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Progress in Pediatric Cardio
Cardiopulmonary bypass and the coagulation system
Thomas Yeh Jr.a,*, Minoo N. Kavarana b,1
aThe University of Texas, Southwestern Medical Center and Children’s Medical Center Dallas, Department of Cardiothoracic Surgery,
Division of Pediatric Cardiothoracic Surgery, 1935 Motor Street, Suite EO3-320.Z, Dallas, TX 75235, United StatesbUniversity of Louisville, Department of Cardiothoracic Surgery, 201 Abraham Flexner Way, Suite 1200, Louisville, KY 40202, United States
Abstract
Cardiopulmonary bypass exerts intended and unintended effects on the enzymatic and formed elements of the coagulation and inflammatory
systems. Compared with adults, children are at special risk for known, and unknown, differences in their hemostatic systems. Management of
these risks will be presented from a surgical perspective, supporting those strategies with a combination of peer-reviewed data and empiric
experience. Preoperatively, strategies discussed are management of preoperative anticoagulants, autologous and directed donation, erythropoietin,
and special considerations in the care of pediatric Jehovah’s Witnesses. Intraoperatively, strategies discussed include basic management
of cardiopulmonary bypass, heparin and heparin monitoring, protamine, alternative anticoagulant strategies for heparin sensitivity, and
intraoperative pharmacologic adjuncts promoting postoperative hemostasis. Postoperative strategies discussed include blood product utilization,
recombinant factor VII, the use of thromboelastography to guide therapy, topical strategies, cell saver therapy, and surgical reexploration.
D 2005 Published by Elsevier Ireland Ltd.
Keywords: Jehovah’s Witness; Cardiopulmonary bypass; Heparin; Coagulation system
1. Introduction
Cardiopulmonary bypass was originally pioneered in
children. In 1952, F. John Lewis performed the first open
heart operation using fibrillatory arrest [1]. C.W. Lillehei
was the first to use cross-circulation and hypothermia to
repair an atrial septal defect [2]. After developing his
prototype ‘‘heart lung machine,’’ John Gibbon repaired an
atrial septal defect in 1953 [3]. Although this landmark
enabled the performance of intracardiac surgery, disturban-
ces in hemostasis still persist today.
Cardiopulmonary bypass leads to a whole body inflam-
matory response involving the formed blood elements,
coagulation, complement and kallikrein/kinin systems.
Hemodilution is directly related to the volume of crystalloid
and colloid required to prime the circuit and the patient’s
own blood volume and can dilute blood components by as
1058-9813/$ - see front matter D 2005 Published by Elsevier Ireland Ltd.
doi:10.1016/j.ppedcard.2005.09.011
* Corresponding author. Tel.: +1 214 456 5000.
E-mail addresses: [email protected] (T. Yeh),
[email protected] (M.N. Kavarana).1 Tel.: +1 606 862 9280.
much as 40% [4]. Although children have relatively larger
circulating blood volumes when compared with adults (e.g.,
preterm infants have an estimated blood volume of 90–100
ml/kg compared to 70–80 ml/kg in an adult [5,6]), their low
absolute blood volume accentuates their dilutional coagul-
opathy. Further, their small blood volume creates practical
limitations on the use of certain blood conservation
strategies such as autologous donation and cell saver.
A profound thrombotic reaction involving both the
extrinsic and intrinsic coagulation pathways is initiated by
continuous exposure of heparinized blood to the perfusion
circuit and to the wound during cardiac surgery. Despite
large doses of heparin during cardiopulmonary bypass,
heparin does not block thrombin generation; but partially
inhibits thrombin after it is produced. Thrombin is
continuously generated and a consumptive coagulopathy is
initiated [7–9]. If thrombin formation could be completely
inhibited during cardiopulmonary bypass, the consumption
of coagulation proteins and platelets could largely be
prevented.
Seconds after heparinized blood contacts any biomaterial
(including heparin-coated surfaces) [9], plasma proteins are
logy 21 (2005) 87 – 115
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11588
adsorbed onto that surface to form a single layer of proteins
[10]. Adsorbed factor XII and fibrinogen undergo confor-
mational changes, triggering activation of the contact
pathway and platelet surface adhesion, respectively. Thus
heparin is not an ideal anticoagulant during cardiopulmo-
nary bypass, which is indicated by the high concentrations
(3–4 mg/kg, initial dose) that are required for efficacy.
Circulating thrombin, surface-adsorbed fibrinogen, com-
plement, platelet activating factor, and cytokines lead to
platelet adhesion [4]. Platelets appear to be structurally normal;
[11] however, their function is abnormal, as a result of being
activated. Hypothermia also exacerbates thrombocytopenia
through hepatic sequestration and increased fibrinolysis
[12,13]. Bleeding time remains prolonged for several hours
after protamine administration [14]. This increased bleeding
tendency can be reversed by rewarming [15,16].
Similar changes in complement proteins participate in
activation of the complement system [17]. The inflammatory
response to cardiopulmonary bypass is mediated by the
contact system and consists of four primary plasma proteins
[factor XII, prekallikrein, high molecular weight kininogen
(HMWK), and C-1 inhibitor] which lead to complement and
neutrophil activation. However, when blood contacts a
negatively charged surface in cardiopulmonary bypass, small
amounts of factor XII are adsorbed and undergo a confor-
mational change to factor XIIa. Factor XIIa in the presence of
HMWK activates factor XI and initiates the intrinsic
coagulation pathway. Thrombin also activates factor XI,
and is the predominating agonist in vivo in pathologic states.
The intrinsic coagulation pathway probably does not
generate thrombin in vivo, but is initiated when blood
contacts nonendothelial cell surfaces such as the perfusion
circuit [18,19]. The extrinsic coagulation pathway is a major
source of thrombin generation during cardiopulmonary
bypass and is initiated from tissue factor in the surgical
wound [20–22]. Tissue factor is a cell-bound glycoprotein
that is constitutively expressed by fat, muscle, bone,
epicardial, advential, injured endothelial cells, wound mono-
cytes, and many other cells except pericardium [22–24].
Intrinsic and extrinsic tenase complexes catalyze the
activation of factor X to factor Xa. The extrinsic tenase
complex is formed by the combination of tissue factor,
factor VIIa, calcium, and a phospholipid surface to cleave a
small peptide from factor X to form factor Xa. Extrinsic
tenase also generates small amounts of factor IXa, which
greatly accelerates formation of intrinsic tenase and is the
major pathway for the formation of factor Xa. The intrinsic
tenase is produced by the combination of factor IXa, factor
VIIIa, and calcium on the surface of an activated platelet,
and catalyzes production of factor Xa 50 times faster than
extrinsic tenase. Factor Xa activates factors V and VII in
feedback loops.
Blood contact with the biomaterials of the perfusion
circuit was initially thought to be the major stimulus to
thrombin formation during cardiopulmonary bypass. Increas-
ing evidence indicates that the wound is the major source of
thrombin generation during cardiopulmonary bypass [7,25].
This has encouraged the development of strategies to reduce
the amounts of circulating thrombin during clinical cardiac
surgery by either discarding wound blood or by exclusively
salvaging red cells by centrifugation in a cell saver. The
reduced thrombin formation in the perfusion circuit has also
supported misguided strategies for reducing the systemic
heparin dose during first-time coronary revascularization
procedures using heparin-bonded circuits. While there is no
good evidence that heparin-bonded circuits reduce thrombin
generation, there is strong evidence that discarding wound
plasma or limiting exposure of circulating blood to the
wound (e.g., less bleeding in the wound) does reduce the
circulating thrombin burden [26–28].
The coagulopathy induced by cardiopulmonary bypass
affects children more profoundly than adults. Neonates are
particularly affected, as a result of their unique cardiac
lesions, immature hematopoietic and coagulation systems,
and small blood volumes [29]. After birth, erythropoiesis
profoundly decreases, accompanied by the cessation of
fetal hemoglobin production. This physiologic anemia
results in hemoglobin nadirs of 9–11 g/dl at 8–12 weeks
of age. Neonates have inherent deficiencies in vitamin K-
dependent factors II, VII, IX and X which may be
corrected by administering vitamin K at birth [30].
Deficiencies in contact factors (XI, XII, prekallikrein,
and high molecular weight kininogen are also present at
birth [4,31]). Hepatic immaturity and decreased factor
synthesis and accelerated clearance of factors through
higher metabolic rates also play a role. Coagulation
inhibitors are also low. Protein C, Protein S, heparin
cofactor II, and antithrombin III levels are also 40–60% of
adult values, slowly achieving adult levels by 180 days
[31]. Platelet aggregation may be impaired [32], and
fibrinogen exists in a dysfunctional fetal isoform [31].
Notably fibrinogen, platelet counts, and factors V, VIII,
von Willebrand factor, and XIII are normal at birth [31]. In
spite of the preceding, prothrombin time, and thrombin
clotting time are normal within a few days of birth [31].
Thromboelastography has shown that neonates and infants
actually develop faster and stronger clots than adults [33].
Acquired coagulation defects have been reported in 58%
of children with noncyanotic defects (decreased fibrinogen
levels, platelet counts, prolonged bleeding times, and
fibrinolytic activity, especially in infants) and 71% of
patients with cyanotic defects (prolonged PT, aPTT,
decreased levels of fibrinogen, factor II, V, VII, VIII, IX,
X, and thrombocytopenia) [34–39].
Older children with cyanotic defects are much more
likely to be polycythemic and manifest platelet dysfunction
with prolonged bleeding times [35,40]. Polycythemia results
in an artificially increased PTT because the heparin dose in
specimen tubes is not calibrated for the reduced plasma
volume accompanying polycythemia. The high incidence of
stroke associated with polycythemia is variably attributed to
hypercoagulability or to the poor deformability and sludging
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 89
of iron deficient cells [41,42]. Chronic hepatic congestion
from the same mechanism or heart failure may lead to liver
dysfunction and a decreased production of coagulation
factors. Finally, older children are frequently undergoing
reoperative surgeries and some are therapeutically anti-
coagulated. Younger children with polycythemia appear to
be hypercoagulable prior to the onset of polycythemia with
increased platelets, fibrinogen, and factors V and VIII [34].
Although much of our clinical practice in managing
cardiopulmonary bypass in children is extrapolated from
adult clinical practice, we will attempt to summarize empiric
guidelines and published data where available. The text is
organized into issues and strategies encountered before,
during and after cardiopulmonary bypass.
2. Before cardiopulmonary bypass
2.1. Management of preoperative anticoagulants before
cardiopulmonary bypass
With the increased utilization of anticoagulants and a
plethora of new antiplatelet agents it is imperative that the cardiac
surgeon be knowledgeablewith theirmechanisms and duration of
action, in order to make appropriate decisions regarding the
timing of surgery. In Table 1, a brief summary of agents,
mechanisms, and recommended delays in surgery is provided.
These topics are covered in more detail in other chapters.
2.2. Preoperative strategies to minimize postoperative blood
requirement
2.2.1. Autologous donation
2.2.1.1. Preoperative autologous donation. Preoperative
autologous donation was first reported in 1818 [46], and
first used for cardiac surgery in the 1980s [47]. While
advantages include avoiding the risks of transfusion,
disadvantages include the logistical requirements as outlined
in the American Association of Blood Bank Guidelines,
namely: (1) adequate patient size, (2) adequate time for
collection and red cell regeneration (generally 2 weeks per
unit of blood in adults or 0.46 units per week [48]), and (3)
adequate starting hematocrit (>33%) and red cell mass.
Further, patients should be in adequate health and hemody-
namically stable enough to withstand phlebotomy, thereby
eliminating patients with important left ventricular outflow
tract obstruction, congestive heart failure, active endocardi-
tis or systemic infection.
In children, current recommendations are that no more
than a maximum of 15% of a patient’s effective blood volume
be removed at any given time. Preoperative autologous
donation is safe in children over 30 kg, and has even been
safely performed in children under 30 kg [49,50]. Iron
therapy should be initiated to facilitate red cell regeneration.
Smaller children are subject to difficulty with compliance
during donation, more difficult venous access, and more
hemodilution during cardiopulmonary bypass [50]. Autolo-
gous donation has been shown to be safe and effective in the
pediatric population, resulting in better postoperative recov-
ery of hemoglobin levels and higher reticulocyte counts [51].
2.2.1.2. Intraoperative autologous donation. As an alter-
native to preoperative autologous donation, others have
sequestered heparinized blood just prior to cardiopulmonary
bypass and given the sequestered blood postoperatively.
This blood has the advantage of not having undergone
clotting factor destruction or platelet activation on cardio-
pulmonary bypass [52]. Although hematocrit is not allowed
to recover prior to surgery and heparin is administered when
the blood is returned, this strategy may be a good
compromise in small or hemodynamically unstable patients,
since hematocrits can be adjusted on cardiopulmonary
bypass. This strategy has been shown to be safe and
effective in avoiding homologous blood transfusion [52].
2.2.2. Directed donation
Directed donation utilizes blood donated from a relative
or family friend screened by the same criteria as regular
donors. There is no established medical advantage in using
directed donors. Directed donation requires the donor to be
of matching blood type, advanced planning to schedule a
donor’s blood collection, processing, testing, and shipping,
as well as crossmatching at the hospital. Females of child-
bearing age should not receive donations from husbands or
sexual partners because of the risk of sensitization to minor
blood group antigens and hemolytic disease of the newborn.
Directed donations between blood relatives are gamma-
irradiated using 2500 cGy to minimize the risk of
transfusion-induced graft-vs.-host disease. Unused units
may be ‘‘crossed-over’’ for general use. In Australia,
pediatric directed donation served a community need but
did have a high wastage rate, was expensive, and was time
and labor-intensive when compared with conventional
blood [53]. In Canada, similar results led to the conclusion
that directed donation was not justified [54].
2.2.3. Erythropoietin administration
Recombinant erythropoietin can be used to accelerate red
cell production in anemic patients, (as it is in Jehovah’s
Witnesses prior to surgery) but does require a finite period
of time to be effective [55]. Allogenic blood transfusions
can be reduced with preoperative autologous donation and
erythropoietin. In anemic patients undergoing coronary
artery bypass grafting, preoperative erythropoietin (vs.
control) significantly increased hemoglobin 2.1T0.9 vs.
0.5T0.4 g/dl, respectively, and allogenic transfusion was
significantly reduced. Recommended erythropoietin dosing
was 500 U/kg once a week for 3 weeks preoperatively [56].
Preoperative erythropoietin significantly increased he-
moglobin and avoidance of blood products in pediatric
Jehovah’s Witnesses undergoing open heart surgery [57]. In
Table 1
Common Clinical Anticoagulants
Drug Binding Mechanism Half-life Clearance Recommended delay
in surgery
Heparin unfractionated Reversible Binds antithrombin III (AT III)
enhancing thrombin–AT III
complex formation.
30 min–2 h Liver and RES 4–6 h
Can be acutely reversed
with protamine
Inhibits factor Xa
Inhibits platelet function
LMW heparin
(Enoxaparin)
Reversible Factor Xa inhibition 6 h–10 h Liver 24–48 h
Binds ATIII but too small to
bind thrombin
Only partially reversed
by protamine
Minimal platelet interaction
Warfarin (Coumadin) Reversible Inhibits vitamin K-dependent
clotting factors II, VII, IX and X
37–89 h Liver 3–4 days
Can be acutely corrected
with Vitamin K and FFP
administration
Aspirin Irreversible Cyclooxygenase acetylation
inhibiting thromboxane A2
(TXA2) production
15 min
(Biologic
half-life 6–12 h)
Renal 7–10 days (aspirin
increases postop CT
drainage [43]
but does not increase
transfusion [44] or
reoperation rate) [45]
Inhibits release of vitamin
K-dependent factors
Dipyridamole
(Persantine)
Irreversible Platelet adhesion inhibitor,
phosphodiesterase and TXA2
inhibition
10 h Liver 24–48 h
Clopidogrel (Plavix) Irreversible ADP blocker mediated platelet
aggregation and subsequent
GPIIb/IIIa inhibition
8 h Liver 7 days
Ticlopidine (Ticlid) Irreversible ADP blocker 12 h–4 days Liver 7 days
Abciximab (ReoPro) Noncompetitive GP IIb/IIIa receptor antagonist,
inhibition (monoclonal antibody,
long binding)
30 min Binds tightly to
platelets for at
least 15 days
12 h
Tirofiban (Aggrastat) Reversible GP IIb/IIIa receptor antagonist
(nonpeptide fiban)
2.2 h Renal 12 h
Eptifibatide (Integrillin) Reversible GP IIb/IIIa receptor antagonist
(cyclic peptide)
2.5 h Renal 12 h
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11590
a 3 year old Jehovah’s Witness, erythropoietin at 2550 U/
week for 4 weeks increased his hemoglobin level from 12.1
to 13.2 g/dl [58]. A larger pediatric study (n =11) that used
erythropoietin at 100 U/kg three times a week for 3 weeks
prior to open heart surgery resulted in a median 8% increase
in the reticulocyte count and a 6% increase in hematocrit
[59]. Another study compared 39 children treated consec-
utively with erythropoietin (100 U/kg three times a week for
3 weeks preoperatively, and IV on the day of surgery) with
39 consecutive age-matched controls who underwent open
heart surgery. Allogenic blood was administered to 3/39
(7.7%) children receiving erythropoietin vs. 24/39 (61.5%)
controls. They concluded that erythropoietin increased
limits of autologous collection and significantly minimized
allogenic transfusions [60].
In term infants awaiting heart transplant who require
multiple transfusions secondary to iatrogenic blood losses,
daily erythropoietin administration helped maintain stable
hematocrits and minimized the need for blood transfusion
[61]. Adverse effects with recombinant erythropoietin are
very rare and include hypertension, rashes, epilepsy, head-
aches, flu-like symptoms and bone and muscle pains.
2.2.4. Jehovah’s Witnesses and cardiopulmonary bypass
The Jehovah’s Witness faith proscribes any allogenic or
autologous blood products that have been separated from
the body for any period [62,63], based on their interpretation
of the Bible (Genesis 9:3–6; Leviticus 17:10; Acts 15:20,
28, 29; 21:25). Major products, i.e., red cells, white cells,
platelets, and plasma are not acceptable. Other fractions are
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 91
variably accepted, i.e., hemoglobin-based blood substitutes,
interferons, interleukins, wound healing factors, hormones,
albumin, globulins, fibrinogen, and clotting factors. Lead-
ership of the faith leaves these fractions to an individual’s
conscience. Most drugs such as iron dextran, aprotinin,
desmopressin and synthetic blood substitutes are accepted
by Jehovah’s Witnesses as they contain no human blood
products. Jehovah’s Witnesses will generally accept cardio-
pulmonary bypass, dialysis, intraoperative blood salvage
and reinfusion by cell-saver [64], as long as the blood
remains in continuous circulation with the patient’s blood.
Cell-saver and autotransfusion techniques that maintain a
closed circuit with an intravenous line from the collection
device to the patient meet this requirement [65,66].
Great effort has been exerted to allow open heart surgery
without transfusion [67]. In children, their smaller blood
volumes and greater hemodilution make this more difficult
[68]. Congenital cardiac surgery without blood products has
been performed in Jehovah’s Witness children [69,70].
Recombinant erythropoietin is accepted by most Jehovah’s
Witnesses [55], even though it does contain small amounts
of albumin. Cardiopulmonary bypass without transfusion
has been reported in children under 10 kg using preoperative
erythropoietin [59]. Van Son et al. demonstrated an 8%
increase in reticulocytes and a 6% increase in hematocrits in
children pretreated with erythropoietin (100 U three times a
week) and recommended preoperative, intraoperative and
postoperative strategies to avoid transfusion [59]. Other
strategies include decreasing the priming volume with
vacuum-assisted venous drainage [71], hemodilution [72],
modified ultrafiltration [73,74] and hemostatic adjuncts to
attenuate blood loss in the perioperative period.
Naturally the management of Jehovah’s Witnesses is
ethically charged for patients, families, and physicians.
Caregivers must balance honoring a family’s religious
beliefs with a caregiver’s sworn duty to the best medical
interests of their patient, a child who may or may not
ultimately accept the Jehovah’s Witness faith for herself.
Families should be informed and consented in detail
regarding the poorer neurologic outcomes with lower
hematocrits on cardiopulmonary bypass and the possible
fatality of avoiding transfusions. Many centers prophylac-
tically obtain preoperative court orders to transfuse a patient
so a child could be transfused in the case of life-threatening
hemorrhage or anemia.
3. During cardiopulmonary bypass
3.1. Routine cardiopulmonary bypass
3.1.1. Surgical vs. coagulopathic causes of bleeding
For surgeons, coagulopathic bleeding is a diagnosis of
exclusion. Although beyond the focus of this chapter, no
hematologic strategy will effectively overcome true surgical
bleeding. Intraoperatively it is incumbent on the surgeon to
repeatedly rule this possibility out in a bleeding patient. The
importance of well-placed hemostatic sutures remains the
best defense against bleeding. Systematically organized
inspection of all suture lines, cannulation sites, cut pleural
and pericardial edges, and the chest wall is essential.
3.1.2. The role of hypothermia and rewarming
Hypothermia leads to coagulopathy by suppression of
platelet aggregation by blocking thromboxane synthesis
[75]. Increased transfusion and chest tube output have been
documented with a lower core body temperatures in the
intensive care unit after cardiopulmonary bypass [75].
Significant prolongation of prothrombin and plasma throm-
boplastin times has been demonstrated with hypothermia
[76]. Some groups have even suggested that platelet
transfusion may be beneficial [77,78]. In the ICU, warming
blankets and overhead heaters especially in infants are
essential.
3.1.3. Bypass circuits: volume, tubings, filters
Advances in oxygenator technology now provide a
reduction in the priming volume [79]. Circuit volume can
be further reduced by maximizing replacement of the
crystalloid prime with autologous blood drained from the
arterial cannula into the circuit immediately prior to
cardiopulmonary bypass, called retrograde autologous
priming (RAP), as well as displacing the venous prime
when initiating cardiopulmonary bypass [80]. Leukocyte
filters and heparin-bonded circuits reduce the inflammatory
response and decrease the requirement for transfusion
[81,82]. Priming methods have a controversial effect on
blood loss. Some investigators conclude that using 5%
albumin, rather than fresh frozen plasma reduced postoper-
ative bleeding [83]. In contrast, another prospective
randomized study showed reduced blood requirement when
fresh frozen plasma was used in the prime [84].
Heparin-bonded circuits have been shown to reduce the
inflammatory response and improve oxygenation in chil-
dren, suggesting that improved biocompatibility reduces
pulmonary complications [85,86] and provides other bene-
fits [85,87]. A prospective randomized study in children
revealed that heparin-bonded circuits significantly reduced
cytokines and complement generation, lowered interleukin
levels, and improved pulmonary and coagulation function
after bypass [88].
3.1.4. Modified ultrafiltration
The systemic inflammatory response induced by cardio-
pulmonary bypass increases morbidity and mortality
through capillary leak, fluid overload, poor alveolar gas
exchange, and delayed extubation [89]. In children, the
relatively more severe hemodilution disproportionately
depletes platelets and coagulation factors. Although cell
salvage can yield a significant number of red blood cells, in
children, ultrafiltration is superior in terms of platelet
number and function, and concentration of plasma proteins
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11592
including fibrinogen [90–92]. Others have shown a more
negative fluid balance, in addition to preserved platelet
number and function, fibrinogen, antithrombin III, total
protein and colloid osmotic pressure [93]. Ultrafiltration
also removes inflammatory mediators including C3a, C5a,
interleukin-6 and tumor necrosis factor-a. Ultrafiltration has
been shown to improve early hemodynamics, oxygenation,
blood loss, and ventilator days after cardiac surgery [94].
Ultrafiltration is strongly recommended, especially in
smaller children undergoing cardiopulmonary bypass.
3.1.5. Importance of maintaining hematocrit on
cardiopulmonary bypass
Historically, many centers permitted marked hemodilu-
tion on cardiopulmonary bypass to avoid transfusion.
Recent studies question that approach and provide evidence
of improved neurologic function when higher hematocrits
are maintained during cardiopulmonary bypass. Although
pigs demonstrate increased cerebral blood flow and metab-
olism with hemodilution [95], a randomized controlled
clinical study in infants undergoing cardiopulmonary bypass
demonstrated adverse perioperative and developmental out-
comes with hemodilution [96]. Others have shown that
increasing hematocrit with modified ultrafiltration improved
outcomes after the Norwood procedure [97]. This issue
remains controversial, although the clinical data in support
of higher hematocrits are compelling.
3.2. Heparin anticoagulation during cardiopulmonary
bypass
3.2.1. Heparin variability
The mechanism of heparin’s action is well-described in
other chapters; however, one important aspect of using
heparin is its variability between individual batches and in a
patient’s response.
3.2.1.1. Variability resulting from source (porcine intestinal
mucosa vs. bovine lung). The advantages of heparin
extracted from porcine intestinal mucosa, or heparin
extracted from bovine intestinal or lung tissue have been
studied in some detail. In 100 randomized patients, beef
lung heparin had greater anticoagulant activity than pork
mucosal heparin during a preoperative heparin tolerance test
and also during cardiopulmonary bypass [98]. Supplemental
heparin was needed in many more of the patients receiving
porcine mucosal heparin. Notably less bleeding occurred in
patients who received beef lung heparin.
In another study, 113 patients were randomized to receive
bovine or porcine heparin [99]. Heparin was infused at 4.5
mg/kg during bypass and administered at the lesser of 70
units/kg or 5000 units/dose at 12-h intervals postoperatively.
Platelet counts decreased to 45% of baseline during the first
3 postoperative days (porcine, 44T13%, n =50; bovine,
46T15%), but normalized by day 7. The porcine group had
significantly more blood loss than the bovine heparin group
(350.7T727.8 ml vs. 1059.6T381.0 ml, respectively,
p <0.01). Consequently, the platelet transfusion requirement
was greater in the porcine vs. bovine heparin group
(1.7T3.9 units vs. 0.5T1.7 units; p <0.05). Except for
platelets, blood and blood component transfusion was not
different. When patients receiving anticoagulants or antiin-
flammatory agents, were compared, four patients in the
porcine group received a mean of 8.5 units of packed cells
plus supplemental platelets, while seven patients in the
bovine group received a mean of 3.0 units of packed cells
with no platelets. Porcine heparin resulted in a generalized
increase in postoperative bleeding with increased manage-
ment problems in patients undergoing cardiopulmonary
bypass. Additionally, bovine lung heparin has a more
reliable protamine neutralization response [100].
Medical patients receiving porcine heparin had a much
higher frequency of thrombocytopenia than those receiving
bovine heparin [101,102]. Unfortunately, in randomized
studies of acute thrombosis, bovine lung heparin was more
likely to cause heparin-induced thrombocytopenia (HIT)
than porcine heparin [103–107]. Soon porcine heparin
became preferred at many medical centers.
In cardiac surgery patients, HIT occurs in 0.75% to 3%
[108]. A prospective, randomized study of HIT antibody
seroconversion in 98 cardiac surgical patients, found no
difference between bovine and porcine heparins (34% vs.
28%, respectively, p =0.74) [109]; however, samples were
not tested after postoperative day 5, because it is too early
to detect most cases of HIT [110]. A more recent
randomized trial found that bovine vs. porcine heparin
was associated with a significantly higher seroconversion
rate: 49.5% vs. 35.2%; respectively, as well as late
seroconversion: 46.8% vs. 32.0% [111]. Now, with the
outbreak of bovine spongiform encephalopathy (‘‘mad cow
disease’’), only porcine heparin is used in the United States
and Europe [112].
3.2.1.2. Variability resulting from batch variability and
potency standardization. Heparin cannot be prepared with
conventional methods. Small-scale batch processing is
required and significant batch variability results. The
potency of each batch must be standardized using a United
States Pharmacopoeia (USP) reference standard yielding
units of activity per milligram. A discrepancy of at least
10% in heparin activity was found when the USP reference
was compared with the 4th International Standard (IS)
[113]. Similarly, a collaborative study by the World Health
Organization found that the USP and EP (European
Pharmacopoeia) standards differed from their labeled
potencies by 10.6% and 2.6%, respectively, when assayed
against the 5th International Standard by all methods.
Today’s heparin preparations have higher mean molecular
weights and narrower molecular weight distributions which
yield higher specific activities (180–210 IU/mg). Better
agreement is observed when heparins are calibrated against
a reference with similar properties.
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 93
3.2.1.3. Variability resulting from patient specific fac-
tors. The response to a fixed heparin dose varies
significantly between patients. A patient’s physiologic state
at heparinization is often acute. Increases in acute phase
reactant proteins such as factor VIII and fibrinogen
commonly shorten the APTT and may appear as heparin
resistance [114]. Alternatively, warfarin or factor deficien-
cies may prolong the APTT. In these cases, less heparin may
be required [115]. The common lupus anticoagulant,
monoclonal gammopathies, and dysfibrinogenemia may
also prolong the APTT but increase the risk of inadequate
heparinization [116]. Some acute phase reactants bind
heparin, preventing complex formation with ATIII and
successful anticoagulation [117]. Weight and age influence
the response to heparin through altered intravascular volume
and binding of heparin to vascular surfaces.
3.2.2. Heparin monitoring during and after
cardiopulmonary bypass
To prevent catastrophic hemorrhagic or thrombosis,
heparin requires close monitoring by two complementary
modalities: functional assays which monitor clotting
time and quantitative assays which monitor heparin
concentrations.
3.2.2.1. Activated clotting time (ACT). Development of
the ACT clotting time was seminal in managing cardiopul-
monary bypass. ACT tests whole blood clotting and protein
function. Thrombin time and PTT will not clot at the large
heparin doses required for cardiopulmonary bypass and
therefore are not useful. ACT monitoring was developed by
placing whole blood in a glass or plastic receptacle with
premeasured activator [118]; however, variability in mea-
surement led to the development of automated methods.
The two most common activators are kaolin (aluminium
silicate) and celite-diatomaceous earth (sodium silicate).
Kaolin is an artificial product. Celite is isolated from clay
deposits that are heavily laden with microskeletons of
diatoms (prehistoric protozoan-like creatures). Both activate
Hageman factor which leads to factor IX and then factor Xa
production. Kaolin is preferred if aprotinin is being used
because kaolin absorbs 98% of aprotinin on contact,
therefore negating the effect of aprotinin on the ACT. Celite
does not absorb aprotinin and aprotinin significantly pro-
longs the ACT [119]. Aprotinin, because of its ability to
inhibit kallikrein, decreases thrombin–antithrombin III
complexes, fibrin-split products, fibrinopeptide 1 and 2,
prothrombin fragments, and all markers of thrombin
formation, thereby prolonging the ACT [120].
A roughly linear relationship exists between heparin dose
and the ACT if certain criteria are maintained [118], namely:
normal ATIII and factor XII activities, normothermia, near
normal platelet function, a platelet count greater than
50,000, and fibrinogen concentration greater than 100 mg/
dl. Before cardiopulmonary bypass, a dose–response curve
can be drawn both to monitor the ACT and calculate the
protamine reversal dose. An ACT between 300 and 600 s is
recommended to prevent clot formation in the oxygenator
and minimize bleeding complications [118]. Alternatively,
others employ a heparin protocol to reduce heparin rebound
and postoperative bleeding [121]: including administration
of 300 U/kg heparin IV initially with additional heparin if
required to achieve ACT greater than 300 s prior to and
during normothermic cardiopulmonary bypass and greater
than 400 s during hypothermia (under 30 -C).
3.2.2.2. Heparin levels. Given the variability in the ACT,
heparin concentration can also be measured directly.
Acceptable levels during cardiopulmonary bypass are
3.5–4 U/ml. Heparin concentration is measured by bubbling
air through individual specimens in glass wells, each of
which contain incrementally larger amounts of protamine.
The first tube to clot contains the optimal ratio of heparin to
protamine and yields a heparin concentration.
The combined use of ACT and heparin levels have
decreased perioperative bleeding and transfusion when
compared with the ACT alone; however, heparin monitoring
is expensive [121] and some investigators believe heparin
levels correlate well with ACT [122]. Others have shown
weak correlation between these modalities [121]. This is
particularly true with antithrombin III deficiency and
heparin resistance [123] in which 2–3 times the standard
heparin dose may be required to achieve the desired ACT of
480 s. If cardiopulmonary bypass were initiated based on
heparin levels without benefit of functional (ACT) testing,
catastrophic thrombosis may result. The etiology of
antithrombin III deficiency is usually a previous dose-
dependent exposure to heparin [124]. The treatment is
antithrombin III replacement with fresh frozen plasma or
antithrombin III concentrate.
3.2.3. Heparin dosing, metabolism, and management on
cardiopulmonary bypass
Initial heparin doses range from a 200–400 U/kg bolus
before cannulation, 200–400 U/kg in the circuit, and 50–
100 U/kg ongoing administration every 30–120 min.
Heparin’s peak therapeutic effect occurs within 2 min.
Cardiopulmonary bypass may delay the peak effect by 10–
20 min from hypothermia or hemodilution. Plasma binds
95% of heparin with some uptake by the extracellular fluid,
alveolar macrophages, splenic/hepatic endothelial cells and
vascular smooth muscle. The plasma half-life is dose-
dependent, i.e., 126T24 min at a dose of 400 U/kg vs. 93T6min at a dose of 200 U/kg [125]. Heparin is metabolized by
the reticuloendothelial system and eliminated by the
kidneys. Hypothermia and renal impairment, but not hepatic
impairment, delay elimination.
An ACT is measured before heparinization and repeated
a minimum of 3 min after giving heparin. A two-point
(straight line) dose–response curve assists in judging how
much additional heparin to administer. Cardiopulmonary
bypass is not initiated until an adequate ACT or heparin
Table 2
Protamine reactions
I Hypotension from rapid administration (histamine related)
II Anaphylactic shock-hypotension, bronchospasm, flushing
and edema
IIA IgE and IgG mediated, systemic capillary leak
IIB Immediate nonimmunologic anaphylactoid reaction
IIC Delayed reaction related to complement activation
III Catastrophic pulmonary vasoconstriction, elevated pulmonary
artery (PA) pressures, decreased left atrial (LA) pressures and
myocardial depression
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11594
level is confirmed. The optimal ACT for cardiopulmonary
bypass is controversial. Although the minimum recommen-
ded ACT is 400 s, others recommend 480 s [118], since
heparin only partially inhibits thrombin formation. This is
done to minimize the consumptive coagulopathy that may
result from barely adequate anticoagulation. Failure to
achieve a satisfactory ACT may be due to inadequate
heparin or to low concentrations of antithrombin III, or
‘‘heparin resistance.’’ If 500 U/kg of heparin fails to achieve
an adequate ACT, ATIII deficiency becomes more likely,
and fresh frozen plasma or recombinant ATIII [126] is
necessary to increase antithrombin concentration.
During bypass, the ACT or heparin level is measured
every 30 min and more heparin is given to maintain target
levels. Usually one third of the initial heparin bolus is given
every hour even when the ACT is therapeutic. Heparin
levels are more reproducible than the ACT, but ACT has a
long and generally safe track record. Although excessively
high ACTs (i.e., >1000 s) may cause bleeding remote from
operative sites, low concentrations increase circulating
thrombin and risk low grade thrombosis in the circuit and
a post-bypass consumptive coagulopathy [127].
One study prospectively evaluated whether heparin and
protamine doses administered using a standardized protocol
based on body weight and activated clotting time values
were associated with either transfusion of hemostatic blood
products or excessive postoperative bleeding in 487 cardiac
surgical patients. Prolonged duration of cardiopulmonary
bypass, lower pre-bypass heparin dose, lower core body
temperature in the intensive care unit, combined procedures,
older age, repeat procedures, a larger volume of salvaged
red cells reinfused intraoperatively and abnormal laboratory
coagulation results (prothrombin time, activated partial
thromboplastin time, and platelet count) after cardiopulmo-
nary bypass were associated with both increased transfusion
and chest tube drainage. Female gender, lower total heparin
dose, preoperative aspirin use and the number of hemostatic
blood products administered intraoperatively were associat-
ed only with increased chest tube drainage. A larger total
protamine dose was associated only with perioperative
transfusion of hemostatic blood products. Preoperative use
of warfarin or heparin was not associated with excessive
blood loss or perioperative transfusion of blood products
[75].
3.3. Protamine
3.3.1. Heparin reversal
Protamine is a positively charged basic polypeptide
isolated from salmon sperm which binds electrostatically
to negatively charged heparin and reverses its anticoagulant
effect. One to three mg/kg of protamine is given for each
100 units of the initial heparin dose. A randomized study of
26 infants and children compared heparin reversal using
standard 1 mg/1 mg ratio of total administered heparin for
patients in one group and of the individualized residual
heparin concentration in the other group. They found that
individualized management of anticoagulation and its
reversal results in less activation of the coagulation cascade,
less fibrinolysis, and reduced blood loss and need for
transfusions [128]. After 1/3 to 1/2 of the planned protamine
dose is administered, blood from the surgical field must not
be returned to the cardiotomy reservoir to avoid circuit
thrombosis. An ACT or heparin level confirms adequate
heparin neutralization. More protamine (0.5–1 mg/kg) can
be given if either test remains prolonged and bleeding is a
problem.
3.3.2. Protamine anticoagulant effect
Although protamine’s neutralizing dose is 1:1 (1 mg to
100 Units), in large doses protamine exerts an anticoagulant
and antiplatelet effect that requires an excess of 3:1, by
inhibiting the proteolytic activity of thrombin on fibrinogen
[129,130]. This prolongation is paradoxically reduced by
heparin. Protamine decreases the platelet count by electro-
statically adhering to platelet membranes forming micro-
aggregrates [131] and causes the release of tissue
plasminogen activator from endothelium [132].
3.3.3. Protamine reactions
Hypotensive protamine reactions can occur when prot-
amine complexes with heparin because complement is
released. This is much less common in children than adults.
This hypotension can be attenuated by adding calcium (2
mg/1 mg protamine).
Rarely 0.6%–2% of patients receiving protamine have
anaphylactic reactions from antibodies to protamine insulin
[133]. Patients who are insulin-dependent diabetics on NPH
(neutral protamine Hagedorn), who have undergone vasec-
tomy, or who are allergic to fish are at particular risk.
Pediatric protamine reactions are rare occurring in 1.7–
2.8% of patients undergoing cardiopulmonary bypass [134].
Life-threatening reactions to protamine represent true
allergic reactions and are classified in Table 2. Protamine
reactions are treated with calcium chloride, volume resus-
citation, phenylephrine, norepinephrine, and other inotropic
support as required. For severe reactions, it may be
necessary to readminister heparin and resume cardiopulmo-
nary bypass.
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 95
3.3.4. Heparin rebound
Heparin rebound is a delayed anticoagulant effect after
protamine neutralization due to the rapid metabolism of
protamine and to the release of ‘‘stored’’ heparin from
lymphatic tissues and other deposits. A significant amount
of heparin is nonspecifically bound to plasma proteins and is
incompletely neutralized by protamine. Heparin rebound
manifests postoperatively by increases in thrombin clotting
time, antifactor Xa activity, and protein-bound heparin 1–6
h after surgery [135].
A prospective randomized study of heparin rebound in
300 adults undergoing cardiopulmonary bypass evaluated
the effect of a small dose of protamine (25 mg/h for 6 h) on
bleeding. Every control patient manifested heparin rebound
with increased thrombin clotting time, antifactor Xa activity,
and protein-bound heparin between 1 and 6 h after surgery.
Heparin rebound was eliminated in the experimental group
with normal thrombin clotting times and nearly undetectable
heparin levels and protein-bound heparin. Bleeding was
reduced by 13%, although transfusions were not changed.
No adverse events were attributable to the extra protamine
[135].
3.4. Alternative anticoagulants for cardiopulmonary bypass
with heparin sensitivity
While heparin-induced thrombocytopenia will be cov-
ered in other chapters, Table 3 summarizes alternative
anticoagulants that can be used to manage cardiopulmonary
bypass when heparin is contraindicated. The alternative
direct thrombin inhibitors inhibit fibrin-bound thrombin
able 3
lternate anticoagulants
eneric Name
Trade Name)
Source Mechanism Half-life Dosing for CPB Reversible Elimination Monitoring
epirudin
(Refludan)
Recombinant
(modified leech
salivary protein)
Direct thrombin
inhibitor
[136–139]
1.3 h Load with 0.25 mg/kg
IV 0.2 mg/kg in the
prime volume infusion
of 0.5 mg/min until
15 min before stopping
bypass [140]
No Renal Difficult, modified
ecarin clotting time,
APTT, aiming for
lepirudin levels
between 3.5–4.5
micrograms/ml
[141,142]
ivalirudin
(Angiomax)
Recombinant
(modified leech
salivary protein)
Direct thrombin
inhibitor
[136,137]
25 min,
requires
infusion
1 mg/kg bolus–2.5
mg/kg/h
Yes Renal ACT
rgatroban
(Argatroban)
[143,144]
Synthetic l-arginine
derivative
Direct thrombin
inhibitor
[136,137]
39–51 min 2 Ag/kg/h No Hepatic,
good for
renal failure
APTT
rgaran
(Danaparoid)
[145,146]
Natural LMW
heparinoid
(glycosaminoglycan
with heparan sulfate,
dermatan sulfate,
and chondroitin
sulfate) [147]
Direct thrombin
inhibitor
[136,137]
24 h factor Xa
activity; 7 h
for thrombin
inhibition
5000 U bolus [145] Danaparoid plasma
levels 10 min after
initial bolus and 10
min after institution
of CPB, 1–2 checks
during CPB to keep
levels 1.0–1.5 U/ml
T
A
G
(
L
B
A
O
independent of antithrombin [136], do not require access to
the heparin binding site of thrombin, and inhibit both fibrin-
bound and fluid-phase thrombin.
3.5. Pharmacologic adjuncts to decrease bleeding after
cardiopulmonary bypass
Antifibrinolytic agents are commonly used in cardiac
surgery and they act not only by inhibiting fibrinolysis but
also by protecting platelets. They are optimally given before
the fibrinolysis initiated by cardiopulmonary bypass.
3.5.1. Aprotinin
Aprotinin is a low molecular weight serine protease
inhibitor, isolated from bovine lung. Its antifibrinolytic
effect is via the inhibition of plasmin and kallikrein.
Reversible complexes are formed with various proteases
that act against trypsin, plasmin, streptokinase-plasma
complex, tissue kallikrein, and plasma kallikrein. Aprotinin
intervenes in the coagulation cascade at multiple loci.
Aprotinin inhibits propagation of ‘‘intrinsic’’ fibrinolysis
through factor XII-mediated kallikrein activation and the
generation of plasmin through ‘‘extrinsic’’ or t-PA-mediated
activation of plasminogen. Aprotinin reduces thrombin-
mediated consumption of platelets by preserving adhesive
platelet receptors (GpIb). Aprotinin is excreted via the
kidney and raises ACT.
When aprotinin was first used in cardiac surgery,
hemostasis was rapidly established in 5 patients manifesting
a coagulopathy after cardiopulmonary bypass [148]. The
currently accepted regimen of high-dose aprotinin in adults,
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11596
5–6 million KIU average total dose (2 million KIU pre-
bypass, 2 million KIU in the pump prime and 500,000 KIU/
hr) is derived from the Hammersmith group [149], who
were attempting to reduce lung inflammation and observed
improved hemostasis [150].
One study showed an increase in neurologic and renal
deficits during circulatory arrest and concluded that patients
undergoing hypothermic arrest may require additional
heparin [151]. However another study demonstrated that
the converse was true [152]. A meta-analysis demonstrated
a significant reduction in the incidence of postoperative
stroke in patients undergoing coronary artery bypass
grafting [153]. Aprotinin has demonstrated reduced blood
loss, transfusion requirements and rates of reexploration in
the adult cardiac surgery population [154], including
decreased blood loss in patients with preoperative platelet
dysfunction [155].
The efficacy of aprotinin in children is controversial. A
small prospective randomized study of cardiopulmonary
bypass in children showed no clinical benefit [156]. Two
other small randomized studies in children found no
significant reduction in perioperative blood loss with either
low or high dose aprotinin [157,158]. The low dose group
received 20,000 units/kg after anesthesia, 20,000 units/kg in
the prime, and another 20,000 units/kg given every hour of
cardiopulmonary by pass. The high dose group received
35,000 units/kg after anesthesia, 35,000 units/kg in the
prime, and an infusion of 10,000 units/kg/min until the end
of the operation. Possible reasons why the efficacy of
aprotinin could not be demonstrated in these studies are that
there exists a known variability of plasma aprotinin levels in
children undergoing CPB [159] which often results in
subtherapeutic plasma levels, especially in the low-dose
group, and that small underpowered studies may have failed
to reach significance.
In contrast, several recent studies have shown significant
improvements in blood loss and blood product usage with
high dose aprotinin [160,161]. Some studies have demon-
strated the efficacy of only high dose aprotinin in
reoperative and highly complex malformations [162,163].
Patients undergoing repair of ventricular septal defect repair,
tetralogy of Fallot, and transposition of the great vessels
received low dose (500,000 KIU in the pump prime only)
and high dose (50,000 KIU/kg after anesthesia, 50,000 KIU/
kg in pump prime, and 20,000 KIU/h continuous infusion)
aprotinin [163]. Only complex patients benefited, and of
those, only those receiving the high dose regimen benefit-
ted. No benefit was seen with the low dose regimen. In
reality, there is no true low/high dose regimen but several
weight/BSA-based protocols developed to achieve and
maintain a plasma level (200 KIU/ml).
Recently, the variability of plasma aprotinin levels was
highlighted in children undergoing cardiopulmonary bypass
using current weight-based protocols [159]. Neonates and
smaller children were at a high risk of reaching subthera-
peutic levels of aprotinin. The authors concluded that dosing
regimens aimed at achieving ‘‘target’’ aprotinin concen-
trations for pediatric patients of all weight groups need to be
developed to better define the role of aprotinin in blood
conservation. Several strategies are summarized in Table 4.
A hypersensitivity phenomenon to aprotinin has been
observed. The incidence is <1% during the first exposure,
and increases to 5–6% on repeat exposure [164,165].
Children frequently require sequential reoperations and
possible risk of an allergic reaction must be considered;
however, in children, the risk of hypersensitivity was much
lower even after multiple reexposures, ranging from 1%
after the first exposure to 2.9% after the third or higher
exposures [164,166].
A comprehensive review of pediatric patients undergoing
cardiopulmonary bypass suggests that children undergoing
reoperative cardiac surgery have improvements in postop-
erative blood loss, but that blood loss is not reduced in
children undergoing primary surgical repair [167]. The
potential antiinflammatory and antifibrinolytic benefits are
unclear because of the wide range in dosing and plasma
levels found in these studies. It is clear that achieving a
plasma concentration between 200 KIU/ml and 400 KIU/ml
is important [167]. A known discrepancy exists in pediatric
dosing because of age-related differences in body surface
area to weight ratio. Neonates are particularly affected. In
children less than 10 kg, some have recommended that a
minimum of 500,000 KIU be added to the pump prime to
offset the dilutional effect of priming volume [168].
The current literature suggests that aprotinin be used in
high risk and reoperative patients to reduce blood loss and
transfusion requirements. Further weight-based dosing
regimens need to be developed to achieve plasma levels
of 200–400 KIU/ml [167].
Despite an early study suggesting increased graft
thrombosis after reoperative coronary artery bypass [169],
a meta-analysis on all prospective randomized placebo
controlled trials using aprotinin has demonstrated no
increased risk of thrombosis in the adult population [170].
In the pediatric population there is no evidence of increased
thrombosis in the current literature and to date [167].
3.5.2. Epsilon aminocaproic acid (Amicar)
Epsilon aminocaproic acid (EACA) is a synthetic
antifibrinolytic agent which forms reversible complexes
with either plasminogen or plasmin, saturating the lysine
binding sites and displacing plasminogen, and therefore
plasmin, from the surface of fibrin. This blocks plasminogen
activation and fibrinolysis.
EACA has been used successfully to treat patients
undergoing coronary artery bypass grafting with coagulation
disorder [171]. It has also been used prophylactically to
reduce blood loss in patients undergoing cardiopulmonary
bypass, having an impact on both blood loss and transfusion
of autologous blood and blood products [172]. Low-dose
aprotinin and EACA have shown similar effects on the
reduction of intraoperative and postoperative bleeding in the
Table 4
Pharmacologic adjuncts for hemostasis
Mechanism Dosing Evidence
of efficacy
Evidence of risks
Aprotinin
(Trasylol)
Serine protease inhibitor
w multifocal effects (see text)
Concentration: 1 cm3=1.4
mg=10,000 KIU
Strong Adults report
Adults: (need 200 KIU/ml
plasma level)
Renal impairment after DHCA
(not seen in children)
Hammersmith dosing protocol
Dysfhythmias
5–6 million KIU average total dose
Neurologic events
2 million KIU pre-bypass
Thrombotic problems
2 million KIU in the pump prime
Allergic reactions: avoid repeat with-
in 6 months, give test dose of 1 ml
(10,000 KIU) before loading dose,
delay load until CPB can be easily
instituted, do not put aprotinin in
pump until loading dose has been
safely given, have H1 and H2 block-
ers ready as well as epinephrine and
steroids
0.5 million KIU/h
Pediatrics: (no manufacturer or dosing
recommendations but a plasma level of
200 KIU/ml is probably advisable)
Regimen 1:
Load Pt/Pump: 30,000 KIU or
4.2 mg/kg each
Infusion: none
Regimen 2:
Load Pt/Pump: 35–50,000 KIU
(or 4.9–7.0 mg KIU/kg) each
Infusion 10–20,000 KIU
(or 1.4–2.8 mg/kg/h)
Regimen 3
Load Pt/Pump 240 mg/m2 each
Infusion 56 mg/m2/h
Note: BSA-based dosing yields higher
doses of aprotinin
Epsilon
aminocaproic
acid (Amicar)
Complexes with plasminogen
at lysine-binding sites, and
blocks adhesion to fibrin
Adults: Yes No significant evidence
Load: 100 mg/kg, Infusion: 1 g/hr
Load: 150 mg/kg, Infusion: 30 mg/kg/hr
Load: 50 mg/kg, Infusion: 25 mg/kg/hr
Pediatrics:
Load 75 mg/kg, infusion 15 mg/kg/h
Load 150 mg/kg, infusion 30 mg/kg/
h (this dose was felt appropriate to
achieve desired plasma level of 130
mcg/ml)
Load 75/mg/kg, 75 mg/kg into pump
circuit, Infusion 75 mg/kg/h (to achieve
plasma level 260 mcg/ml)
Tranexamic
Acid
Complexes with plasminogen
at lysine-binding sites, and
blocks adhesion to fibrin
Adults: Yes No significant evidence
Load 10 mg/kg, infusion 1 mg/kg/h
2� and 4� did not change blood loss
in adults
Pediatrics:
Load 100 mg/kg, Infusion: 10 mg/kg/hr
DDAVP Stimulates endothelium to
release von Willebrand factor,
tPA and prostacyclin
0.3 mcg/kg single dose
None
[183,184]
None [180,182]
Conjugated
Estrogens
Unknown 0.6 mg/kg/day�5–6 days OR
50 mg/day
None None
Steroids Unknown Solucortef 100 mg IV None None
Recombinant
factor VII
Activation of factor X via the
VIIa-TF enzymatic complex to
the enzyme factor Xa and
subsequent thrombin generation
50–60 mcg/kg per dose�3–4 doses
up to 225 mcg/kg
Yes Thromboembolic complications
as high as 10% [192]
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 97
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–11598
adult cardiac surgery population [173]. A prospective
randomized study compared low dose aprotinin with EACA
in the pediatric population and found a significant decrease
in perioperative blood loss and transfusion requirement with
both drugs but no difference between both drugs [174].
3.5.3. Tranexamic acid
Similar to EACA, tranexamic acid forms a complex with
plasminogen through lysine-binding sites, thus blocking
their adhesion to fibrin. In contrast to EACA, tranexamic
acid is approximately 10 times more potent. A prospective
randomized study in children undergoing cardiopulmonary
bypass compared tranexamic acid (100 mg/kg, followed by
10 mg/kg/h) with placebo and found significantly decreased
blood loss [175]. As with EACA, postoperative bleeding
and homologous blood requirements were similarly de-
creased with the use of tranexamic acid patients undergoing
cardiopulmonary bypass [176]. A dose comparison study in
children found that a triple dose regimen using 10 mg/kg on
induction, once on cardiopulmonary bypass, and after
protamine resulted was most effective in reducing perioper-
ative blood loss [177]. Further, in adults undergoing
cardiopulmonary bypass pretreated with aspirin, aprotinin
was no better than tranexamic acid in curtailing blood loss
and was much cheaper [178].
3.5.4. Desmopressin (DDAVP)
DDAVP is a synthetic analogue of vasopressin with
decreased vasopressor activity. It stimulates the vascular
endothelium to release von Willebrand factor, tissue
plasminogen activator and prostacyclin. DDAVP results in
a 2 to 20-fold increase in factor VIII levels and mediates
platelet adherence to the vascular subendothelium. A
prospective randomized study in adults undergoing cardio-
pulmonary bypass for various indications demonstrated
significantly reduced mean operative and early postopera-
tive blood loss (1317T486 ml in the treated group vs.
2210T1415 ml in the placebo group). However the
excessive blood loss in both groups and the absence of
data on transfusion requirement cast some doubt on their
findings [179]. Another nonrandomized study demonstrated
a significant decrease in transfusions (especially platelets) in
patients treated with DDAVP [180].
In contrast, a prospective randomized double blind study
in adults undergoing cardiopulmonary bypass for a variety
of indications demonstrated no overall reduction in blood
loss or transfusions for patients receiving DDAVP, but did
show a significantly lower intraoperative blood loss [181].
Another similar randomized double blind study in adults
showed no benefit for DDAVP in routine coronary artery
bypass surgery [182].
In children several reports have demonstrated no significant
benefit of DDAVP compared with placebo. A randomized
double-blind study in children undergoing cardiopulmonary
bypass found no difference in blood loss and transfusion
requirement between both groups [183]. A similar study
demonstrated no difference in blood loss in children under-
going repair of complex congenital heart defects [184].
The current literature in children undergoing cardiopul-
monary bypass shows no compelling evidence that DDAVP
reduces perioperative blood loss, except in patients with
hemophilia, von Willebrands Disease, uremic platelet
dysfunction, or chronic liver disease.
3.5.5. Conjugated estrogens
Reports have demonstrated shortened bleeding times and
reduced bleeding with conjugated estrogen in adult patients
with uremia [185]. Although the mechanism is unknown, the
effect lasts longer than DDAVP and cryoprecipitate in the
setting of uremic platelet dysfunction [186]. One study shows
improvement in perioperative blood loss [187], while another
showed no reduction in blood loss or transfusion requirement
[188]. Conjugated estrogens can be given intravenously or
orally. A single daily infusion of 0.6 mg/kg, repeated for 4–5
days, shortened the bleeding time by approximately 50% for
at least 2 weeks. A daily oral dose of 50 mg shortened the
bleeding time after an average of 7 days of treatment. The
pediatric literature offers no support for the routine use of
estrogens and the adult evidence is not compelling.
3.5.6. Steroids
Although salutary effects of steroids have been suggested
in a few studies in the adult cardiac surgery population
[189,190], a recent prospective randomized study in
children undergoing cardiac surgery showed no benefit
[191]. At the present time there is no compelling data to
support the routine use of steroids for the prevention of
bleeding after cardiopulmonary bypass.
4. After cardiopulmonary bypass
4.1. Transfusion/blood products
Much literature is dedicated to transfusion medicine and
is beyond the scope of this chapter. The brief discussion of
conventional products will be given, followed by more
detailed discussion of fresh whole blood and new compo-
nent therapies.
4.1.1. Platelets
Platelets are decreased in number and effectiveness by
cardiopulmonary bypass. Hemodilution accounts for most
of the decreased platelet count; sequestration, adhesion, and
destruction from contact with artificial surfaces account for
the rest [193]. In seconds, contact of blood with foreign
surfaces leads to platelet adherence, release of cytoplasmic
granules, and thromboxane A-2 production. This is medi-
ated by von Willebrand factor which acts as a bridge
between a specific glycoprotein on the surface of platelets
(GPIb/IX) and collagen fibrils, binding to and stabilizing
coagulation factor VIII. Binding of factor VIII by vWF is
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 99
required for normal survival of factor VIII (extremely labile
otherwise) in the circulation. Plasma levels of thromboxane
A-2 and platelet specific proteins rise at onset of bypass.
Platelet stores of ADP and ATP are depleted. Microemboli
formation contributes to platelet consumption.
Platelet counts decrease to 40–50% of baseline in the first
10–15min and then stabilize. This is followed by a passivation
of foreign surfaces which is characterized by reduced platelet
adhesiveness. Platelet counts rarely drop below 40–50% of
baseline and usually rise by 50% by postoperative day
2, returning to normal 3–7 days postoperatively, probably
from release after sequestration in the liver [193].
Acquired platelet dysfunction may also result from
therapeutic platelet inhibitors (e.g., aspirin and clopidogrel).
Stopping these agents prior to elective surgery is recom-
mended though not always feasible [194]. In these
instances, aprotinin is protective against platelet dysfunction
via preservation of platelet membrane bound glycoprotein
receptors [195].
Platelet transfusions may be used in the bleeding thrombo-
cytopenic patient. Even when counts are normal, platelets
may not be functioning properly. Platelets are frequently
the first line of product administration in children because
of the general activation that occurs on cardiopulmonary
bypass, abnormal function of remaining platelets, and not
infrequent use of platelet inhibitors. Single-donor or multiple-
donor pooled platelets are available. Single-donor platelets
reduce infection and risk of alloimmunization but are more
expensive. When pooled, platelets are typically from
5–8 donors. Platelets are not required to be ABO compatible
with the recipient; however, Rh negative recipients should
receive Rh negative donor platelets, because platelets
can contain enough erythrocytes for Rh sensitization.
4.1.2. Fresh frozen plasma (FFP)
FFP is separated from whole blood by centrifugation and
stored at �18 -C within 6 h of collection. Fifty percent
of factors V, VII, and VIII may be lost from lability, while
all other factors are 100% preserved. FFP can be stored at
�20 -C for up to 1 year. After cardiopulmonary bypass,
FFP is indicated when there is evidence of significant
coagulation factor deficiency with a prothrombin time (PT)
and plasma thromboplastin time (PTT) more than 1.5 times
the control. Ten ml/kg of FFP should raise the factor levels
by 2–3%. FFP must be ABO compatible with the recipient’s
red cells. The volume of FFP in each pack is stated on the
label and may vary between 180 and 400 ml. The traditional
dose of 5 to 10 ml of plasma per kilogram body weight may
have to be exceeded in massive bleeding. Therefore, the
dose depends on the clinical situation and monitoring.
The use of FFP in pump prime has been hypothesized to
avoid dilution of fibrinogen, decreasing the need for
subsequent product transfusion. Twenty infants less than
8 kg undergoing cardiopulmonary bypass were prospectively
randomized to receive 1 unit of FFP in the prime (vs. none in
the control group) [84]. Infants receiving FFP in the prime
had significantly less dilutional hypofibrinogenemia, need
for cryoprecipitate after bypass, and tended to have less mean
exposure to blood products [84]. A prospective randomized
study from theMayo clinic found that patients who received 1
unit of FFP in the prime (vs. 5% albumin) had significantly
higher total transfusions (8.0T4.2 vs. 6.1T4.5 U, respective-ly; p =0.035). A post hoc analysis suggested that patients
with cyanosis and those requiring complex operations had
less blood loss with FFP, than did those receiving albumin in
the prime. Conversely, noncomplex, acyanotic patients had
fewer transfusions with albumin prime [196].
4.1.3. Cryoprecipitate
Cryoprecipitate is prepared by thawing frozen plasma at
4 -C and recovering the precipitate. The cryoprecipitate
derived from one unit of whole blood contains 80–100 units
of factor VIII and vWF and 150 mg of fibrinogen. In the
bleeding patient after cardiopulmonary bypass, cryoprecipi-
tate transfusion is indicated at a dose of 5 ml/kg if the
fibrinogen level falls to less than 100 mg/ml [197].
4.1.4. Packed red blood cells
Packed red cells are indicated in the treatment
of postoperative anemia to increase oxygen transport and
intravascular volume. One unit contains 300–350 ml and with
additives can be stored for up to 42 days. Depending on the
type of congenital defect, packed red blood cells are used
to maintain hemoglobin levels at optimum levels postopera-
tively in order to preserve or augment oxygen carrying
capacity. A commonly used formula for determining the
volume of packed red cells transfusion in infants and children
is: (DesiredHgb (g/dl)�Actual Hgb)�Weight (kg)�3 [197].
4.1.5. Fresh whole blood
To avoid multiple exposures associated with individual
component therapy, fresh whole blood has been utilized to
replete all components of lost blood with one exposure
[198]. In children under 2 years of age and those undergoing
complex repairs with fresh whole blood less than 48 h old,
perioperative blood loss and exposure were decreased [199].
Mohr et al. compared recovery of platelet count and
function in 27 patients who were randomized preoperatively
to receive either 1 unit of fresh whole blood (15 patients) or
10 units of platelet concentrates (12 patients) after cardio-
pulmonary bypass. Platelet thromboxane formation was
higher after 1 unit of fresh whole blood than after 10 platelet
units (95T25 vs. 46T35 ng/ml, p less than 0.05), as was
platelet aggregation response to collagen and epinephrine.
The 24-h blood loss was smaller in the fresh whole blood
group (560T420 ml vs. 770T360 ml), although the
difference was not statistically significant. The authors
therefore concluded that one unit of fresh whole blood
was equal to 10 units of platelets [198]. Another study
compared the effects of fresh vs. old blood in the pump
prime and found that although stored blood had a lower pH,
a higher lactic acid level, and a higher potassium concen-
2 This section was developed with the assistance of Phillip Millman who
discloses a financial interest in thromboelastography. The proposed
management of bleeding herein has been more carefully studied in adults
than children and has yet to be completely validated in pediatrics
Nevertheless, a discussion of current thinking with respect to thrombelas
tography is presented.
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115100
tration than fresh whole blood, this resulted in a minimal
effect on the final constitution of the priming solution before
and during cardiopulmonary bypass in children [200].
A randomized double-blinded study comparing the use of
fresh whole blood with combined packed red cells and FFP
(reconstituted blood) for priming in 200 children under 1 year
of age found no advantage to fresh whole blood. In fact,
patients receiving fresh whole blood had a significantly
longer stay in the intensive care unit (70.5 h vs. 97.0 h,
p =0.04) and a larger cumulative fluid balance at 48 h (�6.9
ml/kg of bodyweight vs. 28.8ml/kg, p =0.003) [201]. As part
of routine management, however, those patients generally
received intraoperative autologous donation (sequestration of
heparinized blood just upon initiation of cardiopulmonary
bypass). Therefore the use of autologous blood in both
experimental and control groups may have minimized any
added benefit of fresh whole blood in the experimental group.
Many institutions routinely use fresh whole blood during
cardiac surgery. The factors limiting its routine use are the
availability of donors, and logistical constraints necessary
for preoperative screening. Additionally, fresh whole blood
is generally stored at 4 -C, a temperature that depresses
platelet function when compared with storage at room
temperature [202]. Current recommendations are that in
neonates and smaller children fresh whole blood may offer
hemostatic and antiinflammatory benefits however in larger
patients this may not be clinically significant or practical.
4.1.6. Recombinant factor VII
Recombinant factor VIIa has been effective in the
treatment of post-bypass bleeding in patients who have a
high titer of factor VII inhibitors [203,204]. In congenital
heart surgery patients, factor VIIa has been shown to
effectively reduce intractable hemorrhage [205,206]. The
half-life is at least several minutes and the patient’s
prothrombin time is corrected rapidly.
There are several hypotheses as to how recombinant
factor VIIa promotes the localized generation of thrombin, a
prerequisite for fibrin clot formation [204]. Normal blood
clotting depends on the complex formed by factor VIIa with
its cofactor, tissue factor. When recombinant factor VIIa is
administered, it may saturate the tissue factor expressed at
the site of endothelial injury. This complex activates factor
X to Xa and initiates thrombin generation [207]. A second
line of evidence suggests that recombinant factor VIIa
generates thrombin (independent of tissue factor) on the
surface of activated platelets accumulating at the site of
endothelial injury. In spite of factor VIIa’s low affinity for
activated platelets, therapeutically it appears to achieve
adequate concentrations to generate local thrombin forma-
tion [208]. Finally, evidence in hemophiliacs suggests that
recombinant factor VIIa activates thrombin-activatable
fibrinolytic inhibitor, a zymogen which protects fibrin clots
from premature lysis; however, no evidence supports this as
a clinically important mechanism in patients with normal
coagulation systems [209].
The role of recombinant factor VIIa in adult cardiac
surgery is unclear. In coronary revascularization, tissue factor
released at the anastomoses or unstable coronary plaquesmay
lead to thrombosis and subsequent graft occlusion [210].
Recombinant factor VIIa was studied in children undergoing
cardiac surgery with excessive blood loss after failure of
conventional treatment [211]. Blood loss significantly
decreased (7.8 ml/kg/h), nearly eliminating the need for
additional blood products with normalization of the pro-
thrombin time. In two patients with thrombocytopathy,
recombinant factor VIIa discriminated surgical bleeding from
defects in hemostasis, a further evidence that recombinant
factor VIIa is safe and effective when other means fail [211].
To date use of recombinant factor VIIa has been reported
in 20 cardiopulmonary bypass patients in the adult
population. Hemostasis was achieved in all patients. In 14
patients (70%), rapid hemostasis was achieved following a
single dose (mean 57 mcg/kg). In 6 patients (30%)
hemostasis was eventually achieved after a mean of 3.4
doses (mean cumulative dose 225 mcg/kg). In 2 patients
(10%), thromboembolic complications were noted. One was
fatal and in another, intracoronary thrombosis was suspected
but was not confirmed [192].
In patients experiencing postoperative hemorrhage with
no surgical source and refractory to blood product admin-
istration and hemostatic agents, recombinant factor VIIa
may be considered; however data are limited and further
research is needed to define the role of recombinant factor
VIIa in children.
5. Thrombelastography to guide transfusion therapy
Because of the acute nature of bleeding after cardiopul-
monary bypass, blood product administration has developed
empirically. The thrombelastogram (TEG\) was introduced
in 1947 [212] and is now marketed as a proprietary analysis
of the dynamics of hemostasis.2 Whole blood clotting is
plotted against time from the initial clot formation, through
clot acceleration, to maximum clot strength, and ultimately
to clot lysis. Parameters derived from this bullet-shaped
graph are used to target therapy. Thrombelastography is the
single best predictor of post-bypass hemorrhage [213–215]
and is useful in decreasing that hemorrhage in children
[216–220]. Blood samples on bypass are activated with
kaolin (both with and without heparinase) to guide therapy
after bypass [216]. Baseline thrombelastograms in children
undergoing cardiac surgery have been established and
facilitate interpretation [221].
.
-
Fig. 1. Thrombelastography parameters.
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 101
Thrombelastography measures dynamic clot formation
using a pin suspended in a cup containing 0.36 ml of whole
blood and kaolin (with or without heparin) to stimulate the
intrinsic cascade. The cup is radially oscillated through an
angle of 4-–45Vevery 10 s. The torque between the cup and
pin is transduced and plotted against time as the clot forms
and lyses (Fig. 1).
Interpreting the thrombelastogram requires understanding
the sequence of clot formation. Convergence of the intrinsic
and extrinsic pathways leads to the formation of one-
dimensional thrombin fibers. This creates the initial ‘‘split
point’’ (SP) of the thrombelastogram. Thrombin then cleaves
soluble fibrinogen into fibrin monomers that polymerize into
Table 5
Normal thromboelastography parameters
Parameter Normal time Description
R 4–8 min R is the time elapsed from placement of blood
thrombelastogram first splits (‘‘split point’’). R in
activation (i.e., conversion of prothrombin to t
fibrinogen). If R is prolonged without heparinase a
after heparinase, then hemodilution, factor deficie
R�SP
[delta]
<1.1 min If R minus split point (R�SP) is normal, hemod
Hemodilution: R prolonged, R remains prolonged
Heparin excess: R prolonged, R normalizes with
Factor deficiency: R prolonged, R prolonged wit
K 1–4 min K is useful as a determination of the initial cros
While it is not used to guide clinical therapy, it is
takes the angle (a) to reach 20 mm.
a 47–74- a measures the rapidity of fibrin build-up and cro
function. A higher angle indicates hypercoagulab
MA 55–73 mm Maximum amplitude is perhaps the most import
platelet bonding, and is an important measure of
unless consumptive coagulopathy is at work.
EPLY30 0–15% True percent lysis at 30Vis calculated by the formul
Normal clots do not lose more than 15% of their
Estimated percent of lysis from maximum amplitu
decision making.
Gmax 6.0 k–13.2
kdyn/s2G =5000 MA/(100�MA). This relationship is c
may translate into larger changes in clot strength
three-dimensional strands, producing the early acceleration
of clot strength after the split point. Thrombin also activates
platelets which, via GPIIb/IIIa receptors, form bonds
between fibrin strands to produce a rigid, elastic, clot or
maximum amplitude achieved by the clot. The strength and
stability of this clot to resist the deforming shear stress of
flowing blood, determine its ability to impede hemorrhage.
Clot strength diminishes as the clot gradually lyses during
vascular recovery or more rapidly with fibrinolysis.
Clinically, thromboelastography is directed at restoring a
normal tracing by targeting specific coagulation defects, in
theory increasing efficacy with fewer transfusion exposures.
First normal parameters will be reviewed in Table 5.
in the cup until 2 mm have elapsed graphically from the point where the
dicates initial thrombin formation and is the best indicator of early factor
hrombin, prefactor XIII thrombin cross-linking, and cleaving of soluble
nd corrects with heparinase, then heparin excess is present. If R is prolonged
ncy, or drugs (coumadin, direct thrombin inhibitors) are likely responsible.
ilution or heparin excess is likely and factor transfusion can be avoided.
with heparinase, normal R�SP, normal clot strength.
heparinase, normal R�SP, normal clot strength.
h heparinase, R�SP prolonged, clot strength (MA low).
s-liking of fibrin strands via factor XIII (after thrombin formation above).
used to determine a below. K determined from the end of R to the time it
ss-linking (clot strengthening). The lower the a, the poorer the fibrinogen
ility.
ant parameter, indicating the ultimate strength of the clot from fibrin and
platelet function. If the MA is normal, thrombocytopenia is not problematic
a 100 [MA�A30]/MA, where A30 is the amplitude noted 30 min into lysis.
strength by 30 min.
de is calculated with proprietary formulas to save time and expedite clinical
urvilinear and logarithmic, therefore small changes in maximum amplitude
[222].
Fig. 2. Typical thrombelastograms.
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115102
Next, typical pathophysiologic tracings are shown in
Fig. 2. Table 6 summarizes the stereotypical patterns
generated with these pathophysiologies. Table 7 provides
more detailed clinical recommendations for those
abnormalities.
5.1. Example 1
It is common to observe simultaneous clotting abnor-
malities after cardiopulmonary bypass. Hemodilution, a
surgical source of bleeding, excess heparin, clotting factor
deficiency, and platelet dysfunction may manifest simul-
taneously. After cardiopulmonary bypass, thrombelasto-
grams are run with kaolin (plain cup) and kaolin with
heparinase (to look for excess heparin). The early
parameters reveal:
R (plain cup)=16 min (prolonged, normal 4–8 min)
R (heparinase cup)=12 min (still prolonged, normal 4–
8 min)
R�SP (delta)=0.9 min (normal)
Here heparinase normalization of a prolonged R identifies
heparin excess. Nevertheless, the R is still prolonged in the
heparinase cup. The normal R�SP (or delta), indicates that
hemodilution is present but is not affecting the early function
of the clot. If the patient is still bleeding, surgical causes are
suggested.
5.2. Example 2
This example illustrates the philosophy of sequential
correction of a patient’s coagulopathy. A patient continues
to bleed after protamine administration.
R (plain cup)=9.9 min (prolonged, normal 4–8 min)
R (heparinase cup)=9.9 min (prolonged, normal 4–
8 min, no excess heparin)
R�SP (delta)=2 min (prolonged, normal <1.1 min)
G =3.0 kdyn/cm2 (low, normal 6.0–13.2 kdyn/cm2)
This patient is not simply hemodiluted (because the
R�SP is prolonged). The patient has no excess heparin
on board (as no change occurs in the heparinase cup).
Rather, factor deficiency is indicated by the prolonged R
and prolonged R�SP. FFP is the first product of choice,
because the thrombin must be present in order to
activate platelets. If R is corrected but clot strength
does not normalize with FFP, then platelets are indicated.
In general, algorithmic interpretation of the TEG is
sequentially directed at the dynamics of the clotting
process.
(1) A normal thrombelastogram defect points to surgical
bleeding, defective platelet adhesion (with a pump-
induced defect or platelet inhibiting drugs as a
cause).
(2) Simple hemodilution (as indicated by prolonged R,
normal G, and normal R�SP) requires no treatment
but also points to the same etiologies in [1].
(3) Heparin excess (as indicate by a prolonged R that
corrects with heparinase) indicates a need for more
protamine.
(4) Normal clot strength (G) generally requires no
treatment in spite of abnormalities in other parameters
(R, a, K). Surgical bleeding must be evaluated.
(5) Low clot strength requires interpretation with other
parameters
(a) Clotting factor deficiency (as indicated by a
prolonged R that does not correct with heparinase
and a long R�SP) indicates a need for FFP.
(b) Low a (and high K) indicates a need for
cryoprecipitate.
(c) Low MA indicates a need for platelets.
(6) Low EPLY30 indicates thrombolysis and indicates
that antifibrinolytics should be administered.
We should point out that the use of thromboelastog-
raphy in children is in its infancy and much of the
discussion has been generalized from the adult recom-
mendations. The algorithms presented may have to be
modified in children. For instance, one study of throm-
boelastography in children [217] found that platelet
administration alone was sufficient to control bleeding,
and return platelet counts and thrombelastogram parame-
Table 6
Profiles of typical abnormalities and directed treatment
Cause Treatment Thrombelastogram pattern
R plain cup
(kaolin only)
R heparinase (kaolin
and heparinase)
R�SP difference K/a MAG EPL
Surgical Sutures Normal Normal Normal Normal Normal Normal
Hemodilution No treatment
necessary
High High Normal Normal Normal Normal
Excess heparin Protamine High Normal heparinase
neutralizes residual
heparin
Normal Normal Normal Normal
Factor deficiency FFP High High heparinase has
no effect on factor
deficiency
High, because
thrombin is not
formed normally
Low or normal
because of
antecedent defect
Low or normal
because of
antecedent defect
Normal
Fibrinogen
deficiency
Cryo Normal Normal High Low Low or normal
because of
antecedent defect
Normal
Platelets low or
dysfunctional
Platelets Normal Normal Normal Normal Low Normal
Fibrinolysis primary Antifibrinolytic
TXA aprotinin
Normal Normal Normal Normal Low High
Fibrinolysis (DIC) Treat DIC Low Low Low High High High
NormalStage 1
Hypercoagulability
with fibrinolysis
Fibrinolysis (DIC) Treat DIC Low Low Low Low Low Low
Stage 2
Hypocoagulable
after consumption
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 103
ters to normal in 40% of children. Subsequently cryopre-
cipitate raised fibrinogen levels to normal and further
improved thrombelastograms. Interestingly, fresh frozen
plasma did not increase fibrinogen, worsened multiple
thrombelastogram parameters, increased ICU chest tube
output and transfusion requirement. Smaller children
required cryoprecipitate to correct their coagulopathy. This
discrepancy is currently being studied in additional
pediatric trials.
6. Topical hemostasis
Many topical hemostats have been developed over the
years and are summarized in Table 8.
6.1. Oxidized cellulose (Surgicel\)
Surgicel\ is a topical hemostatic agent consisting of
porous sheets of oxidized cellulose. Its was developed for
use in World War II after an American scientist observed
that cellulose (indigestible and unresorbable by humans)
can, by oxidation, be transformed into an effective,
resorbable hemostatic material [223], believed to provide a
lattice for clot formation through its ability to bind with
hemoglobin. Other hypothesized mechanisms are aggrega-
tion of erythrocytes or acceleration of fibrinogen formation
[224,225]. Surgicel\ consists of two components: a soluble
glucuronic acid component cleared by an early degradation
and systemic clearance within 18 h, and a fibrous
component degraded much more slowly requiring phago-
cytosis by macrophages at the site of implantation
[226,227]. Surgicel\ has also been shown to directly
activate the extrinsic coagulation pathway [228].
In addition to its hemostatic action it has demonstrated in
vitro bactericidal activity against Staphylococcus epidermi-
dis, Staphylococcus aureus, Beta streptococcus, Strepto-
coccus faecalis, Klebsiella aerogenes, Escherichia coli,
Proteus vulgaris, Pseudomonas aeruginosa, Bacteroides
fragilis and Clostridium perfringens [229,230].
Current evidence suggests that Surgicel\ does not
adversely affect adhesion formation and in fact may reduce
it. In animal studies, surgicel decreased the incidence of
peritoneal adhesions in rats [231,232]. In humans, surgicel
Table 7
TEG; Detailed Explanation and Clinical Recommendations
Thrombelastogram description:
likely etiology
Description Parameter ranges Adult treatment in OR Pediatric treatment in OR
Normal thrombelastogram:
1) Surgical Bleeding
2) Defective Clot Adhesion:
clot forms but bleeding
continues
This graph depicts normal
hemostasis with normal enzymatic
and platelet function and no lysis.
Thrombin has cleaved soluble
fibrinogen into fibrin and is
indicated by normal R, K, and avalues. Platelet function is also
normal with a normal MA value.
The G value (clot strength) is
within normal range and there is no
evidence of clot lysis (EPL=0%).
See normal ranges above Treatment is DDAVP (directed
at the platelet inhibitors) or
cryoprecipitate (directed at factor
VIII 2deficiencies). Incidentally,
when using thromboelastography,
cryoprecipitate is rarely indicated.
Cryoprecipitate or FFP (cryo
preferred by most centers)
Conventional thrombelastograms
are insensitive to platelet inhibitors
(aspirin, platelet inhibitors,
nonsteroidal antiinflammatory agents),
because in vitro thrombin
formulation overwhelms this
inhibition in vitro. Recently new
methodologies have been
developed. Lupus anticoagulants
are not detected nor has the
methodology to assay aprotinin
been developed, in part because
aprotinin’s mechanism via the
P2Y12 receptor or sub ADP
receptor is incompletely understood.
If a patient is bleeding with a
normal thrombelastogram (or
slightly abnormal thrombelastogram
with normal clot strength, G), then
the most likely sources of bleeding
are:
(1) surgical bleeding
(2) defective clot adhesion: i.e.,
manifests by normal clot formation
in chest or chest tube but continued
bleeding from failure of the clot to
adhere to the injured vessel wall,
etiologies are:
(a) von Willebrand’s
syndrome (absence of factor VIII)
(b) deficient factor VIII
after cardiopulmonary bypass
(c) platelet inhibiting drugs
(aspirin, platelet inhibitors such as
clopidogrel) are not detected by
conventional thromboelastography.
A platelet mapping technique has
been developed but is beyond the
scope of this chapter.
Prolonged R that corrects
with heparinase:
Heparin Excess
A bleeding patient with a prolonged
R in the kaolin cup that corrects
with heparinase indicates that
heparin is still present.
R >8 min (kaolin cup)
R 4–8 min (kaolin+heparinase cup)
R�SP normal
G normal
50 mg protamine 0.5 – 1.0 mg/kg protamine
(no clinical data to confirm
this dosage)
Prolonged R with normal clot
strength (G) and normal
R�SP:
Hemodilution
A bleeding patient with hemodilution
requires no blood products,
but rather requires careful exploration
for surgical source.
R >8 min (even with heparinase)
G normal
R�SP normal
Diuretic or do nothing Unknown (consider diuretic
but no clinical data to
support this treatment)
Prolonged R that does not
correct with heparinase:
Clotting Factor Deficiency
A bleeding patient with a prolonged
R and R�SP>1.1, typically has an
enzymatic defect as a source of
bleeding, either from excess
anticoagulation, factor deficiencies
(from pump consumption or
hemophilia) which would be best
treated with FFP.
R =8–10 min
R�SP>1.1 min
R =11–14 min
R�SP>1.1 min
R >14
R�SP>1.1 min
1 FFP
2 FFP
4 FFP
4 ml/kg FFP
8 ml/kg FFP
10–20 ml/kg FFP
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115104
Thrombelastogram description:
likely etiology
Description Parameter ranges Adult treatment in OR Pediatric treatment in OR
Low a (or high K):
Fibrinogen Deficiency
Formation of fibrinogen monomers
is responsible for the a portion of
the curve. If R is normal but a is
low, then fibrinogen deficiency is
likely and should be repleted with
cryoprecipitate.
Angle<45-
(fibrinogen typically<75 mg/dl)
0.03 U/kg cryoprecipitate 3 –5 ml/kg cryoprecipitate
1 –2 units (10 –20 ml) per
neonate up to 8 units
Low maximum amplitude
Low G:
Platelet Dysfunction
Maximum amplitude is determined
by platelet bonds with the fibrin
matrix. If maximum amplitude is
low after correcting other
abnormalities, then poor platelet
function or low number is suggested
and platelets should be administered.
MA 45–55 or G 4.7–5.7
Poor platelet function
1 U pheresis platelets (¨5 U)
DDAVP 0.3 mcg/kg in 50 ml
normal saline over 30 min,
if CO stable
10 ml/kg plts
1 unit plts=50–60 ml
1 pheresis unit=250 ml
DDAVP not proven
in children
MA<45 or G <4.7
Very poor platelet function
2 U pheresis platelets (¨5 U)
DDAVP 0.3 mcg/kg in 50 ml
NS over 30 min
10 ml/kg plts
DDAVP not proven
in children
High EPL:
Primary Fibrinolysis
Bleeding from primary fibrinolysis
can be from exogenous or
endogenous tissue plasminogen
activator (TPA). TPA inhibits
thrombin’s ability to activate
GPIIb/IIIa on platelets and can be
responsible for clots that form then
disappear. Antifibrinolytics should
be used. Bleeding should subside
within minutes and tracings should
return to normal after administration.
EPL>15% (no hypercoagulability)
R normal
MA normal
Angle normal
Antifibrinolytic of choice (see
dosing discussions above on:
TXA, Amicar, aprotinin)
Antifibrinolytic of choice
(see dosing discussions
above on: TXA,
Amicar, aprotinin)
Short R or high MA:
Hypercoagulability
Hypercoagulability results from
overactivation of thrombin and/or
platelets. Thrombin overactivation
results in a short R and clinically as
manifest as a ‘‘red clot’’. Platelet
overactivation results in a ‘‘white
clot’’ and is manifest by a high MA
value. Therapy should be directed
against factors (i.e., heparin, LMW
heparin, coumadin) or platelets (i.e.,
platelet inhibitors).
EPL>15%
R <6
Angle>74-
MA>73 or G >13.2
Low EPL:
DIC, Stage I Hypercoagulability
and Secondary Fibrinolysis
The first stage of disseminated
intravascular coagulation (DIC) is
defined as hypercoagulability with a
small amount of lysis. Secondary
fibrinolysis exhibits
hypercoagulability with
plasminogen activator inhibitor
(PAI1). Antifibrinolytics are
contraindicated. Heparin is
recommended to combat
hypercoagulability and antibiotics to
treat the underlying sepsis
(if clinically indicated).
R <6
Angle>74-
MA>73
EPL>15%
Heparin
Antibiotics
Heparin
Antibiotics
Low MA:
DIC, Stage II Consumptive
Stage Hypocoagulability
The second stage of DIC is a
consumptive phase, late in
vascular collapse after clotting
factors have been generally consumed.
Corrective treatment includes FFP
and cryoprecipitate.
R >8
Angle<47-
MA<55
FFP
Cryoprecipitate
FFP
Cryoprecipitate
Table 7 (continued)
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 105
and thrombin-soaked gelfoam neither increased nor de-
creased postoperative adhesions [233], while a prospective
randomized study of surgicel after laparoscopy for endo-
metriosis revealed significantly fewer adhesions [234].
6.1.1. Gelatin sponge and thrombin (Gelfoam\ and
thrombin)
Gelfoam\ is a water-insoluble, nonelastic, porous,
pliable, absorbable sponge prepared by milling absorbable
Table 8
Topical hemostats
Source of components Exposure risks Best used for, recommended. Contraindicated
Surgicel\ Cellulose None
Gelfoam\ and
thrombin
Porcine gelatin Porcine Hypersensitivity to bovine protein
Bovine thrombin Bovine
Avitene\ Bovine protein Bovine Best used on dry surfaces Hypersensitivity to bovine protein
Tisseel\ Pooled Human thrombin and fibrinogen
(vapor heated and freeze dried)
Bovine Requires dry field to be effective Hypersensitivity to bovine protein
Human
Aprotinin (Bovine)
FloSeal\ Gelatin Bovine Can be used on actively bleeding field Hypersensitivity to bovine protein
Thrombin
CoSeal\ Synthetic None Requires dry field to be affective None
BioGlue\ Bovine serum albumin,
glutaraldehyde
Bovine More effective in a dry field Hypersensitivity to bovine protein
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115106
gelatin sponge from purified pork skin. Though it has no
intrinsic hemostatic action, Gelfoam\ induces hemostasis
through its intense porosity, enabling it to absorb 45 times
its weight in blood. As it fills with blood, platelets come into
close contact and initiate the extrinsic clotting cascade
[235]. The addition of thrombin to gelfoam adds to its
hemostatic ability. Absorption is dependent on several
factors, including the amount used, degree of saturation
with blood or other fluids, and the site of use. In soft tissues,
Gelfoam is usually absorbed completely from 4 to 6 weeks,
without inducing excessive scar tissue [236]. In fact, studies
have shown the contrary [233,234]. Though a mainstay in
topical hemostasis, the limited efficacy of surgicel and
Gelfoam\ led to the development of products that directly
activate the clotting cascade.
6.1.2. Microfibrillar collagen hemostat (Avitene\)
Avitene is a microfibrillar collagen hemostat which is
available in the form of flour, sheets, or sponge. Avitene\works best when applied dry. When this is not possible the
surface to be treated should be compressed with dry gauze,
covered with Avitene\, and moderate pressure applied over
the Avitene\ with a dry gauze. Avitene\ should not be used
in the closure of skin incisions as it may interfere with the
healing of the skin edges due to simple mechanical
interposition of dry collagen and not to any intrinsic
interference with wound healing. Avitene\ is inactivated
by autoclaving and should not be resterilized. Moistening it
or wetting with saline or thrombin may impair its hemostatic
efficacy and it should be used dry. As it is a foreign
substance, use in contaminated wounds may enhance
infection. Avitene\ contains a low, but detectable, level of
intercalated bovine serum protein which reacts immunolog-
ically as does beef serum albumin. Increases in anti-beef
serum albumin titer have been observed. Nearly 2/3 of
individuals exhibit antibody titers because of ingestion of
bovine food products. Intradermal skin tests have occasion-
ally shown a weak positive reaction to bovine serum
albumin microfibrillar collagen but these have not been
correlated with IgG titers. Testing has not revealed any
significant elicitation of antibodies of the IgG class against
bovine serum albumin following use of Avitene\. Care
should be exercised to avoid spillage on nonbleeding
surfaces, particularly in abdominal or thoracic viscera.
Avitene\ (MCH) should not be used in conjunction with
autologous blood salvage circuits. Fragments of Avitene\may pass through filters of blood scavenging systems. The
reintroduction of blood from cell saver or cardiotomy
suction of area treated with Avitene\ should be avoided.
Teratology studies in rats and rabbits have revealed no harm
to the animal fetus but the lack of well-controlled studies in
pregnant women should restrict its use in pregnant women
only when clearly needed. The most serious adverse
reactions reported which may be related to the use of
Avitene\ are potentiation of infection including abscess
formation, hematoma, wound dehiscence, and mediastinitis.
Other reported adverse reactions possibly related are
adhesion formation, allergic reaction, and foreign body
reaction.
A randomized clinical study in patients undergoing
ascending aortic aneurysm repair and reoperative coronary
artery bypass surgery compared the efficacy of Avitene\and surgicel [237]. The group that received Avitene\ had
significantly decreased chest tube outputs over all and in the
first postoperative hour. Another study compared the
efficacy of several topical agents after sutured end-to-end
aortic anastomoses in rabbits and found that fibrin sealant
controlled hemorrhage more effectively than the other
agents (Gelfoam\– thrombin, Surgicel\, Avitene\,
Floseal\). In addition although all the other agents did
significantly reduce blood loss there was no significant
difference between the individual topical agents [238].
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 107
6.1.3. Fibrin sealant (Tisseel\)
Tisseel VH\ (Baxter Healthcare Corp., Glendale, CA) is
a proprietary, topical protein solution sealer which is
sprayed onto hemorrhagic surfaces. This fibrin sealant
contains pooled human fibrinogen, thrombin, calcium
chloride, and Aprotinin (bovine) and takes 25–45 min to
prepare. It was developed as an alternative to fibrin glue.
The advantages of Tisseel\ over fibrin glue are that it is
vapor-heat treated for viral inactivation. When the protein
and thrombin solutions are mixed and topically applied, a
viscous solution that rapidly sets into an elastic coagulum is
produced. Studies have shown that Tisseel\ is safe with
regard to viral transmission and highly effective in
controlling localized bleeding in cardiac operations [239].
It is the only product that can cause clot without a
contribution from the patient. Its components are a Sealer
protein concentrate (human), heat treated, dried and sterile
with a total protein concentration of approximately 130 mg/
ml; a fibrinolysis inhibitor (aprotinin) at a concentration of
3000 KIU/ml; bovine, dried; thrombin at a concentration
500 IU/ml and calcium chloride solution, 40 mmol/l.
A multicenter randomized trial of 333 patients in 11
centers in the US undergoing reoperative sternotomy
compared the hemostatic ability of fibrin sealant with
conventional topical agents and demonstrated a significant
reduction in postoperative blood loss and reoperation for
bleeding in patients treated with the sealant [239].
Fibrin sealant had a 92.6% success rate in controlling
bleeding within 5 min of application, compared to only
12.4% success with conventional topical agents ( p <0.001)
[239]. Postoperative blood loss was significantly less
( p <0.05), and there were no documented adverse reactions,
or viral transmission of viral infection (hepatitis B, non-A/
non-B hepatitis, or HIV). Reexploration for bleeding after
redo operations were significantly lower in the fibrin sealant
group (5.6%) than in controls (10%) ( p <0.008). There were
no significant differences in hospital stay or blood products
received between the fibrin sealant group and matched
historical controls and no difference in mortality between
the fibrin sealant group and nonmatched historical controls.
Its disadvantage is that it has to be applied to a dry field and
given a chance to cure.
In congenital heart surgery, fibrin sealants have de-
creased bleeding and transfusion requirements. In a pro-
spective study, patients with postoperative coagulopathy
after cardiopulmonary bypass were randomized to receive
fibrin sealant on anastomotic sites and microvascular
bleeding points or no intervention. Children treated with
fibrin sealant, required a significantly less packed red blood
cells, FFP and platelets. The operating room time and
bleeding during surgery at 4 h, and at 24 h were all
significantly reduced. Nevertheless, there were no differ-
ences in ventilation time, nor ICU or hospital stays [240].
Similar reduction in bleeding was observed using fibrin
sealant in a prospective randomized evaluation of neonates
undergoing ECMO [241].
6.1.4. FloSeal\FloSeal\ (Fusion Medical Technologies, Inc., Mountain
View, CA) is a proprietary, gelatin-based hemostatic sealant
which consists of a combination of specially engineered
collagen-derived particles and topical thrombin which
activates the clotting cascade and simultaneously forms a
nondisplacing hemostatic plug. The kit contains a bovine-
derived gelatin matrix and a bovine-derived thrombin
component. It is composed of a cross-linked gelatin matrix
combined with thrombin to produce a highly viscous gel.
Although its hemostatic function requires adequate circu-
lating fibrinogen, no platelet activation is required and a
bloodless field is not required. It mixes in 1–2 min, is
biocompatible and is reabsorbed in 6 to 8 weeks.
The Fusion Matrix Group studied FloSeal\ vs.
Gelfoam\–Thrombin in cardiac surgical procedures in
which standard surgical means were ineffective at control-
ling bleeding [242]. FloSeal\ stopped bleeding in a
significantly higher number of patients than conventional
therapy with Gelfoam\–Thrombin and showed no differ-
ences in adverse events. The major advantage to this
product is that it has been formulated for application to an
actively bleeding field. Although there have been no
reported cases, Floseal\ contains animal/bovine products
and carries a risk of viral transmission including bovine
spongiform encephalopathy.
6.1.5. CoSeal\CoSeal\ surgical sealant (Baxter Healthcare Corpora-
tion, Freemont, CA) is a proprietary topical agent which
contains no pooled human blood components. It consists of
two polyethylene glycol polymers. A hydrogel can be
prepared and applied in 3 min and the material is completely
resorbed in 4–6 weeks after treatment. This agent should be
applied to relatively dry surfaces prior to the release of
clamps. A multi-center randomized study showed that
CoSeal\ was superior to conventional topical methods in
aortic reconstructive surgery [243]. Another multicenter
randomized trial demonstrated that CoSeal\ offers equiv-
alent anastomotic sealing performance compared with
Gelfoam\/thrombin, and that it provided the desired effect
in a significantly more rapid time frame [244]. Since it
contains no human or animal proteins, CoSeal\ carries no
risk of viral transmission. Although it is resorbed within 6
weeks, no long-term data exist with respect to scarring.
6.1.6. BioGlue\ surgical adhesive
BioGlue\ (Cryolife, Inc., Kennesaw, GA) is a propri-
etary, biological glue initially approved for use in the
repair of aortic dissection. It is composed of purified
bovine serum albumin (BSA), and glutaraldehyde. The
action is almost instantaneous because glutaraldehyde
exposure leads to the tenuous binding of lysine molecules,
proteins, and tissue surfaces. The glutaraldehyde molecules
covalently bond (cross-link) the albumin molecules which
polymerize within 20 to 30 s (65% strength) and reaches
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115108
full bonding strength within 2 min. BioGlue\ has been
used in aortic reconstructive surgery [245] and in the repair
of acute aortic dissections [246]. However, there are many
cautions in its use, including the avoidance of valve
leaflets, intracardiac structures, and circulating blood (as it
can result in local or embolic vascular obstruction). Repeat
exposure may lead to hypersensitivity reactions. Although
this glue has successfully reduced blood loss and achieved
hemostasis in congenital heart surgery [247] it should be
used with utmost caution as it has been shown to impair
vascular growth and cause stricture when applied circum-
ferentially around an aorto-aortic anastomosis in 4-week
old piglets [248].
6.2. Mechanical adjuncts
Other blood conservation strategies include acute nor-
movolemic hemodilution, reduced priming volume of
cardiopulmonary bypass, blood salvage by filtration or cell
processing, modified ultrafiltration and autotransfusion of
shed blood. Controlling hypertension (hypotensive hemo-
stasis), reinfusing shed blood and cell saver, minimizing
circuit size and ultrafiltration are current mechanical
techniques used to attenuate postoperative blood loss after
cardiopulmonary bypass.
The first report to demonstrate a less than 10%
transfusion rate in Jehovah’s Witnesses was from the
Cleveland Clinic in adults which demonstrated transfusion
rates of only 6% with a mean of 0.06 units per patient
receiving blood. Cosgrove et al. described 6 principal
techniques of blood conservation which were, intraoperative
autologous donation, nonblood prime, return of all residual
cardiopulmonary bypass circuit blood, intraoperative sal-
vage, use of the lowest safe level of anemia during
cardiopulmonary bypass as well as in the postoperative
period and the reinfusion of shed mediastinal blood [249].
Ovrum et al. in two consecutive studies demonstrated
extremely low rates of transfusion (2.4% of patients) using
this 6-step blood conservation program and found it to be
simple, safe, and cost-effective [250,251].
6.2.1. Controlled hypotension
The concept of controlled hypotensive hemostasis was
introduced in the 1940s to reduce intraoperative blood loss
and transfusion requirement [252]. A review of 13
prospective studies on multiple surgical specialties, pre-
dominantly orthopedic patients undergoing total hip re-
placement demonstrated a 50% reduction in blood loss with
this technique [253]. Controlled hypotension is defined as
reducing mean arterial blood pressure to 50–75 mm Hg.
Although this technique has been widely studied in
orthopedic surgery, several reports in adult cardiac and
thoracic surgery have shown benefit in reduction of blood
loss [254,255]. Modalities that have been used include
epidural blockade, inhalation anesthetics, intravenous beta
blockade and direct vasodilators.
In the pediatric population reduction in mean arterial
pressure to 50–65 mm Hg (or a 30% reduction) did limit
intraoperative blood loss and favored sevoflurane and
fenoldepam as their agents of choice [256,257]. The benefits
of reduced blood loss and transfusion requirement obtained
with this technique have to be weighed against the potential
for inadequate perfusion of vital organs and may be
detrimental over a prolonged period in patients with
significant cardiovascular disease, cerebrovascular disease,
severe pulmonary disease, renal disease, hepatic disease,
pregnancy, anemia and hypovolemia.
6.2.2. Shed blood controversy and cell saver
The concept of using autologous blood transfusion was
first introduced in 1818 [46]. In 1968 a known process of
collection, washing, processing and reinfusing shed blood
was described [258]. After cardiopulmonary bypass, resid-
ual blood can be processed by cell saver using centrifuga-
tion, ultrafiltration or reinfusion of unprocessed blood. In
comparison with cell saver, ultrafiltered blood has higher
red cell concentrations and has less platelet and coagulation
factor depletion [259]. Shed mediastinal blood has shown to
have higher titers of fibrin degradation products and has
been implicated in worsening coagulopathy [260] through a
potentiation of platelet dysfunction secondary to tissue type
plasminogen activator activity [261]. Other studies have
found either no difference [262] or higher fibrin degradation
titers which did not translate into clinically significant
bleeding after washing the infusate [263].
In the pediatric heart surgery population, two studies
have demonstrated no increase in coagulopathy with
reinfusion of shed blood [262,264]. Although one group
has shown increased chest tube drainage with cell saver
[261], no studies have been able to conclusively
demonstrate increased bleeding in patients receiving shed
mediastinal blood. Based on current inconclusive evi-
dence against its use, the reduction in the therapeutic
benefit by withholding reinfusion of shed blood is not
justified.
6.3. When to reexplore a bleeding patient
As previously mentioned, when a patient is bleeding
postoperatively, a surgical cause of bleeding must remain in
the differential. When to reexplore is a complex decision
that must integrate disparate sources of information. The
surgeon who did the case generally has a feel for the
likelihood of surgical bleeding based on (1) his intimate
understanding of the operation, (2) the operation performed
(i.e., complex arterial reconstruction vs. simple atriotomy),
(3) whether reoperative surgery was performed, and (4) the
appearance of the operative field at the time of the closure.
The nature of chest tube output is also an important
information. Bright red blood is more likely to be arterial
bleeding; dark blood is more likely to be venous. Non-
clotting blood in the chest tube implies ongoing coagulop-
T. Yeh Jr., M.N. Kavarana / Progress in Pediatric Cardiology 21 (2005) 87–115 109
athy requiring further correction. Clotting of blood in the
chest tube makes surgical bleeding more likely. Guidelines
for pediatric reexploration are typically 10–15 ml/kg/h for
3–4 successive hours or 20–25 ml/kg/h total at the end of 4
h with normal coagulation studies and/or hemodynamic
instability.
7. Conclusion
Children undergoing cardiopulmonary bypass suffer
disproportionate adverse effects because of their size and
immature hematopoietic system. Postoperative bleeding is
exacerbated by hemodilution, induction of a systemic
inflammatory response, along with platelet and coagulation
factor activation and depletion. Effective management of
bleeding after cardiopulmonary bypass in children requires
that physicians understand and are familiar with every
technique available to balance competing needs of mini-
mizing blood loss and transfusion, while maintaining good
perfusion so that a child’s perioperative and long-term
outcome is optimized.
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