www.elsevier.com/locate/ppedcard

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: Thomas.Yeh@UTSouthwestern.edu (T. Yeh),

MKavarana@att.net (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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