Pediatric Anesthesia ISSN 1155-5645

SPECIAL INTEREST ARTICLE

Cyanotic congenital heart disease (CCHD): focus on

hypoxemia, secondary erythrocytosis, and coagulation
alterations
Luis M. Zabala1 & Nina A. Guzzetta2
1 Department of Anesthesiology, University of Texas Southwestern Medical Center - Children’s Health Dallas, Dallas, TX, USA
2 Department of Anesthesiology, Emory University School of Medicine, Children’s Healthcare of Atlanta, Atlanta, GA, USA

Keywords
congenital heart disease; neonate;
coagulation; blood transfusion; heparin;
antifibrinolytic
Correspondence
Luis M. Zabala, Department of
Anesthesiology, Section of Pediatric Cardiac
Anesthesia, Children’s Health Dallas, 1935
Medical District Drive, Dallas, TX 75235,
USA
Email: Luis.zabala@childrens.com
Section Editor: Greg Hammer
Accepted 7 May 2015
doi:10.1111/pan.12705
Summary
Children with cyanotic congenital heart disease (CCHD) have complex alter-
ations in their whole blood composition and coagulation profile due to long-
standing hypoxemia. Secondary erythrocytosis is an associated physiological
response intended to increase circulating red blood cells and oxygen carrying
capacity. However, this response is frequently offset by an increase in whole
blood viscosity that paradoxically reduces blood flow and tissue perfusion. In
addition, the accompanying reduction in plasma volume leads to significant
deficiencies in multiple coagulation proteins including platelets, fibrinogen
and other clotting factors. On the one hand, these patients may suffer from
severe hyperviscosity and subclinical ‘sludging’ in the peripheral vasculature
with an increased risk of thrombosis. On the other hand, they are at an
increased risk for postoperative hemorrhage due to a complex derangement
in their hemostatic profile. Anesthesiologists caring for children with CCHD
and secondary erythrocytosis need to understand the pathophysiology of
these alterations and be aware of available strategies that lessen the risk of
bleeding and/or thrombosis. The aim of this review is to provide an updated
analysis of the systemic effects of long-standing hypoxemia in children with
primary congenital heart disease with a specific focus on secondary erythrocy-
tosis and hemostasis.

a comprehensive and updated review on systemic hypox-

Introduction
The perioperative management of patients with cyanotic
congenital heart disease (CCHD) relies on a clear under-
standing of the underlying anatomic defect and physio-
logic implications. Irrespective of their primary cardiac
lesion, patients with chronic hypoxemia (resulting from
venous to arterial mixing) suffer from a wide variety of
alterations in their hematologic, endothelial, and hemo-
static systems and thus should be recognized as having a
multisystem disorder. It is critical that anesthesiologists
understand and recognize these effects given that hypox-
emia will continue to be a common feature throughout
infancy and early childhood in patients undergoing
staged palliation of their congenital heart disease and
that many of these patients may live well into their third
or fourth decade of life. Thus, our objective is to provide
emia in patients with CCHD with emphasis on second-
ary erythrocytosis as a compensatory mechanism and its
effects on normal hemostasis.
Polycythemia and secondary erythrocytosis
Erythrocytosis is frequently encountered in children
with CCHD and refers to an isolated increase in red
blood cells (RBCs), more specifically an increase in RBC
mass. This is in contrast to the primary polycythemias,
such as polycythemia rubra vera, that result from
factors intrinsic to red cell precursors and are associated
with a marked increase in all three blood cell lines
including RBCs, white blood cells and platelets (leuko-
cytosis and thrombocytosis) (1). Despite the common
finding of an elevated hematocrit, these disorders

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Pediatric Anesthesia 25 (2015) 981–989
Cyanotic congenital heart disease
represent two different entities and thus therapeutic
interventions are specific to each disease state. In
CCHD, long-standing hypoxemia and reduced tissue
oxygenation stimulate erythropoietin (EPO) production
from the kidney causing a secondary erythrocytosis. This
secondary erythrocytosis is an adaptive physiologic
mechanism intended to compensate for inadequate tis-
sue oxygenation. However, in the presence of persistent
and fixed hypoxemia (i.e., from a significant right-to-left
shunt), tissue oxygenation cannot improve beyond a cer-
tain limit. Nevertheless, EPO secretion continues leading
to a further increase in red cell mass and blood viscosity
with paradoxically negative effects on tissue oxygena-
tion (2).
There are two distinct forms of secondary erythrocy-
tosis, compensated and decompensated, based on eryth-
rocyte indices and hyperviscosity symptoms (Table 1)
(1,3,4). In compensated erythrocytosis, a new equilib-
rium is established with an appropriately elevated
hematocrit in response to the chronic hypoxemia. Iron
metabolism is preserved and hyperviscosity symptoms
are absent. Conversely, in the presence of decompensat-
ed erythrocytosis, EPO titers remain elevated despite the
adaptive increase in red cell mass (5). Iron store depletion
eventually occurs as the dietary intake of iron is incapa-
ble of keeping up with physiologic demands. As a conse-
quence, a negative iron balance and ‘iron-deficient
erythropoiesis’ develop. This results in reduced levels of
ferritin and decreased RBC production. Ultimately, an
iron-deficiency anemia develops. These iron-deficient
states are important because erythrocytes formed in
their presence are microcytic and less deformable within
the microcirculation than their normocytic equals. The
change in the viscoelastic properties of the erythrocyte
affects blood viscosity at any hematocrit level and is
responsible for many of the clinical symptoms of hyper-
viscosity (6).
In patients with compensated erythrocytosis, Broberg
et al. found that the optimal hemoglobin for any given
O2 saturation could be predicted based on a linear
regression equation [Predicted Hgb = 61 – (O2sat/2)]
and correlated with improved exercise capacity (six min-
ute walk test and treadmill exercise duration). Con-
versely, in patients with decompensated erythrocytosis
and O2 saturations <75%, it was impossible to calculate
an optimal hemoglobin level without serious symptoms
of hyperviscosity (7). These findings correlate with previ-
ous studies suggesting aortic saturations <75% are fre-
quently associated with increased EPO measurements
and represent a critical saturation level below which
many patients cannot mount an adequate erythrocytic
response (5). Other adaptive mechanisms to enhance
survival in the presence of chronic hypoxemia include
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L. M. Zabala and N. A. Guzzetta
Table 1 Types of erythrocytosis
Compensated Patients with an established equilibrium at
erythrocytosis an elevated hematocrit level to hypoxemia;
iron replete-state exists and hyperviscosity
symptoms are absent.
Decompensated Patients with ongoing erythrocytosis noted
erythrocytosis by an increase in erythropoietin (EPO)
secretion without improvement in tissue
oxygen concentration; increase in
erythrocyte mass continues despite harmful
effects; iron deficiency commonly present;
hyperviscosity symptoms are moderate to
severe
an increase in cardiac output to achieve optimum oxy-
gen delivery, an increase in the release of nitric oxide
(NO) from the endothelium of coronary arteries to pro-
mote vasodilation, and a rightward shift of the oxygen
(O2) dissociation curve to encourage off-loading of O2
at the tissue level. The mechanism responsible for this
shift in the O2 dissociation curve is the increase in tissue
production of 2,3- diphosphoglycerate (2,3 – DPG) that
occurs in the presence of diminished O2 availability. As
the O2 dissociation curve shifts to the right, the p50
increases consequently making it easier for O2 to be dis-
placed from hemoglobin into the surrounding tissue.
Thrombosis and infarction are clinically devastating
complications of decompensated erythrocytosis and hy-
perviscosity, and may occur in areas of the circulation
where flow is sluggish. A significant inverse relationship
exists between cerebral blood flow (CBF) and hemato-
crit and between CBF and blood viscosity (8). Increased
RBC mass has been linked with an increased risk of
cerebrovascular events in neonates and infants with
CCHD (9,10). Although the risk of stroke in adults with
CCHD is less clear; three independent factors (atrial
fibrillation, arterial hypertension, and microcytosis)
have been identified as significantly associated with
stroke and underscore the importance of iron balance
and erythrocyte deformability in the etiology of cerebral
vascular events (11). Theoretical concerns exist for pul-
monary infarcts in the presence of polycythemia; how-
ever, this holds more true for the ‘vera’ form of the
disease than for the CCHD (12). In addition, two studies
failed to demonstrate an elevated risk of arterial or
venous thrombosis in patients with secondary erythrocy-
tosis, including patients with CCHD (13,14).
Erythrocytosis and its effect on hemostasis
Hemostatic abnormalities have been reported in patients
with CCHD since the 1950s (15,16). Although the
tendency for increased bleeding in this population was
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 981–989
L. M. Zabala and N. A. Guzzetta
initially attributed to an increase in tissue vascularity, it
is now recognized to result from a complex interplay of
coagulation abnormalities including thrombocytopenia,
shortened platelet survival, deficiency of von Willebrand
factor multimers, and a range clotting factor deficiencies
(2,17–20).
Historically, thrombocytopenia was cited as the main
hemostatic abnormality present in patients with CCHD.
In the early 1970s, Goldschmidt et al. (21). showed that
patients with CCHD had abnormalities of platelet turn-
over secondary to an increase in their peripheral destruc-
tion. Recent data suggest that the thrombocytopenia of
CCHD is primarily related to a decrease in platelet pro-
duction and an increase in platelet activation (22,23).
Platelet-derived microparticles (MPs) are a sensitive mea-
sure of platelet activation and show significant correla-
tion with increasing hematocrit, especially at levels above
60–65% (Figure 1) (22). The increased platelet activation
is likely induced by the high shear stress generated by
blood hyperviscosity in the presence of secondary erythr-
ocytosis. Lill et al. (23) reported a reduction in absolute
reticulated platelet counts with normal to elevated plate-
let factor 4 (PF4) and b-thromboglobulin (bTG) in 105
CCHD patients with hematocrits between 62% and 74%
and normal iron indexes. These results are consistent with
decreased platelet production and increased platelet acti-
vation. The authors hypothesize that these patients expe-
rience a continuum that begins with low platelet counts
and ends with thrombocytopenia in cases of severe ery-
throcytosis. Indeed, platelet counts and hematocrit levels
are inversely related (Figure 2).
Recent studies using thromboelastography (TEG) dis-
pute thrombocytopenia as the primary cause of
impaired hemostasis in the setting of CCHD. Because
TEG is performed with whole blood, not just plasma, it
reveals a global, more dynamic analysis that reflects the
different phases of the hemostatic process. Cui et al.
employed TEG to characterize the hemostatic profile of
31 children with severe CCHD and secondary erythrocy-
tosis (24). Baseline TEG tracings of children with a
preoperative HCT >54% showed a significant impair-
ment in hemostatic function compared to those children
with a HCT <54%. The peak amplitude (maximum
amplitude, MA) was significantly lower than normal
(44.1  6.8 mm) with the fibrinogen component (MAf)
contributing the most to the overall hemostatic dysfunc-
tion (MAf = 3.9  1.5 mm). Although platelet counts
were low, platelet function (MAp) was surprisingly well
preserved. All three measurements (MA, MAf, and
Map) displayed a significant negative correlation with
preoperative HCT, and all parameters were lower than
in children with a HCT <54%. Overall, the authors
concluded that the majority of hemostatic abnormalities
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 981–989
Cyanotic congenital heart disease
(%) 40
n = 19
r = 0.68
Platelet microparticle
30 P = 0.002
20
10
30 40 50 60 70 (%)
Hematocrit
Figure 1 Relationship between platelet-derived microparticles and
hematocrit. There is significant correlation between platelet MPs and
Hct in the cyanotic congenital disease group (CCHD). The regression
line was drawn based on the value of the CCHD group. Solid cir-
cles = CCHD group; open circles = acyanotic congenital heart dis-
ease group. (From Horigome H, Hiramatsu Y, Shigeta O, Nagawasa
T, Matsui A. Overproduction of platelet microparticles in cyanotic
congenital heart disease with polycythemia. J Am Coll Cardiol 2002;
39:1072–1077, with permission).
in children with CCHD and secondary erythrocytosis
were directly related to impaired fibrinogen function
and that clot strength was negatively correlated with an
elevated hematocrit level. A more recent study by Jensen
et al., also in patients with CCHD and a HCT >57%,
showed that the TEG angle (A), primarily representative
of the fibrinogen contribution to clot formation, was the
variable which was most severely affected by secondary
erythrocytosis (25). Plasma fibrinogen concentrations
were in the high normal range. The investigators con-
cluded that, despite the raised fibrinogen concentration,
it’s functionality was impaired. Furthermore, Af and
MAf negatively correlated with an elevated HCT while
Ap and MAp did not. Thus, it may be that, despite a
low platelet count, platelet function is not as severely
affected as assumed earlier, and that fibrinogen dysfunc-
tion is the major culprit to normal clot formation in
these children.
Another proposed mechanism responsible in part for
the coagulopathy observed in patients with CCHD and
secondary erythrocytosis is the presence of low-grade
disseminated intravascular coagulation (DIC). The hyper-
viscosity derived from increased red cell mass and vascu-
lar stasis predisposes patients to the intravascular
deposition of fibrin and platelet thrombi leading to a
low-grade consumptive coagulopathy. Although some
studies support this idea by confirming elevated levels of
D-dimers in a large proportion of children with CCHD
(26), others do not (27,28). A recent study in adults with
CCHD also reported normal values of prothrombin
time (PT), activated partial thromboplastin time
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Cyanotic congenital heart disease
350
300
250
Platelets 109·l–1
200
150
100
50
0 these abnormalities and their correction may help mini-
0 10 20 30 40 50 60 70
Hematocrit
Figure 2 Inverse relationship between platelet counts and hemato-
crit levels in patients with cyanotic congenital cardiac disease. (From
Lill MC, Perloff JK, Child JS. Pathogenesis of thrombocytopenia in
cyanotic congenital heart disease. Am J Cardiol 2006; 98:254–258,
with permission).
(aPTT), and D-dimers again questioning DIC as a
major contributor to the coagulopathy seen in second-
ary erythrocytosis (23).
Finally, other coagulation deficiencies seen in children
with CCHD and secondary erythrocytosis include
reduced levels of coagulation factors II, V, VII, IX, and
X and a state of accelerated fibrinolysis based on raised
levels of D-dimers and plasminogen activator inhibitor
type 1 (29,30). The deficiency of vitamin-K-dependent
factors is likely related to poor cardiac output, hypox-
emia, chronic passive congestion of the liver and/or neo-
natal age. It is unclear if the presence of accelerated
fibrinolysis is due to low-grade intravascular thrombo-
sis, primary fibrinolysis or simply increased catabolic
turnover of fibrinogen (29).
In summary, the hemostatic abnormalities described
in patients with CCHD are complex and include throm-
bocytopenia, impaired fibrinogen function, conflicting
reports of DIC, and multiple coagulation factor defi-
ciencies. The direct effects of hypoxemia and secondary
erythrocytosis on the hemostatic system predispose
these patients to both bleeding and thrombosis. Despite
our best efforts at minimizing the effects of cardiopul-
monary bypass (CPB) on hemostasis, excessive postop-
erative bleeding is a common problem in pediatric
cardiac surgery and more so in the CCHD population.
Next, we will review several perioperative strategies
designed to mitigate the risk of postoperative bleeding
(Table 2).
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L. M. Zabala and N. A. Guzzetta
Preoperative preparation
During the preoperative evaluation of patients with
CCHD and secondary erythrocytosis, practitioners
should perform a complete history and physical exami-
nation with pertinent laboratory testing. These children
often manifest abnormal liver function secondary to
systemic hypoperfusion, heart failure, hypoxemia, and
hyperviscosity. Specifically, they should be thoroughly
questioned about symptoms of hyperviscosity syndrome
—headache, dizziness, irritability, anorexia, myalgias,
paresthesias, depressed mentation, and chest and
abdominal pain. As discussed in the previous section,
synthesis and metabolism of platelets and other coagula-
tion factors is often impaired. Because the detection of
80 mize the risk of bleeding during the intraoperative per-
iod, it is recommended that a basic electrolyte panel,
complete blood cell count with differential, coagulation
profile, and liver function tests be obtained. When col-
lecting blood for laboratory analysis, accurate prepara-
tion of blood samples may require special consideration.
The increase in red cell mass reduces the amount of
plasma in any given volume of whole blood so that the
amount of anticoagulant in the collection tube must be
appropriately reduced. Failure to do so results in an
excess of anticoagulant and results in a prolonged acti-
vated partial thromboplastin time (aPTT), prothrombin
time (PT) and may explain earlier studies suggesting the
presence of DIC in patients with secondary erythrocyto-
sis and CCHD (31). As described in Table 3, there are
two commonly used formulas to accurately determine
the amount of anticoagulant required (1,2,32). Addi-
tional tests such as an echocardiographic examination
or cardiac catheterization, if required, should also be
performed prior scheduled palliative or corrective sur-
gery. Consideration should be given to hospital admis-
sion the night before surgery for children with CCHD
and secondary erythrocytosis presenting for cardiac sur-
gery in order to optimize intravenous hydration. On
occasion, carefully instructed hydration as an outpatient
may be offered to adult patients and pediatric patients
with strong family support.
Table 2 Perioperative strategies to decrease blood loss in patients
with cyanotic congenital heart disease
Preoperative coagulation testing and screening
Phlebotomy/Intraoperative autologous blood donation
Individualized heparin–protamine dose management strategy
Antifibrinolytics
Intraoperative whole blood coagulation monitoring with
thromboelastography
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Pediatric Anesthesia 25 (2015) 981–989
L. M. Zabala and N. A. Guzzetta
Clinical management
The hyperviscosity of severe erythrocytosis has signifi-
cant hemodynamic as well as hemostatic consequences.
As blood viscosity increases, it negates the beneficial
effects of an increase in oxygen carrying capacity and
causes a substantial decrease in tissue perfusion espe-
cially within the brain. Cerebrovascular events and/or
stroke are common seen in children with CCHD and
secondary erythrocytosis, and are related to the
increased RBC mass and iron-deficient anemia. Iron-
deficient RBCs are less deformable than normal RBCs
and do not pass smoothly through the microcirculation.
Thus, the clinical management of these children focuses
on optimizing their circulatory dynamics and hemostatic
parameters.
Phlebotomy: justification, when and how much
Phlebotomy in patients with secondary erythrocytosis is
a topic of great controversy. The early literature justified
the use of routine or prophylactic phlebotomy based on
the association between an increase in RBC mass and an
increased risk of cerebrovascular accidents (CVAs)
(9,10). However, more recent studies report a paradoxi-
cal increase in CVAs in patients undergoing routine
phlebotomy presumably due to the sudden reduction in
red cell volume and systemic blood flow (33). Phlebot-
omy may also precipitate seizures, cyanotic spells, and
cardiovascular collapse if stroke volume and systemic
blood flow are not maintained. Today, the medical man-
agement of hyperviscosity syndrome is more conserva-
tive and phlebotomy is used only when significant
symptoms of hyperviscosity are present. Specifically, in
children with CCHD and secondary erythrocytosis pre-
senting for cardiac surgery, there are two clinical indica-
tions for perioperative phlebotomy. The first is strictly
to relieve symptoms of moderate to severe hyperviscosi-
ty and is usually performed preoperatively. The second
is for autologous blood donation especially if the hemat-
ocrit level is above 65%, and is more commonly per-
formed intraoperatively.
Preoperative or intraoperative acute red cell reduc-
tion, when performed correctly with replacement of
blood by an equivalent volume of plasma or albumin, is
Table 3 Formulas for calculating the amount of anticoagulant adjust-
ment for coagulation testing in patients with erythrocytosis(2,28)
Dr. Perloff’s Anticoagulant in mls of whole blood =
formula (100-hematocrit)/(595-hematocrit)
The Toronto Anticoagulant (3.8% citrate) in mls = 1.6
formula [(100-hematocrit)/100] + 0.02 for a draw
of 10 ml of whole blood
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 981–989
Cyanotic congenital heart disease
often beneficial to both the circulatory and hemostatic
systems. As long as blood volume is maintained, acute
red cell reduction is associated with a significant increase
in cardiac output and cerebral blood flow. Systemic vas-
cular resistance (SVR) decreases while stroke volume
and systemic blood flow increase without a change in
heart rate (34). Systemic oxygen transport also increases
as hyperviscosity, shear stress, and SVR are reduced
(33). It should be noted, however, that in children with
right ventricular outflow tract obstruction or high pul-
monary vascular resistance and the presence of a ven-
tricular septal defect (VSD), acute red cell reduction is
associated with a fall, not a rise, in systemic oxygen satu-
ration (Figure 3) (33). This is most likely the result of a
decrease in SVR leading to an increase in right-to-left
shunting. Regarding the hemostatic system, platelet
counts and function increase dramatically within hours
after phlebotomy, especially when the hematocrit is
>65% (17). Previous episodes of bleeding may even
spontaneously resolve. The mechanisms responsible for
this prompt increase are unknown, but the rapidity of
the response suggests that platelets are released from a
reservoir rather than from an increase in production
(23). Although intravascular volume is expanded in the
presence of severe erythrocytosis, overall plasma volume
is reduced. Thus, the restoration of blood volume after
the removal of whole blood may best be achieved with
equivalent volumes of plasma rather than crystalloid in
order to replace factor deficiencies. However, there is
lack of data in the pediatric literature to support this
statement. Unfortunately, there are also no studies
defining the optimal ‘higher’ level of hematocrit for nor-
mothermic or hypothermic CPB cardiopulmonary
bypass in patients with decompensated erythrocytosis.
Isovolemic red cell reduction to achieve a hematocrit
<50% seems rational.
Intraoperative autologous blood donation (IAD) is a
blood conservation technique that involves the removal
of a portion of the patient’s blood intraoperatively with
re-infusion of this blood immediately after CPB. The
technique was designed to limit allogeneic transfusion
by preserving the withdrawn blood from destruction by
the CPB circuit and by providing a fresh autologous
source of red blood cells, platelets, and coagulation fac-
tors for reinfusion after CPB. However, based on the
deficiencies in the coagulation proteins of children with
CCHD and erythrocytosis, it is questionable whether or
not platelets and coagulation factors contained in the
IAD blood would help postoperative bleeding (35). The
question—’what is the best use of the collected
blood?’—thus arises .One option is to collect the blood
(in a sterile citrate-phosphate-dextrose-adenine bag)
prior to the administration of heparin and re-transfuse
985
Cyanotic congenital heart disease
(a) 100 (b) 100
Group I
90 90
80 80
Art. O2 Art. O2
Sat. (%) Sat. (%)
70 70
60 60
50 50
Before After
following CPB despite the coagulation deficiencies
described above. Some reports suggest that the retained
coagulation proteins still may be of some benefit, and
transfusion requirements can be decreased (36) or even
totally eliminated (37). Another option is to collect the
blood from the venous cannula after heparinization and
the institution of CPB. This latter approach may pro-
vide greater hemodynamic stability for the patient dur-
ing the blood collection process. However, it also results
in heparinized blood that requires either additional prot-
amine at the time of re-transfusion or washing through
the cell saver prior to re-transfusion thus depleting the
blood of residual heparin and all nonserythrocytic com-
ponents. There is little scientific evidence to support the
use of one technique over the other and further studies
are necessary to evaluate their respective pros and cons.
Intraoperative management
Heparin/protamine management
Unfractionated heparin is the most commonly utilized
anticoagulant for CPB. It is administered not only to
prevent gross clot formation within the CPB circuit but
also to prevent subtle activation and consumption of
coagulation system components when blood comes into
contact with the nonphysiologic surface of the extracor-
poreal circuit (38). Heparin’s anticoagulant effect is
directly dependent on the action of antithrombin (AT),
the major physiologic inhibitor of thrombin. Heparin
binds to AT causing a conformational change in its
molecular structure and thus transforming it from a
slow to a rapid inhibitor of circulating thrombin. Hepa-
rin dosing regimens for children undergoing CPB have
been extrapolated from adult protocols despite their
inherent deficiencies in AT, higher metabolic rates that
make heparin clearance by the kidney significantly fas-
ter, greater degree of hemodilution from the CPB cir-
cuit, and lack of pediatric specific pharmacokinetic and
pharmacodynamic data on anticoagulant agents (38–
986
L. M. Zabala and N. A. Guzzetta
Group II
Figure 3 Arterial oxygen saturation values
before and after red cell volume (RCV) reduc-
tion in polycythemic patients with severe pul-
monary stenosis or pulmonary vascular
obstructive disease. (a, group I) and those
with D-transposition of the great arteries and
no significant pulmonary vascular obstructive
disease. (From Rosenthal A, Nathan DG,
Marty A, Button, LN, Miettinen MD, Nadas
AS. Acute hemodynamic effects of red cell
volume reduction in polycythemia of cyanotic
Before After congenital heart disease. Circulation 1970;
42: 297–307, with permission).
41). Because children with CCHD and secondary erythr-
ocytosis have a reduced plasma volume with lower levels
of coagulation factors, including AT, measuring AT
activity preoperatively and supplementing its activity
prior to CPB may be warranted to preserve heparin’s
effectiveness in these children.
Most anticoagulation practices for pediatric CPB are
based on an empirical weight-based heparin and prot-
amine-dosing regimen using the activated clot time
(ACT) to monitor the adequacy of anticoagulation. In
general, an ACT of 400–480 s is considered adequate
for the institution of CPB. However, it has been repeat-
edly demonstrated that the ACT is a poor indicator of
heparin effect in the pediatric population (42,43). Given
the dependence of the ACT on adequate platelet func-
tion, the thrombocytopenia commonly encountered in
secondary erythrocytosis may lead to an ‘acceptable’
prolongation of the ACT even if heparin levels are inad-
equate. As an alternative, an individualized heparin and
protamine management strategy, using a whole blood
hemostasis management system (HMS), has proven
more effective in suppressing thrombin generation dur-
ing pediatric CPB than conventional weight-based hepa-
rin dosing and monitoring. The HMS-calculated
heparin concentration may improve and optimize hepa-
rin responsiveness during CPB, especially in patients
who may be deficient in AT such as children with
CCHD and secondary erythrocytosis. It also targets a
smaller protamine dose than predicted by traditional
weight-based heparin protocols which is important
because an excess of unbound protamine also has signif-
icant anticoagulant effects (44).
Antifibrinolytics
Although the clinical contribution of primary fibrinoly-
sis to bleeding in children with CCHD and secondary
erythrocytosis is unclear, activation of the fibrinolytic
system during CPB is well documented and one of the
primary mechanisms leading to post-CPB bleeding
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Pediatric Anesthesia 25 (2015) 981–989
L. M. Zabala and N. A. Guzzetta
(45,46). Pharmacologic inhibition of fibrinolysis has
been shown to reduce clinical bleeding in cardiac
surgery, trauma, orthopedic, liver transplantation, gyne-
cological surgery, and obstetrics surgery (47). Epsilon
Aminocaproic acid (EACA) and tranexamic acid (TA)
are two widely available lysine analogs used to inhibit
the fibrinolytic process. They produce a reversible block-
ade of the lysine-binding sites on plasminogen thereby
inhibiting the activation of plasminogen, interfering with
the formation of plasmin, and stopping the lysis of poly-
merized fibrin. In addition to the role plasmin plays in
clot lysis, it has also been shown to interrupt normal
platelet aggregation induced by both thrombin and col-
lagen. Theoretically, the reduced amount of plasmin
produced in the presence of EACA and TA should aid
in the preservation of platelet function in the post-CPB
period. Another nonspecific serine protease inhibitor
with antifibrinolytic effects is Aprotinin. Aprotinin was
recently withdrawn from clinical practice due to serious
concerns about its safety raised by the Blood Conserva-
tion Using Antifibrinolytics in a Randomized Trial or
BART study (48). Although it has been reinstated for
use in both Canada and Europe (49,50), aprotinin
remains unavailable for use in most countries. Because
of its early termination, the BART trial never answered
the question of whether or not the lysine analogs were as
efficacious as aprotinin in their blood-sparing effects,
although there was a trend supporting the aprotinin’s
superiority to prevent massive bleeding in comparison to
both lysine analogs (RR 0.79; 95% CI 0.61–1.01) (48).
Unfortunately, an insightful analysis of the literature
on the administration of TA and EACA for pediatric
CPB is near impossible because of the significant incon-
sistencies between different studies. Multiple variables,
including the age of patients studied, types of cardiac
procedures performed, CPB priming volumes and proto-
cols, and dosing regimens for the antifibrinolytic admin-
istered, vary greatly among differing institutions. The
best evidence supporting the ability of the antifibrinolyt-
ic agents to decrease bleeding and transfusion require-
ments in children after CPB is the numerous studies
repeatedly demonstrating that the use of these agents is
superior to placebo (51). In addition, there is little evi-
dence supporting one antifibrinolytic agent over another.
A recent study of 22 258 pediatric cardiac patients utiliz-
ing data from the Pediatric Health Information Systems
Database showed no difference in efficacy or safety out-
comes between EACA and aprotinin. Conversely, TA
was associated with lower bleeding and in-hospital mor-
tality rates when compared to aprotinin (52). The
authors did not directly compare EACA to TA. Other
studies have found no difference regarding blood loss,
transfusion, and outcome when comparing EACA and
© 2015 John Wiley & Sons Ltd
Pediatric Anesthesia 25 (2015) 981–989
Cyanotic congenital heart disease
TA (53). However, serious concerns for increased seizure
activity postoperatively are associated with the use of
TA. A study in pediatric cardiac patients weighing
<20 kg reported a fourfold increase in the incidence of
postoperative seizures with the use of TA vs EACA (TA
3.5% vs EACA 0.8%, P = 0.203), although this value
did not reach statistical significance. Thus, although
there is no concrete support for antifibrinolytic therapy
specifically in children with CCHD and secondary ery-
throcytosis, evidence suggests that antifibrinolytic agents
are advantageous in reducing blood loss during complex
pediatric cardiac surgery and should be considered as
part of a comprehensive blood conservation strategy.
Dynamic intraoperative coagulation monitoring - Throm-
boelastography (TEG)
Conventional coagulation assays, specifically the pro-
thrombin time (PT) and activated partial thromboplastin
time (aPTT), are performed in plasma alone and conse-
quently do not reflect the interactions of cellular compo-
nents in blood such as platelets, leukocytes, and
phospholipid-bearing cells. In addition, as previously
mentioned, the plasma contribution to whole blood in
patients with secondary erythrocytosis is significantly
decreased and requires special handling. Thus, the use
of coagulation devices capable of assessing the viscoelas-
tic properties of whole blood [thrombelastography
(TEGÒ; Hemoscope Corp., Niles, IL, USA) and rota-
tion thromboelastometry (ROTEMÒ; Pentapharm
GmbH, Munich, Germany)], rather than just plasma,
has become increasingly common. Normal values have
been described for both healthy children and children
with congenital heart disease (54,55). Modification of
the test with a contact activator allows for the rapid
attainment of thromboelastogram variables so that the
use of TEG has become a real-time point-of-care coagu-
lation monitor for assessing coagulopathies in children
undergoing cardiac surgery and CPB. TEG tracings
may be obtained in the immediate pre-bypass period to
define the baseline effects of cyanosis on the hemostatic
system or post-CPB to rapidly assess coagulopathy. In
addition, with the use of heparinase, important predic-
tive TEG data may be obtained during CPB thus allow-
ing pertinent objective data to be immediately available
(56). TEG is also beneficial in assessing the contribution
of functional fibrinogen to the developing clot, a defect
which might otherwise go unnoticed if only measuring
plasma based values. A clinical study of children with
secondary erythrocytosis comparing postoperative out-
comes between a post-CPB transfusion protocol guided
by TEG vs one guided by clinical experience found that
the TEG-guided therapy resulted in greater intraopera-
tive administration of fibrinogen concentrate but
987
Cyanotic congenital heart disease L. M. Zabala and N. A. Guzzetta

significantly less postoperative transfusion of FFP. In gaining recognition. It is clear that the coagulation
addition, the TEG-guided transfusion group had abnormalities associated with secondary erythrocytosis
improved outcomes including a reduction in the dura- are complex and that no one mechanism is at play.
tion of mechanical ventilation, length of ICU stay, and Understanding the pathophysiology and implementing
total hospitalization time (57). a comprehensive strategy to lessen the risk of postopera-
tive bleeding or thrombosis is warranted when caring
for these children.
Conclusion
In summary, patients with long-standing hypoxemia
Ethics approval
have complex and often severe alterations in their whole
blood viscosity and coagulation profile. Chronic hypox- No ethics approval needed.
emia triggers a variety of compensatory mechanisms
aimed at optimizing the tissue oxygen delivery and over-
Funding
all organ function. Alterations in the coagulation profile
of these patients are expected due to the reduction in The study was funded by departmental resources.
plasma volume that accompanies the increase in red cell
mass. Although thrombocytopenia is well documented
Conflict of interest
as a part of the bleeding diathesis associated with sec-
ondary erythrocytosis, the contribution of other dys- No conflict of interest.
functional coagulation proteins, such as fibrinogen, are

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