Blo o d Conser vation

Strate gies in Pe diatric

Anesthesia
ShilpaVerma, MBBSa,*, Michael Eisses, MDa,b,
Michael Richards, BM, MRCP, FRCAa,b

KEYWORDS
 Blood  Coagulation  Management  Pediatric
 Anesthesia  Surgery

It is widely accepted in modern medical practice that the use of blood products is an
integral part of many aspects of patient care. Even with advances in the knowledge of
blood cross-matching, there remains a small but significant risk of morbidity and
mortality associated with any form of blood product administration. Because coagu-
lation is inherently intertwined with blood conservation, a good understanding of the
options to manipulate the coagulation pathways is an integral aspect of the following
discussion.
There are undoubtedly certain specific aspects of pediatric physiology that present
their own distinct challenges to the management of transfusion in children. Through
this article, the authors aim to highlight the challenges that the pediatric anesthesiol-
ogist may face when encountering a situation requiring blood transfusion and to
address some of the modalities available to minimize the necessity and frequency
of blood product use.

WHY SHOULD WE GIVE BLOOD AND BLOOD PRODUCTS?

The replacement of blood or blood products in a patient who is deficient in blood cells
or protein complexes seems a natural goal; however, there are little or no data to
define the absolute benefit. The practice of transfusion was adopted long before the
advent of randomized trials. As with many advances in medicine, the widespread
adoption of transfusion occurred during a time of conflict; the use of blood products
undoubtedly saved many lives before the risks associated with it were identified.1 In

The authors have no external funding interests.

a
Department of Anesthesiology and Pain Medicine, University of Washington, Box
356540BB-1469 Health Sciences, 1959 NE Pacific Street, Seattle, WA, USA
b
Seattle Children’s Hospital, 4800 Sandpoint Way NE, PO Box 5371/W9824, Seattle, WA
98105-0371, USA
* Corresponding author. Department of Anesthesiology and Pain Medicine, University of
Washington, Box 356540BB-1469 Health Sciences, 1959 NE Pacific Street, Seattle, WA.
E-mail address: [email protected] (S. Verma).

Anesthesiology Clin 27 (2009) 337–351

doi:10.1016/j.anclin.2009.05.002 anesthesiology.theclinics.com
1932-2275/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
338 Verma et al

simplistic terms, the following rationale cannot be debated: Red blood cells contain
hemoglobin, which is used to transport oxygen. If a patient is deficient in red cells,
then oxygen delivery is impaired; by increasing the concentration of red cells, the
oxygen carrying capacity of blood and hence oxygen delivery can be increased.
In vivo blood contains the primary components of the coagulation cascade; when
these become depleted, they can only be replaced by synthesis or transfusion.
Synthesis is limited by the speed of production; transfusion allows rapid resolution
of coagulation deficiencies in a state of ongoing blood loss.
With blood loss, the intravascular volume becomes depleted. There are many intra-
vascular volume expanders; however, none of them have an intravascular life span of
more than a few hours. Red blood cells have a far greater longevity in the intravascular
space and are therefore much more effective in volume replacement therapy than any
other product available.

WHY SHOULD WE AVOID BLOOD PRODUCTS WHEN POSSIBLE?

Although in recent years the mainstream media have extensively covered the risks
associated with human immunodeficiency virus (HIV) transmission from blood trans-
fusion, there are many other blood-borne diseases, specifically the hepatitides,2,3
that have a higher incidence of transmission through transfusion and arguably
a greater impact on morbidity and mortality.
The potential immunologic consequences of transfusion are also a major cause of
morbidity. In particular, the immunomodulation associated with the exposure of the
critically ill patient to non–leukocyte-reduced transfusions has been shown to signifi-
cantly worsen outcome data on intensive care units,4 whereas transfusion-related
acute lung injury is probably the most common cause (1 in 2000 patients) of major
organ dysfunction secondary to blood product administration.5

WHY IS THE PEDIATRIC PATIENT DIFFERENT?

The neonate is born with a predominance of hemoglobin (Hb) F, a variable but usually
high hemoglobin level (about 16 g/dL), an oxygen dissociation curve that is shifted to
the left as a consequence of existing in a hypoxic environment for the previous
9 months, and an immature coagulation system.
From the hemoglobin perspective, most authorities treat children older than
4 months as adults, with regard to transfusion guidelines.6 For children younger
than this age, there are very little data to support any guidelines.7,8 In the situation
of ongoing blood loss, then, the decision to transfuse is obvious; however, when trans-
fusion should be triggered is a moot point. During the 10 weeks after delivery, the
hemoglobin falls to 11 g/dL; however, by this age, virtually all hemoglobin is Hb A.
So, although the decrease in hemoglobin concentration reduces oxygen delivery,
the Hb A enhances oxygen extraction at the tissue level.
The coagulation system of the neonate is immature and does not reach a level
comparable with the adult coagulation cascade until at least 6 months of age.9 The
key differences are the vitamin K–dependent factors (II, VII, IX, and X) that are less
than 70% of adult levels, the inhibitors of coagulation (including antithrombin III and
proteins C and S) that are 50% of adult levels, and platelets, whose numbers are at
a similar level to that of adults but take 2 weeks to develop adult levels of reactivity.10
All the factors briefly highlighted earlier leave us in a quandary; there is no conclusive
evidence as to what, how, or when blood and blood products should be used in
children, particularly in neonates. There are inherent risks associated with use of blood
products; however, it is unlikely that there will ever be definitive guidelines based on
 Blood Conservation Strategies 339

irrefutable evidence. What physicians can do is have a good awareness of the under-
lying physiology and developmental changes that occur within the child and try to coor-
dinate management to maintain the patient’s physiology as close to normal as possible.
Through the rest of this article, the authors try to identify patients who are at high risk
of requiring blood products, and they review the options available for prophylaxis
against blood loss, which help to minimize the need for blood products. They also
examine some of the strategies for acute management of blood loss and look at which
blood products should be administered, including discussion of transfusion
thresholds.

THE HIGH-RISK PATIENT

In determining that a patient is at significant risk of transfusion, there are 4 factors that
should be considered: patient-, drug-, physician-, and procedure-related risk.

Patient-Related Risk
Concurrent pathology and current physiologic status can have profound implications
on patients’ potential for blood loss during any form of surgical procedure. Increased
bleeding potential, either from direct means such as thrombocytopenia or indirectly
from pathology such as renal impairment–induced platelet dysfunction, needs to be
recognized. Preoperative anemia will limit the patient’s reserve to deal with intraoper-
ative blood loss.
Something that should be mentioned at this juncture is a patient’s moral choice not
to receive blood products. This can provide a challenging ethical problem that is made
all the more difficult with children, when one has to determine who has the ‘‘right’’ to
make such decisions: the parent or guardian, the child (a minor), the medical practi-
tioner, or a court of law. It is imperative that every establishment that deals with
children in a situation such as this, where medical, moral, ethical, and religious beliefs
may produce disagreement and conflict, institute a well-publicized, legally approved
protocol for patient management, which is transparent and easily available for both
health care practitioners and families.

Drug-Related Risk
In pediatric practice, the two major categories of drugs that are likely to be encoun-
tered that increase the likelihood of intra- and postoperative bleeding are antiplatelet
agents (nonsteroidal antiinflammatory drugs [NSAIDs]) and anticoagulants (heparin
and warfarin). NSAIDs (used for either acute or chronic indications) act by reversibly
inhibiting cyclooxygenase, thereby inhibiting platelet activity. They require an
adequate lag time of 5 to 7 days from cessation of therapy until platelet function is
restored, which needs to be considered; however, the urgency of the surgical proce-
dure may eliminate NSAIDs as a prophylactic option.
Heparin enhances the effects of antithrombin III and inhibits platelet aggregation.
When used intravenously, it has a half-life of 90 minutes with clinical effects persisting
for 4 to 6 hours; hence it can almost invariably be stopped appropriately before
a surgical procedure. The advent of prophylactic and therapeutic treatment with
low–molecular weight heparin has made management slightly more complicated
with its longer half-life of 2 to 4 times that of standard heparin, independent of dosage.
Most authorities would advocate, if time permits, waiting at least 12 hours for prophy-
lactic and 24 hours for therapeutic treatment to normalize. In the eventuality of emer-
gency, both normal and low–molecular weight heparin can be reversed with protamine
sulfate, which forms an inert complex with circulating heparin.11
340 Verma et al

Warfarin competes with vitamin K in the synthesis of factors II, VII, IX, and X and has
a half-life of 30 hours. The dosage is adjusted according to coagulation studies.
Although careful scheduling and institution of alternate anticoagulation usually allow
for straightforward management of patients receiving warfarin, clinical urgency may
override this situation. In this circumstance, the effects of warfarin can be reversed
with fresh frozen plasma (FFP) to replace the absent coagulation factors or by cautious
titration of intravenous vitamin K. There have also been reports of activated factor VII
being used to shorten the prothrombin time.12
In the pediatric population, other drugs that provoke an increased risk of bleeding,
such as antithrombotics and thrombolytics, may rarely be encountered. In most
cases, these can be stopped after appropriate discussion with the primary prescriber
or surgical team. However, when the ongoing use of these drugs is considered to be in
the patient’s best interests, appropriate preoperative counseling of the increased risk
is necessary. At this juncture, it is worth mentioning the increasing use of herbal reme-
dies within the general public; some of these have been implicated as modulators of
the clotting pathway and others have been noted to have a significant impact on the
metabolism of particularly procoagulant drugs that medical practitioners use.

Physician-Related Risk
Individual physicians and even institutions have dramatically different blood product
use and blood product transfusion protocols that vary enormously, nationally and
internationally. This variation is because of personal and institutional preference rather
than national and international guidelines. Adherence to guidelines is of course at the
individual’s discretion. Within surgery per se, there is also significant inter-individual
surgical practice that undoubtedly exists. Some surgeons are ‘‘more bloody’’ than
others while performing the same procedure; that is not to say that they are worse
or better, just that their practice involves greater blood loss to get to the same end
result, hence greater use of blood products.

Procedure-Related Risk
Although it may seem to be stating the obvious that different procedures have different
risks for the requirement for blood product administration, there is considerable vari-
ation with what seems superficially to be the same procedure. A single surgical
description can cover a multitude of impending actual procedures that, depending
on the patient in question, can have enormous variation in time duration, physiologic
and anatomic upheaval, and subsequent circulatory compromise. For example,
a patient listed for a ‘‘craniosynostosis repair’’ could represent a repair of one suture,
or many sutures and therefore have significantly different blood-loss potential. Any
reoperations should give rise to extreme caution because of the inevitable adhesions
that need to be addressed at the primary operative site.
As is the essence to the majority of clinical practice, the most important aspect of
preoperative preparedness involves a team approach, with adequate discussion
with the surgical practitioner and research into the patient’s preoperative physiologic
condition. This should allow the perioperative physician to be prepared for the
expected, and a healthy degree of caution allows the physician to be prepared for
the unexpected.

STRATEGIES FOR BLOOD TRANSFUSION PROPHYLAXIS

Strategies to avoid intraoperative administration of blood or blood products can be

divided into preoperative and intraoperative interventions.
 Blood Conservation Strategies 341

Preoperative Interventions
These options are useful when one anticipates a high degree of blood loss in surgical
procedures that are elective in nature.

Recombinant erythropoietin
Erythropoietin (EPO) is an endogenous hormone produced in the kidney. It has a high
affinity for the erythropoietin receptor expressed on the surface of erythroid cells. It is
necessary for the survival of developing erythroid progenitor cells and controls the
proliferation and differentiation of these cells. The recombinant alfa form of EPO has
been available in the United States since 1997. EPO’s role to increase red blood
cell mass in pediatric patients has precedence through its use to treat anemia asso-
ciated with end-stage renal disease, malignancies, and also anemia of prematurity.
As a result, its safety profile has been well evaluated.
There are several case reports and reviews exploring the use of EPO preoperatively
to avoid, or at least minimize, allogeneic blood transfusions in children. Jadhav and
colleagues13 administered EPO with iron supplementation 3 times a week for 6 weeks
to 3 children scheduled for major elective surgery who were Jehovah’s Witnesses.
There was a rise in hemoglobin by a mean of 4.1 g/dL and hematocrit by a mean of
14%, and none required allogeneic blood products intraoperatively or postoperatively,
demonstrating that red blood cell mass can increase considerably just weeks before
scheduled surgery. There are also studies demonstrating EPO’s role as an adjunct
with other blood conservation techniques. In a retrospective review14 of 19 patients,
10 patients, with a mean age between 11 and 13 months, received EPO and iron for
several weeks before craniosynostosis repair and oral vitamin K the previous night.
Coupled to that strategy was intraoperative aprotinin, acute normovolemic hemodilu-
tion (ANH), and controlled hypotension. Patients receiving EPO increased their red cell
mass within 4 weeks by an average of 28% (hematocrit 34.9%–44.5%). Compared
with those not receiving EPO, the incidence of transfusion and total volume of blood
products were lower. Although many blood conservation strategies were used in
conjunction with EPO, clouding the individual contribution of EPO, the investigators
did find an increase in allowable blood loss measurements having used EPO preoper-
atively. To them, this represented an advantage to preoperative EPO administration by
allowing more patients to qualify for ANH.
With EPO administration, the rate of hematocrit increase varies in patients and may
be dose dependent;15 therefore consultation with a hematologist to guide candidacy
of intervention, response to dosage, and potential side effects is advisable. The first
sign that EPO has taken effect is an increase in reticulocyte count within 10 days,
whereas a clinically significant increase in hematocrit should be visible by 2 weeks.
Iron supplementation is necessary to provide for increased requirements during
expansion of red cell mass secondary to marrow stimulation by EPO.

Preoperative autologous blood donation

When considering preoperative autologous donation (PAD) as another preoperative
blood conservation strategy, the differences between adults and children must be
noted. Each donation results in a significant alteration in intravascular volume, which
through oral rehydration can easily be compensated for in adults by increasing left
ventricular stroke volume and heart rate. Children older than 4 years have adult-like
cardiovascular physiology16 and demonstrate a similar compensatory mechanism
to blood loss. Infants do not have this buffer because of their immature myocardial
infrastructure, which results in a limited ability to increase stroke volume in response
to hypovolemia. Without supplementation of iron, it can take 3 months to naturally
342 Verma et al

replenish iron stores after one autologous donation.17 However, if one takes into
consideration the weight and estimated blood volume of the child and allows for
appropriate intravascular volume replacement, PAD can successfully be tolerated
by the pediatric patients without hemodynamic consequences. Longatti and
colleagues18 report PAD in patients as young as 3 months and weighing as little as
6.7 kg.
One important advantage to PAD is the potential for a decreased incidence in
alloimmunization, which can have a huge impact on future blood transfusion, preg-
nancy, and organ transplantation. Autologous programs may increase the donor
pool because many autologous donors subsequently become allogeneic donors
and, at the same time, decrease the demand for allogeneic blood.
The principle concern regarding PAD use is that accurate prediction of blood loss is
necessary to maintain its advantage of reducing allogenic blood product exposure. In
a study by Letts and colleagues,19 surgeons were asked to predict the number of
autologous units required for a given procedure to determine the volume of blood
needed for predonation; the reported accuracy was 53.8%. PAD does not prevent
septicemia from a bacterially contaminated unit. It does not avoid clerical or laboratory
error leading to transfusion of a wrong unit. The scheduling of surgery may have to be
altered to permit donation or avoid wastage of the predonated autologous blood. The
cost of a blood unit obtained via PAD is higher than that which is obtained via a random
donor. Given these concerns, the potential benefits in a carefully chosen population
may outweigh the risks.
Similar transfusion thresholds should be used as with administering allogeneic
blood. EPO and iron supplementation are useful in helping to offset preoperative
anemia associated with the technique. Successful programs address the psychoso-
cial issues of the predonation process and have a deep commitment to the multidis-
ciplinary team approach.

Intraoperative Interventions
Acute normovolemic hemodilution
ANH involves the removal of whole blood from the patient shortly before the anticipated
surgical blood loss and the restoration of the circulating blood volume with a crystalloid
or colloid solution to maintain normovolemia. The premise is that the blood lost during
the surgery will consist of blood with a lower hematocrit and, hence, proportionately
less of the patient’s red blood cell mass is lost. The oxygen carrying capacity can
then be restored by administering the previously withdrawn blood, once the major
blood loss has abated.
There are a few potential concerns when instituting ANH in pediatric patients.
Infants younger than 4 months have a higher Hg F concentration. Hg F has a decreased
ability to unload oxygen to the tissues, which would be undesirable in a situation where
there is already a reduced oxygen supply (dilutional anemia). Children younger than
4 years may not tolerate hypovolemia well because of their limited ability to increase
stroke volume and a predominant reliance on increases in heart rate to maintain
cardiac output. Although there are very few studies addressing ANH in infants less
than 6 months, Friesen and colleagues20 showed benefits in limiting blood loss
when ANH was used before cardiac surgery, where the replacement fluids included
the banked blood already used to prime the cardiopulmonary bypass (CPB) pump.
In general though, caution is advised in using this technique in the younger infant.
There are many alternate algorithms that calculate the amount of blood that is drawn
from the donating patient and also how one cares for the drawn blood. The option of
keeping the donated blood warm allows for the preservation of the maximum level of
 Blood Conservation Strategies 343

platelet function; however, if there is significant delay before readministration, then the
blood should be refrigerated.
ANH in spinal fusion surgeries have shown to be beneficial especially if combined
with other blood conserving strategies. Pouliquen-Evrard and colleagues21 retrospec-
tively examined four groups of children who underwent orthopedic surgery, for alloge-
neic blood use. The groups included (1) patients solely using allogeneic blood
transfusions, (2) patients using ANH only, (3) patients using PAD and ANH, and (4)
patients using PAD, ANH, and controlled hypotension. The hemoglobin target for
hemodilution was 8 g/dL, and transfusion was dependent on both clinical indications
and hemoglobin with lower limit of 7 g/dL. Overall, 98%, 46%, 19%, and 5% blood
loss was replaced by allogeneic blood transfusion in the first, second, third, and fourth
groups, respectively. This study demonstrated that ANH can significantly reduce allo-
geneic blood transfusion, especially when used in conjunction with additional blood
conservation techniques.
In craniosynostosis surgeries, ANH has been less successful. Reasons suggested
for this include a smaller pediatric population and a smaller volume of red cells, which
in turn limit the volumes of whole blood being harvested before a postdilutional hemat-
ocrit level is reached.6 In a study22 in which infants undergoing craniosynostosis
surgery were randomly assigned to receive ANH or standard fluid management, the
combined intraoperative blood loss and postoperative blood loss was large enough
in the ANH group that the volume of reinfused blood was inadequate to avoid alloge-
neic transfusion in the majority of patients. If preoperative hematocrit level had been
higher, more blood could have been obtained and used for reinfusion. Therefore,
the use of preoperative EPO and iron combined with ANH can potentially prove
beneficial.

Cell salvage
Cell salvage is a technique by which blood lost during a procedure is processed in
a way that can be given safely back to the patient in the form of fresh platelet-free
autologous packed red cells with normal oxygen affinity; however, it has no clotting
factor potential.
Early models of cell salvage devices required large shed-blood volumes before
processing for reinfusion, making their use technically difficult in pediatric populations.
Newer models use smaller processing reservoirs, making this issue less of a problem,
therefore extending their usability to smaller patients. Some have argued that at least
2 units of blood needed to be recovered for cost-effectiveness.23 However, a study by
Nicolai and colleagues24 found that cell saving technique was extremely beneficial in
children with cerebral palsy undergoing acetabuloplasty; they found allogeneic blood
transfusion was avoided in 82% of patients. Similarly, cell salvage was found useful in
limiting allogeneic blood transfusion in infants undergoing surgical correction of
craniosynostosis.25,26 Concerns about renal injury, coagulopathy, and cytokine
activation with unwashed red cell reinfusion are the same for children as for adults.6

Deliberate hypotension
Deliberate hypotension (DH) is the technique of purposely lowering the blood pressure
through the use of intravenous agents or inhaled anesthetic agents leading to less
blood loss. Concerns regarding impaired oxygen delivery to tissues during hypoten-
sion are not as significant in children compared with adults with preexisting athero-
sclerotic disease of the heart, brain, or kidney. However, caution still must be taken
in the pediatric population. According to Gibson,27 DH can obscure the findings of
spinal cord monitoring during surgical correction of scoliosis secondary to spinal
344 Verma et al

cord hypoperfusion. To avoid spinal cord hypoperfusion, there is now less reliance on
DH and an emphasis on proper patient positioning and the use of antifibrinolytics in
patients undergoing scoliosis repair. However, as with other blood conservation tech-
niques, DH has its application in a chosen population undergoing specific surgeries. It
has been found to significantly reduce blood loss and surgery time and to improve
surgical operative conditions by enhancing visualization and allowing better delinea-
tion and dissection of lesions and structures.28,29 Dolman and colleagues30 compared
DH to normotension in a randomized, double-blind, controlled study in patients
scheduled to have Le Fort I osteotomies. They found that the quality of the surgical
field was improved, and there was a significant reduction in blood loss.
Contraindications to DH in children are similar to those in adults: any pathology
involving significant reduction in the availability of oxygen to the tissues, including
decreased oxygen saturation, cardiac output, or anemia; cardiac, cerebral, or renal
disease; and increased intracranial pressure. Factors enhancing the safety of the tech-
nique include the proper selection of cases, maintenance of near-normal acid-base
balance, accurate monitoring of pressure, maintenance of high arterial oxygen
tension, and avoidance of hyperventilation, as this may significantly reduce cerebral
blood flow.28 Of all the hemodynamic variables, mean arterial pressure correlates
best to the degree of blood-loss reduction.14

Pharmacologic agents: aprotinin, 3-aminocaproic acid and tranexamic acid

In discussions of pharmacologic agents to reduce bleeding, the drug aprotinin usually
receives significant attention. However, because of newer studies, especially the
BART study31 from 2008, which raised serious safety concerns, aprotinin has been
removed from the market by its maker, Bayer. It can only be used for investigational
purposes according to the Food and Drug Administration (FDA).32 Its use in children
for reducing blood loss in a variety of procedures has been mixed; many of its bene-
ficial effects with respect to bleeding were reported in studies involving adults only.
3-Aminocaproic acid and tranexamic acid are synthetic lysine analogs that compet-
itively inhibit activation of plasminogen to plasmin, thus serving as alternatives to apro-
tinin. Tranexamic acid has a longer half-life, is 7 to 10 times more potent, and is more
active in tissue than aminocaproic acid, with no greater toxicity.15 Studies on amino-
caproic acid and tranexamic acid in children have been promising. Chauhan and
colleagues33 compared the efficacy of aminocaproic acid and tranexamic acid in
reducing postoperative blood loss and blood and blood product requirements in
children with cyanotic congenital heart disease. Children from age 2 months to
14.5 years (150 total) underwent corrective surgery on CPB. Patients were randomized
into 3 groups based on receiving aminocaproic acid, tranexamic acid, or no antifibri-
nolytic (control). The control group had the maximum blood loss at 24 hours and
maximum requirements of blood products. There was no significant difference in
postoperative blood loss or blood product requirement in the two groups given anti-
fibrinolytics; however, both agents were equally effective compared with controls.
Similar beneficial effects have been shown in noncardiac surgery. Studies in scoliosis
surgery,34,35 despite different dosing between studies, demonstrated a reduction in
blood loss and allogeneic blood transfusion requirements in pediatric patients.
A Cochrane systematic review of antifibrinolytic agents36 concluded similarly.

Surgical technique
Surgical technique is an integral component of both blood loss and blood conserva-
tion. There are well-established and seemingly obvious aspects of surgical technique
that have had a profound impact on blood component usage for years, such as
 Blood Conservation Strategies 345

electrocautery and the application of tourniquets. Some newer developments such as

fibrin sealants have also significantly changed surgical practice. Fibrin sealant is
prepared from two plasma-derived protein fractions: a fibrinogen-rich concentrate
and a thrombin concentrate.37 Mixing fibrinogen and thrombin mimics the last step
of the blood coagulation cascade, resulting in formation of a fibrin clot that adheres
to the application site and acts as a fluid-tight sealing agent able to stop bleeding.
Resorption of the clot is achieved within days to weeks following application. It has
been used to successfully reduce the amount of clotting factor replacement in children
with hemophilia A undergoing circumcision.38 As this product is derived from donor
plasma, one must keep in mind the potential for transmission of infection. The fibrin-
ogen and thrombin fractions are exposed to several robust viral inactivation steps,
such as solvent-detergent, pasteurization, vapor-heat treatment, and nanofiltration.
However, there have been case reports of possible transmission of parvovirus B19
(B19V) by 1 commercial product identified in Japan. Implementation of nucleic acid
tests to screen for B19V may reduce this risk.37
Temperature control
Infants, particularly the neonate, are highly susceptible to hypothermia in the operating
room environment. There is a fairly high rate of heat loss in proportion to heat produc-
tion in the infant; this is caused by an immature thermoregulatory mechanism, a rela-
tively thin layer of subcutaneous brown fat for insulation,39 and extensive superficial
circulation that facilitates rapid dissipation of heat from the body. Studies dating
back to the 1970s have demonstrated the effect of hypothermia on coagulation in
the newborn. Chadd and Gray40 found that infants whose temperature was allowed
to drift to 34 C and below had a reduced platelet count and prolonged thrombin times.
Hypothermia-related coagulation disorders are caused by anomalies in clotting factor
enzyme function, platelet function, and fibrinolytic activity.41

TRANSFUSION TRIGGERS

There is little evidence to suggest absolute levels at which one should transfuse blood
products to patients. However, there are certain ‘‘accepted’’ levels or ‘‘triggers,’’ as
reported in the latest American Society of Anesthesiologists (ASA) Practice Guide-
lines.42 Although these guidelines were targeted for adult patients and not infants or
neonates, these recommendations, for lack of other evidence, are often extrapolated
to younger patient groups. When discussing transfusion triggers surrounding surgery,
findings in the medical history, physical examination, and preoperative testing will
likely have significant impact. For example, one’s threshold for red cell transfusion
may be different for the cyanotic patient versus the acyanotic patient. Also, a patient
with certain religious preferences (eg, Jehovah’s Witness) may persuade one to
consider a lower trigger than in patients without such preferences. These types of
factors, and thus the preoperative evaluation and preparation, cannot be ignored
when discussing transfusion triggers. A good understanding of factors affecting
thresholds for transfusion can lead to better use of blood products and therefore
conservation.
Red Cells and Whole Blood
Transfusion of red cells, whether in the form of packed red blood cells or whole blood,
is intended to increase the red cell mass within the bloodstream, with potential
benefits to blood pressure, viscosity, and oxygen carrying capacity. Generally, most
practitioners use the hemoglobin or hematocrit to determine when such a transfusion
should occur. As stated earlier, the absolute level at which this should occur has not
346 Verma et al

been well established. However, according to the latest practice guidelines from the
ASA Task Force on perioperative blood transfusion and adjuvant therapies, a hemo-
globin level less than 6 g/dL generally requires red cell transfusion, and a hemoglobin
level greater than 10 g/dL generally does not require red cell transfusion.42 Within that
range, whether one administers red cells to the infant or child patient will depend on
their vital signs, adequacy of oxygenation and perfusion, acuity and degree of blood
loss, and other physiologic and surgical factors. Above that range, the decision to
administer red blood cells to a neonate or infant should take into account a high base-
line concentration of hemoglobin, high oxygen consumption, and high affinity of
residual fetal hemoglobin for oxygen. In addition, the patient’s absolute blood volume
(85 mL/kg in full-term neonate, 100 mL/kg in preterm neonate) should also be consid-
ered, especially in procedures where considerable blood loss is expected, and initial
vigorous replacement with crystalloid followed by red cell transfusion rather than just
red cell replacement may be unfavorable from the standpoint of volume status.
Therefore, the threshold for red cell transfusion in a healthy neonate may be much
higher than that outlined in the Task Force guidelines, especially in nonhealthy
neonates, for example, those with significant lung disease requiring mechanical venti-
lation, cyanotic congenital heart disease and/or heart failure, or chronic lung
disease.43,44 For the preterm infant, one must keep in mind that the risks of hypovo-
lemia, hypotension, acidosis, and postoperative apnea may be amplified in the setting
of operative blood loss and anemia.

Platelet Concentrates
Transfusion of platelet concentrates, whether in the form of single whole blood plate-
lets, pooled platelet units, or apheresis units, is designed to increase the platelet
volume, which is necessary for primary hemostasis. Consensus committees have
reviewed platelet concentrate use and report similar guidelines: generally, platelet
counts less than 50  109/L will require platelet transfusion in the perioperative period,
whereas platelet counts greater than 100  109/L usually do not.8,45 Within that range,
the decision to transfuse platelets depends on the patient’s underlying condition, prior
platelet transfusions, surgical bleeding, and all other factors that may affect platelet
function and turnover. Procedure-related effects (eg, CPB) may warrant even higher
transfusion thresholds. Consideration of medication effects on platelet function may
also encourage higher thresholds in the setting of surgical bleeding, especially for
patients still on aspirin or nonsteroidal antiinflammatory medications. Sevoflurane
and propofol have demonstrated platelet inhibition properties in vitro that may show
to be deleterious in vivo and therefore may play a role in the decision to transfuse
platelets.46

Fresh Frozen Plasma and Cryoprecipitate

Transfusion of FFP in the setting of coagulation is designed to increase primary
clotting factors in the blood, whereas cryoprecipitate is designed to increase fibrin-
ogen levels and factor VIII and vonWillebrand factor, all of which are necessary for
normal clotting function. The guidelines for FFP transfusion state that generally FFP
is indicated when correcting microvascular bleeding in the presence of a prothrombin
time greater than 1.5 times normal or an international normalized ratio over 2.0.42 It
may also be necessary for acute warfarin reversal or heparin resistance (antithrombin
III deficiency).
Cryoprecipitate transfusion is considered appropriate with fibrinogen counts less
than 100 mg/dL in the presence of microvascular bleeding. It may also be useful in
patients with vonWillebrand disease, where specific concentrates are unavailable
 Blood Conservation Strategies 347

for treatment. Transfusion of cryoprecipitate may be necessary at higher fibrinogen

levels, when bleeding persists despite replacement of both FFP and platelets.

Transfusion Algorithms
Implementation of algorithms based on guidelines for transfusion thresholds have
shown a reduction in blood replacement in some settings. Mallett and colleagues,47
in an audit of their transfusion practices, revealed that there were several instances
where blood transfusion was instituted with hemoglobin levels greater than 10 g/dL.
After implementing a simple protocol of measuring a hemoglobin concentration
before transfusion coupled with a transfusion algorithm based on patient ASA
status, they demonstrated a 43% reduction in red cell transfusions for several types
of noncardiac surgery, with no change in outcomes. In another study by Brevig and
colleagues,48 the use of a Blood Conservation Coordinator, whose job was to opti-
mize cardiac patients’ preoperative conditions, especially anemia (eg, checking iron
stores), led to a decrease in red cell transfusions from 43% to 18% during
a 4-year period. Conservation techniques were not only limited to preoperative
optimization but were also coupled with standardization of surgical and postopera-
tive techniques. Modifying variable transfusion practices based on reasonable
thresholds for transfusion of blood products should remain a significant blood
conservation strategy.

Recombinant Factor VIIa

Recombinant activated factor VIIa (NovoSeven; Novo Nordisk, Copenhagen,
Denmark) is a drug approved for use in patients bleeding from complications of hemo-
philia. It is increasingly being used ‘‘off-label’’ for the treatment of acute hemorrhage
resulting from non-hemophilia–related events, such as surgery and trauma. It remains
attractive for these indications because of its supposedly ‘‘local’’ response to
bleeding. Normally, activated factor VII (VIIa) interacts with exposed tissue factor
(TF) at endothelial disruption sites, creating a complex that readily converts factor X
to its activated form, which serves to convert prothrombin to thrombin, the main
substance needed for clot formation. The recombinant form of factor VII (rVIIa) acts
in the same way as endogenous VIIa, leading to significant thrombin generation.
Therefore, it needs to complex with exposed TF to initiate its effects of thrombin
formation. Because of its ‘‘supposed’’ local response, complications rates of throm-
boembolism have been considered to be low by many. However, there remain very
few data to support this notion, because most of its off-label use has been reported
in case reports and retrospective reviews in adult populations.
Despite the scarcity of data, one can hypothesize how rVIIa could potentially serve
as a means for improved blood conservation. Jen and Shew49 report their review of 32
nonhemophiliac infants who received rVIIa at their institution in critical bleeding situa-
tions. They demonstrated a significant reduction in red cell transfusion during the
8 hours after receiving rVIIA by around 36 mL/kg compared with the previous 8 hours.
They also showed significant reductions in platelet and cryoprecipitate transfusions.
Although none of the patients in their group who required extracorporeal circulation
support had any signs of clots, there were 4 other patients of the 32 (13%) who did
have ‘‘spontaneous’’ thromboembolism complications after receiving rVIIa. However,
they claimed it was not related to the number or size of the doses. The overall survival
of the 32 patients was around 34%.
In one of the few randomized controlled trials that compared rVIIa in its off-label
use in pediatrics, Ekert and colleagues50 looked at its usefulness in infant cardiac
surgery patients to significantly reduce blood usage. As opposed to the previous
348 Verma et al

study that looked at critically ill patients with significant ongoing bleeding, this study
chose patients at risk of bleeding and chose to use rVIIa prophylactically. Doses of
rVIIa were given after patients separated from cardiopulmonary bypass and had
been reversed from the effects of heparin with protamine. In this study, there were
no differences in the amount of red cell or platelet transfusions. Despite a significantly
decreased prothrombin time in the rVIIa group compared with placebo, the time to
chest closure was actually longer in the rVIIa group. The case reports and retrospec-
tive studies certainly suggest rVIIa as potentially playing a role in blood conservation
for certain situations in pediatrics; however, this randomized study keeps the debate
open.

THE CARDIAC PATIENT

Patients undergoing congenital cardiac surgery represent a unique population with

regards to blood conservation. Certainly, most of the techniques described thus far
in this review apply to this population; however, there are aspects of these surgeries
that bear further mention. One of the unique aspects of these cases is the use of CPB
to facilitate surgical exposure and repair. A consequence of CPB is the requirement for
anticoagulation to prevent clots forming in the CPB pump. Heparin is the predominant
anticoagulant during CPB; however, patients with allergy or immune reactions to
heparin will require the use of direct thrombin inhibitors. One of the benefits of heparin
is that there is an agent to ‘‘reverse’’ its effects, namely protamine, which is not the
case with direct thrombin inhibitors. Furthermore, CPB also has systemic effects
that essentially disrupt the normal regulatory pathways of coagulation. The mecha-
nism of this disruption is still under debate and is clearly multifactorial in nature.
Much of the research into the mechanisms of blood loss in these surgeries has
centered on specific interventions, such as using antifibrinolytic agents, using biocom-
patible surfaces in the CPB pump tubing to reduce activation of hemostatic
processes, reducing the reinfusion of shed blood during the surgery, and reducing
the degree of hemodilution (especially true for children), to name a few. It is becoming
clearer that combining several of these interventions may be necessary to significantly
affect bleeding and promote blood conservation.51

SUMMARY

There is little doubt that management of bleeding in the neonate, infant, or child
presents its own set of dilemmas and challenges. One of the primary problems that
perioperative pediatric physicians have to deal with is the lack of good scientific
evidence regarding the best management strategies for children rather than for adults;
this scenario is unlikely to change dramatically in the near future. This leaves us reliant
on extrapolated adult data, and we are all too aware that children are not just small
adults.
The key to success in the predicament is firstly to ensure that the physician has
a clear understanding of the underlying normal physiology of the young child’s
hematologic status. Then by adding knowledge of the abnormal pathology that is
being presented, the physician can at least understand what anomalies he or she is
facing. Once all the available information has been well digested—concerning the
patient’s clinical condition and the options available—a multidisciplinary approach
allows the optimal use of all available resources. Good teamwork, understanding,
and communication between all vested parties allows for a synergistic relationship
to enhance patient care and to give the best available end result.
 Blood Conservation Strategies 349

REFERENCES

1. Ferraris VA, Ferraris SP, Saha SP, et al. The Society of Thoracic Surgeons & the
Society of Cardiovascular Anesthesiologists. Perioperative blood transfusion
and blood conservation in cardiac surgery: clinical practice guideline. Ann
Thorac Surg 2007;83:S27–86.
2. Goodnough LT, Shander A, Breccher ME. Transfusion medicine: looking to the
future. Lancet 2003;361:161–9.
3. AuBuchon JP, Birkmeyer JD, Busch MP. Safety of the blood supply in the United
States: opportunities and controversies. Ann Intern Med 1997;127:904–9.
4. Bilgin YM, van de Watering LM, Eijsman L, et al. Double-blind randomized
controlled trial on the effect of leukocyte-depleted erythrocyte transfusions in
cardiac valve surgery. Circulation 2004;109:2755–60.
5. Siliman CC, Paterson AJ, Dickey WO, et al. The association of biologically active
lipids with the development of transfusion-related acute lung injury: a retrospec-
tive study. Transfusion 1997;37:719–26.
6. Weldon CB. Blood conservation in pediatric anesthesia. Anesthesiol Clin North
America 2005;23:347–61.
7. Hume HA, Limoges P. Perioperative blood transfusion therapy in pediatric
patients. Am J Ther 2002;9:396–405.
8. Gibson BE, Todd A, Roberts I, et al. The British Committee for Standards in Hae-
matology. Transfusion guidelines for neonates and older children. Br J Haematol
2004;124:433–53.
9. McEwan A. Aspects of bleeding after cardiac surgery in children. Paediatr
Anaesth 2007;17:1126–33.
10. Williams MD, Chalmers EA, Gibson BE. The investigation and management of
neonatal haemostasis and thrombosis. Br J Haematol 2002;119:295–309.
11. Monagle P, Michelson A, Bovil E, et al. Antithrombotic therapy in children. Chest
2001;119(1 Suppl):344S–70S.
12. Goodnough LT, Shander AS. Recombinant factor VIIa: safety and efficacy. Curr
Opin Hematol 2007;14(5):504–9.
13. Jadhav MN, Lobdell D, Stanitski D, et al. Use of preoperative erythropoietin in
children undergoing major surgery to reduce the need for allogenic blood trans-
fusions [abstract]. Pediatr Res 1998;43(2 Suppl):134.
14. Meara JG, Smith EM, Harshbarger RJ, et al. Blood-conservation techniques in
craniofacial surgery. Ann Plast Surg 2005;54:525–59.
15. Auer IK. The role of pharmacologic agents in blood conservation. AACN Clin
Issues 1996;7:260–76.
16. Streitz SL, Hickey PR. Cardiovascular physiology and pharmacology in children:
normal and diseased pediatric cardiovascular systems. In: Cote, Ryan, Todres,
editors. A practice of anesthesia for infants and children. 2nd edition. Philadel-
phia: WB Saunders; 1993. p. 271–89.
17. Murto KT, Splinter WM. Perioperative autologous blood donation in children.
Transfus Sci 1999;21:41–62.
18. Longatti PL, Paccagnella F, Agostini S, et al. Autologous hemodonation in the
corrective surgery of craniostenosis. Childs Nerv Syst 1991;7:40–2.
19. Letts M, Perng R, Luke B, et al. An analysis of a preoperative pediatric autologous
blood donation program. Can J Surg 2000;43(2):125–9.
20. Friesen, Perryman KM, Weigers KR, et al. A trial of fresh autologous whole blood
to treat dilutional coagulopathy following cardiopulmonary bypass in infants.
Paediatr Anaesth 2006;16(4):429–35.
350 Verma et al

21. Pouliquen-Evrard M, Mangin F, Pouliquen JC, et al. Autotransfusion and hemodi-

lution in orthopaedic surgery in children. Rev Chir Orthop Reparatrice Appar Mot
1981;67:609–15.
22. Hans P, Collin V, Bonhomme V, et al. Evaluation of acute normovolemic hemodi-
lution for surgical repair of craniosynostosis. J Neurosurg Anesthesiol 2000;12(1):
33–6.
23. Goodnough LT, Mont TG, Sicard G, et al. Intraoperative salvage in patients under-
going elective abdominal aortic aneurysm repair; an analysis of cost and benefit.
J Vasc Surg 1996;24:213–8.
24. Nicolai P, Leggetter PP, Glithero PR, et al. Autologous transfusion in acetobulo-
plasty in children. J Bone Joint Surg Br 2004;86:110–2.
25. Jimenez DF, Barone CM. Intraoperative autologous blood transfusion in the
surgical correction of craniosynostosis. Neurosurgery 1995;37:1075–9.
26. Fearon JA. Reducing allogeneic blood transfusions during pediatric cranial vault
surgical procedures: a prospective analysis of blood recycling. Plast Reconstr
Surg 2004;113:1126–30.
27. Gibson PR. Anaesthesia for correction of scoliosis in children [Review]. Anaesth
Intensive Care 2004;32(4):548–59.
28. Salem MR, Wong AY, Bennett EJ, et al. Deliberate hypotension in infants and chil-
dren. Anesth Analg 1974;53:975.
29. Diaz JH, Lockhart CH, et al. Deliberate hypotension for craniectomies in infancy.
Br J Anaesth 1979;51:233.
30. Dolman RM, Bentley KC, Head TW, et al. The effect of hypotensive anesthesia on
blood loss and operative time during Le Fort I osteotomies. J Oral Maxillofac Surg
2000;58(8):834–9.
31. Fergusson DA, He bert PC, Mazer CD, et al. A comparison of aprotinin and lysine
analogues in high-risk cardiac surgery. N Engl J Med 2008;358(22):2319–31.
32. Available at: http://www.fda.gov/CDER/DRUG/infopage/aprotinin/default.htm.
Accessed May, 2008.
33. Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic acid and
tranexamic acid in pediatric cardiac surgery. J Cardiothorac Vasc Anesth 2004;
18(2):141–3.
34. Senthna NF, Zurakowski D, Brustowicz RM, et al. Tranexamic acid reduces intra-
operative blood loss in pediatric patients undergoing scoliosis surgery. Anesthe-
siology 2005;102:727–32.
35. Neilipovitz DT, Murto K, Hall L, et al. A randomized trial of tranexamic acid to
reduce blood transfusion for scoliosis surgery. Anesth Analg 2001;93:82–7.
36. Tzortzopoulou A, Cepeda MS, Schumann R, et al. Antifibrinolytic agents for
reducing blood loss in scoliosis surgery in children. Cochrane Database Syst
Rev 2008;3:CD006883.
37. Burnouf T, Radosevich M, Goubran HA. Local hemostatic blood products: fibrin
sealant and platelet gel. Treatment of Hemophilia 2004;36:1–7.
38. Kavakli K, Kurugol Z, Goksen D, et al. Should haemophiliac patients be circum-
cised? Pediatr Hematol Oncol 2000;17(2):149–53.
39. Phillips NF, Berry EC, Kohn ML et al. Room technique; 2003. p. 123.
40. Chadd MA, Gray OP. Hypothermia and coagulation defects in the newborn. Arch
Dis Child 1972;47(255):819–21.
41. Doufas AG. Consequences of inadvertent perioperative hypothermia. Best Pract
Res Clin Anaesthesiol 2003;17:535–49.
42. American Society of Anesthesiologists Task Force on Perioperative Blood
Transfusion and Adjuvant Therapies. Practice guidelines for perioperative blood
 Blood Conservation Strategies 351

transfusion and adjuvant therapies: an updated report by the American Society of

Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant
Therapies. Anesthesiology 2006;105(1):198–208.
43. Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red
blood cell transfusions: developed by the Red Blood Cell Administration Practice
Guideline Development Task Force of the College of American Pathologists. Arch
Pathol Lab Med 1998;122(2):130–8.
44. Gibson BE, Todd A, Roberts I, et al. Transfusion guidelines for neonates and older
children. Br J Haematol 2004;124(4):433–53.
45. Samama CM, et al. Perioperative platelet transfusion: recommendations of the
Agence française de se curite
 sanitaire des produits de sante  (AFSSaPS) 2003.
Can J Anaesth 2005;52(1):30–7.
46. Dogan IV, Ovali E, Eti Z, et al. The in vitro effects of isoflurane, sevoflurane, and
propofol on platelet aggregation. Anesth Analg 1999;88(2):432–6.
47. Mallett SV, Peachey TD, Sanehi O, et al. Reducing red blood cell transfusion in
elective surgical patients: the role of audit and practice guidelines. Anaesthesia
2000;55(10):1013–9.
48. Brevig J, McDonald J, Zelinka ES, et al. Blood transfusion reduction in cardiac
surgery: multidisciplinary approach at a community hospital. Ann Thorac Surg
2009;87(2):532–9.
49. Jen H, Shew S. Recombinant activated factor VII use in critically ill infants with
active hemorrhage. J Pediatr Surg 2008;43(12):2235–8.
50. Ekert H, Brizard C, Eyers R, et al. Elective administration in infants of low-dose
recombinant activated factor VII (rFVIIa) in cardiopulmonary bypass surgery for
congenital heart disease does not shorten time to chest closure or reduce blood
loss and need for transfusions: a randomized, double-blind, parallel group,
placebo-controlled study of rFVIIa and standard haemostatic replacement
therapy versus standard haemostatic replacement therapy. Blood Coagul Fibri-
nolysis 2006;17(5):389–95.
51. Eisses MJ, Seidel K, Aldea GS, et al. Reducing hemostatic activation during
cardiopulmonary bypass: a combined approach. Anesth Analg 2004;98(5):
1208–16.