors or proteins. Age-related
differences in concentration of factors are not necessarily “abnormal” but reflect
physiologic development ( Revel-Vilk 2012 ; Arnold 2014 ). Because proteins that
mediate hemostasis play roles in angiogenesis, wound repair, and inflammation
( Ignjatovic et al. 2011 ), “levels” of these factors may reflect a variety of activities
other than hemostasis. For example, in addition to its potent effects on
anticoagulation, antithrombin (after proteolytic processing) possesses antiangiogenic
functions that downregulate proangiogenic genes and upregulate antiangiogenic
genes ( O'Reilly 2007 ). The newborn's level of antithrombin (<50% of the adult's)
and the pattern of expression of isoforms differ from those of adults. One hypothesis
suggests that lower levels of antithrombin may be beneficial during the prolific
angiogenesis of the neonatal period. Similarly, in addition to its role as an inhibitor
of thrombin, alpha-2-macroglobulin (levels twofold to threefold higher during
childhood compared with adult levels) participates in various aspects of immunity
and inflammation ( Ignjatovic et al. 2011 ).
Because these large molecules do not readily cross the placenta, the fetus must
produce coagulation factors. Although levels increase throughout pregnancy, plasma
concentrations (and, in some cases, the function) of most procoagulation and
anticoagulation proteins and factors are low in fetuses and newborns. Interestingly,
the low concentrations of procoagulants are matched with lower levels of inhibitors
and lower activity of fibrinolysis ( Arnold 2014 ). The elevated level of alpha-2-
macroglobin, an inhibitor of thrombin, may compensate for the low levels of
antithrobin ( Revel-Vilk 2012 ). Thus a low level of a clotting factor does not imply an
increased risk for bleeding. Even if levels of procoagulants are low, if the
anticoagulation proteins are similarly low, the “balance” is preserved. Levels of
factors have been measured in both fetuses ( Andrew et al. 1990 ) and preterm
infants at birth (e.g., <28 weeks and 28 to 34 weeks) ( Christensen et al. 2014 ), but
estimates of “normal ranges” for both levels and function have not been clearly
defined for ELBW infants.
Although not directly related to liver function, any discussion of hemostasis must
include the role of platelets. Samples from more than 47,000 newborns confirm that
during the first 3 days of life, the initial platelet counts of preterm newborns (22 to 35
weeks' gestation) are lower than those of late preterm and term infants. The platelet
count increases throughout gestation from a lower limit (5th percentile) of
104,200/µL at 32 weeks to 123,000/µL for late preterm and term newborns. Over
the first 2 weeks of postnatal life, the level increases and then stabilizes for the
following 2 weeks. A second peak occurs at 6 to 7 weeks. The 95th percentile is
frequently higher than 450,000/µL ( Wiedmeier et al. 2009 ). In general, the
platelets of newborns function normally despite the fact that surface glycoproteins
show decreased responses to various agonists over the first 2 to 3 postnatal weeks.
Some investigators have proposed that the higher levels of von Willebrand factor
contribute to maintaining a normal bleeding time during the period after birth when
the newborn's hematocrit is high ( Revel-Vilk 2012 ).
Because of differences in the levels of hemostatic factors, laboratory tests of clotting

function (e.g., prothrombin time [PT] and activated partial thromboplastin time
[APTT]) differ in healthy full-term and preterm infants compared with adults ( Table
23-5 ). Variability in function leads to wider ranges of “normal” for healthy
newborns. Arnold (2014) recently emphasized that tests that detect defects in
coagulation via in vitro procedures do not account for factors that generally are only
activated in the presence of proteins bound to the endothelium. In addition to unique
age-specific normal values, the vast number of diagnostic devices and reagents
available for testing add to the challenge of accurately diagnosing abnormal risk for
bleeding or thrombosis in the newborn ( Ignjatovic et al. 2012 ). Finally, laboratory
results must be interpreted in the context of the clinical status. Interpreting and
using laboratory values to guide therapy is difficult because the mechanisms of action
and systems for metabolism are unique and incompletely defined in the newborn
( Ignjatovic et al. 2011 ). For example, the half-life, volume of distribution, clearance,
and peak concentration of unfractionated heparin vary in infants and children
compared with adults ( Newall et al. 2010 ).
TABLE 23-5
Screening Laboratory Tests for Hemostasis: Newborns vs. Adults
From Revel-Vilk S. The conundrum of neonatal coagulopathy. Hematology Am Soc Hematol
Educ Program. 2012;450-454.)
Premature vs. Term Newborn vs. Children Adult Age, Adu
aPTT Longer Longer 16 years
Prothrombin time Longer Same or longer 16 years
INR Higher Same or higher 16 years
Premature vs. Term Newborn vs. Children Adult Age, Adu
Thrombin time Longer Same or longer 5 years
ROTEM/TEG
Clotting time Same Shorter 3 month
Clot formation time Same Shorter 3 month
Max clot firmness Stronger Stronger 3 month
View full size
INR, International normalized ratio; ROTEM, rotating
thromboelastometry; TEG, thromboelasography
Recently, levels of factors (factors II, V, VII, VIII, IX, X, XI, XII, and XIII;
plasminogen; protein C; total and free protein S) were reported as a function of age
(newborn, days 1 and 3; 28 days to 1 year; 1 to 5 years; 6 to 10 years; 11 to 16 years;
adult) ( Attard et al. 2013 ). In general, data were consistent with the well-described
phenomenon that levels of coagulation proteins increase postnatally. Specifically, the
following data were reported:
 •
Levels of factors VIII and XIII did not change with age; levels of factor VIII were 20%
higher than those in adults until day 3.
 •
Levels of factors VII, IX, and XI, as well as proteins C and S (free and total),
increased steadily from newborn to adult.
 •
Levels of factor V in the newborn were comparable to those of adults, increased

between 1 to 10 years of age, and then decreased to adult/newborn levels by 11 to 16
years of age.
 •
Levels of factors II and XII were low at birth but increased to adult levels between 1
month and 1 year of age.
 •
Levels of factor X were low in newborn infants until 1 year of age and reached adult
levels between 1 and 5 years of age.
Consistent with previous data ( Andrew et al. 19871988 ), plasma concentrations of

vitamin K–dependent proteins (e.g., factors II, VII, IX, and X) are 30% to 50% of
those of adults, while the concentrations of factor V and factor VIII are similar to
those of adults. Low levels of several procoagulation factors correlate with tests of
coagulation (prothrombin time [PT]; thrombin time [TT]; activated partial
thromboplastin time [APTT] ( Lippi et al. 2007 ; Revel-Vlik 2012 ). Because of
“normal” variation among laboratories, qualitative trends rather than specific ranges
of normal are listed (see Table 23-5 ).
In spite of differences between newborn and adult liver function, normal newborns
with adequate levels of vitamin K seldom have clinically significant bleeding. Normal
newborns are not predisposed to coagulopathy or thrombosis, but newborns
(especially preterm infants) may develop sepsis/NEC or hypoxia, which are both
associated with high risks for disseminated intravascular dissemination (DIC) and
thrombocytopenia. These critically ill infants often require indwelling catheters,
which increase the risk for thrombosis.
The preoperative evaluation initially should establish the presence or absence of

bleeding. If no clinical bleeding has been noted and the PT and PTT are normal for
age, no further preoperative evaluation of the coagulation system or treatment is
indicated.
Even if laboratory studies are “abnormal,” without evidence of bleeding, the benefits
of treatment must be carefully weighed against the risks of transfusion or other
intervention. As part of the preoperative evaluation, consulting experts may be
necessary to define the availability of and indications for transfusing blood products.
If significant physiologic derangements, clinical instability (e.g., hypotension,
tachycardia, poor urine output), nutritional deficiencies, and/or abnormal laboratory
studies are identified, with or without overt bleeding, aggressive treatment may be
indicated, especially when surgery is planned. This complex scenario deserves
collaborative care. An abnormal laboratory value in a stable infant may only require
monitoring in the NICU, but it may have to be “corrected” preoperatively.
Recently, treatment of coagulopathy following massive transfusion (e.g., dilutional

coagulopathy) has shifted away from fresh frozen plasma (FFP) toward platelets,
fibrinogen, cryoprecipitate, and other specific factor concentrates, as well as strategic
use of antifibrinolytic drugs ( Franchini and Lippi 2012 ; Arnold 2014 ). This
approach is frequently beneficial in newborns during surgery with significant blood
loss and/or tissue trauma (e.g., NEC). Because FFP contains low amounts of
fibrinogen, large volumes of this product must be transfused to replete fibrinogen.
Although FFP remains a widely available source of a multitude of clotting proteins,
many now caution against transfusing this preparation unless the intravascular
volume is low and resuscitation due to blood loss is indicated; transfusing large
volumes of FFP to euvolemic patients is inappropriate and increases the risk for
transfusion-related complications (e.g., transfusion-related acute lung injury and
transmission of viruses). In the presence of active bleeding, experts recommend
correcting fibrinogen levels to above 1 g/dL. Preoperative levels should probably
exceed 0.5 g/dL ( Arnold 2014 ). While cryoprecipitate provides exogenous
fribrinogen, the preparation also contains von Willebrand factor, factor XIII, and
other plasma proteins. If intravascular volume is adequate, cryoprecipitate is a
superior product for correcting deficiencies of fibrinogen and factor VIII.
Preoperative analysis of responses to various therapies (fibrinogen, cryoprecipitate,

platelets) will help to prioritize the choice and availability of specific products for
maintaining hemostasis intraoperatively. At times, ensuring access to experts during
surgery should be established preoperatively.
Severe bleeding in the newborn is most commonly associated with cardiac surgery
secondary to the combined effects of multiorgan dysfunction (e.g., renal and hepatic
injury), intraoperative anticoagulation for cardiopulmonary bypass, and prolonged
surgical procedures (hypothermia, tissue trauma).
Hyperbilirubinemia
Because the normal placenta efficiently clears bilirubin in utero, newborns are
seldom jaundiced. However, by 12 to 48 hours after birth, because efficient placental
clearance has been eliminated, the rate of production of the same amount of bilirubin
that occurred in utero may cause jaundice postnatally. With increasing bilirubin
concentrations, the skin becomes progressively more yellow (icteric) in a
cephalocaudad pattern ( Knudsen 1990 ). Total serum bilirubin usually peaks
between 3 and 5 days after birth and decreases to adult levels over the next several
weeks.
Clinical jaundice (total bilirubin >5 mg/dL) secondary to unconjugated bilirubin has

been estimated to affect 85% of newborns during the first postnatal week ( Watchko
and Tiribelli 2013 ). The term physiologic jaundice refers to the common, transient,
indirect (unconjugated) hyperbilirubinemia in normal newborns. The following
criteria characterize abnormal jaundice:
 •
Presents in the first 36 hours of life
 •
Persists beyond 10 days of life
 •
Increases to more than 12 mg/dL
 •
Includes direct (conjugated) bilirubin of more than 2 mg/dL and more than 30% of
the total bilirubin concentration
Disorders of increased bilirubin production (e.g., hemolysis secondary to a maternal-

fetal blood group incompatibility, hemoglobinopathies, reabsorption of red blood cell
breakdown products from a hematoma, and polycythemia) or decreased excretion
(e.g., genetic diseases, hypothyroidism; in an infant of a diabetic mother) must be
considered in infants with nonphysiologic jaundice. Preterm infants develop elevated
levels of bilirubin more commonly and are more vulnerable to bilirubin-induced CNS
toxicity at lower serum concentrations of bilirubin.
Bilirubin is primarily derived from hemoglobin metabolism, but other heme-

containing proteins (e.g., cytochromes, catalases, and myoglobin) also contribute. In
the reticuloendothelial system, heme is converted to bilirubin, a molecule of carbon
monoxide, and an atom of iron. Normal newborns produce at least two to three times
more bilirubin than adults per kilogram of body weight ( Bartoletti et al. 1979 ). The
cause is a high rate of production (higher hematocrit and red blood cells with shorter
life spans) combined with reduced clearance (immature bilirubin uptake and
intracellular transport, transient deficiency of enzymes for conjugation) in the setting
of increased intestinal absorption via the enterohepatic circulation (i.e., intestinal
bacteria deconjugate bilirubin that is then reabsorbed into the blood) ( Rubaltelli
1993 ). These factors will be discussed in detail.
Uptake of bilirubin into hepatocytes for conjugation requires glucuronic acid and the
organic anion transporter (OATP2) ( Cui et al. 2001 ). Uridine diphosphate
glucuronic acid donates the glucuronic acid. Most bilirubin is excreted in bile as
bilirubin diglucuronides. Once conjugated bilirubin enters the intestinal lumen, a
variety of pathways exist for further disposal. In children and adults, gut bacteria
metabolize bilirubin to urobilinogens for excretion in feces. Because the neonatal
gastrointestinal tract lacks the same bacterial flora as adults, some bilirubin may be
reabsorbed into the circulation, leading to increased serum concentrations.
Postnatally, β-glucuronidase can deconjugate bilirubin, allowing reabsorption of
bilirubin from the gut (so-called enterohepatic circulation). Water-soluble
conjugated bilirubin is excreted in the urine.
The high level of β-glucuronidase in breast milk has been proposed as one cause of
“breast milk jaundice” ( Gourley and Arend 1986 ). However, no specific causative
agent for breast milk jaundice has been identified. Breast milk jaundice typically
develops between days 4 to 7 of life in healthy term infants; breastfeeding jaundice
results from inadequate hydration owing to poor production of and/or intake of
breast milk.
Uridine 5′-diphosphate glucuronosyl transferase 1 (UGT1A1) catalyzes conjugation of

bilirubin and, therefore, plays a significant role in eliminating bilirubin. Expression
of isoenzymes of UGT1A1 is developmentally regulated; activity is 0.1% of adult levels
at 17 to 30 weeks of gestation and 1% of adult values between 30 and 40 weeks; adult
levels are attained by 14 weeks of postnatal life. Unconjugated bilirubin induces
upregulation of hepatic UGT1A1 activity independent of gestational age ( Watchko
and Lin 2010 ). Glutathione S-transferase contributes to intracellular binding of
bilirubin. Although low at birth, concentrations of this enzyme reach adult levels 1 to
2 weeks after birth ( Wolkoff et al. 1979 ).
Defects in the UGT1A1 gene are linked to hereditary unconjugated

hyperbilirubinemia, including Crigler-Najjar syndrome (types I and II) and Gilbert
syndrome. In some cases, mutations in this gene are responsible for variations of
these and similar diseases in various ethnic populations ( Rosenthal 2014 ). Recently,
a specific mutation in this enzyme (homozygosity for UGT1A1*6) was associated with
breast milk jaundice in a group of Japanese newborns ( Maruo et al. 2014 ). At
present, no direct implications for anesthesia care in patients with breast milk
jaundice have been proposed. Identification of variants in a key enzyme (UGT1A1)
that catalyzes glucuronidation of many endogenous substances and xenobiotics,
including drugs, suggests that in the future this common neonatal phenomenon may
be linked with disorders of drug detoxification.
Although hyperbilirubinemia is usually a benign, transitional process in newborns,

bilirubin-induced neurologic damage (BIND) persists as a devastating complication
of hyperbilirubinemia ( Johnson and Bhutani 2011 ; Watchko and Tiribelli
2013 ; Bhutani and Johnson-Hamerman 2015 ). Because experts apply the
term BIND inconsistently, the literature categorizing the neurologic complications of
hyperbilirubinemia is confusing. In some manuscripts, BIND includes the entire
spectrum of acute and chronic injury, both mild and severe ( Bhutani and Wong
2013 ; Watchko and Tiribelli 2013 ). Acute bilirubin encephalopathy refers to
neurologic abnormalities occurring during the first few postnatal weeks. If untreated,
acute bilirubin encephalopathy progresses to a chronic permanent disorder,
kernicterus. In other cases, experts reserve BIND for a subtle, less severe type of
injury (bilirubin-induced neurodevelopmental dysfunction) without the findings of
classic kernicterus. In these patients, BIND only includes abnormalities of sensory
integration, central auditory processing, coordination, and muscle tone ( Shapiro
2010 ; Lunsing 2014 ).
In the early phase (days 1 to 3), acute bilirubin encephalopathy includes poor suck,
lethargy, and hypotonia. In the intermediate stage (days 4 to 6), symptoms include
hypertonia that alternates with hypotonia and fever. During stage 2 and later,
opisthotonos/retrocollis, seizures, and even coma appear. The first year is
characterized by hypotonia, active deep-tendon reflexes, and delayed motor skills.
Later phases are marked by profound movement disorders, including dystonia and
athetosis, choreoathetoid cerebral palsy with tremor, ballismus, gaze (usually
upward) abnormalities, sensorineural hearing loss or auditory neuropathy, and, in
some cases, cognitive delays ( Watchko and Maisels 2003 ). This chronic phase of
bilirubin neurotoxicity correlates with pathologic findings in the CNS secondary to
deposition of bilirubin in the globus pallidus, subthalamic nucleus,
midbrain/pontine/brainstem nuclei (especially related to visuomotor function),
hippocampal neurons, diencephalon, central and peripheral auditory pathways, and
cerebellar cells. Other infants incur a more restricted injury to neural pathways that
results in less severe neural hearing deficits (auditory dyssynchrony or neuropathy)
and minor fine or gross motor deficits.
Although the incidence ranges between 0.4 and 2.7 cases/100,000 in Europe and
North America, kernicterus may be as much as 100 times more common in
developing nations ( Watchko and Tiribelli 2013 ).
As a nonpolar, lipid-soluble molecule (i.e., insoluble in water), unconjugated

bilirubin is transported in blood bound to albumin; approximately 8 mg of bilirubin
are bound to each gram of albumin. Total serum bilirubin refers to this albumin-
bound bilirubin. Inflammatory and infectious disorders and prematurity itself seem
to decrease albumin's ability to bind bilirubin ( Bender et al. 2007 ). The “free”
(unbound) bilirubin fraction includes the small amount of bilirubin not bound to
albumin or other serum proteins. Free bilirubin has relatively easy access to tissues,
including the brain. Unconjugated bilirubin enters brain tissue when the bilirubin-
binding capacity of blood (mostly albumin) is exceeded or when substances such as
sulfonamides, ceftriaxone, or ibuprofen compete for bilirubin-binding sites on
albumin (i.e., displacing bilirubin). Compared with total serum bilirubin
concentrations, unbound bilirubin levels are more likely to accurately predict the risk
for neurotoxicity. Unfortunately, clinical laboratories cannot measure free, unbound
bilirubin.
Indices such as the ratio of total serum bilirubin to serum albumin seem to correlate
with unbound bilirubin levels. However, using this value instead of the total serum
bilirubin level to guide care has not decreased the incidence of BIND. Recently, the
“bilirubin-binding capacity” combined with total bilirubin levels was proposed to
better predict the risk for bilirubin-induced neurotoxicity ( Lamola et al. 2015 ), but
this system has not been evaluated in depth in the clinical setting. The overall view is
that when the level of bilirubin overwhelms neuroprotective mechanisms, brain
damage ensues. The risk of brain injury is not only due to the actual level of unbound
bilirubin but also to complex interactions of other events, including the duration of
exposure, permeability of the blood-brain barrier, intrinsic vulnerability of the brain
(e.g., gestational and postnatal age, acidosis, inflammation, sepsis), and response to
aggressive treatment. Neurons undergoing differentiation at the time of exposure to
bilirubin may be most susceptible to apoptosis inducement by bilirubin ( Watchko
and Tiribelli 2013 ). Neuronal necrosis is a predominant feature of the neurologic
injury and is most commonly identified in the basal ganglia, brainstem, and
occulomotor and cochlear nuclei. The high risk for neurotoxicity in premature
infants is exacerbated by a high incidence of concurrent disease (e.g., sepsis,
respiratory acidosis), nutritional deficits (e.g., hypoalbuminemia), and frequent drug
therapy (i.e., hepatic dysfunction, competition for binding to albumin and other
serum proteins) ( Bhutani and Wong 2013 ).
Data focused on bilirubin's role as an antioxidant have been controversial (in vitro vs.
in vivo studies) ( Dani et al. 2004 ). While bilirubin was recently reported to exert
antioxidant effects in a dose-dependent pattern, no protection was confirmed at
levels above 200 mg/L (20 mg/dL) in normal full-term newborns ( Shekeeb Shahab
et al. 2008 ).
Consistent with recommendations from the American Academy of Pediatrics

( Subcommittee on Hyperbilirubinemia 2004 ), Bhutani and colleagues
(1999) generated a normogram correlating total bilirubin concentrations with
postnatal age in hours for infants beyond 35 weeks' gestation ( Bhutani et al.
19992010 ). Although the nomogram was generated for follow-up of at-risk term and
late preterm newborns after discharge from the hospital, the normogram has also
been adapted to guide care of hospitalized infants. As a function of gestational age,
premature infants require close scrutiny owing to the higher risk of neurologic injury
at lower bilirubin levels. Because of limited evidence-based data, recommendations
for management of hyperbilirubinemia in premature infants evolved from a
consensus-based process ( Maisels et al. 2012 ). Both sets of data should serve as
references for perioperative care.
During the preoperative visit, the levels and trends of both total and direct bilirubin
should be examined, because they can reflect either normal postnatal development or
abnormal physiology (e.g., sepsis, other metabolic derangements). In association
with other laboratory values (e.g., alanine aminotransferase [ALT], aspartate
aminotransferase [AST], lactate dehydrogenase [LDH]), hyperbilirubinemia can
estimate hepatic dysfunction (e.g., secondary to asphyxia, sepsis, neonatal hepatitis).
Impaired bile flow or cholestasis often is associated with abnormalities in alkaline
phosphatase, γ-glutamyltransferase (GGT), and 5-nucleotidase (5-NT). Because
albumin is synthesized only in the liver, abnormal levels may reflect hepatic
dysfunction. However, hypoalbuminemia also results from protein loss in the
gastrointestinal tract or kidney or from chronic infection and/or poor nutrition.
Abnormal ammonia concentrations suggest a urea cycle defect.
The goals during preoperative assessment are to understand the functional status of
the liver and estimate its effect on drug metabolism, blood loss, surgical trauma, and
the need for coagulation factors. Aggressive red blood cell transfusion may increase
the volume of hemoglobin presented to the liver after surgery; cardiorespiratory
instability (acidosis, hypercarbia) may exacerbate hepatic dysfunction and increase
the permeability of the blood-brain barrier perioperatively, so monitoring and
aggressive treatment of hyperbilirubinemia may be indicated for the preoperative,
critically ill newborn.
Renal Function
Metabolic stability and electrolyte homeostasis are maintained in utero via the
placenta, and intrauterine renal growth and development do not appear to be linked
or regulated by function. Appreciating the complexities of renal development
provides a framework for understanding the impact of congenital
malformations/anomalies, prematurity, and other disorders on acid-base
homeostasis and fluid and electrolyte balance.
Early Growth and Development of the Renal System

In humans, the ureteric bud appears on approximately day 28 of gestation. Nephrons
appear during the eighth week, initially in the juxtamedullary region and cortex. A
complex interaction of genes, such as the Wilms' tumor gene 1 (Wnt1) and SOX gene,
the c-RET signaling pathway, transcription factors (PAX2 and PAX8), and growth
factors such as glial cell line−derived neurotrophic factor (GDNF), orchestrate this
process ( Taeusch, Ballard, and Gleason 2005 ; Dziarmaga, Quinlan, and Goodyer
2006 ). By 20 weeks' gestation, one-third of the final number of nephrons has
developed; by 35 to 36 weeks, the total number is present ( McDonald and Emery
1959 ). The reduced number of nephrons associated with fetal growth abnormalities
and/or prematurity may result from genetic and/or environmental factors ( Lelièvre-
Pégorier and Merlet-Bénichou 2000 ; Faa et al. 2012 ). Polymorphisms of the RET
gene reduce the number of nephrons ( Zhang et al. 2008 ). Kidneys developing
without RET/GDNF have branching abnormalities ( Faa et al. 2012 ). Expression of a
variant of PAX2 has been associated with smaller kidneys at birth ( Quinlan et al.
2007 ). Some mutations lead to excessive apoptosis in the ureteric bud ( Faa et al.
2012 ).
More than 60% of nephrons form during the last third of pregnancy ( Gubhaju et al.
2011 ), and during this period, kidney growth correlates directly with gestational age.
Thus late gestation is critical for normal nephrogenesis. Infants born prematurely
continue to develop new nephrons postnatally but only for about 40 days ( Rodríguez
et al. 2004 ). Consequently, at 25 weeks' gestation, an infant will have reached the
postconceptual age of only 31 weeks when nephrogenesis ceases; compared with
infants born at or after 36 weeks' gestation, ELBW infants have fewer nephrons. In
addition to the absence of nephrogenesis after 40 days of postnatal life ( Rodríguez
et al. 2004 ), investigators noted that as many as 18% of glomeruli were abnormal
(e.g., were cystic, had increased volume, were poorly vascularized), especially in the
outer cortex. That is, the most mature glomeruli are juxtamedullary, so postnatal
development primarily affects the outer areas of the cortex ( Gubhaju et al. 2011 ).
Others also have documented that because growth of the fetal kidney begins deep in
the medulla, the juxtamedullary nephrons are more mature than other nephrons at
birth ( Evan et al. 1983 ) and have greater tubular length than outer and inner
cortical nephrons. In several autopsy studies of ELBW infants, glomerular number
correlated with gestational age, but injury during the neonatal period (e.g., renal
failure) added variability to the relationship ( Rodríguez et al. 20042005 ; Faa et al.
2010 ; Sutherland et al. 2011 ).
Among healthy full-term infants, the number of nephrons varies at least fourfold to
fivefold (300,000 to ≈1.5 million per kidney) ( Merlet-Bénichou et al. 1999 ). Others
( Georgas et al. 2009 ) suggest that variation may be as high as ninefold (210,000 up
to 1.825 million) ( Hughson et al. 2003 ; Bertram et al. 2011 ). Data from a
prospective cohort of healthy subjects who were followed from the second trimester
of pregnancy to 5 to 8 years of age have expanded the database linking in utero
events to later health (so-called Developmental Origins of Health and Disease,
DOHaD) ( Barker 19902004 ; Gluckman et al. 2008 ; Norman 2008 ; Fanni et al.
2012 ; Zohdi et al. 2012 ). Fetal growth was correlated with renal size and GFR.
Prematurity and in utero growth restriction predicted smaller kidney volumes and
lower estimated GFRs at school age. Similarly, higher second-trimester fetal weights
predicted higher GFRs in early childhood; higher birth weights also correlated with
higher kidney volume and GFR ( Bakker et al. 2014 ). Also consistent with the
DOHaD, studies suggest that having fewer nephrons shortly after birth correlates
with hypertension later in life ( Brenner, Garcia, and Anderson 1988 ; Keller et al.
2003 ) and with development of focal glomerulosclerosis with proteinuria
( Rodríguez et al. 2004 ; Hodgin et al. 2009 ). Brenner and Mackenzie
(1997) suggested that early loss of nephrons associated with prematurity induces
“hyperfiltration” by the normal units. These hypertrophied, overworked nephrons
slowly sclerose, leading to progressive renal dysfunction later in life.
Vascular growth and development parallel nephrogenesis. Neonatal oxidative injury

is associated with decreased capillary density and fewer nephrons in adult rats
( Yzydorczyk et al. 2008 ), but these same effects were not found in mice ( Sutherland
et al. 2013 ).
Urine is formed by 10 weeks' gestation, and the volume increases from about 2 to
5 mL/hour by 20 weeks to 10 to 12 mL/hour at 30 weeks, 12 to 16 mL/hour at 35
weeks, and 35 to 50 mL/hour at 40 weeks ( Engle 1986 ; Rabinowitz et al.
1989 ; Chevalier 19962008 ). Urine is hypotonic early in gestation (100 to
250 mOsm/kg), and tonicity decreases throughout gestation (i.e., always less than
plasma, similar to patients with diabetes insipidus). For example, urinary sodium is
120 mEq/L at midgestation and decreases to 50 mEq/L by 32 to 35 weeks' gestation
( Spitzer 1996 ; Moritz et al. 2008 ). Large quantities of hypotonic urine are essential
for maintaining normal amniotic fluid volumes, especially after 18 weeks. Oliguria
leads to oligohydramnios and constraint of the fetus in utero, which may be
associated with dysmorphic features, including a flattened nasal bridge and low-set
ears, clubfeet, limb contractures, and, in some cases, life-threatening pulmonary
hypoplasia. High fetal urine volumes are required for normal development of organs
outside the urinary tract.
Fetal and neonatal renal function is characterized by low renal blood flow, GFR, solid
excretion, and concentrating power ( Chevalier 1996 ). In utero, blood flow is low
because renal vascular resistance is high. After birth, renal blood flow and the
percentage of the cardiac output distributed to the kidneys (2% to 4% in utero, 10%
at 1 week of age, 25% in adults) increase markedly as arterial blood pressures and
renal transcapillary hydraulic pressures increase and renal vascular resistance
decreases. Renal blood flow is approximately 20 mL/min at 25 weeks' gestation and
60 mL/min near term ( Veille et al. 1993 ). Postnatally, the increased distribution of
cardiac output to the kidney further increases renal blood flow (80 mL/1.73 m 2 at
term, 250 mL/min/1.73 m 2 8 days after birth, and 770 mL/min/1.73 m 2 at 5 months)
( Guignard and Sulyok 2012 ) (see Chapter 5 , “Regulation of Fluids and Electrolytes”).
Distribution of Total Body Water

The quantity and distribution of total body water changes throughout fetal life
( Friis-Hansen 1983 ; Brans 1986 ). At 16, 32, and 40 (term) weeks' gestation, body
water accounts for approximately 94%, 82%, and 75%, respectively, of body weight.
The extracellular compartment decreases with increasing gestational age (65% at 16
weeks, 60% at 24 to 25 weeks, and 50% at term). At the same time, the intracellular
compartment increases from 34% in early gestation to 50% at term. Of note, most
extracellular water resides in the interstitial space, an extracellular subcompartment.
The differences in distribution of water are exaggerated in preterm neonates,
especially ELBW neonates; extracellular water compartments are much larger
compared with term newborns and older infants.
During the first 3 to 7 days of extrauterine life, healthy term infants lose
approximately 5% to 10% of their body weight, primarily through contraction of the
extracellular water space ( Fig. 23-15 ). Preterm infants follow a similar pattern but
often lose more than 15% of birth weight and tend to establish steady growth later
than full-term infants. Cardiorespiratory abnormalities and treatment, infections and
side effects, and pharmacologic interventions alter normal patterns of renal growth
in both term and preterm neonates.

FIG 23-15
A, The effects of gestation on transepidermal water loss. Measurements were made from
abdominal skin and carried out in the first few days of life. B, Insensible water loss (IWL) as a
function of birth weight in premature infants nursed under radiant warmers. C, Transepidermal
water evaporation from the skin of premature neonates with gestational ages of 25 to 40 weeks,
followed longitudinally from birth over the first month of life. Dehydration is the most dangerous in
the first week of life for the most immature babies of less than 28 weeks' gestation, before skin
keratinization occurs. D, Premature weight chart.
( A, From Hammarlund K, Sedin G. Transepidermal water loss in newborn infants, III: Relation to
gestational age. Acta Paediatr Scand. 1979;68:795. B, Adapted from Costarino AT, Baumgart S.
Controversies in fluid and electrolyte therapy for the premature infant. Clin
Perinatol. 1988;15:863. C, From Sedin G, et al. Measurements of transepidermal water loss in
newborn infants. Clin Perinatol. 1985;12:79. D , From Klaus MH, Fanaroff AA. Care of the high-
risk neonate. Philadelphia: Saunders; 1973. Data from Dancis J, O'Connell J, Holt L. A grid for
recording the weight of premature infants. J Pediat. 1948;33:570.)
Glomerular Filtration Rate
The GFR of preterm infants correlates directly with both gestational and postnatal
age. On day 3 of life, the GFR of infants born at 27 to 28, 28 to 29, 29 to 30, and 31 to
32 weeks' gestation is approximately 4 to 8, 5 to 12, 10 to 15, and 9 to
17 mL/min/1.73 m 2 , respectively ( Gallini et al. 2000 ). By day 52, creatinine
clearance has increased to 35 to 45 mL/min/1.73 m 2 in all infants, except those
younger than 27 weeks' gestational age (22 to 28 mL/min/1.73 m 2 ). This pattern of
development was recently confirmed when premature infants were compared with
adults. At 4 weeks after birth, no differences in creatinine clearance were identified
in infants of 28, 29 to 31, or 32 to 36 weeks' gestational age. However, in term
infants, clearance was approximately 1.5-fold greater than in premature infants
( Gubhaju et al. 2014 ). Reference data for GFR were recently reported from a large
multicenter, prospective study of 275 infants. Although trends were similar to those
from other studies, the authors expanded knowledge of creatinine clearance by
providing normal 3rd and 97th percentile values for five gestational ages at weekly
intervals over the first month of life. The GFR of infants at 27 weeks' gestational age
increased from 7.9 to 18.9 mL/min/1.73 m 2 on day 7 to 15.5 to
26.5 mL/min/1.73 m 2 on day 28. The GFR of infants at 31 weeks' gestational age
ranged between 19.3 and 30.2 mL/min/1.73 m 2 on day 7 and 26.9 and
37.9 mL/min/1.73 m 2 on day 28 ( Vieux et al. 2010 ).
Although the GFR increased at a slower rate in ELBW infants, in those without
acquired renal insufficiency, the GFR doubled by 2 weeks of age and tripled by 3
months. Thereafter, the GFR increased more slowly; adult values for the GFR are
reached by 12 to 24 months. Because of rapid renal maturation after birth, a 3-week-
old ex-27 weeks gestational age infant may have significantly more mature renal
function than a healthy 6-hour-old full-term infant. Postnatal renal maturation
apparently occurs in response to demand (separation from the placenta plus solute
exposure). Renal filtration and concentrating ability increase when the kidneys are
challenged.
Because creatinine is totally filtered, not reabsorbed, and is minimally secreted by

the glomeruli of infants (but not premature infants), children, and adults, serum
creatinine concentration is often considered a relatively accurate estimate of renal
function. However, levels are highly variable during the first 1 to 3 weeks after birth,
especially in premature infants. For the first few hours after a full-term gestation, the
infant's serum creatinine appears to reflect maternal levels. By 24 to 48 hours, levels
often exceed those at birth but then gradually decrease to a stable value (i.e., 0.4 to
0.5 mg/dL) over 1 to 3 weeks. In contrast, the serum creatinine level of preterm
infants is often higher than the maternal level, in part due to reabsorption of
creatinine via immature renal tubules ( Bueva and Guignard 1994 ; Guignard and
Drukker 1999 ). For approximately 3 weeks, serum creatinine levels of three groups
of LBW infants (1 to 1.5 kg, 1.5 to 2 kg, 2 to 2.5 kg) were higher than those of full-term
infants. By 1 month, the values for all groups were similar ( Bueva and Guignard
1994 ). Thus after 3 to 4 weeks of age, serum creatinine levels varied as a function of
postnatal, not gestational, age. Interestingly, another study showed that initial serum
creatinine concentrations at 1 to 2 hours of life were similar among VLBW infants
when those born before 27 weeks' gestation were compared with those born between
27 to 28, 29 to 30, and 31 to 32 weeks. Serum creatinine concentrations increased in
all groups over the first 3 days of life and then gradually decreased to below
50 mmol/L (i.e., 0.56 mg/dL) ( Gallini et al. 2000 ). However, maximum serum
creatinine concentrations were higher and reached later (day 3.5 vs. day 1) in the
most immature neonates. The variability of the GFR during development implies
that drugs primarily eliminated by renal filtration may be eliminated differently as a
function of gestational and postnatal age.
Renal Tubular Function

The proximal tubules (especially the early portions) reabsorb all filtered amino acids,
glucose, 80% of filtered bicarbonate, and 65% of filtered chloride ( Rector
1983 ; Gattineni and Baum 2015 ). Most solutes are actively reabsorbed in the
proximal tubules via apical membrane sodium-dependent transporters, driven by the
electrochemical gradient generated by Na + , K + -ATPase located on the basolateral
membrane. Passive mechanisms also exist. The distal tubules primarily concentrate
urine and secrete potassium but also fine-tune sodium balance.
The polarized membrane of renal tubular cells allows the selective absorption and
secretion of a wide variety of molecules. The apical membrane faces the lumen of the
tubule, and the basal membrane faces the capillaries. The selective sodium-coupled
transporters located on the apical (brush border) membrane of the proximal tubules
salvage compounds such as amino acids, glucose, phosphate, and lactate. The Na + ,
K + -ATPase pump located on the basolateral membrane maintains the normal
extracellular-to-intracellular sodium gradient essential for active transport of the
substrates across the apical membrane. Activity of the Na + , K + -ATPase pump
accounts for approximately 70% of renal oxygen consumption. About 60% to 80% of
sodium reabsorption occurs in the proximal tubules. Another 10% to 15% occurs in
the distal tubules (i.e., responsive to aldosterone) and collecting tubules (responsive
to arginine vasopressin [AVP], which regulates water permeability). The quantity of
sodium presented to the distal tubules depends in part on the efficiency of the
proximal tubules ( Holtbäck and Aperia 2003 ).
Maintenance of normal extracellular fluid volume, water balance, and the

concentrations of sodium and other electrolytes are interrelated and undergo
significant postnatal changes. In addition to the marked changes in nephron number,
glomerular function, and renal blood flow, renal tubules undergo dramatic
development throughout fetal and postnatal life. Both tubular immaturity and the
metabolic demands of rapid growth and illnesses add to the complexity of managing
fluids and providing adequate nutritional support for the newborn. The following
factors should be considered:
 1.
Newborns, especially premature newborns, cannot reabsorb or excrete sodium as

efficiently as older infants, children, and adults ( Fig 23-16 ). Reabsorption of sodium
by the proximal tubule increases with gestational and postnatal age; at least 5% of
the filtered sodium is excreted in the urine of infants younger than 30 weeks'
gestational age, but only 0.2% is excreted in full-term infants ( Bueva and Guignard
1994 ; Gallini et al. 2000 ; Gubhaju et al. 2014 ). By 28 days of postnatal life,
fractional excretion of sodium remains higher in infants younger than 27 weeks'
gestational age compared with those who were more mature at birth. In those of
more than 28 weeks' gestational age, the value decreased to less than 1% by 28 days
( Gubhaju et al. 2014 ) and 52 days ( Gallini et al. 2000 ). Hypoxia, respiratory
distress, and hyperbilirubinemia may increase fractional sodium excretion.

FIG 23-16
Scattergram Demonstrating the Inversion Correlation Between Fractional Sodium Excretion and
Gestational Age.
(From Siegel SR, Oh W. Renal function as a marker of human renal fetal maturation. Acta
Paediatr Scand. 1976;65:481.)
Sodium chloride is actively transported in the proximal tubule by two exchangers:
Na + /H + and Cl − /base. In the proximal tubules of neonatal rabbits, both the quantity
and activity of the Na + /H + exchanger are approximately one-third that of adults;
adult levels are achieved by approximately 6 weeks ( Baum 1990 ). The energy for
this and other Na + -driven transport is the inwardly directed gradient maintained by
the basolateral Na + , K + -ATPase pump. This driving force is lower in newborns
because the activity of this pump in the proximal tubule ( Baum 2008 ) is only 50%
of that in the adult ( Schwartz and Evan 1984 ).
After birth, activity of renal Na + , K + -ATPase increases 5-fold to 10-fold ( Holtbäck
and Aperia 2003 ). Because most renal tubular transport depends on transmembrane
(extracellular to intracellular) sodium gradients, which are maintained by Na + , K + -
ATPase activity, developmental changes of this enzyme dramatically affect many
solute transporters (e.g., glucose, amino acids). Perinatal increases in glucocorticoids
and thyroid hormones seem to contribute to the postnatal increases in Na + , K + -
ATPase activity ( Gattineni and Baum 2015 ). Increases in apical sodium transport
may be important for maturation of Na + , K + -ATPase activity ( Fukuda and Aperia
1988 ).
 2.
In part, the 25% increase in expression of the α-unit of the apical amiloride-sensitive
epithelial Na + channel located on the distal nephron between 24 and 36 weeks'
gestation may account for decreased fractional sodium excretion postnatally
( Delgado et al. 2003 ). Aldosterone induces trafficking of the epithelial Na+ channel
to the apical membrane, allowing sodium to move intracellularly along an
electrochemical gradient maintained by Na + , K + -ATPase ( Edinger et al. 2014 ). The
resulting negative potential within the tubular lumen produces a driving force for
several responses, including potassium secretion via a channel (ROMK), proton
secretion, and paracellular reabsorption of chloride.
Throughout early infancy, the kidney maintains the positive sodium balance required
for normal growth and development, especially in ex-prematures. Sodium uptake
into rapidly growing tissue at 4 to 6 weeks of age can cause so-called late
hyponatremia ( Drukker and Guignard 2002 ).
 3.
Metabolism of potassium in newborns dramatically differs from that of adults

( Gurkan et al. 2007 ) in that growing infants maintain a positive potassium balance,
while adults maintain a zero balance. Serum potassium concentrations that exceed
5 mmol/L are relatively common in newborns, particularly premature newborns, in
part due to a mild metabolic acidosis. Hyperkalemia is defined as a potassium
plasma concentration of more than 6.5 mmol/L ( Bockenhauer and Zieg 2014 ).
Although potassium is filtered by the glomerulus and reabsorbed along the proximal
tubule, the distal nephron primarily maintains potassium homeostasis via tightly
regulated potassium secretion in response to metabolic needs. However, newborns
secrete a potassium load much less efficiently than adults. The balance between
potassium secretion (principal cells) and potassium absorption (intercalated cells) in
the collecting ducts is essential for net flux of this ion. A simplistic view of
maturation of these processes focuses on the limited number of potassium secretory
channels (SK/ROMK) in the principal cells and the marked activity of a pump that
reabsorbs potassium in exchange for protons (hydrogen, potassium adenosine
triphosphatase [H+, K+-ATPase]) in the intercalated cells ( Gurkan et al. 2007 ).
Nonoliguric hyperkalemia, which is characterized by a rapid rise of serum potassium
during the first 1 to 3 days of life, is reported in approximately 50% of VLBW infants
( Gruskay et al. 1988 ; Shaffer et al. 1992 ) and seems to be related, at least in part, to
the immature state of the collecting ducts. In some cases, nonoliguric hyperkalemia
requires aggressive treatment (e.g., insulin/glucose, calcium/bicarbonate, albuterol).
A recent review concluded that no “firm recommendations” could be made for
specific treatment but noted that the combination of insulin and glucose and
albuterol inhalation deserves further study ( Vemgal and Ohlsson 2012 ).
 4.
An appropriate response to AVP determines an infant's ability to concentrate and

dilute urine in response to changes in serum osmolality. Although newborn infants
can achieve approximately the same level of minimal urine osmolality as adults, at 1
to 3 weeks of age, both preterm and term infants have limited ability to concentrate
urine in response to desmopressin (DDAVP) (245 to 450 mOsm/L in premature
infants vs. 350 to 450 mOsm/L in full-term infants). By 4 to 6 weeks, both age
groups (premature, 425 to 550 mOsm/L; full-term, 480 to 625 mOsm/L) had
increased concentrating ability but not to the level commonly seen in adults (1200 to
1400 mOsm/L). By approximately 1 year of age, maximum concentrating ability is
1200 mOsm/L ( Polacek et al. 1965 ). Although preterm infants secrete AVP, the
response of immature kidneys is limited. Dehydration may elicit a urine osmolality of
only 500 mOsm/L or less. The limited capacity of the immature kidney to conserve
water is in part related to low levels of aquaporins (AQPs), water channels that
respond to AVP ( Iacobelli et al. 2006 ).
At least 13 isoforms of AQP have been identified. At least seven are expressed in
various areas of the nephron and allow either constitutive or AVP-induced water
permeation. For example, AQP2 is translocated from intracellular vesicles to the
apical membrane of the collecting duct in response to AVP; urinary levels of AQP1
and AQP2 increase in response to AVP release. At term, AQP1 (the major aquaporin
in the proximal tubule) and AQP2 (collecting duct) are expressed at approximately
50% of normal adult kidney levels ( Yasui et al. 1996 ; Moritz et al. 2008 ). In a group
of infants at 27 to 34 weeks' gestational age, AQP2 excretion increased by day 3,
which coincided with the normal diuresis and loss of body weight ( Iacobelli et al.
2006 ). Others have documented that by 3 weeks of age in infants born between 26
and 39 weeks' gestation, urine levels of AQP2 correlated with gestational age
( Zelenina et al. 2006 ).
 5.
Although lower serum bicarbonate concentration is well documented in premature

infants (12 to 16 mEq/L in ELBW infants, 18 to 20 mEq/L in infants at 30 to 35
weeks' gestational age, 20 to 22 mEq/L in term infants, and 25 to 28 mEq/L in
adults), it gradually increases postnatally. Because these levels are common in
apparently normal healthy premature infants, some recommend avoiding the
term late metabolic acidosis when discussing the lower bicarbonate levels of these
infants. This avoids confusing this “normal acidosis” with pathologic acidosis that
accompanies poor perfusion (e.g., sepsis) or metabolic disorders ( Schwartz et al.
1979 ). Serum bicarbonate levels reflect the low renal threshold for bicarbonate
( Drukker and Guignard 2002 ) that is in part secondary to immature membrane
transporters. For example, studies in rabbits demonstrated that transport rates for
bicarbonate and glucose were only 25% to 35% those in adults ( Schwartz and Evan
1983 ). The loss of bicarbonate increases urine pH until the serum bicarbonate level
is below the renal threshold.
The kidneys both reabsorb bicarbonate and excrete fixed acids to maintain acid-base
homeostasis. The proximal tubules are the primary site for bicarbonate reabsorption
(80%), while the thick ascending limb of Henle resorbs 10%, and the distal nephron
resorbs 9%. Proton secretion is coupled to bicarbonate reabsorption. Hydrogen is
actively secreted and reacts with bicarbonate to produce carbonic acid and carbon
dioxide. These substances enter tubular cells through the action of carbonic
anhydrase. Bicarbonate again forms and exits the cell via another transporter. The
immaturity of the Na + -H + exchanger (NHE), the critical transporter for mediating
sodium reabsorption and proton secretion, contributes to the newborn's relatively
low serum bicarbonate concentrations. At least 10 isoforms of this protein have been
identified, and most have age-related expression ( Gattineni and Baum 2015 ). For
example, NHE3 populates both the proximal tubule and the thick ascending limb
and is primarily responsible for reabsorption of bicarbonate. NHE3 expression is low
in newborn rodents and increases dramatically over the first few postnatal weeks
( Holtbäck and Aperia 2003 ; Gattineni and Baum 2015 ). Immature carbonic
anhydrase activity and impaired NHE function explain in part the normal mild
metabolic acidosis characteristic of newborns, especially premature infants.
 6.
Both the transport maximum (T m ) and tubular reabsorption of glucose are decreased
in newborns (150 mg/dL in term neonates, 180 mg/dL in older children and adults),
especially in ELBW infants. Fractional excretion of glucose is variable, and glucosuria
may occur even during normoglycemia, especially in very premature infants
( Wilkins 1992 ). Maturation of glucose transport correlates with increasing numbers
of transporters and with increases in Na + , K + -ATPase activity ( Gattineni and Baum
2015 ). Transcellular transport of glucose depends on isoforms of two families of
proteins: the sodium-glucose apical symporter (SGLT) and the uniporter (GLUT) on
the lateral membrane of the proximal tubular cell. Each of these transporters
undergoes early postnatal developmental changes.
 7.
Calcium homeostasis normally depends on a balance between its gastrointestinal and

renal absorption and renal excretion. Parathyroid hormone (PTH) regulates calcium
homeostasis by three mechanisms: bone resorption, synthesis of 1,25-
dihyroxyvitamin D 3 , and reabsorption by the kidney. Normally, 98% to 99% of
filtered calcium is reabsorbed (70% in the proximal tubule, 20% in the thick
ascending limb of Henle, and 5% to 10% in the distal convoluted tubule). Calcium
reabsorption is passive in the proximal tubule and loop of Henle but correlates with
sodium resorption. Volume expansion and alkalosis decrease sodium and calcium
absorption in the proximal tubules. In contrast to the process in the proximal tubule,
resorption in the distal tubule and collecting duct is active, independent of sodium,
and dramatically responsive to PTH. Preterm and term infants have unique
requirements for calcium. Elimination of the placenta as a source of calcium is
accompanied by a decrease in serum calcium in the newborn, which elicits release of
PTH. The response to hypocalcemia is blunted during days 1 to 3 after birth, even in
term infants. In most cases, with normal oral intake, the nadir at 24 hours is followed
by a slow rise. In contrast, preterm infants, infants of diabetic mothers, and
asphyxiated infants respond to hypocalcemia with a minimal surge in PTH and often
require calcium supplementation for days to weeks after birth. Increased urinary
losses of calcium by immature kidneys have been linked to low Ca 2+ channel activity
(apical membrane) and to fewer Na + -Ca 2+ exchangers (basolateral membrane)
( Guignard and Sulyok 2012 ).
 8.
About 80% of filtered phosphate is actively reabsorbed in the proximal tubule via the
sodium-dependent transporter (Na + -phosphate cotransporter). Compared with
adults, newborns normally maintain a positive phosphate balance (similar to
potassium) and a higher serum phosphate concentration, which are essential for
growth. For any level of filtered load, newborn animals reabsorb at least twice as
much phosphate (normalized to mass and GFR) as adults ( Gattineni and Baum
2015 ). PTH and fibroblast growth factor may have roles in regulating total body
phosphate, including the higher serum levels present in newborns. Immature
animals have decreased responses to PTH (i.e., it elicits a phosphaturic response)
( Johnson and Spitzer 1986 ).
Hormonal Control of Fluids and Electrolytes

Hormone control of fluid and electrolyte homeostasis is complex and unique. The
renin-angiotensin-aldosterone (RAS), atrial natriuretic peptide (ANP), vasopressin,
and catecholamine (i.e., dopamine and noradrenalin) systems regulate renal and
cardiovascular homeostasis during normal fetal and postnatal periods, during the
transition from fetal to neonatal life, and during disturbed labor and delivery.
However, compared with the well-known functions of these mediators after birth,
their specific roles in organogenesis, growth, and the transitional circulation have not
been clearly elucidated.
Angiotensin II is considered the primary effector peptide of the RAS system, acting
via two receptors: angiotensin receptor type 1 (AT1R) and angiotensin receptor type 2
(AT2R). While AT1R has been clearly linked to regulation of arterial blood pressure,
renal function, response to thirst, and sympathetic responses, the specific role(s) of
AT2R are less well known. In general, AT1R mediates vasoconstriction effects of
angiotensin II, whereas AT2R counterbalances this action with vasodilatation. In
contrast to AT1R, which has been associated with growth and proliferation, AT2R
seems to mediate apoptosis and inhibition of growth. Some experts have suggested
that the two receptors act in concert as a kind of coregulatory system, with the final
physiologic activities resulting from the relative balance of the two systems. Others
disagree with this simplistic view ( Kaschina and Unger 2003 ; Paul et al.
2006 ; Porrello et al. 2009 ; Vinturache and Smith 2014 ).
Components of the RAS system are present early in gestation ( Schütz et al. 1996 ).
Developmental changes in angiotensin receptor distribution imply functional
differences during maturation. For example, AT2Rs predominate in the kidney of
fetal and neonatal tissue and decline postnatally. AT2Rs again become important
later in life in patients who have hypertension and/or diabetes mellitus ( Porrello
et al. 2009 ; Vinturache and Smith 2014 ). AT1Rs develop later in fetal life, peak
postnatally, and gradually decrease to adult levels in the postnatal period. In
summary, both receptors may have a role in nephrogenesis, although their relative
and specific roles remain controversial.
The following are examples:
 1.
Some experts propose that urinary aldosterone excretion (UAE) provides a reliable
index, at least in part, for evaluating sensitivity to secretion of this hormone. UAE
concentrations inversely correlate with gestational age, birth weight, and plasma
sodium levels ( Costa et al. 2012 ). Immature kidneys are less responsive to the
sodium- and water-conserving effects of these hormones, or so-called physiologic
partial aldosterone resistance ( Martinerie et al. 2009 ). Prostaglandins may partially
counterbalance the vasoconstrictive effects of these hormones. Treatment with the
prostaglandin inhibitor indomethacin when attempting to close a PDA may be
associated with renal dysfunction, perhaps related to unopposed vasoconstriction.
Less renal insufficiency may be associated with ibuprofen than with indomethacin
( Ohlsson et al. 2013 ).
 2.
The higher plasma vasopressin (AVP) concentration of newborns (compared with

concentrations later in life), especially following vaginal delivery, may be responsible
in part for the low urine output during the first 24 hours of life. AVP may also
participate in contraction of the extracellular volume immediately after birth. Along
with other hormones (e.g., aldosterone, angiotensin, natriuretic peptides), AVP may
contribute to the indomethacin-induced renal dysfunction in premature infants.
Hypoxemia, atelectasis, intraventricular hemorrhage, and bronchopulmonary
dysplasia increase urine AVP concentrations in both preterm and term infants. In
part, this nonosmotic secretion of AVP accounts for the dilutional hyponatremia of
newborns, especially premature newborns ( Wiriyathian et al. 1986 ). Thus the
limited ability of fetuses and newborns to concentrate urine correlates with an
immature concentrating ability of the medullary system, decreased response to AVP
(in part, secondary to differences in AQP2 (see above), and immaturity of the
aldosterone system.
 3.
Natriuretic peptides (e.g., atrial natriuretic peptide [ANP]) inhibit the production
and action of renin and aldosterone. Plasma concentrations of ANP remain high in
normal newborns during the initial days of life and then decrease rapidly over the
remainder of the first week. Adult levels of ANP are achieved by 3 months of age.
High circulating concentrations of ANP, plus prostaglandins and progesterone,
correlate with the 10% to 15% perinatal weight loss that occurs during the first few
days ( Tulassay et al. 1986 ). In fact, the weight loss per kilogram of premature
infants is often much higher than that of older infants, especially ELBW infants.
Other clinically specific effects remain controversial, but oliguria induced by positive
end-expiratory pressure might be linked to inadequate release of ANP.
 4.
In addition to the challenges associated with normal immature kidney function,

critically ill newborns are highly susceptible to acute renal injury secondary to
asphyxia, infection/sepsis, prematurity, and nephrotoxic medication. Although the
incidence of acute kidney injury (AKI) varies by definition and population examined
( Gubhaju et al. 2014 ), AKI is now recognized as a risk factor for poor outcomes
( Jetton and Askenazi 2012 ), including chronic kidney disease, hypertension, and
death ( Askenazi et al. 2009 ; Bruel et al. 2013 ). In one recent study, 8.8% of all
admissions to the NICU met criteria for AKI, with the incidence being highly
correlated with gestational age: 37% at less than 28 weeks, 8% at 28 to 32 weeks, 4%
at 32 to 36 weeks, and 2% at 37 weeks or later ( Lunn et al. 2006 ). Others have
reported higher incidences of AKI (79% in infants <1500 g) ( Cataldi et al. 2005 ).
To emphasize the heterogeneous nature of this disorder, Jetton and Askenazi

(2012) have proposed that the term acute renal failure be replaced with acute
kidney injury . In addition, these authors recommend assessing AKI by examining
specific markers of injury. For example, neutrophil gelatinase−associated lipocalin
(NGAL) is rapidly upregulated and detectable in the urine several hours after injury
( Jetton and Askenazi 2012 ). However, its specific relevance in clinical medicine has
not been completely elucidated.
Efforts have been made to stratify the risk for death or a poor neurodevelopmental
outcome based on the critical serum creatinine levels (>1.6 mg/dL at 24 to 27 weeks'
gestational age, 1.1 mg/dL at 28 to 29 weeks, and 1 mg/dL at 30 to 32 weeks) ( Bruel
et al. 2013 ). Jetton and Askenazi (2014) caution that serum creatinine reflects
function rather than degree or nature of an injury and does not increase until as long
as 24 to 48 hours after the initial injury and only after 25% to 50% of function is lost
( Jetton and Askenazi 2014 ). In addition to these “critical values,” efforts to
categorize and standardize definitions of AKI now include systems that stratify
severity. Recently, a work group integrated data from the pRIFLE group
( p ediatric r isk, i njury, f ailure, l oss, and e nd-stage renal disease) with data from
the adult RIFLE group and the Acute Kidney Injury Network to define stages of AKI
based on urine output and serum creatinine levels ( Jetton and Askenazi 2014 ).
In summary, experts generally agree that in the newborn, an increase in serum

creatinine of 0.3 mg/dL within a 48-hour period requires meticulous monitoring for
AKI and its complications. Clearly interpreting these recommendations requires
considering the patient's clinical condition and the normal changes in serum
creatinine during the early postnatal period (see above). Long-term follow-up of
renal function and arterial blood pressure should be routine after preterm births, due
to the potential consequences associated with a reduced number of nephrons at birth
and the narrow window of postnatal renal growth, especially in ELBW infants.
Based on the complex interactions of renal development, illness, prematurity, and

therapy, fluid and electrolyte management in newborns should take the following
factors into account:
 1.
Normal postnatal diuresis, which is greater in preterm infants, contracts the

extracellular space. This normal negative fluid and electrolyte balance does not
require aggressive intervention if the cardiorespiratory status is stable. Oral or
intravenous fluid intake should compensate for transepidermal and other fluid losses
( Table 23-6 ). The preoperative patient may require additional interventions.
TABLE 23-6
Maintenance Fluid Requirements During the First Month of Life
Adapted from Veille JC. AGA infants in a thermoneutral environment during the first week of
life. Clin Perinatol. 1988;15:863; Taeusch HW, Ballard RA, Avery ME. Schaffer and Avery's
diseases of the newborn, 6th ed. Philadelphia: Saunders; 1991; and Lorenz J, Kleinman LI,
Ahmed G, et al. Phases of fluid and electrolyte homeostasis in the extremely low birth weight
infant. Pediatrics. 1995;96:484.
Birth Weight (g) Insensible Water Loss (mL/kg/day) WATER REQUIREMENTS (ML/KG/DAY
Day 1–2 Day 3–7 Day
<750 100–200 100–200+ 150–200+
750–1000 60–70 80–150 100–150
1001–1500 30–65 60–100 80–150
>1500 15–30 60–80 100–150
View full size
 2.
Transepidermal fluid loss is related to gestational age and can be as much as 60 to

100 mL/kg/day in ELBW infants. Over the first 5 days of life, fluid losses decrease
dramatically from 45 g/m 2 /hour to about 19 g/m 2 /hour in infants at 25 to 27 weeks
of gestation (see Fig. 23-15 ) ( Sedin, Hammarlund, and Strömberg 1983 ). During the
first few postnatal days, naked preterm infants lose up to 15 times more water
through evaporation than naked full-term infants ( Hammarlund, Sedin, and
Strömberg 1983 ). Consequently, naked VLBW infants may lose as much as 10% of
their body weight through evaporation during the first 24 hours of life. The increased
respiration of premature infants also increases water loss. Although the specific
contribution of water loss by evaporation is unknown in premature infants, this
process is responsible for 40% of baseline total water losses in children and
adolescents. The epidermis of preterm neonates is thinner and more permeable.
Coupling this with the premature infant's larger surface area–to–volume ratio
suggests that insensible evaporative water loss must be several magnitudes greater
than that of older patients. To maintain normal water and electrolyte balance,
meticulous attention to intake and output of fluid, body weight, urine output, and
urine and serum electrolyte concentrations (especially in ELBW infants) is critical,
especially during the first 3 to 5 days of life.
 3.
Providing a warm, humidified environment/inspired gases and/or covering the child

with a plastic shield reduce transepidermal fluid loss, especially in ELBW infants.
Except for warm, humidified gases, these systems are difficult or impossible to
continue during surgery.
 4.
Following the trends of serum and urine electrolytes, glucose, and hemoglobin
concentrations and correlating these values with body weight and intake of fluid and
output of urine provide the framework for fluid and electrolyte therapy. Over
decades, experts have attempted to link the incidence of PDA, NEC, and BPD to
overhydration, hypernatremia, or hyponatremia, but no conclusive evidence exists to
confirm causal relationships.
 5.
An intravenous infusion of calcium is usually required in asphyxiated preterm, LGA,

and SGA infants until adequate enteral nutrition has been established.
Meeting the high caloric requirements to achieve growth is challenging with the
newborn's limited ability to excrete or reabsorb a variety of solutes and nutrients.
Along with this high anabolic rate, the increased solute load in early postnatal life
coincides with the narrow therapeutic index for fluid and electrolytes (especially in
VLBW infants). Insensible water losses are enormous, and renal immaturity and/or
insufficiency and multiorgan effects of prematurity and infection are common.
Hematologic Function
Developmental hematopoiesis takes place in three stages and locations: the
embryonic yolk sac, fetal liver, and bone marrow ( Sacher and McPherson
1986 ; Rappaport 1997 ). Each stage is critical to survival.
Embryonic hematopoiesis begins at about day 14 of gestation, when mesodermal

pluripotential stem cells of the ventral yolk sac form primitive megaloblastic
nucleated red cells (mean corpuscular volume [MCV] 400), primitive macrophages,
and megakaryocytes. At 5 weeks, these stem cells migrate from the aorta-gonad-
mesonephros (AGM) region to populate the liver and spleen, which become
temporary sites for hematopoiesis. These uncommitted stem cells divide and produce
progeny that either replenish the stem cell pool or mature to committed cell lines and
produce erythrocytes, macrophages, and myeloid and lymphoid cells. By 9 weeks,
lymphopoiesis is occurring in the lymphoid plexuses and thymus.
At 8 weeks' gestation, AGM stem cells begin to populate bone marrow, which
initiates the complex regulatory hematopoietic interactions that are sustained over a
lifetime. As progenitor cells populate the maturing extracellular bone marrow matrix,
adhesion molecules such as integrins, selectins, and CD14+ cells promote progenitor
cell−stromal binding that creates protected microenvironments. These
microenvironments allow cytokines, colony-stimulating factors, interleukins, and
other growth factors to exert a selective influence on cell growth and maturation. At
birth, a large percentage of umbilical cord cells are progenitors. The hematopoietic
capacity of term infants is comparable to that of adults.
Embryonic erythrocytes contain hemoglobin Gower-1 (unpaired globin chains, many

of which form tetramers), are nucleated, are macrocytic (MCV 400), and are not
controlled by erythropoietin. The fetal erythrocytes present by the sixth week of
gestation are sensitive to erythropoietin and primarily contain fetal hemoglobin
(α2γ2) but also have small amounts of hemoglobin A (α2β2). At birth, erythrocytes
are macrocytic (MCV 110) and contain 60% to 80% fetal hemoglobin, which less
effectively binds 2,3-diphosphoglycerate (2,3-DPG) and shifts the oxygen
dissociation curve to the left (P 50 18). This shift allows more effective uptake of
oxygen but less efficient release to the tissues. While anti-A and anti-B isoagglutinins
are present during the first 6 months of life, alloimmunization to red cell antigens is
rare following neonatal red blood cell transfusion.
Myelopoiesis is active at 5 months' gestation, but granulocytopoiesis is only half that

of adults and gradually increases throughout the third trimester to reach adult levels
at term. The absolute number of granulocytes present at birth usually exceeds that of
older children but decreases over the first few postnatal days. As granulocytes
decrease, lymphocytes become more numerous and remain so for the first 4 years of
life. Megakaryocytes are present in bone marrow, and platelets are present in blood
by 11 weeks' gestation. At birth, the platelet count varies in both term and preterm
infants. Although one-third of SGA infants are thrombocytopenic on the first day of
life (e.g., secondary to platelet consumption by placental infarcts), the platelet count
of SGA infants usually ranges between 102 and 292 × 10 9 . In some cases,
thrombocytosis develops during the first week of life, and the platelet count may
increase to greater than 250 × 10 9 ( Table 23-7 ).
TABLE 23-7
Normal Hematologic Values for Appropriate for Gestational Age (AGA), Small for Gestational
Age (SGA), and Premature Infants
Data from Obladen M, Diepold K, Maier R, the European Multicenter rhEPO Study Group.
Venous and arterial hematologic profiles of very low birth weight
infants Pediatrics. 2000;106:707-711; Özyürek E, S. Çetintaş S, Ceylan T, et al. Complete blood
count parameters for healthy, small-for-gestational-age, full-term newborns. Clin Lab
Haem. 2006:28;97-104; Christensen RD, Henry E, Jopling J, et al. The CBC: Reference ranges
for neonates. Semin Perinatol. 2009;33:3-11; Jopling J, Henry E, Wiedmeier SE, et al. Reference
ranges for hematocrit and blood hemoglobin concentration during the neonatal period: Data from
a multihospital health care system. Pediatrics. 2009;123:e333-e337.
Test AGA SGA PREMATURE
Day 1 Day 7 Day 1 Day 7 Day 3
Hb (g/dL) 17.0 ± 0.4 16.2 ± 0.4 18.2 ± 0.4 15.4 ± 0.3 15.5
(Range) (17–23) (10.3–20.0) (14–22.5) (9.8–20.2)
Hct (%) 47.1 ± 1.0 44.6 ± 1.0 53.3 ± 0.8 44.4 ± 1.0 47
(Range) (36.7–62.8) (28.5 ± 54.7) (32.6–66.9) (28.8–60.3)
RBC (109/uL 4.7 ± 0.1 4.5 ± 1.0 5.1 ± 0.8 4.4 ± 0.1 4.2
(Range) (3.6–6.2) (3.0–5.6) (3.8–6.5) (2.7–6.0)
WBC (103) 15.0 ± 7.0 10.6 ± 3.3 13.3 ± 0.9 9.6 ± 0.4 9.5
(Range) (7.1–25.4) (6.6–15.4) (4.6–16.5) (3.8–15.5)
Plts (109/L) 214.7 ± 6.0 321.3 ± 13.6 182 ± 8.0 287.7 ± 15.7 261
Test AGA SGA PREMATURE
Day 1 Day 7 Day 1 Day 7 Day 3
(Range) (102–292) (134–594) (55.9–344) (134–594) (120–407)
View full size
Jopling and colleagues (2009) reported a linear increase in hemoglobin
concentration from 14 g at 25 weeks' gestation, 16 g at 30 weeks, and 17 g at 35 weeks
to 18 g in AGA neonates at term; gender does not affect hemoglobin concentration.
At birth, SGA infants often have higher hemoglobin concentrations than full-term
babies, primarily to compensate for intrauterine hypoxia and in response to elevated
erythropoietin levels ( Snijders et al. 1993 ). However, in these infants, hemoglobin
concentration decreases about 10% over the first week of life (see Small-for-Gestational-
Age Infant ). In contrast, the hemoglobin concentrations of preterm infants are lower
at birth than those of SGA or AGA infants and decrease significantly after birth
(see Table 23-7 ) ( Obladen, Diepold, and Maier 2000 ).
Erythrocyte production decreases after birth because erythropoietin concentrations

are low. In addition, if deficient in iron, preterm infants fail to respond to
erythropoietin ( Obladen et al. 2000 ). On the other hand, low iron concentrations
may protect neonates from free radical injury (Khawaja and Volpe 2008 ).
The white blood count of newborns varies widely at birth, especially after an in utero
infection or if the mother was given betamethasone to induce fetal lung maturity
(see Table 23-7 ) ( Cohen et al. 1993 ). Some healthy infants have white blood cell
counts as high as 25,000/µL at birth. Although 21% of SGA neonates are neutropenic
at birth, white blood cell counts are normal by 7 days of age ( Ozyürek et al. 2006 ).
Preoperative Hematologic Evaluation

The preoperative evaluation should focus on assessing the history of bleeding (e.g.,
petechiae or skin hemorrhages; recent active bleeding into the bowels, lungs, or
brain) and response to treatment for bleeding (e.g., amount and frequency of
transfusions of specific products/agents). Trends in the platelet count, especially
over the prior 12 to 24 hours, and the requirement for platelet transfusions to
maintain the desired platelet count (usually >100,000/mm 3 ) should be analyzed.
Similarly, trends in PT, PTT, and international normalized ratio (INR) should be
correlated with frequency of delivery and response to fibrinogen, cryoprecipitate,
fresh frozen plasma, or other factors. For example, the total volume of blood
products should be appreciated to plan for quantity and types of blood products
needed preoperatively and intraoperatively.
Trends in total and differential white blood cell counts often correlate with infection.
However, a newborn may develop either a high or low neutrophil count in response
to systemic infection/sepsis. The anesthesiologist should determine the hemoglobin
concentrations required to maintain a stable cardiorespiratory status. For example,
some fragile infants are hemodynamically unstable unless the hemoglobin
concentration is maintained between 16 to 18 g/dL. Of course, the hemoglobin
concentrations must be correlated with the findings on physical examination. If
peripheral perfusion (e.g., capillary refill times) is inadequate and/or tachycardia
and/or hypotension are present, despite having a hemoglobin concentration of 16
to18 g/dL, an isotonic crystalloid or non−red blood cell colloid should be delivered to
improve perfusion. On the other hand, with similar physical findings, patients who
have hemoglobin concentrations of 12 to 14 g/dL sometimes require packed red
blood cell transfusion. Extracellular potassium levels are elevated in blood stored for
more than 3 to 5 days (at times, levels >10 mEq/L). Rapidly administering such
blood to newborns may precipitate a potassium-induced cardiac arrest ( Brown,
Bissonnette, and McIntyre 1990 ).
Survival and Outcomes

The concept that many adult diseases can be traced to intrauterine events has gained
traction over the last several decades. Premature birth is probably the most common
and dramatic example of how such events can significantly influence the patient's
cardiovascular, respiratory, central nervous, and renal systems in later life.
Prematurity is now included under the paradigm of Fetal Origins of Adult Diseases
( Barker and Osmond 1986 ; Barker 1990 ) and, more recently, Developmental
Origins of Health and Disease (DOHaD) ( Barker 2004 ; Gluckman et al.
2008 ; Hanson and Gluckman 2014 ). As noted in a recent review, abnormal fetal
growth does not directly cause long-term consequences but should be considered a
marker of a “coordinated fetal response to a limiting intrauterine environment,
resulting in changes in tissue and organ development that are not necessarily evident
at birth but that result in perturbed responses later in life” ( Gluckman et al. 2008 ).
In the United States, the birth rate has steadily declined (≈9%) during the last decade
(4.28 million in 2007 to 3.95 million in 2011 to 3.93 million in 2013). Similarly, the
rate of preterm birth has steadily decreased for seven consecutive years ( Martin et al.
2015 ). Although ELBW infants (<1000 g) are less than 1% of all newborns, they are
approximately 6% of all preterm newborns. Compared with other nations, the
premature birth rate in the United States ranks in the lower third (54th of 184)
( http://www.who.int/pmnch/media/news/2012/preterm_birth_report/en/index5.html ).
Although comparing outcomes across various decades is difficult, certain patterns

have emerged. First, improvements in survival have been accompanied by persistent
or increased neonatal and long-term morbidity ( Fig. 23-17 ). Second, incurring just
one of three common disorders, (BPD, brain injury, or ROP) doubled the incidence
of death or neurosensory abnormality at 18 months of age. Having two of these
morbidities tripled the incidence of these outcomes ( Schmidt et al. 2003 ). Although
the effect is less dramatic, infection (e.g., sepsis, meningitis, or NEC) also is a factor
in death and neurodevelopmental outcome at 18 months of age ( Glass et al.
2008 ; Bassler, Stoll, and Schmidt 2009 ).

FIG 23-17
Mortality and Short-Term Outcomes of VLBW According to Birth Weight.
(From Eichenwald E, Stark A. Management and outcomes of very low birth weight. N Engl J
Med. 2008;358:1700.)
Survival of ELBW infants (<1000 g) increased from 49% during the 1980s to 68% in
the 1990s to 71% in the early 2000s ( Wilson-Costello et al. 2007 ). This improved
survival rate is associated with a concern for increased morbidity. As gestational age
decreases, risks for lifelong deficits increase secondary to complications such as IVH,
NEC, BPD, chronic lung disease, severe visual and hearing impairments, cerebral
palsy, and cognitive developmental delay.
Reporting morbidity rates (not simply mortality rates) across narrow bands of
gestational age appears to be crucial. Accordingly, investigators have examined the
impact of gestational age on short-term outcomes in a cohort of infants from the
National Institute of Child Health and Human Development Neonatal Research
Network (NICHD NRN) born between 1997 and 2002. Survival without
complications (NEC, BPD, severe IVH) was reported over narrow ranges of birth
weights (≈20% at 501 to 750 g; ≈50% at 751 to 1000 g; ≈70% at 1001 to 1250 g; and
≈90% at 1251 to 1500 g). When compared with data from earlier eras (1991 to 1996
vs. 1997 to 2002), outcomes for the recently born group included improved survival
rates but also persistently high rates of morbidity (see Fig. 23-17 ) ( Eichenwald and
Stark 2008 ). Continuing to report data from the NICHD NRN, Stoll and colleagues
(2010) identified similar trends in outcomes among infants born between 2003 and
2007. In addition to infants born at 24 to 28 weeks' gestation, this later report
included those born after only 22 to 24 weeks. The parameters included to determine
outcomes also were expanded (i.e., PVL, ROP stage III, early/late sepsis/meningitis,
NEC, BPD, and severe IVH). Compared with infants born in earlier eras (see Fig. 23-
17 ), infants born in 2003, 2005, and 2007 had similar rates of survival without
morbidity (0% at 22 weeks; 5% to 11% at 24 weeks; 20% to 22% at 25 weeks; 32% to
34% at 26 weeks; 44% to 46% at 27 weeks; and 54% to 62% at 28 weeks) ( Stoll et al.
2010 ). Thus, for each week of gestation added after 23 weeks, the survival rate
without morbidity increases approximately 10%. The Norwegian Extreme
Prematurity Study group reported that 100% of infants born at 22 to 25 weeks had
some degree of BPD, with approximately 80% having moderate to severe disease.
The incidence of moderate to severe disease decreased to 31% to 43% for infants born
after 26 to 30 weeks ( Farstad et al. 2011 ). Experts have concluded that in spite of
optimal prenatal care (e.g., steroid and appropriate antibiotics) and postnatal care
(e.g., surfactant, gentle ventilation, aggressive nutrition), high rates of morbidity
persist among survivors of extreme prematurity.
Although gestational age predicts both mortality and morbidity rates and imparts
definite and significant effects on both short-term and long-term outcomes, other
factors should be considered. For example, Tyson and colleagues (2008) noted that
female gender, singleton birth, higher birth weight (i.e., 100-g increments), and
exposure to antenatal steroids improved outcomes similar to those associated with a
1-week increase in gestational age.
Although outcomes of premature infants from multicenter studies seem to have

remained static over the last three decades, mortality and morbidity rates for infants
born at the edge of viability (22 to 23 weeks) vary dramatically among medical
centers ( Smith et al. 2012 ). When infants born at 22 to 24 weeks were separated
from infants born at 25 to 27 weeks, marked differences in survival rates were
identified among the centers (39% vs. 81%). As expected, morbidity rates were higher
in infants after 22 to 24 weeks of gestation. Both survival and morbidity rates varied
as a function of differences in obstetric interventions (prenatal steroids, cesarean
section) and neonatal interventions (resuscitation) among the centers. For example,
administering antenatal corticosteroids (i.e., to the mother) at 22 to 24 weeks'
gestation affected outcomes of the infants when born 2 weeks later (at 24 to 26
weeks). The significant variability among medical centers with respect to care for
infants born at 22 to 24 weeks' gestation must be considered in the context of
multicenter outcome studies.
In utero and postnatal inflammation and oxidative stress have been linked to adverse
long-term pulmonary and neurologic outcomes. Attempts to interrupt the injurious
effects of both processes have been hampered by the fact that the cause of injury is
often an exaggerated normal process. For example, although reactive oxygen species
(ROS) and reactive nitrogen species (RNS) damage cells (e.g., peroxidation of
membranes, structural proteins, and enzymes) during hypoxia-ischemia and
reperfusion, both also regulate normal cell function, immunity, circulation, and
growth ( Maltepe and Saugstad 2008 ). For example, nitric oxide has been safe and,
in some cases, therapeutic in treating acute hypoxemic respiratory failure and
pulmonary hypertension in near-term and term infants ( Clark et al.
2000 ; Barrington and Finer 2007 ; Arul and Konduri 2009 ). However, nitric oxide
has not been effective in preventing BPD in ELBW infants ( Jensen and Kirpalani
2014 ; Kinsella et al. 2014 ). In addition, this agent has widespread epigenetic and
potentially toxic effects. Thus various pharmacologic and nutritional interventions
(including nitric oxide) may be beneficial but at the same time inflict dramatic
programming effects on the immature infant ( Kalhan and Wilson-Costello 2013 ).
Chronic Lung Disease and Bronchopulmonary Dysplasia

Childhood chronic lung disease (CLD) results from a variety of congenital anatomic
lesions (e.g., congenital diaphragmatic hernia, cystic pulmonary airway
malformation, cardiac malformations) and acquired disorders (e.g., sepsis,
meconium aspiration), but the overwhelming majority of infants and children with
this disorder are ex-premature infants who required supportive care in the NICU,
including oxygen and ventilatory support. Bronchopulmonary dysplasia (BPD) is the
CLD associated with prematurity. Although routine surfactant therapy dramatically
decreased the overall impact of BPD, residual lung disease persists as a critical
determinant of mortality and life-long morbidity rates after preterm birth. Despite
dramatic changes in neonatal care, the incidence of BPD has remained stable for the
last 30 years ( Fawke et al. 2010 ) and clearly correlates with gestational age ( Stoll
et al., 2010 ). After a 24-week gestation, 100% of infants had some degree of BPD
(mild, 26%; moderate, 35%; severe, 39%), while only 39% of those born after a 28-
week gestation developed BPD (mild, 16%; moderate, 15%; severe, 8%) ( Table 23-8 ).
TABLE 23-8
Incidence of Bronchopulmonary Dysplasia (%)
Data from Stoll BJ, Hansen NI, Bell EF, et al. Neonatal outcomes of extremely preterm infants
from the NICHD neonatal research network. Pediatrics. 2010;126:443-456.
23 Weeks 26 Weeks 28 Weeks
Mild 26 35 16
Moderate 35 26 15
Severe 39 17 8
View full size
After 23-weeks' gestation, all infants incurred some degree of bronchopulmonary dysplasia
(BPD) (mild, 26%; moderate, 35%; severe, 39%). Although still prevalent, BPD was less common
in the 28-week gestation group (mild, 16%; moderate, 15%; severe, 8%). Incidence of BPD
varies markedly among subgroups of infants based on gestational age.
Diagnostic criteria for BPD have been revised as survival of preterm infants has
increased. One commonly applied definition includes grading according to severity
( Jobe and Bancalari 2001 ):
 1.
Oxygen dependence for at least 28 postnatal days
 2.
Severity is graded at 36 postmenstrual weeks for infants born before 32 weeks'

gestation and at 56 days for those born at more than 32 weeks' gestation; severity is
graded as
o Mild: Fi o 2 0.21
o Moderate: Fi o 2 0.22 to 0.29
o Severe: Fi o 2 more than 0.30, CPAP, or mechanical ventilation
An “addendum” (physiologic definition) has been recommended to avoid

overdiagnosing BPD. At 36 weeks' postmenstrual age, the inspired oxygen is reduced
to room air in a timed stepwise process. Clearly defined criteria for “passing” or
“failing” the challenge have been established ( Walsh et al. 2003 ). Determining if an
infant maintains an adequate oxygen saturation with an FiO 2 of 0.21 avoids
misclassifying a survivor as “requiring” supplemental oxygen.
Because the entire bronchiolar tree is established by 17 to 18 weeks' gestation, severe
postnatal injury to the airways of ELBW infants can inflict widespread permanent
sequelae. The hallmark of the canalicular stage of lung development (23 to 25 weeks'
gestation) is development of the capillary network. Lung capillaries appear by 20
weeks, just 3 to 4 weeks before the “limit of viability” of the ELBW infant. Injury to
the lungs of infants at this gestational age predisposes to irreversible pulmonary
vascular injury, trauma to the airways, and delayed or arrested alveolar growth
( Speer 2009 ; Carraro et al. 2013 ; Filippone et al. 2013 ; O'Reilly and Thébaud
2013 ).
Over the last decade, “new BPD” has been differentiated from “old BPD.” New BPD
primarily develops in ELBW infants who are born during the late canalicular or early
saccular phase of lung development ( Baraldi and Filippone 2007 ) and who were
exposed to gentler ventilator strategies, prenatal steroids, postnatal surfactant, and
lower concentrations of supplemental oxygen. In contrast, old BPD refers to the
pulmonary disease in preterm infants born during the presurfactant era (before
1990) who were born at a later gestational age (primarily > 32 weeks) during the late
saccular and alveolar stages of lung development. These infants were often exposed
to vigorous mechanical ventilation and high concentrations of supplemental oxygen.
Intense airway inflammation, cysts, fibrosis, severe epithelial injury, and smooth
muscle hyperplasia characterize old BPD ( Fig. 23-18 ).

FIG 23-18
A, The pathologic description of classic chronic disease or “old BPD” is a fibroproliferative
process with epithelial metaplasia, interstitial fibrosis, and air space obliteration from the fibrosis.
This correlates with the radiologic findings of nonhomogeneity of the lung parenchyma with
densities secondary to volume loss from fibrosis extending to the periphery coexisting with cystic
emphysema (note cysts in both lung bases, right > left) and hyperinflation (note the flattened
diaphragms). This is a pattern of repair of a response to injury. B, The abnormal pathology in the
new BPD is abnormal growth of alveoli and vasculature, dilation of distal sites of gas exchange
(alveolar ducts), but no prominent fibrosis. This correlates with a fine, hazy, uniform parenchymal
pattern with modest hyperinflation but no cysts. This is a pattern of arrested
development. C, Differences between old bronchopulmonary dysplasia and new
bronchopulmonary dysplasia. (See text for specifics.)
ELBW infants born during midgestation undergo much of the complex process of
lung development postnatally. At this stage, the lungs are extremely vulnerable to
injury by inflammation/infection, ventilatory support (including CPAP), and even
appropriate levels of supplemental oxygen. Postnatal damage occurring during the
early saccular or late canalicular stage is associated with new BPD, which includes
fewer but larger alveoli and abnormal vascular growth but less evidence of
inflammation, smooth muscle hypertrophy, and fibroproliferation. New BPD leads to
arrest of both alveolar septation and vascular development, which reduces the
amount of surface area available for gas exchange ( Baraldi and Filippone
2007 ; Carraro et al. 2013 ; O'Reilly and Thébaud 2013 ).
Despite the well-described differences in the pathology of new and old BPD, children
born prematurely over the last 3 decades and subjected to various treatments (e.g.,
surfactant, gentle ventilation) have remarkably similar types of long-term pulmonary
dysfunction ( Fawke et al. 2010 ) that persists into late childhood and early
adulthood.
Increasingly, the critical role of pulmonary blood vessels in promoting alveolar

growth and development has been emphasized. Abnormal signaling by VEGF has
been identified as a common pathway for injury caused by a variety of prenatal
factors (e.g., chorioamnionitis, intrauterine growth retardation, genetic
susceptibility) and postnatal factors (e.g., mechanical ventilation, supplemental
oxygen) that converge to decrease angiogenesis and alveolarization in patients with
BPD ( Abman 2010 ; Baker et al. 2014 ). Abnormal VEGF signaling in the placentas
of growth-impaired fetuses seems to be associated with postnatal pulmonary
hypertension in patients who develop BPD. In one study, at least 50% of patients
with BPD-associated pulmonary hypertension had birth weights below the 25th
percentile ( Check et al. 2013 ). Thus disrupted pulmonary vascular development and
decreased alveolar number seem to define morbidity and mortality in ELBW infants
who have BPD ( Mourani and Abman 2013 ).
In fact, recent reviews ( Collaco et al. 2012 ; Ali et al. 2013 ; Berkelhamer et al.

2013 ; Baker et al. 2014 ) and a prospective study ( Bhat et al. 2012 ) attest to the
significant incidence of pulmonary hypertension (17% to 43%) and high mortality
(14% to 38%) of this lesion among ELBW infants. However, because of difficulty in
accurately diagnosing pulmonary hypertension in these patients, predicting
outcomes in specific patients remains challenging ( Mourani et al, 2015 ).
In summary, birth during the canalicular or early saccular stage of lung development
predisposes ELBW infants to growth retardation of both the airways and the
pulmonary vascular system. This consequence most likely evolves secondary to
interference with a variety of cell-signaling pathways essential for lung development.
These signaling pathways are affected by genetic factors, inflammation, infection,
mechanical ventilation, and oxygen toxicity ( Baraldi and Filippone 2007 ; Lavoie
and Dubé 2010 ; Baker et al. 2014 ).
Mechanical Ventilation, CPAP, and Bronchopulmonary Dysplasia

At birth, the fluid-filled fetal lung must be inflated with air for successful oxygen and
carbon dioxide exchange postnatally. Because of mechanical disadvantages (e.g.,
high chest wall compliance, inadequate surfactant), neurologic immaturity (e.g.,
immature control of breathing), and weakness of respiratory muscles, preterm
infants commonly require ventilatory assistance (e.g., CPAP, mechanical ventilation,
and/or supplemental oxygen) to effectively make the transition to postnatal
breathing. In one report, 60% to 70% of infants born before 26 to 28 weeks' gestation
and all of those born before 25 weeks were treated with positive pressure ventilation
after tracheal intubation ( Morley et al. 2008 ). However, because positive pressure
ventilation may initiate both a local (in the lung) and systemic inflammatory
response ( Hillman et al. 2007 ), avoiding this intervention is now a major goal of
newborn care, especially for premature infants.
To minimize barotrauma and volutrauma, current efforts focus on gentle ventilatory

strategies and the lowest level of supplemental oxygen possible. For almost two
decades, CPAP has been proposed as a technique associated with less lung injury
compared to positive pressure ventilation ( Avery et al. 1987 ; Morley et al. 2008 ). In
fact, data on the short- and long-term advantages of CPAP versus mechanical
ventilation have not completely supported this hypothesis. For example, Vaucher and
colleagues (2012) found no difference in the incidence of death, impairment of
neurodevelopment, or BPD when infants treated with CPAP were compared with
those who were mechanically ventilated (and given surfactant). On the other hand,
longer-term advantages, including lower minute ventilation and better compliance,
were apparent 8 weeks after birth ( Roehr et al. 2011 ). The Surfactant Positive
Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT) also found no
significant differences in the incidence of BPD or death between infants who were
treated with CPAP and those receiving tracheal intubation/surfactant. However, by
18 to 22 months, the early CPAP group had fewer episodes of respiratory illness,
wheezing without an upper respiratory infection, and visits to an emergency room or
physician's office ( Stevens et al. 2014 ). The fact that infants receiving CPAP required
fewer days of ventilation led some investigators to propose CPAP as an alternative to
intubation/delivery of surfactant for premature infants, even those born at less than
28 weeks' gestation ( Morley et al. 2008 ; Finer et al. 2010 ). A recent systematic
review noted a benefit with nasal CPAP only with pooled data for the combined
outcome of death or bronchopulmonary dysplasia at 36 weeks' corrected gestation
( Schmölzer et al. 2013 ).
Finally, in some cases, the INSURE ( in tubate, sur factant, e xtubate) method

effectively avoids mechanical ventilation and allows the use of surfactant; patient
selection seems critical. If a newborn does not require mechanical ventilation
immediately after birth, initiation of nasal CPAP and then brief intubation of the
trachea for surfactant delivery, followed by tracheal extubation and immediate
reinstitution of CPAP, seem to decrease the total time needed for ventilatory support.
The authors caution that a birth weight below 750 g and severe respiratory disease, a
PO 2 /FiO 2 ratio of less than 218 or an arterial/alveolar oxygen tension (a/APO 2 ) of
less than 0.44 on the first blood gas reading were independent risks for failure of this
approach ( Dani et al. 2010 ). This technique may be especially important when
mechanical ventilation is unavailable (i.e., in developing countries). Compared with
nasal CPAP alone, surfactant administration in the first hour of life followed by nasal
CPAP after tracheal extubation was associated with fewer air leaks and less need for
increased oxygen at 36 weeks' postconceptual age. However, the incidence of death
or IVH and PVL was not reduced ( Rojas et al. 2009 ).
Although the goal of minimizing mechanical ventilation is appropriate, some ELBW

infants cannot maintain adequate oxygenation or ventilation during treatment with
nasal CPAP, especially during the first few hours after birth. The Academy of
Pediatrics issued a policy statement for care of the preterm infant at birth
( Committee on Fetus and Newborn and American Academy of Pediatrics 2014 ).
Instead of routine early delivery of surfactant (the standard care in the NICU over the
last two decades), CPAP should be initiated immediately after birth. If the newborn
cannot maintain oxygenation and ventilation, surfactant should be delivered
endotracheally, the trachea extubated rapidly, and CPAP reinitiated. The committee
acknowledged the need for individualized care. In fact, this technique closely
resembles the INSURE technique.
Oxygen Therapy and Toxicity

Oxygen Therapy and Toxicity in Term Infants
The oxygen saturation of the fetus at term is 50% to 60% and may be as low as 30%
intermittently during labor ( East and Colditz 2007 ). After the vaginal birth of a
healthy full-term infant, it generally takes 5 to 10 minutes for the oxygen saturation
to reach 90%; it will take longer after a cesarean birth ( Kamlin et al. 2006 ; Rabi
et al. 2006 ; Dawson et al. 2007 ). Based on data from three merged databases
( Dawson et al. 2010 ), the most recent resuscitation guidelines from the American
Academy of Pediatrics recommend that the targets for oxygen saturation
immediately after birth ( Kattwinkel et al. 2010 ) are:
 60% to 65% at 1 minute
 65% to 70% at 2 minutes
To avoid needless exposure to oxygen, oxygen therapy should be titrated to meet and
not exceed these normal targets in the first minutes of life.
Multiple studies and metaanalyses support the revised guidelines for oxygen delivery
during resuscitation of full-term infants by determining short-term outcomes and
mortality rates after resuscitation with room air versus 100% oxygen ( Davis et al.
2004 ; Saugstad, Ramji, and Vento 2005 ; Saugstad et al. 2008 ). Infants resuscitated
with room air recovered more quickly, as assessed by the Apgar score, time to first
cry, heart rate at 90 seconds, and sustained pattern of respiration ( Saugstad
2005 ; Saugstad et al. 2008 ). Davis and colleagues (2004) reported lower mortality
rates at 1 and 4 weeks of age and no difference in the incidence of hypoxic-ischemic
encephalopathy between the two groups. Accordingly, in 2010, the International
Liaison Committee on Resuscitation guidelines were changed: “In term infants
receiving resuscitation with intermittent positive-pressure ventilation, 100% oxygen
conferred no advantage over air in the short term and resulted in increased time to
first breath or cry or both. Metaanalyses of these studies showed a decrease in
mortality for those resuscitated with air” ( Perlman et al. 2010 ).
Oxygen Therapy and Toxicity in Premature Infants

Experts agree that oxygen plays a role in the long-term consequences of preterm
birth: BPD, ROP, and neurodevelopmental abnormalities. Although supplemental
oxygen is often required during resuscitation and later supportive care, the specific
target for oxygen saturation in the premature infant has not been fully defined, but it
clearly is higher than the normal intrauterine level (PaO 2 25 to 30 mm Hg).
Hyperoxia produces lung injury at any stage of development but is particularly

damaging to immature lungs because of inadequately developed systems for
protecting tissues from oxygen toxicity. An excessive oxygen load may produce a
surplus of free radicals that induce inflammation and damage cellular lipids,
proteins, and carbohydrates ( Maltepe and Saugstad 2008 ). In addition, hyperoxia
inhibits synthesis of surfactant, normal proteins, and DNA and increases pulmonary
vascular reactivity ( Newman et al. 1983 ; Clement, Hubscher, and Junod
1985 ; Jornot, Mirault, and Junod 1987 ). Antioxidant enzymes (e.g., superoxide
dismutase, catalase, glutathione peroxidase, and glutathione reductase) develop on a
time scale similar to surfactant, so concentrations of these enzymes normally
increase just before birth ( Frank and Sosenko 1987 ).
A recent metaanalysis compared the outcomes of two groups of infants who were
both 32 weeks' gestational age or less. One group received an FiO 2 between 0.21 and
0.30 and the other between 0.60 and 1.0. Although the authors identified no
differences in the incidence of BPD and IVH, mortality rates were higher in the group
resuscitated with the higher FiO 2 ( Saugstad et al. 2014 ). Consequently, during
resuscitation, the FiO 2 should be adjusted according to the infant's status.
Unfortunately, the specific target for the premature infant remains elusive.
Attempting to define “appropriate oxygen saturations” for premature infants, five

groups collaborated as NeOProM (Neonatal Oxygenation Prospective Meta-
Analysis), but each trial was designed and managed separately. Specifically, experts
organized five trials to “exclude the possibility that the expected valuable short-term
benefits associated with giving babies less oxygen during resuscitation are not
associated with a small but significant (about 4%) increase in death or serious
neurosensory disability in survivors.” Thus the goal was to determine the lowest
inspired oxygen concentration that maximizes survival and minimizes retinal,
pulmonary, and neurocognitive morbidities in infants of less than 28 weeks'
gestation. The collaborators devised a prospective metaanalysis, including trials that
were designed to be similar in population (e.g., subject eligibility), objectives, and
outcomes (primary and secondary) to allow combining of patient data into a
common dataset ( Askie et al. 2011 ). The five groups included the Surfactant Positive
Pressure Airway Pressure and Pulse Oximetry Randomized Trial (SUPPORT—
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research
Network) ( Carlo et al. 2010 ); the Canadian Oxygen Trial (COT) ( Bancalari and
Claure 2013 ; Schmidt et al. 2013 ); and the Benefits of Oxygen Saturation Targeting
(BOOST II-New Zealand, BOOST II Australia, BOOST II England) ( Stenson et al.
2013 ; Darlow et al. 2014 ).
In each trial, the target oxygen saturation was either between 85% and 89% or 91%
and 95%. Because of disparity in some aspects of the methods, these randomized
controlled, multicenter studies could not definitively define an appropriate range of
oxygen saturation that maximizes survival and minimizes the morbidity of ELBW
infants. Jobe (2014) noted, “Three trials reported almost 5000 randomized infants in
aggregate, and each trial was interpreted by the authors somewhat differently.” The
appropriate oxygen saturation for more mature but premature infants was not
considered in NeOProM.
Several experts have commented on these data ( Schmidt et al. 2014 ), and others
have published a metaanalysis ( Saugstad and Aune 2014 ) of the five trials. The
following are comments from these experts.
 1.
The two narrow ranges were targeted because they are within the commonly
accepted wider range of 85% to 95%.
 2.
Overlap of oxygen saturations in the high and low groups varied among the
individual trials ( Schmidt et al. 2014 ).
 3.
When data from the three BOOST II trials were pooled with those from SUPPORT
and COT, the authors suggested that the targeted oxygen saturations should be
between 90% and 95% for infants less than 28 weeks' gestation until they reach a
postmenstrual age of 36 weeks ( Saugstad and Aune 2014 ).
 4.
Schmidt suggests that “as we try to strike the right balance for our patients between
oxygen deprivation and oxygen toxicity, we must remember that severe ROP remains
an adverse outcome of neonatal intensive care with poor prognosis for child
development” ( Schmidt et al. 2014 ). Schmidt proposed that targeting saturations
between 85% and 95% may be rational, but strictly enforcing alarm limits of 85% and
95% during oxygen therapy is critical ( Schmidt et al. 2013 ).
 5.
Saugstad and Aune (2014) noted that the target saturation must be defined not only
for ELBW infants but also for infants beyond 28 weeks' gestation and postconceptual
ages. In addition, clinical status (e.g., sepsis) may affect the level of oxygen saturation
required.
In summary, in spite of the large number of infants enrolled in these studies,
variability among the five trials resulted in inability to confidently recommend a
narrow range of oxygen saturation that avoids increased mortality and toxicity rates.
Thus, although some clinicians aim to avoid an oxygen saturation of below 90%, the
effect of an occasional “dip” in oxygen saturation to 85% to 89% is unknown.
The instability of ELBW infants prevents reliably maintaining the oxygen saturation
within narrow brackets ( Jobe 2014 ). It is nearly impossible to reliably identify and
prevent complications associated with differences in oxygen saturation of only 2% to
4%. In fact, oxygen saturation in critically ill infants may fluctuate widely beyond the
target range for significant periods of time ( Hagadorn et al. 2006 ). In one study, the
inspired oxygen concentration was adjusted 0.7 to 5.2 times per hour when
attempting to maintain oxygen saturation within the targeted range. Despite this,
oxygen saturation fell outside the alarm limits approximately 50% of the time (van
der Eijk et al. 2012 ). During support with CPAP, the targeted oxygen saturation of
88% to 92% was maintained only 31% of the time. These infants experienced 48
episodes of hyperoxia (SpO 2 >98%) and 9 of hypoxia (SpO 2 <80%), despite
adjusting the FiO 2 an average of 25 times per day ( Jobe 2014 ; Lim et al. 2014 ).
Postconceptual age, inspired oxygen concentration, mode of ventilator support, and
nurse/patient ratios also affect the ability to maintain oxygen saturation within
targeted ranges ( Sink et al. 2011 ).
In summary, hyperoxia and hypoxia interrupt periods of “normoxia” both in the

NICU and during surgery. Unfortunately, repeatedly increasing the FiO 2 in response
to brief episodes of oxygen desaturation to 85% to 89% often causes significant
“overshoot” and exposes the infant to the risks of hyperoxia. Even if the “ideal”
oxygen saturation is identified, maintaining a tight range in a fragile newborn will be
challenging, if not impossible. Although preliminary reports suggest that automated
devices to adjust FiO 2 in response to fluctuation in oxygen saturation may be useful,
none are clinically available ( Lim et al. 2014 ). At this point, Askie's
(2013) manuscript remains relevant: Optimal Oxygen Saturations in Preterm
Infants: A Moving Target .
Outcomes of Ex-Premature Patients Who Have Had Pulmonary

Dysfunction
Gestational age influences not only the neonatal course but also pulmonary function
later in life. The average length of stay is more than sixfold higher for the newborn
with a gestation of less than 28 weeks compared with those born at or after 32 weeks
( Ringborg et al. 2006 ). The prolonged, complicated course after premature birth
(especially for ELBW infants with BPD) is not surprising. In survivors of BPD
(postmortem specimens), the total number of alveoli in a 22-month-old child (31.1
million) and a 28-month-old child (40.4 million) with histories of BPD was less than
that in a healthy term 1-week-old infant (67.2 million) ( Margraf et al. 1991 ).
Although morphometric abnormalities of the lungs of infants who die of BPD may be
more severe in those who survive, poor lung growth also occurs in the premature
survivors. Although the specific cellular and molecular mechanisms have not been
completely unraveled, a genetic predisposition and inflammatory responses persist
as significant factors in the pathogenesis of BPD ( Bhandari 2014 ; Hadchouel et al.
2014 ; Sorensen et al. 2014 ; Thomas and Speer 2014 ). Prematurity clearly interferes
with molecular mechanisms of lung growth, and the resulting decreased alveolar
surface area and airway hyperreactivity have significant clinical implications. In
addition, postmortem studies have documented abnormal elastic fibers in patients
with BPD, primarily as a result of increased elastase activity associated with
hyperoxia. Because these fibers form the framework upon which new alveoli develop
( Bruce et al. 1985 ), damage to this matrix is associated the collagen deposition and
erratic alveolar structure.
Although the details of specific studies that comprise the huge literature devoted to
this topic vary, the following generalizations can be made:
 •
The incidence of moderate to severe BPD is much lower in infants beyond 30 weeks'
gestation or in those who weigh more than 1500 g at birth ( Baraldi and Filippone
2007 ).
 •
Infants with BPD commonly feed poorly and fail to grow normally.
 •
With “new BPD” and increased survival of “micropremature” infants, oxygen therapy
(e.g., often <1 L/min flow) may be necessary for months to years to maintain oxygen
saturations of 90% to 95%. In one recent report, 74% of ex-ELBW weight infants
discharged from the hospital were receiving supplemental oxygen ( Trittmann et al.
2013 ).
 •
Pulmonary dysfunction also occurs in ex-premature infants without a history of BPD.

The spirometric findings of these infants lie between those for healthy full-term
infants and those for premature infants with BPD ( Pelkonen, Hakulinen, and
Turpeinen 1997 ; Baraldi and Filippone 2007 ; Fawke et al. 2010 ).
 •
Impaired pulmonary growth and function result both from injury to developing,
vulnerable lungs (e.g., mechanical ventilation, supplemental oxygen, infection) and
from disordered repair processes.
 •
Rehospitalization is common during the first 2 years of life for ex-prematures born
before 32 weeks' gestation (40%, year 1; 25%, year 2) and is primarily due to
respiratory infections ( Hack and Fanaroff 2000 ; Lamarche-Vadel et al.
2004 ; Greenough et al. 2005 ; Hennessy et al. 2008 ; Ralser et al. 2012 ).
 •
Over the first 1 to 2 years of life, ex-premature infants have significant respiratory
symptoms and illness. Reactive airway disease is common and is exacerbated by
repeated infections. While pulmonary function seems to improve by 6 to 8 years of
life, air flow abnormalities persist in adolescents and adults who were born
prematurely.
 •
Although the ex-premature infant seems to be less responsive to bronchodilators

( Fawke et al. 2010 ; Fillipone et al. 2013), these agents are often part of chronic
supportive care.
 •
Routine surfactant therapy has not changed the incidence of BPD, especially in

ELBW infants. While often milder in the neonatal period, new BPD may affect the
rate and pattern of the normal decline in pulmonary function and pulmonary
vascular resistance in mid- to late adulthood. However, few data exist to predict or
document this aspect of aging in adult ex-prematures.
 •
Neurodevelopmental abnormalities are common in infants who have BPD.
Prematurity, with or without BPD, predisposes the patient to long-term pulmonary

problems ( Baraldi and Filippone 2007 ; Stern et al. 20072008 ; Saigal and Doyle
2008 ; Fawke et al. 2010 ; Lum et al. 2011 ; Filippone et al. 20122013 ; Carraro et al.
2013 ; Joshi et al. 2013 ; Kotecha et al. 2013 ; Vollsaeter et al. 2013 ; Gibson and
Doyle 2014 ). In general, premature infants with BPD have more severe long-term
respiratory abnormalities when compared with gestationally matched ex-premature
infants without BPD and infants born at term. Doyle and colleagues (2006c) noted,
“Tinier or more immature survivors have worse respiratory function than those who
are more mature or larger at birth, whether they have BPD or not.” Routine use of
surfactant did not improve long-term pulmonary outcomes of premature infants
( Halvorsen et al. 2004 ; Korhonen et al. 2004 ; Doyle et al. 2006c ).
Spirometric abnormalities (e.g., FEV 1 , FEF 25%–75% , peak expiratory flow rates) have
been documented repeatedly in ex-premature infants and confirm that those with
BPD are most severely affected. The most pervasive abnormalities are those that
reflect air flow, air trapping, and hyperresponsiveness. In addition, spirometric
values of ex-prematures both with and without BPD fall below those of full-term
infants. For example, a group of ex-prematures (<1000g/<28 weeks' gestation; born
in 1991 and 1992) were studied at 8 to 9 years of age and compared with infants born
at term. Prematurely born infants more often had diminished air flow than those
born at term. Specifically, 27.3% and 15.2% of the BPD and non-BPD preterm
groups, respectively, versus 2.4% of the controls had an FEV 1 less than 75% of that
predicted. Air trapping (increased residual volume, RV/TLC) was more common in
the ex-premature groups, especially those with BPD ( Doyle et al. 2006c ). The same
investigators evaluated another cohort of ELBW infants born in 1997 to determine if
outcomes improved with evolving care. Again, parameters of air flow (FEV 1 and
FEF 25%–75% ) were significantly abnormal in children with BPD compared with the non-
BPD and control group. The overall results were similar to those from the earlier era
when survival rates were lower.
Exercise tolerance and gas diffusion during exercise further define the impact of
residual respiratory abnormalities in ex-premature infants ( Jacob et al.
1997 ; Mitchell et al. 1998 ; Narang et al., 2009 ; Lum et al. 2011 ; Bhandari and
McGrath-Morrow 2013 ; Joshi et al. 2013 ). One study compared exercise
performance in three groups of children 9 to 12 years old: those with a history of
severe BPD, those who had RDS without BPD, and healthy infants born at term. The
BPD group used a greater percentage of ventilatory reserve (V E MAX/40 FEV 1 )
during exercise, especially those with the lowest FEV 1 ( Jacob et al. 1997 ; Smith et al.
2008 ). More recently, in a group of ex-prematures 8 to 12 years old (<32 weeks'
gestation) with and without a history of BPD, Joshi and colleagues (2013) reported a
higher rate of “doctor-diagnosed” asthma, dry cough at night, and exercise-induced
wheezing in the BPD group ( Joshi et al. 2013 ). Few of these patients were receiving
bronchodilators to treat these symptoms. Although both the term and preterm group
without BPD experienced a modestly decreased FEV 1 in response to exercise, the
BPD group displayed a greater decrease (i.e., exercise-induced bronchoconstriction).
In addition, the BPD group had a more dramatic increase in FEV 1 in response to
albuterol, suggesting a component of reversible and undertreated
bronchoconstriction. Although the peak oxygen consumption of both groups was
similar, the BPD group used more ventilatory reserve to achieve this performance.
Maximum voluntary ventilation and ventilatory capacity were lowest in children who
had had BPD and highest in those born at term; performance of the ex-preterm
without BPD ranked between these two groups. Finally, the diffusion capacity of
carbon dioxide was lower in the BPD group than in the other two groups, as reported
by others ( Mitchell, Teague, and Robinson 1998 ; Welsh et al. 2010 ).
Some investigators noted that respiratory symptoms of patients with BPD worsen
during the first year of life ( Baraldi and Filippone 2007 ), especially during acute
viral infections (particularly with respiratory syncytial virus [RSV]). Children born
before 29 weeks' gestation were rehospitalized more often. Because infants and
young children with chronic lung disease (including BPD) have an increased risk for
hospitalization with RSV, prophylaxis with palivizumab (humanized mouse
immunoglobulin [IgG1] monoclonal antibody) is recommended ( American Academy
of Pediatrics Committee on Infectious Diseases 2014 ). Impaired development of
pulmonary parenchyma and vascularity may predispose patients with new BPD to an
exaggerated inflammatory response to RSV ( Carpenter and Stenmark 2004 ).
Long-Term Outcomes in Adolescents and Adults

In 1990, Northway presented a follow-up study of 26 patients (ages 14 to 23 years)
from his original BPD cohort ( Northway, Rosan, and Porter 1967 ; Northway et al.
1990 ). Only one patient in the initial cohort weighed less than 1500 g at birth and/or
was born before 30 weeks' gestation. Seventy-six percent of these patients had
abnormal pulmonary function tests or reactive airway disease, or both. Airway
obstruction was present in 68% of the patients; 24% had fixed airway obstruction.
Although all were leading normal lives and were usually asymptomatic, former BPD
patients had higher incidences of wheezing and pneumonia, limitation of exercise,
and long-term medication use.
Over the last three decades, since the use of surfactant and “improved” approaches to
ventilation and oxygen therapy were introduced, many studies have examined
pulmonary function in ex-prematures who are school-aged and older. Although the
overall incidence of BPD has remained remarkably stable for decades, the incidence
of severe BPD characteristic of the presurfactant era has decreased and has been
uncommon for one to two decades. Therefore, when evaluating long-term outcomes
of premature infants, data from those born after the mid- to late 1990s (i.e., after
surfactant was introduced) should be evaluated separately from the data of children
born earlier. The following factors must be considered when reviewing follow-up
studies:
 •
Prior to 1990, exogenous surfactant was unavailable, and delivery of corticosteroids

(primarily betamethasone) to the mother to induce fetal lung maturity was not
widely incorporated into prenatal care. However, some centers administered
betamethasone from the late 1970s onward.
 •
“Gentle” ventilatory strategies have been applied consistently since the mid-1990s.
 •
Data about outcomes of ex-premature infants must be considered within narrow

brackets of gestational ages, especially within the ELBW category. For example,
morbidity rates vary enormously when survivors at 22 to 24 weeks' gestation are
compared with survivors after 25 to 27 weeks ( Smith et al. 2012 ). Combining data
from these two groups understates the impairment of the more immature group and
overstates that from the more mature group.
 •
When evaluating pulmonary outcomes, ex-prematures with a history of BPD must be

considered separately from those of the same gestational age without BPD.
Doyle and colleagues (2006b) reported outcomes for 8-, 11-, 14-, and 19-year-old
patients as part of a prospective longitudinal study of VLBW survivors. Most
recently, these investigators combined survivors from two presurfactant cohorts
(<1500 g, born between 1977 and 1982) and evaluated changes in lung function
between age 8 to over 18 years of age. Although the data reflect outcomes of ex-
prematures exposed to different neonatal practices than those currently followed, the
report is notable in documenting that abnormal air flows identified at younger ages
persisted into adulthood. Most subjects in the term, control group had normal
function (99% of predicted), but 6% of the non-BPD group had an abnormal FEV 1 .
Eighty-three percent of the non-BPD group had a normal FEV 1 /FVC versus 89% of
the term control group. Not surprisingly, measurements reflecting air flow were
lower in those with a history of BPD compared with the non-BPD group; 30% of the
BPD group but only 8% of the non-BPD group had an FEV 1 of less than 75%
predicted. Similarly, 42% of the BPD group but only 16% of the non-BPD group had
an FEV 1 /FVC of less than 75% predicted. A significant finding in these studies is that
between 8 and 19 years of age, the BPD subjects had a greater decrease in the
FEV 1 /FVC ratio than the non-BPD group, and this difference was greater if the
subjects were smokers. As young adults, the lung function of VLBW survivors with
BPD continued to show significantly restricted patterns of flow compared to the non-
BPD and control groups. These same survivors continued to have airway obstruction
in their mid-20s ( Gibson et al. 2014 ).
In two distinct cohorts, Vollsaeter and colleagues (2013) compared the FEV 1 over

time in three groups: term control, ex-ELBW infants with no BPD, and ex-ELBW
infants with BPD. One cohort born between 1991 and 1995 was studied at 10 and 18
years of age (a significant number had received prenatal steroids and postnatal
surfactant). An older cohort born between 1982 and 1985 was studied at 18 and 25
years of age (patients had not received surfactant) ( Fig. 23-19 ). Significant airway
obstruction was tracked (i.e., no improvement in function) from age 10 to 18 years in
one group and from 18 to 25 years in the other. Thus distinct airway function (i.e.,
FEV 1 ) was identified for three groups of survivors (control versus ex-premature
infants without BPD versus ex-premature infants with BPD); it remained stable over
long periods of time in adult ex-premature infants. Each group seemed to “track” a
pathway that may have been established early in postnatal life or even in utero.

FIG 23-19
Significant Airway Obstruction Tracked (i.e., No Improvement in Function) from Age 10 to 18 in
One Group and Between Age 18 and 25 in the Other.
FEV 1 over time was compared in three groups: term control, ex-ELBW infants with no BPD, and
ex-ELBW with BPD. One cohort born between 1991 and 1995 was studied at 10 and 18 years of
age (a significant number had received prenatal steroids and postnatal surfactant). An older
cohort born between 1982 and 1985 was studied at 18 and 25 years of age (had not received
surfactant).
(From Vollsæter M, Røksund OD, Eide GE, et al. Lung function after preterm birth: Development
from mid-childhood to adulthood. Thorax. 2013;68:767-776.)
The Tucson Children's Respiratory Study also has documented this concept of
“tracking pulmonary dysfunction over time.” These investigators followed a normal,
unselected population of patients from birth to 22 years of age ( Stern et al. 2007 ).
Maximal expiratory flow at functional residual capacity (V max FRC) was measured
between 2 and 3 months of age and again at 11, 16, and 22 years of age. Infants in the
lowest quartile of function shortly after birth remained in that quartile. These data
support the growing literature suggesting that effects of events encountered in utero
or in the neonatal period may persist for a lifetime ( Wilson et al. 2004 ; Bush,
2008 ; Narang and Bush 2012 ; Bolton and Bush 2013 ). Postma and colleagues
(2014) suggested that chronic lung disease (i.e., chronic obstructive pulmonary
disease [COPD]) may actually originate during fetal development.
In summary, the lifelong pulmonary injury associated with prematurity is

exaggerated when there is a history of BPD. Although pulmonary function is
abnormal compared with age-matched formerly term infants, the pulmonary
function of ex-ELBW infants without BPD is less severe than that documented in the
ex-premature with a history of BPD ( Joshi et al. 2013 ; Vollsaeter et al. 2013 ). The
airway obstruction of ex-prematures, especially those who had BPD, often is
associated with coughing and wheezing. BPD is thought to be “the earliest and
perhaps the longest-lasting obstructive lung disease in humans” ( Carraro et al.
2013 ).
Although asthma and the chronic lung disease of ex-prematures share common
clinical features, each has a distinct underlying pathology and etiology. Instead of the
eosinophil-mediated inflammation and atopy typical of asthma, the small conducting
airways of ex-prematures with recurrent bronchoobstruction often collapse during
expiration owing to abnormal lung growth, development, and architecture ( Baraldi
and Filippone 2007 ; Filippone et al. 2013 ). Data from high-resolution CT scanning
suggest that the lung changes of adolescent and young adult survivors of BPD more
closely resemble those of pulmonary emphysema than those of asthma.
Although adolescent and adult ex-premature infants may have far fewer problems
than they experienced as infants and young children, air flow limitation persists. In
addition, this population may achieve a lower “peak” function in early adulthood that
may predispose them to an accelerated rate of the “normal” decline in pulmonary
function with aging, especially ex-prematures with a history of BPD. As noted
by Bolton and Bush (2013) in an editorial, transitioning care of the ex-premature
from the pediatrician to the adult pulmonologist should include documenting the
history of respiratory function. The chronic lung disease of the ex-premature may
require a set of clinical tools distinct from those applied to adults with COPD or other
pulmonary diseases.
Bronchopulmonary Dysplasia, Corticosteroids, and Neurologic

Outcomes
Although the impact of BPD on neurodevelopmental outcome has been scrutinized
for decades, the etiology of this association has not been linked to a specific
molecular or cellular mechanism. General cognitive functioning and academic
performance, attention, language, learning, visual-spatial perception, and executive
skills have been repeatedly documented in patients with neurologic impairment who
also had BPD ( Majnemer et al. 2000 ; Vohr et al. 2000 ; Short et al.
20032007 ; Anderson and Doyle 2006 ). Anderson and Doyle (2006) concluded that
the “independent effect of BPD was difficult to gauge.” Although repeated episodes of
hypoxia and/or therapy with postnatal corticosteroids (see below) may contribute to
neurologic injury, the underlying process by which BPD impairs the CNS has yet to
be pinpointed. In fact, a cause-and-effect relationship may not exist. Perhaps the
same inflammatory, excitotoxic, or infectious processes inflict growth disturbances in
the lungs and the brain simultaneously.
Two studies focused on neurologic outcome in ex-prematures document important

aspects of this association.
 •
Impaired neurologic function persists in spite of optimal care:
o Neurodevelopmental outcomes of ELBW infants with BPD were

compared in two cohorts, one from 1996 to 1999 and the other from 2000 to 2003.
The latter group had the advantage of exposure to prenatal steroids, postnatal
surfactant, and indomethacin, as well as less treatment with postnatal steroids.
Despite this, BPD rates remained stable at 52% to 53%. Between 18 and 20 months of
age, although neurosensory impairment decreased, the incidence of Mental
Developmental Index (MDI) scores (Bayley-II) below 70 (42%) and overall
developmental impairment (50%) did not improve ( Kobaly et al. 2008 ).
 •
Impaired neurodevelopmental outcome evolves from the interaction of multiple

factors:
mperforate Anus (Anal Atresia)

The incidence of anorectal malformations is 1 : 5000 live births. Miller and colleagues
reported an association of anorectal atresia with caffeine intake, cigarette smoking, and
environmental tobacco smoke ( Miller et al. 2009 ). Imperforate anus can range from a mild
stenosis to a complex syndrome with other associated congenital anomalies. The higher the
anatomic relation of the terminal bowel to the puborectalis sling of the levator musculature,
the greater is the incidence of associated anomalies. The incidence of associated
abnormalities ranges from 45% to 65% of patients ( Table 24-2 ) ( deBlaauw et al. 2013 ).
Male infants with imperforate anus may require an operation soon after birth for relief of
obstruction. In female infants, a rectovaginal fistula usually prevents total bowel obstruction
so that surgical treatment is not an emergency.
TABLE 24-2
Associated Anomolies Seen in Newborns with Anorectal Malformations
Revised from de Blaauw I, Wijers C, Schmiedeke E, et al. First result of a European multi-center
registry of patents with anorectal malformations. J Pediatr Surg 2013;48:2530-2535.
Type of Associated Anomalies
Esophageal atresia
Other gastrointestinal anomalies
Cardiac anomalies
VSD
ASD
Renal anomalies
Hydronephrosis
Single kidney
Dysplastic kidney
Double system
Horseshoe kidney
Ectopic kidney
Other
Skeletal anomalies
Type of Associated Anomalies
Upper limb
Lower limb
Vertebrae (not sacral and coccyx region)
Sacral anomalies
Coccyx anomalies
Spinal canal/cord anomaly
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Intraoperative Management
Anesthetic requirements vary depending on the severity of the abdominal distention and
complexity of the surgery: a simple perineal anoplasty, a temporary colostomy, or an
extensive abdominoperineal repair. Anorectal malformation can be classified by the presence
or absence of a fistula and by the fistula's location ( Pena and Hong 2000 ) ( Box 24-9 ).
Perineal fistulas in both male and female infants represent the simplest defect, and treatment
generally consists of an anoplasty performed in the neonatal period. Imperforate anus with no
fistula is the least common, presentation, whereas rectourethral fistulas are the most common,
with the exception of the perineal fistula. The standard surgical approach has generally
involved the following three steps:
BOX 24-9
Therapeutic Classification of Anorectal Malformations
Males
 Cutaneous fistula, no colostomy required
 Anal stenosis
 Anal membrane
 Rectourethral fistula, colostomy required
 Bulbar prostatic
 Rectovesical fistula
 Anorectal agenesis without fistula
 Rectal atresia
Females
 Cutaneous (perineal), no colostomy required
 Vestibular fistula, colectomy required
 Vaginal fistula
 Anorectal atresia
 Rectal atresia
 Persistent cloaca
1. A diverting colostomy is performed in the neonatal period.
2. The main repair is done during infancy.
3. A take-down colostomy is performed later in infancy.
Surgical trends, however, have been aimed at performing the primary repair without a
colostomy. The primary repair involves a posterior surgical approach. Laparoscopic
techniques have been used to assist in the pull-through technique ( Georgeson et al.
2000 , Ming et al. 2014 , Tong et al. 2011 ).
Anesthetic considerations for neonates with intestinal obstruction from any etiology include
airway management of a full stomach, assessment of fluid status, correction of electrolyte
disturbances, treatment of sepsis, and cardiorespiratory evaluation ( Box 24-10 ). Marked
abdominal distention secondary to intestinal obstruction can impede diaphragmatic excursion
and impair ventilation. Gastric (or lower-intestinal) contents often are incompletely emptied
with nasogastric suction, so that the risk for aspiration is significant, especially during
induction of general anesthesia.
BOX 24-10
Anesthesia Management for Imperforate Anus and Bowel Obstruction
Preoperative
 Evaluation for other congenital anomalies
 Fluid and electrolyte resuscitation
Intraoperative
 Standard monitoring
 Airway rapid-sequence induction
 Inhalational anesthesia supplemental with low doses 1 to 2 mcg/kg of fentanyl
 Neuromuscular blocking agents
 Temperature: forced-air warmer
Postoperative
 Postoperative intubation dependent on findings
 Postoperative pain management
 Multidose analgesic and regional anesthesia

Intubation of the trachea of infants with an apparently normal upper airway can be
accomplished with an awake or rapid-sequence technique. If the anesthesiologist suspects
that the upper airway will be difficult to visualize, the usual airway precautions should be
observed. That is, neuromuscular blocking agents, deep sedation, and general anesthesia are
avoided, and an awake technique is attempted. Supplemental support systems for the difficult
airway (e.g., neonatal bronchoscopes, light wand, and LMA) should be available (see Chapter
16 , “Equipment”).
Anesthesia during the surgery can include potent inhalation anesthetics, narcotics, or both. In
general, nitrous oxide is avoided because of the risk for increasing bowel distention.
Intermediate-acting or long-acting nondepolarizing muscle relaxants often improve surgical
conditions at lower inhaled anesthetic concentrations. If early postoperative extubation is
planned, narcotics should be judiciously administered, but in many cases postoperative
mechanical ventilation is required.
Imperforate anus is usually recognized early in the postnatal period, and massive distention
may not develop in the group of infants without total bowel obstruction. Therefore the
complications associated with intestinal obstruction are minimized, as are the complications
from bowel ischemia, third-space fluid loss, electrolyte disturbances, and sepsis. Imperforate
anus without a fistula can be associated with the development of total intestinal obstruction in
utero, leading to severe abdominal distention, bowel perforation, sepsis, or a combination. In
addition, other congenital anomalies often have a dramatic effect on the management of these
infants. For example, imperforate anus is associated with TEF, renal anomalies, and heart
disease (VACTERL association).
During surgery, the management of fluids, blood replacement, and electrolyte delivery are
similar to the principles discussed for NEC and for intestinal obstruction. As with any
intraabdominal surgery in the newborn, a major challenge is maintaining an adequate
intravascular volume. The presence of radiopaque contrast agents, bowel manipulation, and
peritonitis increases third-space fluid requirements. In such cases, 10 mL/kg per hour (or
more) of isotonic saline solution or colloid is generally needed intraoperatively. Monitoring
urine output, quality of heart tones, heart rate, and blood pressure is a basic requirement to
assess continuing fluid needs. Invasive monitors such as an arterial catheter and a CVP
catheter generally are reserved for those with marked cardiorespiratory instability.
Postoperative Management
The preoperative and intraoperative courses and the effects of associated congenital
anomalies set the stage for the postoperative course. Many infants require postoperative
ventilatory support, total parenteral alimentation, cardiovascular support, and treatment of
sepsis. The function and recovery of the gastrointestinal system vary enormously among
infants with imperforate anus and seem to be related to whether the lesion is isolated and
whether the complications of total bowel obstruction have developed.
Outcome
Intestinal obstruction has historically been one of the major causes of death after neonatal
surgery. With more skilled pediatric management and the development of parenteral
alimentation, mortality is now limited primarily to infants whose condition is diagnosed late
and who require extensive excision of the small and large bowels. Long-term complications
from anorectal malformations, especially a high imperforate anus, can be lifelong and involve
sequelae related to fecal soiling, constipation, and sexual inadequacy. Voluntary bowel
movements were seen in 70% of females and 58% of males. Fecal incontinence was 48% in
females and 42% in males, while constipation occurred in 62% of females and 35% of males
( Stenström et al 2014 , Hartman et al. 2011 ). Bai and colleagues noted that there is a high
incidence of behavioral issues in children with anorectal anomalies compared to children who
are continent of feces ( Bai et al. 2000 ). In addition, fecal incontinence has a strong effect on
quality of life ( Grano et al. 2012 ).
Intestinal Obstruction
Intestinal obstruction is a surgical emergency in the newborn, requiring swift intervention
after diagnosis. Bowel obstruction has symptoms and signs similar to those seen at other
ages, such as vomiting, abdominal distention, decreased bowel sounds, and radiologic
evidence of gas-filled loops of bowel. However, in the newborn the list of etiologies includes
a unique set of congenital anomalies.
Delay in the diagnosis and treatment of such lesions may lead to various complications that
can increase morbidity and mortality. As described for the infant with imperforate anus, delay
in diagnosis leads to disturbance of fluid and electrolyte balance and increased abdominal
distention, with subsequent respiratory embarrassment and high risk for aspiration
pneumonitis. Intestinal perforation, necrosis of the bowel, and septicemia are other secondary
consequences if intestinal obstruction is not managed promptly.
Distended bowel forces the diaphragm into a high, fixed position, limiting excursion, causing
severe ventilatory compromise, and increasing the risk for aspiration. Although prompt
surgical repair is imperative, optimizing the patient's metabolic status is critical before
surgery. Initiation of corrective fluid and electrolyte therapy should precede the induction of
anesthesia. Nasogastric suction may decrease gastric distention and the risk for aspiration, but
if the site of obstruction is below the duodenum, the abdominal distention is not drastically
affected.
Although the underlying etiologies of intestinal obstruction are variable (annular pancreas,
intestinal atresia or stenosis, duplication of intestine, meconium ileus, tumors, enterocolitis),
the problems of anesthetic management for surgical correction of these lesions are similar
(see Box 24-10 ).
Elsinga and colleagues determined motor and cognitive outcomes in school-age children who
had undergone surgery (laparotomy) as newborns to treat intestinal obstruction ( Elsinga et al.
2013 ). At school age, 20% of these patients had abnormal motor findings and 15% had
abnormal selective attention issues when compared to population norms. Low birth weight,
IUGR, and intestinal perforation were associated with the poorest outcome. Of note, tests for
intelligence, visual perception, vasomotor integration, and memory were not affected.
Duodenal Obstruction
The incidence of duodenal obstruction in the neonate is 1 : 10,000 to 1 : 40,000 births and is
often associated with other congenital anomalies such as Down syndrome, cystic fibrosis,
renal anomalies, intestinal malrotation, and especially midline defects such as esophageal
atresia and imperforate anus. An intraluminal diaphragm, a membranous web, or an annular
pancreas can also be associated with obstruction of the duodenum. The degree of obstruction
varies from severe or complete atresia to incomplete obstruction or stenosis ( Mustafawi and
Hassan 2008 ). Air contrast films reveal a dilated stomach and a dilated proximal duodenum,
resulting in the “double-bubble” appearance ( Fig. 24-23 ).
FIG 24-23
Duodenal Obstruction.
A, The classic plain-radiographic sign of duodenal atresia. B, The endoscopic view of a duodenal
web.
(From Barksdale EM, Jr: Surgery. In Zitelli BJ, Davis HW, eds. Atlas of pediatric physical
diagnosis, ed 4. St. Louis: Mosby, 2002; p 572.)
Infants with complete obstruction exhibit copious vomiting of bile or bile-stained gastric
contents and minimal abdominal distention. In 10% of infants, the obstruction is proximal to
the ampulla of Vater and the emesis is nonbilious. The infant may or may not pass meconium
in the first day of life. Infants who have incomplete obstruction have intermittent bile-stained
vomiting and usually pass meconium. A delay in the treatment of this condition can result in
dehydration, weight loss, and hypochloremic alkalosis. The surgical approach is either
laparoscopic or open duodenoduodenostomy.
Jejunoileal Atresia
Jejunoileal atresia causes complete obstruction in 1 : 5000 live births. In contrast to duodenal
atresias, jejunoileal atresias are associated with few other anomalies. Prematurity is
associated with 50% of cases, polyhydramnios with 25%, and cystic fibrosis with 20%.
The etiology of jejunoileal atresia is uncertain but is thought to involve intrauterine vascular
accidents. Four types of atresia have been identified ( Fig. 24-24 ). Type I is not a true atresia
but actually is a membranous obstruction of the lumen in an intestine of otherwise normal
length and diameter. Type II, a true atresia, consists of two blind ends that are often
connected by a fibrous strand with slightly shortened intestinal length and an intact
mesentery. Type IIIA lesions have blind ends separated by a V- shaped mesenteric defect.
The type IIIB lesion is also called apple peel or Christmas tree deformity and consists of a
long jejunal atresia with a very short remaining ileum. The superior mesenteric artery is
missing, and the blood supply to the ileum is by retrograde flow via a branch of the ileocolic
artery. Type IIIB lesions are rare but have a very high mortality rate. Type IV lesions involve
multiple intestinal atresias; 20% to 35% of infants with jejunoileal atresia have multiple
atresias.

FIG 24-24
The Various Types of Jejunal Atresia.
(From Grosfeld JL: Jejunoileal atresia and stenosis. In Welch KJ et al. eds.: Pediatric surgery, ed
4, Chicago: Year Book, 1986.)
Meconium Ileus
Meconium ileus is a luminal obstruction of the distal small bowel by abnormal meconium.
Meconium ileus accounts for 9% to 33% of neonatal intestine obstructions. Meconium ileus
is found almost exclusively in patients with cystic fibrosis, but only 20% of patients with
cystic fibrosis have meconium ileus. Because meconium ileus manifests in the neonatal
period, respiratory symptoms of cystic fibrosis generally are not present. Both surgical and
nonsurgical therapies are used to relieve the obstruction. The nonsurgical approach involves
diatrizoate meglumine enemas, which can be both diagnostic and therapeutic. Diatrizoate
meglumine, a water-soluble contrast agent, loosens and softens the meconium, thereby
facilitating its evacuation. When medical management does not succeed, surgery is
performed. After the peritoneal cavity is entered and the obstruction is located, diatrizoate
meglumine or acetylcysteine is injected into the bowel lumen and allowed to mix with the
meconium. When the meconium has loosened, it is massaged into the colon. If this is
unsuccessful, an enterostomy is performed, and the sterile meconium is evacuated from the
small bowel ( Fig. 24-25 ).

FIG 24-25
Thick Tenacious Meconium in a Patient with Meconium Ileus.
Malrotations and Volvulus
Malrotations are rare and generally result from abnormalities in the rotation of the bowel,
which usually occur during the tenth to twelfth weeks of gestation. Consequently, areas of
ischemia and atresia develop, along with volvulus, resulting in strangulation of bowel, bloody
stools, abdominal distention, peritonitis, and hypovolemic shock ( Fig. 24-26 ); 80% of cases
are reported to occur in the first month of life, and 20% present after the first year ( Shalaby
et al. 2013 ). However, in a single-institution series, Nehra and Goldstein (2011) found rates
in infants, children, and adults to be 31%, 21%, and 48%, respectively. In the neonate the
cardinal finding is bilious emesis, while in older patients it is recurrent abdominal pain
( Miyano et al. 2015 , Hagendoorn et al. 2011 ). Nonrotation or malrotation is twice as
common in boys as in girls and often produces symptoms of intestinal obstruction in the first
1 to 2 months after birth. In other cases, symptoms do not appear until later, even adulthood.
The diagnosis of malrotation cannot be excluded if diarrhea is present, clinical symptoms are
mild, or radiographs are normal ( Miller et al. 2003 ). In patients with intestinal malrotation
without volvulus, surgery often involves Ladd's procedure, which can be performed either
open or laparoscopically ( Draus et al. 2007 ). Malrotations are often associated with
duodenal stenosis or atresia or small-intestinal atresia, as well as with cardiac, esophageal,
urinary, and anal anomalies. Major anatomic defects of the abdominal wall (e.g.,
gastroschisis and omphalocele) and CDH universally have intestinal malrotation or
nonrotation.

FIG 24-26
Malrotation with midgut volvulus without ischemia (A) and with infarction (B).
(From Barksdale EM Jr: Surgery. In Zitelli BJ, Davis HW, eds.: Atlas of pediatric physical
diagnosis, ed 4, St. Louis: Mosby, 2002; p 572.)
The operative procedure for a nonrotation complicated by volvulus consists of untwisting the
intestine and then a short intraoperative period of observation to evaluate recovery of
vascular perfusion to the involved intestine. Areas of frank necrosis are excised, and a
primary anastomosis is performed. If the patient has peritonitis or poor perfusion of the
remaining bowel, proximal and distal enteral stomas are formed. The surgical operation,
Ladd's procedure, involves the following five steps: eviscerating the midgut, derotating the
volvulus in a counterclockwise direction, lysis of Ladd's peritoneal band, appendectomy, and
placing the caecum in the lower-left quadrant.
Children with less than 30 to 40 cm of small bowel generally develop short-gut syndrome and
ultimately require TPN. If areas of marginal intestinal viability are present at the time of
surgery, they may be left unresected in the hope that postoperative resuscitation improves the
perfusion. Under these circumstances, a “second-look” operation usually is performed 24 to
48 hours later.
Sacrococcygeal Teratoma
Sacrococcygeal teratomas (SCTs) are the most common congenital neoplasm, occurring in 1
to 2 per 20,000 pregnancies and 1 in 27,000 live births. Approximately 95% of infants are
female. The perinatal mortality in prenatally diagnosed SCT infants ranges from 25% to 37%.
Mortality is related to high output failure and tumor rupture and hemorrhage during delivery.
High output failure is related to the amount of solid tumor component of the mass. In a
nationwide survey from Japan, Usui and colleagues noted that in various series postnatal
death ranges from 12% to 40% ( Table 24-3 ) ( Usui et al. 2012 ). Risk factors for perinatal
adverse outcomes include high output failure, hydrops, maternal mirror syndrome, preterm
delivery, and rate of tumor growth ( Akinkuotu et al. 2015 , Coleman et al. 2014 , Usui et al.
2012 , Van Mieghem et al. 2014 ).

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The Newborn

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The newborn's cardiac output per unit of weight is the highest of any age group

(≈200 mL/kg/min). Teitel and colleagues (1985) hypothesized that the greater

Preoperative Cardiovascular Evaluation

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The Central Nervous System

These lesions occur at any spinal level. Hydrocephalus commonly accompanies

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Following completion of neural tube and prosencephelon development at 2 to 3

Growth of the Fetal Brain

Autoregulation of Cerebral Blood Flow in Newborn Infants

Greisen (2009) emphasized that the cerebrovascular autoregulation of critically ill

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In summary, accurately predicting the response of cerebral blood flow to changes in

Unique and Vulnerable Cell Populations in the Brain of the Fetus

Preoligodendrocytes: Before myelination and during the time of peak vulnerability

Subplate neurons: Subplate neurons are present in subcortical white matter by

Germinal Matrix–Intraventricular Hemorrhage and Periventricular

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Grade I: A subependymal hemorrhage with minimal or no IVH

Volpe (2008) revised the grading system as follows:

Grade I: Germinal matrix hemorrhage; ventricular enlargement is less than 10% of

Grade II: Blood fills 10% to 50% of the ventricle.

Grade IV was eliminated. The presence of an echo density in the periventricular

Although the results from studies of neurodevelopmental outcome are inconsistent,

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In 1964, the Collaborative Study on Cerebral Palsy reported a stronger relationship

Although this is a condensed, simplified description of some of the pathways of

Preoperative Neurologic Evaluation

Preoperative evaluation of the nervous system must include assessment of

Acutely ill infants who require urgent surgery

Preoperative evaluation of neurologically stable infants who require an elective

A prospective study by Liu and colleagues (1983) suggested that a history of apnea

Welborn and colleagues (1986) found no evidence of apnea in a group of healthy

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Other factors predispose infants, especially premature infants, to apnea, including

Hypothermia (body temperature <36° C) increases oxygen consumption and

In view of the uncertainty about the definition and implications of hypoglycemia,

A single glucose measurement of 18 mg/dL

A level of 36 mg/dL and a lower value on the next measurement

A single glucose measurement of 45 mg/dL in a newborn with symptoms of

In contrast to an “operational threshold,” the guidelines of the American Academy of

 Symptomatic with glucose level lower than 40 mg/dL→ Intravenous glucose

 Asymptomatic: birth to 4 hours

Initial feed within 1 hour of birth; screen 0.5 hour later

If glucose is then less than 25 mg/dL→ Feed, recheck glucose in 1 hour

1 hour: glucose 25 to 40 mg/dL→ Refeed, consider intravenous glucose

1 hour: glucose less than 25 mg/dL→ Intravenous glucose

Feed every 2 to 3 hours; measure serum glucose before each feed

If plasma glucose is less than 35 mg/dL→ Intravenous glucose

In addition to glucose levels, treatment of asymptomatic infants depends on their age

Glucose Metabolism in the Fetus and Newborn

When the placental supply is abruptly interrupted at birth, the concentration of

Perioperative Management of Hepatic Function

During a preoperative visit, noting the concentration and rate of delivery of

Ideally, glucose levels can be monitored intraoperatively, but access to sampling is

An age-dependent ability to metabolize compounds matures in an isoenzyme-specific

The CYP3A gene family ( CYP3A4, CYP3A5, CYP3A7, CYP3A43 ) produces the largest

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(≈200 mL/kg/min). Teitel and colleagues (1985) hypothesized that the greater

A single glucose measurement of 18 mg/dL

A level of 36 mg/dL and a lower value on the next measurement

A single glucose measurement of 45 mg/dL in a newborn with symptoms of

 Symptomatic with glucose level lower than 40 mg/dL→ Intravenous glucose

If glucose is then less than 25 mg/dL→ Feed, recheck glucose in 1 hour

1 hour: glucose 25 to 40 mg/dL→ Refeed, consider intravenous glucose

1 hour: glucose less than 25 mg/dL→ Intravenous glucose

If plasma glucose is less than 35 mg/dL→ Intravenous glucose

Consistent with previous data ( Andrew et al. 19871988 ), plasma concentrations of

Clinical jaundice (total bilirubin >5 mg/dL) secondary to unconjugated bilirubin has

Increases to more than 12 mg/dL

In fact, recent reviews ( Collaco et al. 2012 ; Ali et al. 2013 ; Berkelhamer et al.