Pediatric Anesthesia ISSN 1155-5645

REVIEW ARTICLE

Coagulation considerations for infants and children undergoing cardiopulmonary bypass

Michael P. Eaton & Ellen M. Iannoli
Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA

Keywords cardiac surgery; heparin; protamine; antibrinolytic; congenital heart disease; coagulation Correspondence Michael P. Eaton, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 604, Rochester, NY 14642, USA Email: Michael_Eaton@urmc.rochester.edu Section Editor: Greg Hammer Accepted 6 October 2010 doi:10.1111/j.1460-9592.2010.03467.x

Summary Cardiac surgery involving cardiopulmonary bypass imposes a signicant pathophysiologic burden on patients. Pediatric patients are especially predisposed to the adverse effects of surgery and bypass on the coagulation system, with resultant bleeding, transfusion, and poor outcomes. These risks accrue to pediatric patients in inverse proportion to their weight and are attributable to hematologic immaturity, coagulation defects associated with congenital heart disease, bypass equipment, and the nature of congenital heart surgery. Standard anticoagulation does not completely inhibit thrombin generation, and continuous consumption of coagulation factor continues throughout bypass. Conventional measurements of anticoagulation during bypass poorly reect this incomplete anticoagulation, and alternate methods may improve anticoagulant therapy. Emerging therapies for blocking the effects of bypass on the coagulation system hold promise for decreasing bleeding and related complications, and improving outcomes in congenital heart surgery.

Introduction The development of cardiopulmonary bypass (CPB) has brought cardiac surgery from a very limited and hazardous endeavor to a routine and relatively safe practice that addresses an incredible variety of diseases and conditions in patients from a few hours to nine or more decades old. CPB is, however, a remarkably pathological state. The myriad adverse effects in patients on bypass are well described and resistant to prophylaxis and treatment (13). Children are particularly affected by CPB and cardiac surgery, and this risk is inversely proportional to the childs age or weight (4). Our goals for this review are to synthesize published data regarding coagulation in children undergoing cardiac surgery for a global understanding of the pathophysiology involved and to suggest evidence-based therapies both to minimize the hemostatic defects induced by CPB and to treat these defects when they result in excess postoperative bleeding. We review the literature describing the adverse effects of cardiopulmonary bypass on hemostasis and explore how the unique physiology of neonatal and other
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pediatric patients interacts with CPB pathophysiology. We will discuss current therapies to minimize the hemostatic problems associated with CPB, issues associated with the application of those therapies, and other therapeutic modalities supported in the literature but not yet commonly employed in clinical practice. Finally, we review evidence-based treatment of postCPB bleeding, including the use of recombinant activated factor VII. Cardiopulmonary bypass coagulopathy In the intact organism, blood circulates through a cardiovascular system entirely lined with endothelial cells. One of the primary functions of the endothelium is to maintain the uidity of blood by inhibiting platelets and preventing adhesion of brin. Although advances in circuit biopassivation have been made, the CPB circuit remains profoundly nonphysiologic. Administration of high-dose heparin prevents complete thrombosis of blood entering the CPB circuit, but low-level intravascular and intracircuit coagulation continues throughout bypass (5,6) (Figure 1). Initiation of CPB
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CPB
Contact activation Factor XII Kallikrein Inflammation

Plasminogen

Plasmin

Fibrinogen

Fibrin

Thrombin

Platelets

Factor VII Tissue factor Surgical trauma

of these platelets fragment under conditions of shear stress (11). Platelet glycoprotein Ib (von Willebrand) receptors are degraded in the circulation by plasmin, impairing adhesion (12). Once activated prematurely during CPB, platelets are not available for hemostasis after surgery. CPB is also a profoundly proinammatory state, with activation of multiple aspect of humoral (e.g., complement, interleukins) and cellular (monocytes, neutrophils) inammation. Although a complete discussion of the inammatory response to CPB is outside the scope of this review, it is important to understand that the inammatory and coagulation systems interact at multiple levels (13). More effective suppression of thrombin generation during CPB will decrease the inammatory response to CPB (14), and conversely, interventions aimed at decreasing inammation may improve hemostasis (15). Most of these details of the interaction of CPB and hemostasis have been described in adults (5). The same pathophysiology does develop in the infant and child (6) although it is altered by the unique physiology of the young patient with congenital heart disease. Coagulation issues unique to the pediatric patient Developmental hemostasis The human hemostatic system is immature at birth. Most pro- and anticoagulant protein levels are 30 70% lower relative to adults (1618), although some enzymes are in higher concentrations in neonates relative to adults (Figure 2). In addition, some neonatal coagulation proteins, such as plasminogen and brinogen, exist as fetal isoforms with adult amino acid sequences, but signicant differences in glycosylation (17,18). These differences may explain the altered sensitivities of neonatal coagulant proteins to both endogenous (19,20) and exogenous modulation (21). Differences in brinogen and plasminogen structure and function are likely to be particularly important in the effects of CPB, heparin, and medications administered to prevent or reduce bleeding. Thus the hemostatic system of the neonate is fundamentally different than that of the adult, yet balanced so as to allow clotting and clot lysis in response to injury. Maturation of hemostasis approximates the adult system for the most part by 612 months, but in some respects not until signicantly later in childhood. The normal neonate is capable of mounting a competent thrombotic response to vascular injury, with functional brinolysis and remodeling following. However, the response of the neonate and small child to
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Figure 1 Activation of the coagulation, inammatory, and brinolytic systems by cardiopulmonary bypass and surgery.

produces activation of the contact phase of coagulation with cleavage of factor XII to XIIa and prekallikrein to kallikrein (7). Kallikrein has a positive feedback effect on factor XII as well as producing activation of inammation and brinolysis. Factor XIIa initiates the intrinsic cascade of coagulation and, ultimately, thrombin activation. Surgical trauma causes release of tissue factor which further activates thrombin via the extrinsic pathway (8). Thrombin has many diverse effects (9). In addition to cleaving brinogen to brin and activating factor XIII to induce brin crosslinking, it produces platelet activation via the PAR-1 and PAR-4 receptors, has positive feedback effects on other coagulation proteins, activates thrombin-activatable brinolysis inhibitor, and stimulates the endothelium to release tissue factor and von Willebrand factor. It also has antithrombotic effects such as stimulation of endothelial cells to release tissue-type plasminogen activator, nitric oxide, and prostacyclin and binding with thrombomodulin to activate protein C. Upon initiation of CPB, brinogen adheres to the articial surfaces of the circuit. Platelets become activated and bind to the brinogen and degranulate (10). Some
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Coagulation in children on bypass

(a)

(b)

Cyanotic heart disease has been particularly associated with defects in coagulation. Chronic hypoxemia represents a profound stimulant for erythropoiesis. Excess production of red blood cells suppresses platelet production (25), and platelet counts have been reported to vary inversely with hematocrit in patients with cyanotic heart disease (26,27), with thrombocytopenia being relatively common. Waldman et al. (28) have also demonstrated a decrease in mean platelet survival in cyanotic patients. Deciencies in platelet adhesion and aggregation have also been reported (29,30). Increased brinolysis may occur in cyanotic patients (31,32), but this appears to be a relatively infrequent nding, and it is not clear whether this is attributable to low-grade disseminated intravascular thrombosis, primary brinolysis, or simply increased catabolic turnover of brinogen (27). Poor cardiac output, hypoxemia, and chronic passive congestion of the liver may also lead to underproduction of coagulation factors, especially the vitamin-K-dependent factors II, VII, IX, and X (27). Patients with hypoplastic left heart syndrome are particularly affected by factor deciencies, with decreased levels of brinogen, antithrombin (ATIII), factors II, VII, IX, X, V, and VIII, and proteins C and S (33,34). These deciencies are most pronounced prior to rst-stage palliation, but many persist through Fontan completion (34). Given the likelihood of coagulation abnormalities in these patients, heightened vigilance and proactive therapy should be routine practice for cyanotic children. Hemodilution A normal-sized adult with a blood volume of 5000 ml will undergo hemodilution of almost 25% with a typical prime volume of 1600 ml (measuring hemodilution as a percent of the whole system). This moderate dilution does not typically reduce clotting factors to the point of causing coagulopathy, but signicant thrombocytopenia is not uncommon (35). A 3- to 3.5-kg neonate with a blood volume of 270315 ml is likely to undergo 60% hemodilution. Because an infants blood volume is much smaller than that of the prime in the CPB pump, hemodilution alone produces impaired hemostasis related to thrombocytopenia and coagulation factor dilution (6,36,37). This dilution is likely even more signicant given the lower initial concentrations of many factors. Even in the polycythemic cyanotic patient, inclusion of allogeneic red blood cells in the priming volume is nearly universal with neonates and small infants (38). Thus, these high-risk patients begin CPB with an unavoidable donor exposure. Inclusion of donor red cells in the pump prime
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Figure 2 Concentration of procoagulant (a) and anticoagulant (b) proteins over time from birth through adulthood. ATIII, antithrombin III; Alpha-2 MG, alpha-2 macroglobulin. Data from Andrew et al. (16).

CPB-induced hemodilution is qualitatively different to that of adults as hemodilution is more profound, and baseline levels of coagulation proteins are signicantly different. Congenital heart disease and coagulation Congenital heart disease itself has long been known to be associated with coagulation abnormalities (22). Goldschmidt et al. (23) showed that patients with congenital heart disease have abnormalities of platelet turnover, with increased peripheral destruction and a higher proportion of young sticky platelets. Gill et al. (24) reported a series of patients with congenital heart disease with prolonged bleeding times associated with signicantly reduced levels of large multimer von Willebrand factor. Four of ve of the patients studied after correction of their congenital defects had normalization of the von Willebrand factor.
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has been shown to adversely affect cardiopulmonary function and contribute to inammation (39). Transfusion presents signicant risks in all patients. Although the risk of viral disease transmission has decreased with more thorough testing of the blood supply, other adverse effects of transfusion remain, such as transfusion reactions, immune modulation, impairment of microvascular ow, and even mortality (40). Surgical complexity Congenital heart disease is extremely varied and complex. In the 20022005 New York State Congenital Cardiac Surgery database of 5466 cases, (http://www. health.state.ny.us/statistics/diseases/cardiovascular/heart_ disease/docs/2002-2005_pediatric_congenital_cardiac_ surgery.pdf, last accessed June 14, 2010), over 100 different congenital cardiac diagnoses are listed as the primary surgical indication. Twenty-four different diagnoses were present in at least 100 patients. Thus, the congenital heart surgeon has far less experience and familiarity with the operations he/she performs than the adult cardiac surgeon. A trend toward performing complete repairs in infancy and the renement of surgical and CPB techniques have increased the incidence of high-complexity repairs in very small patients (41). Repair of complex congenital anomalies often requires multiple suture lines, long CPB runs, deep hypothermia, and circulatory arrest, increasing the risk of bleeding and transfusion (42). Current and future therapies Anticoagulation It is perhaps counterintuitive that more anticoagulation results in less bleeding, but this is the case for inhibition of the coagulation system during CPB (8,43). Adequate preservation of the coagulation system during CPB minimizes postbypass coagulopathy and postoperative bleeding. An ideal anticoagulation regimen would completely suppress all aspects of coagulation during CPB and be completely reversible at the end of the bypass. There is no single drug that accomplishes this. Heparin Unfractionated heparin is a mixture of polysulfated glycosaminoglycans of molecular weights from 3000 to 30 000 Daltons (44). It was originally discovered in 1926, making it one of the oldest drugs still in use. Heparin exerts its anticoagulant effect by binding to ATIII, multiplying its activity 1000-fold (45). Suf34

ciently large (18 saccharides) heparin molecules produce inhibition of both factor Xa and thrombin, thus interfering with coagulation at two successive steps. However, heparin does not produce complete inhibition of coagulation during CPB; thrombin continues to be generated despite high heparin concentrations (9). Because heparin requires an intrinsic cofactor to work, individuals decient in ATIII will have a diminished anticoagulant response to routinely used doses. Heparin resistance is a relatively commonly encountered issue in adult cardiac surgery (46), and given the baseline lower concentration of ATIII in infants, it is not surprising that the anticoagulant effect of heparin in very young patients is both more variable and less likely to be adequate (47). Other intrinsic molecules, such as heparin cofactor II and a-2 macroglobulin, are more important inhibitors of thrombin in children (48). However, Guzzetta et al. (48) were unable to demonstrate any relationship between preoperative levels of ATIII, heparin cofactor II, or a-2 macroglobulin and heparin effect as measured by the activated clotting time (ACT) in children. Heparins anticoagulant effect is commonly measured using the ACT. Typically, infants and children are managed using an ACT value established in adults as reecting adequate anticoagulation for CPB, usually 400480 s, depending on institutional preference. It has been demonstrated that the ACT is a poor indicator of anticoagulation in infant undergoing CPB, as factors other than heparin, such as hemodilution and hypothermia, prolong the ACT despite diminishing heparin concentrations and ongoing thrombin generation (49,50). Thus, heparin as commonly employed in congenital heart surgery is associated with inadequate anticoagulation and ongoing formation of thrombin and consumption of coagulant proteins. Despite this, heparin remains the preferred anticoagulant for CPB in children. Better use of heparin may be facilitated by alternate strategies for dosing and monitoring in children. In a retrospective study of 90 adults and children receiving heparin for CPB, DErrico et al. (47) found that infants were signicantly less responsive to heparin and had greater variability in that response. The authors suggested an initial heparin dose as high as 500 unitskg)1 may be needed in infants, while 300 unitskg)1 was likely adequate in older children and adults. Guzzetta (51) has shown that ACT values are poorly reective of heparin effect in infants and that the use of patient-specic heparin management using automated heparin doseresponse calculation and heparin level monitoring was more effective in suppressing thrombin generation during CPB than conventional heparin dosing and monitoring (52).
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Although individualized heparin dosing may be the best strategy, point-of-care heparin management systems may not be available at every institution. At the very least, it is important to recognize that standard celite- or kaolin-activated tube-technology ACTs are likely to overestimate heparin anticoagulation. Empiric interval redosing may avoid the effects of inadequate anticoagulation. Based on data from Guzzetta et al. (51,52), heparin levels may be expected to fall 4060% in infants during 80 min of CPB. Redosing with 1/3 to of the original heparin dose after 60 min of CPB may be reasonable. Heparin at least anticoagulates blood to the point that extracorporeal circulation is possible. It is also readily reversible at the completion of CPB with protamine. Protamine reversal of heparin in vivo was originally described by Jaques et al. in 1938 (53). Protamine is associated with a number of adverse reactions including histamine-dependent vasodilation (54), anaphylaxis (55), and catastrophic pulmonary hypertension (56). Severe reactions to protamine may be less common in infants and children than in adults (57,58). Determining the dose of protamine is difcult without ongoing knowledge of circulating concentrations of heparin. Basing the protamine dose on automated heparin/protamine titration will produce a smaller dose than predicted bases on the initial heparin bolus and the last ACT (47). It is important to avoid administering excess protamine, as unbound protamine has anticoagulant properties (59,60). A further complicating factor in heparin reversal is ultraltration, which is used in 75% of centers performing congenital heart surgery (38). As heparin molecules are too large to pass through the lter, heparin levels increase during ultraltration (61) and patients who have undergone high-volume ultraltration may require correspondingly higher doses of protamine. Heparin-induced thrombocytopenia (HIT) is a clinical syndrome resulting from the formation of antibodies to heparinplatelet factor 4 complexes. These antibodies cause platelet aggregation and thrombocytopenia, often complicated by thrombosis. Conversion to positive antibody status is common after adult heart surgery (62), and in older children undergoing congenital heart surgery (63), but is relatively uncommon in infants (64). There is increasing recognition that HIT may be a more common contributor to thrombotic morbidity in congenital heart surgery than previously thought (65). Use of heparin alone for CPB in patients with acute HIT is inadvisable as catastrophic thrombosis has been reported in this setting (66). Ideally, cardiac surgery should be delayed until antibodies have been cleared from the circulation, but
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occasionally, surgery is more urgent. In this setting, an alternative anticoagulant such as a direct thrombin inhibitor should be employed (67). In institutions without experience using alternate agents for CPB, it may be advisable to use heparin in combination with a platelet antagonist such as epoprostenol or tiroban (67). Alternate agents There is some evidence that direct thrombin inhibitors are actually better inhibitors of CPB-induced activation of coagulation than heparin (68). Agents other than heparin have been used successfully to anticoagulate pediatric patients for CPB, but experience is very limited (69,70). The direct thrombin inhibitors r-hirudin (71), argatroban (72), and bivalirudin (73) have all been used for CPB and are likely the best alternatives currently available. Excessive bleeding has been reported with the rst two agents (71,74,75), which have a duration of action too long to be ideal in the CPB setting. Bivalirudin has a shorter elimination halflife and organ-independent elimination and is most likely the best of these three agents as an alternative to heparin for CPB. As bivalirudin undergoes metabolism in the blood, it must be recognized that stasis in both the patient and circuit must be avoided and a continuous infusion used to maintain anticoagulation and avoid thrombosis (73). Early research has demonstrated some advantage to combining heparin and bivalirudin for CPB anticoagulation (76). No clear guidelines exist for dosing or monitoring of direct thrombin inhibitors in children. Antibrinolytics Hyperbrinolysis is one of the primary mechanisms leading to post-CPB bleeding (77,78) although this is perhaps less well established in infants and children than in adults (79,80). The best evidence for brinolysis contributing to post-CPB bleeding in infants is the efcacy of antibrinolytic therapy. The antibrinolytic drugs aprotinin, epsilon-aminocaproic acid (EACA), and tranexamic acid (TA) have been shown to decrease bleeding and transfusion in multiple studies of pediatric cardiac surgery (81). Prior to its withdrawal from marketing, 96% of pediatric cardiac surgery centers used aprotinin (38). However, the evidence of benet in pediatric patients is actually better for the lysine analogs EACA and TA (81). Aprotinin was withdrawn from the market in May 2008 after multiple reports surfaced concerning adverse effects of the drug, most notably renal failure, in adult patients (8284). Controversy continues over the riskbenet balance of this
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drug, particularly for pediatric patients in whom adverse effects have not yet been shown. The lysine analogs EACA and TA inhibit brinolysis by interfering with the binding of plasminogen to brin, a necessary step in the formation of plasmin, the primary brinolytic enzyme (85). Both drugs have been shown in multiple studies to decrease blood loss and transfusion in pediatric patients undergoing surgery with CPB (8694). Dosing schemes for these agents have been quite variable and not based on sound pharmacologic principles. Ririe et al. (95) studied the pharmacokinetics of EACA in 8 infants and children up to 4 years of age. Using these data, they recommended a loading dose of 75 mgkg)1, an infusion of 75 mgkg)1 per hour, and a pump prime dose of 75 mgkg)1. The volume of the CPB pump is relatively xed; it varies in a stepwise fashion based on patient size. The purpose of adding EACA or TA to the pump prime is to maintain plasma levels; therefore, basing the prime dose on the volume of prime rather than on the weight of the patient is more logical. We have found that a modication of Riries dosing scheme, with a prime dose of 250 mcgml)1 of prime volume, establishes and maintains the target concentration (130 mcgml)1) throughout CPB in neonates (96). Neonates however require lower levels of EACA to fully inhibit brinolysis (97), so lower doses may be justied. The pharmacokinetics of TA in the pediatric population has not been established, and pharmacologically based dosing guidelines are unavailable. Chauhan et al. (87) compared four doses of TA in 150 cyanotic children undergoing cardiac surgery. They found the most effective dose to be a 10 mgkg)1 load, 10 mgkg)1 in the pump prime, and a 10 mgmg)1 bolus after separation from CPB. Platelet anesthesia In vivo, the predominant mechanism for blood coagulation is somewhat dependent on environment (98). In the venous system, ow is relatively sluggish, and shear forces are low. Humoral (soluble factor-related) coagulation is predominant in this environment, as is demonstrated by the utility of medications focusing on factor inhibition in prophylaxis and treatment of venous thrombosis. In the arterial system, shear stresses are considerably higher and platelet activity is signicantly more important, as evidenced by the utility of platelet antagonists such as aspirin, dipyridamole and clopidogrel in the prevention of arterial thrombotic events. The CPB circuit also has portions of low (reservoir) and high (arterial line) shear stress. Despite its noted inadequacies, heparin addresses
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humoral anticoagulation with some efcacy. Traditional approaches to anticoagulation do not address platelet activation. Platelet anesthesia is a concept explored in the 1990s and early 2000s in which an agent is administered at the beginning of CPB to minimize platelet activation, with the intention of improving platelet function and hemostasis after CPB. For this to be effective, the agent employed must be of relatively brief duration and highly effective in blocking platelet activation. The glycoprotein IIb-IIIa antagonists tiroban and eptibatide have both been found to protect platelets from activation during CPB (99,100). Koster et al. found that the addition of tiroban to heparin anticoagulation in adult patients undergoing aorto-coronary bypass preserved platelet numbers and decreased measures of inammation after CPB. Blood loss was not signicantly different between tiroban-treated patients and controls at 12 h after surgery despite measurably decreased platelet aggregation after CPB in the tiroban group. Nitric oxide has been shown effective in attenuating platelet activation and preserving post-CPB platelet function in a baboon model (99). Nitric oxide has the advantages of being very short-acting and may be administered via the oxygenator, which has the largest surface area for contact activation of the CPB circuit. The ultrashort-acting glycoprotein IIb-IIIa antagonist FK633 was shown to be effective in preventing CPB-induced thrombocytopenia and preventing platelet adhesion to the circuit (101). Little attention has been given to platelet anesthesia in pediatric cardiac surgery, but attenuation of the platelet response seems an obvious therapy to complete anticoagulation for CPB. Further development and approval of FK633 or other short-acting antiplatelet agents such as cangrelor (102) may spur research in this area. Improving the CPB circuit Technical limitations have dictated a lower limit to the size of perfusion equipment and CPB circuits used in pediatric patients. This has traditionally resulted in much greater degrees of hemodilution in infants and small children relative to adults with functionally important decreases in coagulation factors, platelets, and hematocrit (6,36,37). The conventional response to this has been to include donor red cells in the prime volume with many centers including whole blood or plasma (103). In a 2005 survey, Groom et al. (38) found that 24% of reporting hospitals used whole blood in the prime. The literature is mixed on the efcacy of fresh whole blood in improving outcomes in congenital heart surgery. Manno et al. reported in
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1991 (103) that children receiving very fresh ( 24 h < old) or fresh (2448 h old) whole blood for a variety of congenital heart operations had signicantly less postoperative bleeding than patients treated with reconstituted whole blood (mixed-component red cells, plasma, and platelets). Mou et al. (104) however reported no improvement in hemostasis in infants randomized to receive fresh whole blood ( 48 h old) over < a group receiving a combination of plasma and red blood cells and found an increase in edema and ICU length of stay in the fresh whole blood group. Most recently, Greunwald et al. (105) randomized 64 neonates to receive either reconstituted fresh whole blood (single donor, 2 days old) or standard component therapy, nding less bleeding in the fresh whole blood group, as well as a decreased need for inotropes, shorter time on mechanical ventilation, and shorter length of stay. It should be noted that the mean age of transfused units in the control group in this study was 14 days, as opposed to 2 days in the fresh whole blood group, so it is unclear that these results are simply a reection of the morbidity resulting from transfusion of old blood (106,107). There is a lack of convincing evidence that including any blood products in the prime volume other than a minimum volume of (preferable fresh) red blood cells improves outcomes. Continued technological developments with greatly reduced circuit volumes may obviate discussion of what blood products to add to the prime by eliminating the need for even red cells in all but the smallest patients. Circuit prime volumes as low as 140180 ml are now being used routinely and have enabled the performance of CPB on small infants with an asanguineous prime (108,109). Although avoiding routine exposure to allogeneic blood components by reducing circuit size seems an obviously benecial goal (110), removing certain components of the circuit such as the arterial line lter in an attempt to decrease volume does not yet have sufcient evidence of benet to offset a theoretical increased risk of harm (111). Recently developed circuits incorporate an arterial line lter into the oxygenator, maintaining the safety of ltration while maintaining low prime volumes (112). Although tissue factor released because of surgical trauma may be a major source of coagulation activation during CPB, contact with the articial surfaces of the CPB circuit initiates activation of the coagulation, inammatory, and brinolytic systems (7). Making the circuit components more biocompatible should theoretically decrease contact activation and downstream consequences. Several biopassive coatings have been developed to enhance the biocompatibility of CPB circuits and minimize hemostatic and inammatory actiPediatric Anesthesia 21 (2011) 3142 2010 Blackwell Publishing Ltd

vation by mimicking some of the properties of endothelium, such as negative ionic charge and hydrophilicity. Partially (oxygenator) or completely coated circuits are currently used by the majority of institutions performing pediatric heart surgery (38). Original coated circuits employed heparin, bound to the circuits surfaces either ionically (Durao II; Baxter Healthcare, Deereld, IL, USA) or covalently (Carmeda; Medtronic Cardiovascular, Minneapolis, MN, USA). Recently, polyanionic hydrophilic or amphiphilic polymers have been developed such as polymethoxyethylacrylate (PMEA) (X-coating; Terumo Cardiovascular, Ann Arbor, MI, USA), phosphoryl choline (ECCO/Synergy; Sorin Group, Mirandola, Italy), and polyethylene oxide (Trillium Biosurface; Medtronic Cardiovascular, Minneapolis, MN, USA). The Trillium coating employs covalently bound heparin and negatively charged sulfate and sulfonate groups in addition to the polymer. (http://www.medtr onic.com/for-healthcare-professionals/products-therapi es/cardiovascular/perfusion-products/biocompatible-sys tems/trillium-biosurface/index.htm, last accessed June 21, 2010). Studies specically investigating the pediatric use of coated circuits are few and generally include small numbers of patients of varying age and diagnosis. Olsson et al. (113) and Jensen et al. (114) each demonstrated a decrease in complement activation in small groups (total N = 60) of children randomized to heparin-coated versus uncoated circuits. Suzuki et al. (115) randomized 11 children to PMEA-coated or uncoated CPB for repair of ventricular septal defects. Decreased thrombin and platelet activation was demonstrated in the PMEA group. Andreasson et al. studied 40 infants <10 kg randomized to a biocompatible circuit (closed circuit, centrifugal pump) including heparin coating to a standard circuit (open reservoir, roller pump) without heparin coating. Activation of brinolysis was lower in the biocompatible group, but there was no signicant difference in thrombin activation. Eisses et al. performed an observational study of 26 patients undergoing repair of atrial or ventricular septal defects using an uncoated or PMEA-coated oxygenator. They showed no difference in thrombin generation and a paradoxical increase in brinolysis in the PMEA group, but higher platelet counts and less bleeding at 12 and 24 h after surgery. Deptula et al. (116) compared 16 patients <15 kg undergoing CPB with a PMEA-coated circuit with retrospective matched controls. They found the PMEA patients received fewer transfusions of red blood cells and plasma and had a lower lactate level for the rst 12 postoperative hours. In the largest pediatric study,
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Miyaji et al. (117) retrospectively compared 100 selected patients <10 kg who had undergone cardiac surgery using a heparin-coated circuit with a matched group of 50 operated on with noncoated circuits. No differences in bleeding outcomes of length of stay were found, but the heparin-coated group was mechanically ventilated for 2 fewer days than the uncoated group. Given moderate evidence of benet even with very small studies and the clear evidence of poor control of thrombin generation with conventional heparinization and CPB, it seems reasonable to include biopassive circuits in an extracorporeal perfusion plan for cardiac surgery. Postoperative bleeding Transfusion algorithms Despite our best efforts at minimizing the coagulopathic effects of CPB, appropriate prophylaxis, and optimal anticoagulation, excessive postoperative bleeding is a relatively common problem in pediatric cardiac surgery (118). Treatment of excessive bleeding is often empirical, but guided therapy is more likely to be effective and safer (119). Multiple algorithms have been described to guide hemostatic transfusion in adult cardiac surgery (120123), with guided therapy showing benets of deceased transfusion with equivalent or less bleeding. Currently, no single algorithm has been demonstrated to be superior, so that it is impossible to recommend a specic set of tests (122,123). Although there are less data validating algorithm-guided transfusion in pediatric cardiac surgery, both routine laboratory testing (119) and thromboelastography (124) after bypass have been shown to correlate well with abnormal bleeding. The best choice of coagulation tests to guide post-CPB hemostatic transfusion likely depends most on what test one can obtain in a rapid and reliable fashion at the individual institution. Thromboelastography can be performed during CPB using heparinase correction, thus providing information useful even before weaning and protamine administration (80). Fibrinogen levels and platelet counts can similarly be performed during CPB. Recombinant factor VIIa Recombinant activated factor VII (rFVIIa) (Novoseven; Novo Nordisk Healthcare, Princeton, NJ, USA) is FDA-approved for patients with hemophilia A or B with inhibitors or congenital factor VII deciency. It is able to directly activate factor X in the presence of activated platelets, obviating the need for factors IX and VIII. rFVIIa has been used off-label to treat
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intractable bleeding associated with trauma (125) and surgical bleeding, particularly in cardiac surgery (126,127). Published data on factor rFVIIa use in pediatric heart surgery are limited, with the entire published experience being barely over 100 cases. Individual case reports and case series have mostly shown control of bleeding after administration of VIIa (128 137). In one of the larger series, 24 pediatric cardiac surgical patients, including 12 on ECMO, were compared with retrospective controls. A signicant decrease in bleeding was seen in 23 of the 24 treated patients after rFVIIa administration (128). Six patients (25%) developed thrombotic complications. Karsies et al. (138) reported a case series of 25 patients who had received factor rFVIIa within a week after surgery for congenital heart disease. These were compared with 50 matched retrospective controls. Transfusion volume markedly decreased after administration of rFVIIa, as did chest tube output. No signicant difference in mortality or length of stay between groups was found. Eight percent of treated patients and 4% of controls had thrombotic complications, but this was not statistically signicant. In the only prospective randomized trial of rFVIIa in pediatric heart surgery, Ekert et al. (139) randomized 82 patients under 1 year old undergoing surgery for congenital heart disease to receive a single dose of rFVIIa (40 mcgkg)1) or placebo after protamine administration. No difference was found in bleeding or transfusion outcomes, and the time to chest closure was longer in the rFVIIa group. OConnell et al. (140) reviewed the FDA Adverse Event Reporting System database for thromboembolic events associated with the off-label use of factor VIIa in 2006. Thrombotic complication occurred in 185 adults and children (1 month to 91 years old) and included 50 deaths. Limited clinical evidence suggests that administration of rFVIIa is often effective in reducing coagulopathic bleeding resistant to conventional therapy after congenital heart surgery. This improvement comes with signicant risk of thrombosis in a group of patients already at high risk of thrombotic complications. rFVIIa cannot produce hemostasis alone and should only be administered after transfusion of sufcient platelets, plasma, and brinogen to form the substrate for hemostasis. Conclusions Patients undergoing surgery for congenital heart disease are at high risk of bleeding and transfusion during and after surgery. That risk can be reduced by understanding the issues specic to coagulation and anticoaPediatric Anesthesia 21 (2011) 3142 2010 Blackwell Publishing Ltd

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gulation in children, especially neonates, and using that understanding to craft a multimodal approach to minimizing the physiologic trespass of CPB. The published data upon which one must base a plan of care suffer from small numbers, differing subject populations, and outcomes but nevertheless offers some guiReferences
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