Pediatric Anesthesia ISSN 1155-5645

REVIEW ARTICLE

Blood transfusion risks and alternative strategies in

pediatric patients
Josée Lavoie
Director of Pediatric Cardiac Anesthesia, McGill University, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec,
Canada

Keywords
blood transfusion; transfusion-related risks;
blood conservation; pediatric anesthesia;
acute normovolemic hemodilution;
autologous blood donation
Correspondence
Josée Lavoie, Associate Professor, McGill
University, Director Pediatric Cardiac
Anesthesia, Montreal Children’s Hospital,
McGill University Health Center, 2300
Tupper St, Montreal, Quebec H3H 1P3,
Canada
Email: josee.lavoie@muhc.mcgill.ca
Section Editor: Jerrold Lerman
Accepted 11 October 2010
doi:10.1111/j.1460-9592.2010.03470.x
Summary
Although the safety of the blood supply has been greatly improved, there
still remain both infectious and noninfectious risks to the patient. The inci-
dence of noninfectious transfusion reactions is greater than that of infec-
tious complications. Furthermore, the mortality associated with
noninfectious risks is significantly higher. In fact, noninfectious risks
account for 87–100% of fatal complications of transfusions. It is concern-
ing to note that the majority of pediatric reports relate to human error
such as overtransfusion and lack of knowledge of special requirements in
the neonatal age group. The second most frequent category is acute trans-
fusion reactions, majority of which are allergic in nature. It is estimated
that the incidence of adverse outcome is 18:100 000 red blood cells issued
for children aged less than 18 years and 37:100 000 for infants. The com-
parable adult incidence is 13:100 000. In order to decrease the risks asso-
ciated with transfusion of blood products, various blood-conservation
strategies can be utilized. Modalities such as acute normovolemic hemodi-
lution, hypervolemic hemodilution, deliberate hypotension, antifibrinolytics,
intraoperative blood salvage, and autologous blood donation are discussed
and the pediatric literature is reviewed. A discussion of transfusion triggers,
and algorithms as well as current research into alternatives to blood trans-
fusions concludes this review.

services, finance, people, and ideas across international

Introduction
Current infectious risks associated with blood transfu-
sions have decreased significantly over the last 2 dec-
ades. This is in part because of the introduction of
nucleic acid testing (NAT). This modality has contrib-
uted to earlier detection of infectious agents and has
considerably decreased the window of nondetection of
viral agents such as HIV and HCV. Improved donor
screening has also aided in reducing infection rates.
However, the blood supply is not exempt from new,
emerging as yet unidentified infectious agents. Globali-
zation is also affecting usual national patterns of infec-
tion. The World Health Organisation defines
globalization as ‘the increased interconnectedness and
interdependence of people and countries, … generally
understood to include two interrelated elements: the
opening of borders to increasingly fast flows of goods,
borders; and the changes in institutional and policy
regimes at the international and national levels that
facilitate or promote such flows’. Globalization confers
both positive and negative elements. Positive elements
consist of networking and the exchange of informa-
tion. A negative element might be the spread of infec-
tions.
Significant noninfectious risks are also associated
with blood-product transfusions. Potentially fatal com-
plications such as transfusion-related acute lung injury
(TRALI) are well recognized and better defined.
Hemolytic and nonhemolytic transfusion reactions,
allergic reactions, clerical errors, transfusion-related
circulatory overload (TACO), alloimmunization and
immunomodulation are only some of the noninfectious
complications associated with transfusion of blood
products.

14 Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd

J. Lavoie
These risks serve as an impetus to utilize blood-spar-
ing strategies perioperatively. These strategies include
autologous predonation, hemodilution, deliberate
hypotension, antifibrinolytics, and transfusion algo-
rithms. Research into the development of nonblood
oxygen carriers is on going but has been fraught with
difficulties. One promising venue lies in the fascinating
possibilities of stem cell research.
In this review, the infectious and noninfectious risks
of blood-product transfusions will be defined. Alterna-
tives to allogeneic blood transfusions (ABT), blood
conservation methods, will be provided with an
emphasis on feasibility in the pediatric population. A
discussion of transfusion triggers and algorithms as
well as current research into alternatives to blood
transfusions concludes this review.
Risks of blood-product transfusions
Mortality
According to hemovigilance records from various
countries, mortality associated with transfusions has
decreased greatly over the last 2 decades. The three
main causes of mortality are TRALI, TACO, and
hemolytic transfusion reactions (HTR). Table 1 sum-
marizes the complication categories associated with
fatalities in Canada, France, the United Kingdom, and
the United States. In the Canadian province of Que-
bec, the hemovigilance system was instituted in 2000.
In 2007, there were seven deaths attributed to trans-
fusions of labile blood products (LBP) corresponding
to a rate of two per 100 000 blood products transfused
(1). One death was attributable to TRALI and the
other deaths to TACO. Transfusion of stable blood
products did not result in any mortality. In France,
Table 1 Transfusion-related mortality by complication categories
Canada (Quebec)
Complication 2007 N = 7
TRALI 1 (14%)
HTR
non-ABO
ABO
TACO 6 (86%)
TTI
Anaphylaxis
Inappropriate and unnecessary transfusion
Acute transfusion reaction
Post-transfusion purpura
Other
HTR, hemolytic transfusion reaction; TACO, Transfusion associated circulatory overload; TRALI, Transfusion-related acute lung injury;
TTI, transfusion-transmitted infection.
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
Pediatric transfusion risks and alternatives
eight deaths were reported to the hemovigilance Com-
mittee; however, only four were deemed highly imputa-
ble to transfusion (one TRALI, one allergy, one
hemolytic transfusion reaction, and one post-transfu-
sion purpura) (2). Two more deaths associated with
volemic overload were possibly related to transfusion.
In the United Kingdom, data from the Serious
Hazards of Transfusion (SHOT) annual report of 2009
relates 13 deaths attributable to transfusions: two
TRALI, four TACO, three hemolytic transfusion reac-
tions (HTR), one acute transfusion reaction, one trans-
fusion-transmitted bacterial infection, and two
inappropriate and unnecessary transfusions (3). In the
United States, there were 44 transfusion-related fatal-
ities reported to the FDA in 2009 (4). A further 22
fatalities were reported where transfusion could not be
ruled out as the cause of death. TRALI accounted for
the highest mortality, followed by hemolytic transfu-
sion reactions, TACO, and sepsis. Transfusion-related
mortality has been decreasing in the United States
since 2005 where 62 fatalities were reported. Over that
5-year span, TRALI was accountable for close to half
(48%) of the fatalities, followed by HTR (26%), sepsis
(12%), and TACO (11%). Reports of TACO have
increased significantly over the 5-year span (1–12).
Infectious risks
The transfusion risks for human immunodeficiency
virus (HIV), hepatitis B virus (HBV), hepatitis C virus
(HCV), and human T-lymphotropic virus (HTLV) are
extremely low. Table 2 illustrates the relative risks of
contracting these agents (5–8). Enhancements in test
sensitivity, such as nucleic acid testing (NAT), have
been introduced in the last decade and have allowed a
France 2009 United Kingdom United States
N=4 2009 N = 13 2009 N = 44
1 2 (15%) 13 (30%)
3 (23%) 12 (27%)
1 8 (18%)
1 3 4 (9%)
4 (31%) 12 (27%)
1 (8%) 5 (11%)
1 1 (2%)
2 (15%)
1 (8%)
1
1 (2%)
15
Pediatric transfusion risks and alternatives
Table 2 Residual risk of infections
United Kingdom
Infectious agent 2006–2008 Overall risk 1 in
HBV 0.9 million donations
HCV 71.9 million donations
HIV 1&2 5.4 million donations
HTLV 1 23.9 million donations
HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HTLV, Human T-lymphotropic virus.
reduction of the window period (9). However, the
blood supply is not sheltered from the emergence of
new and as yet undescribed infectious agents. Emer-
gent infections are defined as that whose incidence in
humans have increased within the past two decades or
threatens to increase in the near future. Examples of
emergent agents and infections are West Nile Virus,
vCJD, Babesia, Chagas disease, Malaria, and Dengue.
Global warming with its inevitable environmental
impact, globalization, increased mobility of popula-
tions and appearance of resistant strains are some of
the factors that may contribute to the emergence of
new agents.
In the UK, a cumulative analysis of the SHOT data
from 1996 to 2009 revealed that bacterial contamina-
tion accounted for more than half of total transfusion-
transmitted infections (TTI) (40/66) and is associated
with a high mortality rate (27,5%) (3). Bacterial con-
tamination is the major cause of TTI mortality (73%).
Bacterial contamination results mainly from skin con-
taminants at the time of phlebotomy. Improved blood
product screening (especially platelets which are stored
at room temperature) and aseptic phlebotomy techni-
que have been implemented in the last decade to
decrease the risk of bacterial contamination.
Pathogen inactivation/reduction technologies (PIT).
Pathogen reduction/inactivation technologies consists
in exposing blood or blood components to chemicals
Table 3 Noninfectious risks of blood product transfusions
Immune-mediated
Transfusion-related acute lung injury
Transfusion-associated dyspnea
Hemolytic transfusion reaction
Febrile nonhemolytic transfusion reaction
Allergic/urticarial/anaphylactic transfusion reactions
Nonimmune mediated
Transfusion-associated circulatory overload
Over/undertransfusion
Incorrect blood component transfused
Metabolic derangements
16
J. Lavoie
Canada 2001–2005 United States 2006–2008 (HBV)
Overall risk 1 in 2007–2008 (HCV, HIV)
153 000 280 000
2.3 million 1149 million
7.8 million 1467 million
4.3 million
that will interact with nucleic acids of infectious agents
thus selectively inactivating these agents while preser-
ving the transfusion product. Leukocytes are usually
inactivated during the process. UV light is often uti-
lized in addition to chemical solutions in PIT. Patho-
gen inactivation technologies are highly effective in
inactivating a broad range of viruses, parasites, and
bacteria. However, bacterial spores are generally resis-
tant to PIT, and prions cannot be inactivated by PIT.
Pathogen inactivation technologies for plasma are in
widespread use in many countries (10). However,
although PIT for platelets has been implemented in
some European countries, these have yet to be
approved in North America (11). Although no direct
toxicity of the PIT chemicals has been demonstrated,
damage to some transfusion products such as reduced
platelet recovery and survival has been observed.
Noninfectious risks
The incidence of noninfectious transfusion reactions is
greater than that of infectious complications (Table 4)
(1). Furthermore, the mortality associated with nonin-
fectious risks is significantly higher (1–4). In fact, non-
infectious risks account for 87–100% of fatal
complications of transfusions (Table 1). These risks
can be broken down into immune and nonimmune-
mediated categories (Table 3). The better-known
immune mediated noninfectious risks are HTR, febrile
Post-transfusion purpura
Alloimmunisation
Transfusion-associated graft versus host disease
Transfusion-related immunomodulation
Microchimerism
Coagulopathic complications of massive transfusion
Complications from red cell storage lesions
Iron overload
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J. Lavoie
Table 4 Incidence of transfusion accidents in 2007, Quebec hemo-
vigilance annual report (labile blood products) n = 2294 accidents
Reaction N %
Febrile nonhemolytic transfusion reaction 742
Minor Allergic reactions 549
Delayed serologic reaction 118
TACO 117
Major allergic reaction 33
Wrong product administered 39
Hemolytic transfusion reaction 28
TRALI 7 0.34
TAD 6 0.3
Hypertension 26
Hypotension 17
Vagal shock 6 1.3
Bacterial contamination 0 –
Unknown 16
Subtotal 1659
Procedure errors 635
nonhemolytic reactions and TRALI. TACO and
incorrect blood component transfusion constitute the
most common nonimmune-mediated complications
(Table 4). An exhaustive discussion of noninfectious
risks of transfusions is beyond the scope of this chap-
ter; a selection of the most significant risks will be dis-
cussed. The reader is referred to an excellent recent
review on the subject (12).
Transfusion-related acute lung injury (TRALI). Trans-
fusion-related acute lung injury is defined as new acute
lung injury (ALI) occurring during or within 6 h after
a transfusion, with a clear temporal relationship to
transfusion, in patients without or with risk factors for
ALI other than transfusion (13). The pathophysiology
of TRALI is postulated to be white blood cell (WBC)
alloantibody-mediated. The implicated donor antibo-
dies cause noncardiogenic pulmonary edema by attack-
ing the recipient’s WBC in the lung’s microcirculation.
The clinical manifestation mirrors that of respiratory
distress syndrome. Another theory to explain the
development of TRALI in the absence of antibodies is
the priming of neutrophils by surgical insult or trauma
(14). These neutrophils adhere to the endothelium.
Mediators in transfused plasma activate the neutro-
phils to produce a cascade leading to capillary leak
and ALI. Historically, fresh frozen plasma has been
the product most frequently implicated in TRALI.
Most implicated donors have been multiparous women
because pregnancy can result in alloimmunization. As
such, in order to reduce the risk of TRALI, fresh fro-
zen plasma and single-donor platelets are now col-
lected exclusively from male donors or women without
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
Pediatric transfusion risks and alternatives
a history of pregnancy. In 2006, the American Red
Cross (ARC) started preferential distribution of
plasma from male donors for transfusion. The percen-
tage of plasma from male donors increased from 55%
32.3 in 2006 to 85% in 2008. An analysis of TRALI cases
23.9
reported to the ARC revealed that TRALI involving
5.1
5.1
plasma transfusions was significantly reduced in 2008
1.4 compared to 2006 (7 vs 32 cases) (15).
1.7
1.2 Transfusion-associated circulatory overload (TACO).
There is an increasing incidence of TACO, a poten-
tially avoidable complication. This is not an antibody-
1.1
related phenomenon. The Quebec hemovigilance
0.7
system reported 6 of seven deaths as a result of TACO
in 2007 (1). In France, the incidence of TACO was
0.7 compared between the 2000–2004 and the 2005–2009
72.3 periods (2). The incidence of TACO increased from
27.7 1.97 to 2.82 events per 100 000 LBP transfused. In the
2009 SHOT report, there was an 89% increase in the
number of cases reported compared to 2008 (34 vs 18
in 2008) (3). The associated mortality rate was 12%.
There have been no pediatric cases reported either by
the Quebec hemovigilance system or the SHOT.
Hemolytic transfusion reactions (HTR). HTR are
caused by the presence of a pre-existing antibody in
the recipient, usually immunoglobulin M. The symp-
toms are nonspecific and are characterized by fever,
chills, rigors, chest and abdominal pain, dyspnea,
hypotension, hemoglobinuria, and diffuse bleeding.
Nonimmune-mediated hemolysis may occur secondary
to bacterial contamination, malfunctioning blood war-
mer, infusion through a small-bore intravenous cathe-
ter or mixing with a solution other than normal saline.
Febrile nonhemolytic transfusion reactions. Febrile non-
hemolytic reactions constitute an exclusion diagnosis.
Other causes of fever such as sepsis and hemolysis
must be ruled out. These reactions are defined as a
1C rise in temperature into the febrile range during or
soon after a transfusion. Leukoreduction has contribu-
ted to decreasing the incidence of febrile nonhemolytic
transfusion reactions. In France, the rate of all transfu-
sion reactions decreased from 0.49 to 0.31% after
introduction of leukoreduction (16). The greatest
reductions concerned febrile nonhemolytic transfusion
reactions and allergic reactions.
Alloimmunization. Patients exposed to multiple transfu-
sions may develop alloantibodies to donor antigens.
Alloimmunization against red blood cells or platelets
can result in acute or delayed hemolytic transfusion
reactions; refractoriness to platelet transfusion, post-
17
Pediatric transfusion risks and alternatives
transfusion purpura, febrile nonhemolytic transfusion
reactions, TRALI, transplant rejection, and neonatal
alloimmune thrombocytopenia.
The consequences of alloimmunization in pediatric
patients are long lasting and may be quite significant.
Patients requiring multiple transfusions may develop
antibodies that will make future crossmatching for
blood transfusions or for transplantation very difficult.
Future pregnancies may also be affected as well.
Metabolic derangements. These complications of trans-
fusions include hypothermia, hyperkalemia, and citrate
toxicity. Hyperkalemia is caused by red blood cell
leakage during storage and is greater in blood stored
for a longer period of time. In order to avoid hyperka-
lemia in transfused patients, many blood banks have
policies to issue blood that is <5 days old to neonates
or to patients who will require massive transfusions.
Citrate toxicity leading to hypocalcemia will manifest
in the infant as hypotension, hypomagnesemia, tetany,
and arrhythmias. Hypothermia can be detrimental to
pediatric homeostasis in many ways, as it can increase
the cardiac toxicity of hypocalcemia and hyperkalemia
and contribute to coagulopathy.
Transfusion-related immunomodulation (TRIM). Trans-
fusion of allogenic blood has been associated with
modulation of the recipient’s immune responses. This
phenomenon is not new and was first reported in 1973
by Opelz who observed that renal transplant patients,
who had received pretransplant allogenic blood trans-
fusions, had improved allograft kidney survival (17).
Furthermore, allogenic blood transfusions have been
purported to reduce the risk of recurrent spontaneous
abortions in women with shared HLA antigens with
the father of the fetus as well as to decrease the recur-
rence rate of Crohn’s disease.
Of concern is the mounting literature on increased
cancer recurrence rates postulated to be secondary to
the decreased immunity conveyed by allogeneic blood
transfusions. The decrease in immunity might enhance
the formation of metastasis. As well, ABT has been
associated with the activation of latent, endogenous
CMV or HIV infection. In a recent case–control study
on patients with hematologic malignancies, a history
of allogeneic blood transfusion was associated with an
increased risk for lymphoplasmacytic and marginal
zone lymphomas (18). Equally concerning is the
observed increased rate of postoperative bacterial
infection in surgical patients receiving allogeneic blood
transfusions. With the implementation of universal
WBC reduction, this risk might be decreased. Vamva-
kas conducted a meta-analysis of randomized control
18
J. Lavoie
trials (RCT) comparing recipients of leukoreduced vs.
nonleukoreduced allogeneic blood transfusions. He
found that there was as association of ABT with post-
operative infection across all RCT’s including post-
storage WBC-reduced blood (19). Leukoreduction
performed before storage was not associated with an
increased postoperative infection rate. Van de Water-
ing’s group reported increased short-term mortality in
cardiac surgery patients who received white blood cell
containing (nonleukodepleted) allogenic blood transfu-
sions (20). In an extended analysis of their original
data, the same group concluded that the transfusions
of WBC-containing allogeneic blood transfusions in
cardiac surgical patients might be associated with more
infections with fatal outcome (21).
The exact mechanism of immunomodulation is
unclear. It has been postulated that tissue injury might
be the result of neutrophil priming and endothelial cell
activation caused by mediators in ABT. The two-hit
theory proposes that the first hit is the patient’s under-
lying inflammatory condition, which primes the
patient’s immune system or endothelium. The second
hit, allogeneic blood transfusions, triggers a full-scale
inflammatory activation. Potential mediators are solu-
ble mediators released from WBC’s injured during sto-
rage, soluble HLA peptides in allogeneic plasma and/
or immunologically active allogeneic WBC’s.
Pediatric morbidity and mortality associated with
transfusions
Of the 1279 reports submitted to SHOT in 2009, 8.6%
involved patients <18 years (yr) with 31% of these
from infants <1 yr of age. In this subgroup, 56%
were neonates £4 weeks old (3). It is concerning to
note that the majority of pediatric reports (58%) relate
to human error such as overtransfusion and lack of
knowledge of special requirements especially in the
neonatal age group (irradiation, CMV)). The propor-
tion is even higher for the infant age group, where
error-related reports reached 82%. The second most
frequent category were acute transfusion reactions at
34% of pediatric cases. The majority of these reactions
were allergic. In a cumulative analysis of the 1996 to
2005 SHOT data, Stainsby et al. (22) estimated the
incidence of adverse outcome to be 18:100 000 red
blood cells issued for children aged less than 18 years
and 37:100 000 for infants. The comparable adult inci-
dence is 13:100 000.
The French 2009 hemovigilance report also found
an increased incidence of adverse reactions in children
aged 1–19 years (2). Allergies were more frequent in
the 1–19 years compared to all age groups, whereas
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
J. Lavoie
volemic overload was by far more often observed in
infants.
Alternatives to blood transfusions
In order to decrease the risks associated with transfu-
sion of blood products, a concerted effort must be
made by health-care workers to avoid unnecessary and
inappropriate transfusions as well as overtransfusion.
However, meticulous attention must be given to main-
taining normovolemia. The Pediatric Perioperative Car-
diac Arrest (POCA) registry serves a sobering reminder
that 12% of intraoperative cardiac arrests in children
are secondary to hypovolemia resulting from underesti-
mated blood loss in 50% of cases (23). Furthermore,
strategies to decrease perioperative blood loss and
transfusion algorithms should be implemented. Blood-
conservations strategies include acute normovolemic
hemodilution (ANH), hypervolemic hemodilution,
deliberate hypotension, antifibrinolytics, intraoperative
blood salvage, and preoperative autologous donations
(Table 5). Each of these strategies may be applicable to
the pediatric population albeit with some limitations.
Furthermore, meticulous attention must be given to
surgical technique and positioning of the patient.
Acute normovolemic hemodilution
Acute normovolemic hemodilution consists in the
removal of part of the patient’s blood shortly after
induction of anesthesia. The removed blood is replaced
by a crystalloid or colloid solution to maintain normo-
volemia. A stock of autologous blood is thus available
for later reinfusion.
The blood is kept at room temperature and the
avoidance of cold storage allows for a greater concen-
tration of platelets and clotting factors over banked
blood. Intraoperatively, the blood lost will have a
lower hematocrit and, thus, a smaller red blood cell
mass will be lost. When intraoperative blood loss has
abated, the autologous blood is then transfused back
Table 5 Blood-conservation strategies
Preoperative Intraoperative
Autologous blood donation Hypervolemic hemodilution
Erythropoietin Acute normovolemic hemodilution
Iron supplement Antifibrinolytics
Deliberate hypotension
Intraoperative blood salvage
Surgical technique
Patient positioning
Transfusion algorithm
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
Pediatric transfusion risks and alternatives
to the patient. This technique may be especially useful
in patients with multiple antibodies who are difficult to
crossmatch. Hemodilution leads to decreased viscosity
that improves tissue perfusion by decreasing peripheral
vascular resistance. Decreased peripheral vascular
resistance in turn improves cardiac output through
increased stroke volume.
There have been concerns issued over the safety of
ANH in younger pediatric patients. Concerns purport
to myocardial tolerance to anemia and to the effects of
fetal hemoglobin. Infants may not be able to compen-
sate for anemia by augmenting their stroke volume.
The higher hemoglobin F in infants aged<4–6 months
may be detrimental in situations of dilutional anemia
because of its already decreased ability to unload oxy-
gen to tissues. In a study on the use of ANH in patients
undergoing craniosynostosis repair, patients were ran-
domized to receive ANH or to a control group (24). No
differences were observed between groups with regard
to exposure to homologous blood, the amount of
homologous blood transfused and the hematocrit value
at hospital discharge. However, preoperative hemoglo-
bin values were low in both groups and could account
for these results. Perhaps, preoperative administration
of iron and/or erythropoietin could have palliated this
issue. In pediatrics, ANH has been used mostly in ado-
lescents undergoing scoliosis surgery (25). Most studies
have been performed using a combination of blood con-
servation methods. In a recent retrospective study of 19
Jehovah’ Witness patients undergoing scoliosis surgery,
the combined use of ANH, deliberate hypotension, and
intraoperative cell salvage allowed the completion of
surgery without requirements for homologous blood
transfusions (25). A meta-analysis of 42 randomized
controlled trials compared acute normovolemic hemo-
dilution to usual care or to another blood-conservation
strategy (26). Hemodiluted patients (mostly adults,
some teenagers) were transfused fewer units of allo-
geneic blood; however, the risk of allogeneic transfusion
was similar among all patients. ANH patients had less
total bleeding than patients receiving usual care but had
more intraoperative bleeding. The authors concluded
that the literature supports only modest benefits from
preoperative ANH.
Hypervolemic hemodilution (HH)
Hypervolemic hemodilution is a simple technique that
consists in hemodiluting a patient without blood with-
drawal. It is usually performed by infusing a colloid
solution to a predetermined quantity (approximately
15 mlÆkg)1) or to reach a given hematocrit level
(usually 25%). A mathematical analysis comparing
19
Pediatric transfusion risks and alternatives J. Lavoie

HH, ANH, and no dilution concluded that for blood Antifibrinolytics

losses <40% of estimated blood volume (EBV),
Aprotinin, tranexamic acid, and aminocaproic acid have
ANH, and HH provided almost identical postoperative
all been used in major pediatric surgery as adjuncts to
hematocrits (27). Thus, it would appear that HH being
decrease perioperative blood loss. Aprotinin was with-
simpler to use would be superior for anticipated blood
drawn from the worldwide market in November 2007.
losses below 40% of EBV. A pediatric study of chil-
The withdrawal followed the release of data from the
dren undergoing scoliosis surgery compared the use of
Canadian antifibrinolytic trial Blood conservation using
HH to a control group (28). The HH group received
Antifibrinolytics in a Randomized Trial (BART) (36).
12 mlÆkg)1 Voluven. Intraoperative blood loss was
The 30-day mortality, the incidence of myocardial
similar in both groups. However, HH patients received
infarction, cardiogenic shock, right heart failure, and
significantly less homologous blood replacement (18 vs
the risk of massive blood loss were higher with aprotinin
28 mlÆkg)1). Studies in adult patients have also demon-
than with tranexamic acid or aminocaproic acid. The
strated its efficacy in reducing exposure of patients to
drug remains available under special access programs.
homologous blood (29,30).
Albeit the BART study concerned exclusively high-risk
adult patients, undergoing complex cardiac surgery,
Deliberate hypotension (DH) aprotinin was removed from use in all patient popula-
tions. A recent study of over 12 000 children undergoing
The deliberate induction of hypotension is an older
congenital heart surgery found that aprotinin increased
technique often used in combination with other blood-
neither mortality nor the rate of dialysis (37). Breuer et
conservation techniques. Blood pressure is lowered to
al. (38) also concluded that Aprotinin administration
a predefined mean arterial pressure by using intrave-
did not carry additional risks to the patient when com-
nous agents or inhaled anesthetics leading to decreased
pared to tranexamic acid.
blood loss. A commonly used end point is a mean
Currently, two synthetic antifibrinolytics remain
arterial pressure of 50–60 mmHg. Various agents have
available for use in the pediatric population. They are
been used to induce hypotension such as nicardipine,
the lysine analogs, aminocaproic acid, and tranexamic
esmolol, labetalol, sodium nitroprusside, nitroglycerin
acid. Tranexamic acid produces its effect by competi-
and inhaled anesthetics, including desflurane. Two
tively inhibiting the activation of plasminogen to plas-
excellent reviews of agents used to achieve DH are
min, as well as being a weak inhibitor of plasmin. It is
available (31,32). Short-acting drugs are favoured as
the more potent of the two antifibrinolytics and pos-
they allow rapid restoration of normal blood pressure
sesses a longer half-life. A Cochrane database meta-
with minimal rebound effect.
analysis evaluated the effects of antifibrinolytics on
Much of the experience with DH has been gained in
blood loss during scoliosis surgery in children (39). All
maxillo-facial surgery (33). An often-quoted study is
3 antifibrinolytics (aprotinin, tranexamic acid and ami-
that of Dolman et al. (34) who used DH in young
nocaproic acid) decreased the amount of blood trans-
adult patients undergoing Le Fort 1 osteotomies.
fused by 327.41 ml (95% CI )469.04 to )185.78) and
Patients were randomized to either a normotensive or
the amount of blood loss by 426.53 ml (CI 95%
hypotensive group. Hypotensive anesthesia was asso-
)602.51 to )250.56). The authors recommend using
ciated with reduced blood loss and improved quality
high-dosage regimen, as high doses were used in most
of the surgical field. In children undergoing functional
of the studies reviewed. No adverse effects were found.
endoscopic sinus surgery, DH was induced with either
Sethna et al. (40) used a high-dosage regimen of tra-
total intravenous anesthesia (TIVA) with remifentanil
nexamic acid in a randomized controlled trial of pedia-
and propofol or a balanced anesthesia technique (BA)
tric patients undergoing scoliosis surgery. The authors
with esmolol (35). In this randomized control trial,
used a bolus of 100 mgÆkg)1 followed by an infusion
intraoperative blood loss was less in the TIVA group
of 10 mgÆkg)1Æh)1 during surgery. Estimated blood loss
and the quality of the surgical field was significantly
(EBL) was reduced by 41% in the tranexamic group
better. The mean arterial pressure was maintained at
compared to the placebo group. However, the amount
50 mmHg in both groups.
of blood transfused did not differ between groups.
Deliberate hypotension should not be used in
Another recent meta-analysis on the use of antifibrino-
patients with hypovolemia, elevated intracranial pres-
lytics in major pediatric surgery concluded that tra-
sure or decreased end-organ blood flow. Furthermore,
nexamic acid appeared as effective as aprotinin in
hypocapnia should be avoided as it may decrease cere-
reducing perioperative blood loss and transfusion of
bral blood flow. As well, arterial partial pressure of
blood products (41). The surgeries involved were either
oxygen is best maintained at higher levels.

20 Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd

J. Lavoie
scoliosis or cardiac surgery. Epsilon aminocaproic acid
was used in a retrospective case-controlled study of
patients undergoing neuromuscular scoliosis surgery
(42). Patients in the aminocaproic acid group had sig-
nificantly less blood loss and transfusion requirements.
In congenital heart surgery, a high dose regimen of
tranexamic acid effectively reduced blood loss and
transfusion requirements in cyanotic patients (43).
When compared to aprotinin, it was just as effective.
Intraoperative blood salvage (IABS)
Intraoperative cell salvage systems are commonly used as
a blood-conservation technique. Pediatric sized systems
have been available for some time and consist of down-
sized bowls (as small as 55 ml). It is somewhat difficult
to assess the efficacy of intraoperative blood salvage used
as the sole blood-conservation strategy, as most studies
use a combination of strategies. A Cochrane meta-analy-
sis of trials on the use of IABS in adult patients under-
going cardiac or major orthopedic surgery was recently
published (44). The use of IABS resulted in an absolute
reduction in risk of receiving ABT of 21%.
Most of the pediatric experience has been gained in
scoliosis surgery. In a retrospective case–control study
of patients undergoing posterior spinal fusion, Bowen
et al. (45) found that the use of IABS was associated
with less ABT, especially in surgeries of more than 6 h
duration and EBL superior to 30% EBV. In surgeries
lasting over 6 h, the relative risk of receiving an ABT
was 5.87 in the group without IABS versus 2.04 in the
group using IABS. Cell salvage was also found effective
in reducing ABT and postoperative anemia in patients
undergoing anterior spinal instrumentation (46).
In addition, cell salvage has been used successfully
in craniofacial surgery. Infants undergoing craniosy-
nostosis repair were given preoperative erythropoietin,
and IABS was also used (47). When compared to the
control group, the study group demonstrated a marked
increase in preoperative hematocrit and a significant
reduction in transfusion rates and volumes.
In a systematic review and economic model compar-
ing the effectiveness of blood-conservation strategies,
Davies et al. (48) concluded that IABS was cost-effec-
tive in reducing exposure to ABT. However, the
authors also concluded that ANH might be more cost-
effective than IABS.
Blood recuperated with IABS was analyzed for micro-
biologic contamination in adult patients undergoing
orthotopic liver transplantation (49). In the study,
68.4% of cell-saver blood samples were found to be
positive for micro-organisms. However, none of the
postoperative blood cultures revealed growth of the
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
Pediatric transfusion risks and alternatives
same species. Minute attention to aseptic collection and
processing of salvaged blood should be kept at all times.
Preoperative autologous donations (PAD)
Preoperative autologous donation programs have been
instituted widely to offset the risks of allogeneic blood
and to augment the blood supply. Although PAD con-
tributes to decreasing the incidence of alloimmuniza-
tion, it does not eliminate the risks of clerical errors or
that of bacterial contamination of the blood unit. Most
programs target specific surgical procedures where
blood loss is expected to exceed 20% of the EBV, such
as in scoliosis surgery. Albeit autologous blood dona-
tion has been described in children as young as
6 months, most programs will enroll children starting at
a minimum weight of 20 kg (50). The programs may be
administered by national blood services or at the hospi-
tal level. This results in programs that differ highly
from one hospital to the next with variable inclusion
criteria. After seeing a steady rise in utilization of PAB,
some programs are experiencing a fall of activity
(51,52). Undoubtedly, the administrative structure of
these programs is complex. Furthermore, surgery must
be synchronized with the donations because any delay
might entail loss of the autologous blood.
Nonetheless, PAD programs are being used success-
fully in pediatric patients. Hibino et al. (50) describe
PAD for cardiac surgery in infants and children. While
under light general anesthesia, two donations of
10 mlÆkg)1 each were collected. Transfusion of homo-
logous blood was significantly less in the PAD group
compared to the control group (4.3% vs 44.4%). Lauder
reviewed 17 studies of PAD in children (53). Allogeneic
transfusions were avoided in 63–94% of patients. Only
three studies quoted wastage percentages of autologous
units. Two studies had rates of 15%, whereas 64% of
the autologous units were discarded in the remaining
study. A 2006 study by Bess reported a 31% wastage
rate (54).
A recent study has compared intraoperative blood
salvage to PAD using direct analysis and a validated
model of efficacy (55). Under most conditions, maximal
allowable blood losses (MABL) would have been
greater for patients undergoing intraoperative blood sal-
vage. However, autologous blood donation patients
would tolerate greater MABL if they had a lower initial
hematocrit, if there was a return to baseline hematocrit
or higher before surgery and if a longer time was
allowed between the first donation and surgery.
Compensatory erythropoiesis occurs during the
course of autologous donations. Red blood cell pro-
duction increases with increasing interval from last
21
Pediatric transfusion risks and alternatives
donation to surgery, and this interval should be maxi-
mized. Furthermore, treatment with erythropoietin
during PAD has been shown to increase the amount
of blood collected and decreased ABT during pediatric
heart surgery and spine surgery (56,57). Erythropoietin
has been used to increase hematocrit preoperatively
either alone or as an adjunct to PAD. In a recent
study, neonates undergoing major surgery such as gas-
troschisis, duodenal atresia or congenital diaphrag-
matic hernia repair were randomized to receive either
erythropoietin or placebo for 14 days (58). A strict
transfusion protocol was used. Neonates randomized
to the erythropoietin group demonstrated an increased
absolute reticulocyte count and hematocrit level with-
out adverse effects. Erythropoietin has also been admi-
nistered in conjunction with iron supplements to
increase red blood cell mass prior to ANH in an infant
prior to cardiac surgery (59).
However, in a recent retrospective cohort study of
pediatric patients with neuromuscular scoliosis under-
going anterior and/or posterior spinal instrumentation,
the preoperative use of erythropoietin was not asso-
ciated with a reduction in ABT (60). Erythropoiesis
was stimulated in these patients as demonstrated by
higher preoperative and discharge hematocrits. In a
review of their blood conservation program for spine
surgery, Colomina et al. (61) observed that the use of
preoperative erythropoietin alone allowed for a higher
preoperative hematocrit compared to patients in the
PAD program. Neither group required intraoperative
ABT. The authors also concluded that erythropoietin
improved preoperative autologous blood donations by
minimizing preoperative anemia and increasing the
number of autologous units collected. These findings
were true only in patients with intraoperative blood
losses equal to 50% of their EBV. For EBL around
30% EBV, erythropoietin alone could replace PAD.
In a retrospective review of children (average
12 months) undergoing orbital bar advancement, the
use of preoperative erythropoietin was assessed (62).
Multiple techniques of blood conservation were used
intraoperatively including ANH, hypervolemic
hemodilution, and deliberate hypotension. Patients
receiving preoperative erythropoietin increased their
red cell mass by 28%. These patients were also less
likely to receive an ABT and for those requiring
a transfusion, the volume of blood transfused was less.
Transfusion triggers
The use of transfusion algorithms has been advocated
as a means of reducing allogeneic blood transfusions.
Mallett et al. (63) observed a reduction of 43% ABT
22
J. Lavoie
after implementing a transfusion protocol based on the
use of pretransfusion hemoglobin measurement and a
transfusion algorithm. Restrictive transfusion strategies
have been associated with decreased exposure to
ABT without increasing the incidence of adverse events.
In a randomized trial of 637 critically ill children, a
transfusion threshold of 7 gmÆdl)1 for red blood cell
transfusion was found to decrease transfusion require-
ments by 44% (64). In fact, 54% of patients in the
restrictive-strategy transfusion group received no trans-
fusion compared to only 2% in the liberal-strategy
group. There was no increase in adverse outcome in the
restrictive-strategy group. In two subgroups of pediatric
cardiac surgery and general surgery patients, no new or
progressive multiple organ dysfunction occurred in the
restrictive-strategy group (65,66). In low birth weight
premature infants, the restrictive transfusion strategy
was associated with lower transfusion volumes (27.2 vs
41.7 ml) (67). Furthermore, a transfusion volume
greater that 30 ml was determined to be a risk factor for
the development of chronic lung disease in these infants.
Evidence-based transfusion triggers have been sum-
marized by Morley (68).
Future directions
The development of alternatives to transfusions was
initiated over 50 years ago and has still not come to frui-
tion. Only a few products are currently undergoing phase
III trials (69). Alternatives to blood transfusions can be
grouped into five categories: cell-free hemoglobin-based
oxygen carriers, artificial red cells based on liposomes or
encapsulated in nanoparticles, fluorocarbon-based solu-
tions to dissolve oxygen, a universal red cell (modified
human red cells to inactivate cell type determinants) and
red cells derived from stem cells (69).
Potential adverse effects caused by hemoglobin-
based oxygen carriers include vasoconstriction and
increased pro-coagulant activity associated with NO
scavenging. Oxidative damages caused by an increased
quantity of free radicals have also been described. In
addition, there have been reports of neurotoxicity,
cytokine release as well as vasculitis and thrombosis
secondary to macrophage activation.
Recent advances in stem cell research have provided
interesting perspectives in stem cell–derived erythropoi-
esis. Ex vivo manufacture of red blood cells from stem
cells is the center of active research (70). Human-
induced pluripotent stem cells constitute a potentially
unlimited source of stem cells for erythropoiesis. Cur-
rently, stem cells can produce red cells at a laboratory
level. The difficulty lies in transposing the technology
to a larger scale for mass production.
Pediatric Anesthesia 21 (2011) 14–24 ª 2010 Blackwell Publishing Ltd
J. Lavoie Pediatric transfusion risks and alternatives

more effective than any single modality. No blood-

Conclusion
Despite significant improvement brought to blood
testing and handling, there remain both infectious
and noninfectious risks associated with allogeneic
blood transfusions. Data analysis has demonstrated
that the incidence of adverse events is greater in chil-
dren and especially infants. The long-term repercus-
sions may be significant in the pediatric population.
Blood-conservation modalities can be used safely in
pediatric patients. Combined techniques seem to be
sparing protocol would be complete and efficient
without the use of an evidence-based transfusion
algorithm. Studies have demonstrated that pediatric
patients tolerate lower hemoglobin levels without
incurring adverse events. This evidence-base along
with the patient’s medical condition and planned sur-
gical procedure should be included in the transfusion
decision algorithm. Finally, intense research into man-
ufacture of red blood cells by pluripotent stem cell is
ongoing and promising.

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