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Blood transfusion support in pediatric cardiovascular surgery
Transfusion Science 21 (1999) 63±72
www.elsevier.com/locate/transci
Blood transfusion support in pediatric cardiovascular surgery Janet L. Kwiatkowski a,b, Catherine S. Manno a,b,* a
Division of Hematology, The ChildrenÕs Hospital of Philadelphia, Philadelphia, PA, USA b Department of Pediatrics, School of Medicine, University of Pennsylvania, USA
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Abstract The majority of children who undergo open-heart surgery with cardiopulmonary bypass (CPB) require perioperative blood transfusion. Blood product requirements are aected by factors such as patient age, underlying cardiac disease, complexity of the surgical procedure, and hemostatic alterations induced by CPB. Transfusion support may include the use of whole blood and/or individual blood components with transfusion practices varying widely based on individual preferences and blood product availability. Approaches to limit allogeneic blood exposure include the use of modi®ed ultra®ltration and smaller bypass circuits, preoperative autologous blood donation and intraoperative blood salvage, and adjunctive anti®brinolytic agents. Potential advantages and disadvantages of the dierent blood products and pharmacological agents must be considered in managing the pediatric cardiac surgery patient. Ó 1999 Elsevier Science Ltd. All rights reserved. Keywords: Congenital heart defects; Cardiac surgery; Cardiopulmonary bypass; Blood transfusion; Hemostasis; Anti®brinolytic agents
1. Introduction Congenital heart defects have been reported to occur in approximately 1% of live births. From the ®rst palliative shunts oered by Blalock and Taussig in the 1940s [1], pediatric cardiac surgical technology has advanced tremendously, and today complex corrective procedures are performed on the tiniest of patients. Blood transfusion is integral to the support of most children who require openheart surgery and meeting blood transfusion requirements has become quite challenging. Perioperative blood requirements may exceed 100 ml/kg and are in¯uenced by hemostatic abnormalities related to factors intrinsic to the patient, including
age and underlying cardiac disease, as well as to the surgical procedure itself. Optimal transfusion support of the pediatric cardiac surgery patient must address these issues. Blood transfusion practices vary widely in the context of pediatric cardiac surgery and no one approach has received broad acceptance. Recent advances have included widespread use of hemoconcentration and bypass circuits appropriate for pediatric blood volumes, decreasing the amount of transfusion required to support individual surgical procedures. Newer adjunctive pharmacological therapies have also in¯uenced the use of blood products. This paper will provide a review of several approaches with regard to transfusion. 1.1. Pediatric cardiac surgery ± overview
* Corresponding author. Tel.: +215-590-2263; fax: +215-5903171; e-mail: [email protected] 1 Correspondence address.
With progress in the ®eld of congenital heart surgery, smaller patients are now undergoing
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cardiac surgical procedures. In North America, infants constitute approximately 50% of the pediatric cardiac surgical population [2]. Pediatric cardiac surgeries can be categorized as simple, intermediate, and complex (Table 1). In general, blood product requirements increase with greater Table 1 Classi®cation of operative procedures Simple Aortic valvuloplasty ASD patch repair (closure of ASD) Blalock±Taussing shunta Repair partial anomalous pulmonary venous return Resection subaortic membrane Intermediate Closure of primum ASD with mitral valve replacement ASD repair with mitral valve replacement ASD/VSD patch repair Incomplete AV canal repair Complete AV canal repair Pulmonary valvotomy RV out¯ow tract augmentation; repair total anomalous pulmonary venous return Senning procedureb Patch closure of VSD VSD patch repair with resection of coarctation of aorta Complex Arterial switch Fontan procedure for various forms of single ventricle physiologyc Modi®ed Glenn shuntd Separation of aorta and pulmonary artery with VSD patch repair (Truncus arteriosus repair) Stage I palliation for hypoplastic left heart syndromee a
Subclavian to pulmonary artery anastomosis. An operation used in children with transposition of the great vessels that redirects the venous return using an intra-atrial bae of autologous tissue. The bae directs the pulmonary venous blood across the tricuspid valve into the right ventricle and to the aorta; the systemic venous blood is directed across the mitral valve into the left ventricle and to the pulmonary artery. c An operation used in children with a single ventricle that separates the pulmonary from the systemic circulation. This procedure is based on the principle that the right atrial pressure is adequate to drive blood through the lung, making a ventricle unnecessary. d Superior vena cava to right pulmonary artery anastomosis. e Palliative procedure consisting of (1) transection of main pulmonary artery, (2) creation of neoaorta, and (3) creation of systemic to pulmonary artery shunt. Reprinted with permission from [4]. b
complexity of the surgical procedure [3,4]. Infants may undergo palliative shunting procedures followed by later de®nitive surgical repair. Repeat cardiac procedures are associated with an increased need for blood products [3], due to a propensity to bleed from scar tissue. Newer techniques including transcatheter therapy may limit the need for blood product support in the treatment of congenital heart disease. Transcatheter procedures can now be used in certain instances for repair of lesions including valvular stenosis, coarctation of the aorta, patent ductus arteriosus, and atrial septal defect [5]. Finally, the ®eld of pediatric cardiac transplantation has greatly expanded over the past two decades, and over half of pediatric heart recipients are less than ®ve years old [6]. 2. The problem of hemostasis 2.1. Patient age The coagulation system is immature at birth and continues to develop until late childhood. Neonates have low levels of factors II, VII, IX± XII, prekallikrein, and high molecular weight kininogen [7]. The protime (PT) and activated partial thromboplastin time (aPTT) are also mildly prolonged in newborns, re¯ecting a slower rate of thrombin generation [7]. These dierences are even more pronounced in premature infants. Many of the coagulation factor levels remain signi®cantly lower than adult values until late childhood [8]. Although these hemostatic alterations are physiological in normal infants and children, they may become clinically signi®cant in pediatric cardiac surgery patients when exacerbated by illness or dilution from cardiopulmonary bypass (CPB). Levels of naturally occurring coagulation inhibitors are also altered in neonates. Protein C, protein S, antithrombin III, and heparin cofactor II are decreased [7], and levels of protein C and heparin cofactor II remain signi®cantly lower than adult values until late childhood [8]. Conversely, a2 macroglobulin levels are elevated until adolescence [8]. Altered levels of coagulation inhibitors may make adequate anticoagulation necessary for CPB dicult.
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2.2. Congenital heart disease A variety of hemostatic abnormalities have been described in children with congenital heart disease. Thrombocytopenia may be present, the severity of which inversely correlates with hemoglobin level, and patient age [9]. This may re¯ect shortened platelet survival, which has been demonstrated in thrombocytopenic as well as nonthrombocytopenic patients with cyanotic congenital heart disease [10]. The platelets may also be dysfunctional with prolonged bleeding times and impaired platelet aggregation in vitro reported in children with congenital heart disease [11]. Perioperative medications such as prostaglandins and amiodarone also may adversely aect platelet function. An acquired reduction of the largest von Willebrand factor multimers has also been demonstrated in some children with congenital heart defects [12]. Additionally, coagulation factor levels, including factors V, VIII, and ®brinogen, are often reduced in congenital heart disease [13], which may re¯ect the presence of chronic disseminated intravascular coagulation [14,15]. The combination of such coagulation abnormalities may impair adequate perioperative hemostasis and must be considered when choosing appropriate transfusion support. 2.3. Cardiopulmonary bypass The incidence of severe bleeding associated with CPB in adults has been estimated to be 3±5% [16]. CPB causes hemostatic alterations through a variety of mechanisms [17]. Hemodilution related to the volume of non-blood solutions necessary to prime the pump results in a signi®cant reduction in coagulation factor levels [13,18,19]. This decline is also exacerbated by increased consumption of coagulation factors as a result of activation of the contact system upon exposure of blood to the extracorporeal circuit [13,20]. In adults, factor levels usually do not fall below that needed for adequate hemostasis. This phenomenon is more dramatic in infants in whom the prime volume may be two or three times larger than their blood volume and in whom the foreign surface area exposure is proportionately greater than in older children and adults.
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CPB causes thrombocytopenia related to dilution as well as to platelet activation and consumption. The resultant aberration of platelet function causes a prolongation of the bleeding time, decreased adhesiveness [21], and impaired platelet aggregation in response to agonists such as epinephrine and adenosine diphosphate [16]. Lowered levels of platelet surface antigens including glycoprotein IIb/IIIa, ®brinogen receptors [22], and platelet a2 adrenergic receptors [16], have been reported in association with CPB which may contribute to the pathogenesis. A more recent study found no abnormalities in these surface antigens and suggested that a factor extrinsic to the platelet may instead be causative [23]. Excessive or inadequate amounts of protamine used to reverse heparinization can also cause platelet dysfunction. Finally, deep hypothermia employed in many cardiac procedures alters both platelet function and coagulation parameters [24]. In a study of 22 children older than one year of age who underwent CPB, [19] plasma levels of coagulation factors decreased by an average 56% at the initiation of CPB related to hemodilution and levels of ®brinogen and Factors II, V, and VII continued to decline during CPB. Levels of some of the coagulation factors fell to values less than the minimum necessary for hemostasis. Platelet counts also decreased signi®cantly after CPB to a mean of 117 ´ 109 /l and bleeding times signi®cantly increased. A similar study in 30 neonates undergoing CPB demonstrated comparable reductions of coagulation factor levels [13]. Approximately half of the patients had reduced coagulation factor levels prior to the initiation of CPB, and in these infants, factor levels were reduced to an even greater extent. In particular, ®brinogen values remained low (<1 g/l) throughout the procedure. Platelet levels also fell to 30% of pre-CPB values. 3. Blood product selection 3.1. Whole blood The use of whole blood to meet transfusion requirements can simultaneously address the numerous hemostatic defects in the pediatric cardiac
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surgery patient and may result in fewer donor exposures. A potential disadvantage is the limited availability of the product. Whole blood is often employed in the CPB pump priming mixture as well as to meet transfusion needs during CPB [3]. At the authorsÕ institution, for small infants, the CPB pump is primed with a balanced electrolyte solution such as Plasma-lyte A (Baxter Hyland Healthcare, Glendale, CA) and whole blood to produce a ®nal hematocrit of 25% during cardiopulmonary bypass. We generally use a bloodless prime solution for non-anemic children who weigh more than approximately 7 kg. Whole blood that was recently collected has also been shown to be bene®cial in meeting the post-surgical blood product requirements in certain groups of patients. In a study of 161 children who underwent open-heart surgery, transfusion of fresh whole blood in the early postoperative period was compared with the use of individual blood components reconstituted as whole blood [4]. The use of less than 48 h old whole blood resulted in signi®cantly less blood loss in children less than two years old undergoing complex procedures. There was no signi®cant dierence in postoperative hemorrhage in children greater than two years of age receiving whole blood or blood components, but small numbers may have limited the analysis. Very fresh whole blood (less than 6 h old) conferred no signi®cant advantage over 24±48 h old whole blood. The hemostatic advantage of fresh whole blood is likely related to better preservation of platelet function. Centrifugation of blood for separation of random donor platelet units is associated with platelet loss and activation. In the previous study, platelet aggregation studies were more abnormal in the children who received blood component therapy compared to those who received whole blood [4]. Similarly, in a study of adult cardiac surgery patients, transfusion of six units of platelets were required to attain a rise in platelet count equivalent to one unit of fresh whole blood [25]. Furthermore, eight units of platelets were needed to restore the normal platelet aggregation provided by one unit of whole blood [25]. The platelets in whole blood that is 24±48 h old presumably are less functional than those of whole blood less than
6 h old because storage at 4°C is known to impair platelet function. Nonetheless, the hemostatic ef®cacy of the two products was similar. Transfusion of 24±48 h old whole blood is preferable to very fresh whole blood because it allows time for pre-transfusion testing and transport of the unit without compromising hemostasis. However, newer testing and preparation techniques may not be feasible with 24±48 h old whole blood. Nucleic acid testing (NAT) of blood products for human immunode®ciency virus (HIV) and hepatitis C virus (HCV) has been introduced on an experimental basis in the United States. Because this testing currently requires a minimum of ®ve days, it cannot be completed on fresh whole blood or platelets prior to administration. Universal leukoreduction has also been recommended by the Blood Products and Advisory Committee of the Food and Drug Administration, although this has not been uniformly accepted in the United States. Since the currently available whole blood leukoreduction ®lters also remove platelets, leukoreduction of whole blood is not performed at this time. It is the authorsÕ policy to provide 24±48 h old blood to meet the early postoperative transfusion requirements of all pediatric cardiac surgery patients. Others restrict the use of such fresh whole blood to patients less than two years old in whom a clear bene®t has been demonstrated. During the period of time that NAT is investigational, the hemostatic bene®ts of using 24±48 h old whole blood in pediatric cardiac surgery will have to be weighed against the very small viral safety advantage provided by NAT. It must be emphasized that whole blood that is stored for more than 48 h cannot be expected to be as ecacious as fresh whole blood due to deterioration in platelet function and diminution of levels of coagulation factors. 3.2. Blood components Intraoperative and postoperative transfusion requirements may also be met with the use of individual blood components. Blood components are more readily available than whole blood, but potential disadvantages include less functional
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platelets and increased number of donor exposures. Uniform criteria for postoperative transfusion management of the pediatric cardiac surgery patient have not been established. Practice varies according to the preference of individual surgeons and anesthesiologists and may vary from case to case. Packed red blood cell transfusions have been used by some to maintain a hemoglobin level greater than 10 g/dL [3,26], and to a higher level of 12±13 g/dL in neonates [27] and patients with residual shunts and cyanosis [26,27]. Lower hemoglobin levels of 8 g/dL are acceptable to others [28]. Transfusion of large amounts of additive solutions may cause electrolyte disturbances particularly in small infants. When the equivalent of two blood volumes or more must be transfused, it is often recommended to centrifuge the red blood cell unit and remove the additive solution, although this has not been studied extensively in the pediatric cardiac surgery population. The use of platelet concentrates has been recommended by some to keep the platelet count greater than 100 ´ 109 /L3 routinely on the ®rst postoperative day [3] or in the presence of active bleeding. With active bleeding, platelet concentrates may be bene®cial even in the presence of a normal platelet count due to the platelet dysfunction induced by CPB. Fresh frozen plasma is often used to manage postoperative hemorrhage in the presence of altered coagulation tests [3,26]. The use of cryoprecipitate, instead, has been suggested for neonates due to the high proportion of patients with low ®brinogen levels [13]. In practice, transfusion support must be tailored to the individual patient. 3.3. Estimating blood product requirements A reasonable estimate of the blood product requirement for a given surgical procedure can help tailor preoperative blood product orders to decrease the number of emergent units as well as the cost of unnecessary crossmatching of units. Overall blood product requirements increase with increasing complexity of the cardiac procedure [3,4]. In a retrospective analysis, the average use of blood components in patients less than 12 years old undergoing open-heart surgery was deter-
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mined [3]. Seventy-eight % of the blood products were transfused intra-operatively, and 22% were used postoperatively. The average number of components needed for complex procedures was 6.3 units compared with 2.3 units for simple procedures. The authors were able to extrapolate standard preoperative blood orders for repair of atrial septal defect, ventricular septal defect, tetralogy of Fallot, and single-ventricle defect based on their estimates. 3.4. Blood product testing and preparation 3.4.1. Infectious disease All blood products transfused to pediatric cardiac surgery patients should undergo complete routine infectious disease testing for HIV-1 and 2, HTLV I/II, hepatitis B surface antigen, hepatitis B core antibody, antibody to hepatitis C virus, and syphilis. Fresh whole blood that is 24±48 h old allows sucient time for full screening to be accomplished. 3.4.2. Antibody screening Routine blood typing and antibody screening should be performed. The identi®cation of coldreacting antibody in the patientÕs serum, such as anti-M or anti-P1 elicits concern about potential hemolysis of antigen-positive blood products during deep hypothermia. This area has not been studied extensively. A report of two adult patients with anti-M IgM antibodies demonstrated normal survival of M-positive transfused red blood cells and no transfusion reactions at blood temperatures of 16±28°C [29]. However, there exist anecdotal reports of agglutination and hemolysis of Mpositive red blood cells in the presence of anti-M antibody. Therefore, it is authorsÕ policy to provide M-negative blood to patients with anti-M antibody. We do not routinely prepare P1 or Lewis a or b negative blood for patients with these antibodies. 3.4.3. Irradiation Several indications exist for irradiation of cellular blood products for pediatric cardiac surgery patients due to a risk of developing transfusionassociated graft versus host disease. Cellular blood
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products donated from biological relatives should be irradiated due to a possibility of transfusion of HLA-homozygous lymphocytes into an HLAheterozygous recipient. Additionally, all heart transplant recipients should receive irradiated blood because they will be maintained on immunosuppressive therapy. Certain congenital heart defects may be found in association with the DiGeorge anomaly (Table 2). In addition to cardiac defects, the DiGeorge anomaly consists of absence or hypoplasia of the thymus and parathyroid glands with persistent hypocalcemia, and frequently, dysmorphic facial features [30,31]. It is often associated with deletions involving chromosome 22. Importantly, thymic hypoplasia with impaired cell-mediated immunity places the patient at risk for developing transfusion-associated graft versus host disease. Evaluation of children with cardiac lesions found in association with the DiGeorge anomaly includes serum parathyroid levels, serum calcium levels, chromosome studies, and T cell studies [31]. We routinely irradiate blood for children with the DiGeorge anomaly, or with cardiac lesions found in association with this anomaly unless the DiGeorge anomaly has been de®nitively excluded. 4. Limiting blood product usage The majority of pediatric patients who undergo open-heart surgery require perioperative transfusion support. Decreasing the amount of transfusions is desirable due to the risk of infectious disease transmission. Approaches to limiting the number of donor exposures include newer surgical Table 2 Cardiac defects associated with the DiGeorge anomaly [30,31] Tetralogy of Fallot Interrupted aortic arch type B Truncus arteriosus Right aortic arch Pulmonary atresia Double outlet right ventricle Transposition of the great arteries Hypoplastic left heart syndrome Aberrant left subclavian artery
and cardiopulmonary bypass techniques to limit blood loss, the use of autologous and salvaged blood, and the use of pharmacological agents such as anti-®brinolytics. With some of these modi®cations, and by accepting lower hemoglobin values, pediatric cardiac surgery with CPB has been successfully accomplished without the use of blood products in some pediatric patients whose parents are of the JehovahÕs Witness faith [32]. 4.1. Cardiopulmonary bypass ± modi®ed ultra®ltration Hemodilution during CPB increases blood product requirements in small cardiac surgery patients. Techniques to reduce the extent of hemodilution can decrease transfusion requirements. Since the blood oxygenator comprises the largest portion of the extracorporeal system, reducing its size can substantially decrease the prime volume. Newer oxygenator designs such as the reversephase hollow-®ber membrane oxygenator have enabled priming volumes as low as 80 ml [2]. Another approach to reducing the need for blood transfusions is to reverse the hemodilution caused by CPB. Ultra®ltration is a technique whereby water, electrolytes, and low molecular weight substances are removed as blood passes through a ®lter, resulting in hemoconcentration. Conventional ultra®ltration occurs during CPB and has been shown to increase coagulation factor levels signi®cantly. Modi®ed ultra®ltration is a newer technique that is performed for 10±15 min after weaning from CPB. Multiple studies have demonstrated that modi®ed ultra®ltration results in signi®cantly less blood loss and fewer postoperative transfusions [33±36]. The greatest bene®t may be observed in neonates, patients with preoperative pulmonary hypertension, and those who require extended CPB times of greater than 2 hours [27]. Modi®ed ultra®ltration is now used routinely in many pediatric cardiac surgery centers. 4.2. Directed blood donation Families often request the use of directed blood donations to provide for transfusion needs of pe-
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diatric patients. However, there are no data to suggest that the use of such directed donors decreases infectious disease transmission over properly tested products from the blood supply. The number of donor exposures may be limited by using dedicated donors, a small number of donors to supply all of the patientÕs transfusion needs. Directed donations may be used to provide 48 h old whole blood for pediatric cardiac surgery patients. Special ``rapid turnaround'' directed donor cards are used to identify these units. From a practical perspective, we estimate that for every two units of blood that are donated, one unit will actually become available to the patient due to the possibility of positive infection screening or lack of ABO speci®city in directed donor units. 4.3. Autologous blood transfusion Transfusion of autologous blood is another means of reducing donor exposure. An additional bene®t is a decreased risk of alloantibody production. Autologous blood may be obtained by preoperative blood donation with or without the use of erythropoietin, or autologous blood can be salvaged during the cardiac procedure and returned to the patient postoperatively. Most experience with preoperative autologous blood donation comes from adult patients. The feasibility of this process may be limited in pediatric patients because of their small blood volume. Additionally, patients with preoperative anemia, hypoxemia, or cardiovascular instability may not be candidates. A recent retrospective analysis demonstrated the ecacy of autologous blood transfusions in pediatric cardiac surgery [37]. Eighty children, including 20 under the age of ®ve years and children as small as 12.3 kg, underwent preoperative blood donation prior to surgical correction of anomalies including atrial and ventricular septal defects, complex cardiac defects, endocardial cushion defects, and valve replacements. Patients underwent sequential blood donations and an average total of 735 ml of blood was stored per patient. Adverse events were few and included mild vasovagal reactions and rescheduling of blood draws due to inadequate intravenous access. With supplemental oral iron
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therapy, the hemoglobin level remained stable in most patients. The transfusion of autologous packed red cells resulted in a marked decrease in homologous donor exposure. Ninety-four % of patients did not require homologous blood transfusion compared with only 16% in a similar group of patients who did not receive autologous transfusion. Preoperative autologous blood donations have also resulted in decreased homologous blood use in other pediatric surgical procedures [38]. Therefore, autologous blood collected preoperatively appears to be ecacious and well tolerated in selected children undergoing open-heart surgery. Autologous blood may also be salvaged from the CPB system and used for postoperative transfusion. A prospective study addressed the feasibility of this method in pediatric cardiac surgery patients [39]. Blood recovered from the CPB circuit was stored at room temperature for up to 18 h prior to transfusion. Despite the known hemostatic alterations induced by CPB, transfusion of salvaged blood did not result in increased bleeding compared with patients who did not receive autologous blood. Total blood product requirements were similar between the two groups. Bacterial contamination occurred at a rate of approximately 2% of stored autologous units. Free hemoglobin levels were higher in children who received salvaged blood, but remained in an acceptable range. Thus, the use of salvaged blood may be another feasible adjunct to homologous transfusion in pediatric cardiac surgery patients. The risks of transfusion of salvaged blood stored at 22°C for 18 h must be weighed against the known risks of properly stored blood components. 4.4. Adjunctive pharmacological therapy 4.4.1. Aprotinin A number of pharmacological agents have been employed in an attempt to decrease blood product requirements related to cardiac surgery. One of the most extensively studied medications is aprotinin, a non-speci®c protease inhibitor. Its mechanisms of action include inhibition of plasmin and kallikrein, anti-in¯ammatory eects, and preservation of platelet function [40]. The use of high-dose
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aprotinin in adult patients undergoing open-heart surgery has been shown to reduce blood loss and transfusion requirements [41]. Studies on the bene®t of aprotinin for pediatric cardiac surgery have been more con¯icting. Some have shown decreased blood loss and postoperative transfusion requirements with aprotinin [42±44], while others have not demonstrated any improvement [40]. Pediatric patients with complex cardiac malformations [42] or who are having repeat cardiac surgical procedures [44] appear to derive the greatest hemostatic bene®t from aprotinin, likely because of the higher incidence of bleeding in these patient groups. Allergic reactions may occur with re-exposure to aprotinin because it is derived from a bovine source. The risk of allergic reactions following reexposure to aprotinin has been reported to be as high as 6% [45]. A recent report found a lower incidence of 1.2% in pediatric patients, but most had been pretreated with dexamethasone [46]. Since patients undergoing reoperations may derive the most bene®t from the drug, determining an individual patientÕs risk of allergic reaction upon re-exposure is important. The incidence of allergic reactions appears to be highest when repeat exposures occur within 200 days of the prior treatment [46]. Therefore, it is advisable to delay repeat surgical procedures if possible. Administering a test dose of aprotinin and appropriate monitoring for anaphylaxis is recommended for all repeat exposures [46]. Premedication with steroids or antihistamines has also been used prophylactically to decrease the risk of anaphylaxis. 4.4.2. Tranexamic acid Tranexamic acid inhibits ®brinolysis through competitive inhibition of plasmin and plasminogen. Several studies in adult cardiac surgery patients have demonstrated decreased blood loss and transfusion requirements associated with its use [47,48]. In children, the data are less clear because there are few studies and the doses and methods of administration are not comparable. One study found that only children with cyanotic heart defects had decreased postoperative blood loss with the use of a single 50 mg/kg dose of tranexamic acid [49]. Another report, using a larger bolus dose of tranexamic followed by a
continuous infusion of the medication showed decreased blood loss and transfusion requirements in children undergoing repeat cardiac surgeries [50]. Further studies are needed to demonstrate the ecacy of this medication in the pediatric cardiac surgery population. 5. Conclusion Although tremendous progress has been observed in the ®eld of pediatric cardiac surgery in the past 20 years, blood transfusions are still required to support the majority of young patients who require open-heart surgery with cardiopulmonary bypass. Transfusion practices vary widely and are a re¯ection not only of individual preference based on training and experience, but also of blood product availability. Widespread use of ultra®ltration and intraoperative blood salvage for autologous transfusion will continue to reduce the need for allogeneic transfusion in the future. Other approaches to reducing transfusion requirements for infants and children may include the use of pharmacological agents that have already been demonstrated to reduce blood loss in adults. The theoretical bene®ts of such agents must be carefully assessed in children before widespread acceptance occurs. References [1] Blalock A, Taussig HE. The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. JAMA 1945;128:189±202. [2] Groom RC, Akl BF, Albus R, Lefrak EA. Pediatric cardiopulmonary bypass: a review of current practice. Internat Anesthes Clin 1996;34:141±63. [3] Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open heart surgery. Transfusion 1996;36:150±4. [4] Manno CS, Hedberg KW, Kim HC, Bunin GR, Nicolson S, Jobes D, et al. Comparison of the hemostatic eects of fresh whole blood, stored whole blood, and components after open heart surgery in children. Blood 1991;77:930±6. [5] Mendelsohn AM, Shim D. Inroads in transcatheter therapy for congenital heart disease. J Pediatr 1998;133:324±33. [6] Addonizio LJ. Current status of cardiac transplantation in children. Curr Opin Pediatr 1996;8:520±6.
J.L. Kwiatkowski, C.S. Manno / Transfusion Science 21 (1999) 63±72 [7] Andrew M, Paes B, Johnston M. Development of the hemostatic system in the neonate and young infant. Am J Pediatr Hematol/Oncol 1990;12:95±104. [8] Andrew M, Vegh P, Johnston M, Bowker J, Ofosu F, Mitchell L. Maturation of the hemostatic system during childhood. Blood 1992;80:1998±2005. [9] Gross S, Keefer V, Liebman J. The platelets in cyanotic congenital heart disease. Pediatrics 1968;42:651±8. [10] Waldman JD, Czapek EE, Paul MH, Schwartz AD, Levin DL, Schindler S. Shortened platelet survival in cyanotic congenital heart disease. J Pediatr 1975;87:77±9. [11] Maurer HM, McCue CM, Caul J, Still WJS. Impairment in platelet aggregation in congenital cardiac disease. Blood 1972;40:207±15. [12] Gill JC, Wilson AD, Endres-Brooks J, Montgomery RR. Loss of the largest vonWillebrand factor multimers from the plasma of patients with congenital heart defects. Blood 1986;67:758±61. [13] Kern FH, Morana NJ, Sears JJ, Hickey PR. Coagulation defects in neonates during cardiopulmonary bypass. Ann Thorac Surg 1992;54:541±6. [14] Komp DM, Sparrow AW. Polycythemia in cyanotic heart disease ± a study of altered coagulation. J Pediatr 1970;76:231±6. [15] Inenacho HNC, Fletcher DJ, Breeze GR, Stuart J. Consumption coagulopathy in congenital heart disease. Lancet 1973;1:231±4. [16] Woodman RC, Harker LA. Bleeding complications associated with cardiopulmonary bypass. Blood 1990;76:1680±97. [17] Bevan DH. Cardiac bypass haemostasis: putting blood through the mill. Brit J Haematol 1999;104:208±19. [18] Mammen EF, Koets MH, Washington BC, Wolk LW, Brown JM, Burdick M, et al. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985;11:281±92. [19] Chan AKC, Leaker M, Burrows FA, Williams WG, Gruenwald CE, Whyte L, et al. Coagulation and ®brinolytic pro®le of paediatric patients undergoing cardiopulmonary bypass. Thromb Haemost 1997;77:270±7. [20] Plotz FB, van Oeveren W, Bartlett RH, Wildevuur CRH. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg 1993;105:823±32. [21] Salzman EW. Blood platelets and extracorporeal circulation. Transfusion 1963;3:274±7. [22] Musial J, Niewiarowski S, Hershock D, Morinelli TA, Colman RW, Edmunds Jr LH. Loss of ®brinogen receptors from the platelet surface during simulated extracorporeal circulation. J Lab Clin Med 1985;105:514±22. [23] Kestin AS, Valeri CR, Khuri SF, Loscalzo J, Ellis PA, MacGregor H, et al. The platelet function defect of cardiopulmonary bypass. Blood 1993;82:107±17. [24] Milam JD. Blood transfusion in heart surgery. Surg Clin N Am 1982;63:1127±47. [25] Lavee J, Martinowitz U, Mohr R, Goor DA, Golan M, Langsam J, et al. The eect of transfusion of fresh whole blood versus platelet concentrates after cardiac operations. J Thorac Cardiovasc Surg 1989;97:204±12.
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[26] Guay J, Rivard G. Mediastinal bleeding after cardiopulmonary bypass in pediatric patients. Ann Thorac Surg 1996;62:1955±60. [27] Bando K, Turrentine MW, Vijay P, Sharp TG, Sekine Y, Lalone BJ, et al. Eect of modi®ed ultra®ltration in highrisk patients undergoing operations for congenital heart disease. Ann Thorac Surg 1998;66:821±8. [28] Cooley DA. Conservation of blood during cardiovascular surgery. Am J Surg 1995;170 Suppl:53±9. [29] Kurtz SR, Ouellet R, McMican A, Valeri CR. Survival of MM red cells during hypothermia in two patients with anti-M. Transfusion 1983;23:37±9. [30] Lin AE. Congenital heart defects in chromosome abnormality syndromes. In: Emmanouilides GC, Riemenschneider TA, Allen HD, Gutgesell HP, editors. Heart disease in infants, children, and adolescents including the fetus and young adult. Baltimore: Williams & Wilkins, 1995:633±43. [31] Garson A, Brizker JT, Fisher DJ, Neish SR, editors. The science and practice of pediatric cardiology, 2nd ed. Baltimore: Wilkins & Wilkins, 1998:2660±1. [32] van Son JAM, Hovaguimian H, Rao IM, He G, Meiling GA, King DH, et al. Strategies for repair of congenital heart defects in infants without the use of blood. Ann Thorac Surg 1995;59:384±8. [33] Koutlas TC, Gaynor W, Nicolson SC, Steven JM, Wernovsky G, Spray TL. Modi®ed ultra®ltration reduces postoperative morbidity after cavopulmonary connection. Ann Thorac Surg 1997;64:37±43. [34] Naik SK, Knight A, Elliot M. A prospective randomized study of a modi®ed technique of ultra®ltration during pediatric open-heart surgery. Circulation 1991;84(Suppl III):422±31. [35] Ad N, Snir E, Katz J, Birk E, Vidne BA. Use of the modi®ed technique of ultra®ltration in pediatric openheart surgery: a prospective study. Isr J Med Sci 1996;32:1326±31. [36] Draaisma AM, Hazekamp MG, Frank M, Anes N, Schoof PH, Huysmans HA. Modi®ed ultra®ltration after cardiopulmonary bypass in pediatric cardiac surgery. Ann Thorac Surg 1997;64:521±5. [37] Masuda M, Kawachi Y, Inaba S, Matsuzaki K, Fukumura F, Morita S, et al. Preoperative autologous blood donations in pediatric cardiac surgery. Ann Thorac Surg 1995;60:1694±7. [38] Novak RW. Autologous blood transfusion in a pediatric population: safety and ecacy. Clin Pediatr 1988;27:184±7. [39] Hishon ML, Ryan A, Lithgow P, Butt W. An evaluation of changes in composition and contamination of salvaged blood from the cardiopulmonary bypass circuit of pediatric patients. Heart Lung 1995;24:307±11. [40] Davies MJ, Allen A, Kort H, Weerasena NA, Rocco D, Paul CL, et al. Prospective, randomized, double-blind study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac Surg 1997;63:497±503. [41] Swart MJ, Gordon PC, Hayse-Gregson PB, Dyer RA, Swanepoel AL, Buckels NJ, et al. High-dose aprotinin in
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J.L. Kwiatkowski, C.S. Manno / Transfusion Science 21 (1999) 63±72 cardiac surgery ± a prospective randomized trial. Anaesth Intens Care 1994;22:529±33. Carrel TP, Schwanda M, Vogt PR, Turina MI. Aprotinin in pediatric cardiac operations: a bene®t in complex malformations and with high-dose regimen only. Ann Thorac Surg 1998;66:153±8. Penkoske PA, Entwistle LM, Marchak BE, Seal RF, Gibb W. Aprotinin in children undergoing repair of congenital heart defects. Ann Thorac Surg 1995;60 Suppl:529±32. Miller BE, Tosone SR, Tam VKH, Kanter KR, Guzzetta NA, Bailey JM, et al. Hematologic and economic impact of aprotinin in reoperative pediatric cardiac operations. Ann Thorac Surg 1998;66:535±41. Diefenbach C, Abel M, Limpers B, Lynch J, Ruskowski H, Jugert FK, et al. Fatal anaphylactic shock after aprotinin reexposure in cardiac surgery. Anesth Analg 1995;80:830±1. Dietrich W. Incidence of hypersensitivity reactions. Ann Thorac Surg 1998;65 Suppl:60±4.
[47] Coey A, Pittman J, Halbrook H, Fehrenbacher J, Beckman D, Hormuth D. The use of tranexamic acid to reduce postoperative bleeding following cardiac surgery: a double-blind randomized trial. Am Surg 1995;61:566±8. [48] Horrow JC, Hlavacek J, Strong MD, Collier W, Brodsky I, Goldman SM, et al. Prophylactic tranexamic acid decreases bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990;99:70±4. [49] Zonis Z, Seear M, Reichert C, Sett S, Allen C. The eect of preoperative tranexamic acid on blood loss after cardiac operations in children. J Thorac Cardiovasc Surg 1996;111:982±7. [50] Reid RW, Zimmerman A, Laussen PC, Mayer JE, Gorlin JB, Burrows FA. The ecacy of tranexamic acid versus placebo in decreasing blood loss in pediatric patients undergoing repeat cardiac surgery. Anesth Analg 1997;84:990±6.
www.elsevier.com/locate/transci
Blood transfusion support in pediatric cardiovascular surgery Janet L. Kwiatkowski a,b, Catherine S. Manno a,b,* a
Division of Hematology, The ChildrenÕs Hospital of Philadelphia, Philadelphia, PA, USA b Department of Pediatrics, School of Medicine, University of Pennsylvania, USA
1
Abstract The majority of children who undergo open-heart surgery with cardiopulmonary bypass (CPB) require perioperative blood transfusion. Blood product requirements are aected by factors such as patient age, underlying cardiac disease, complexity of the surgical procedure, and hemostatic alterations induced by CPB. Transfusion support may include the use of whole blood and/or individual blood components with transfusion practices varying widely based on individual preferences and blood product availability. Approaches to limit allogeneic blood exposure include the use of modi®ed ultra®ltration and smaller bypass circuits, preoperative autologous blood donation and intraoperative blood salvage, and adjunctive anti®brinolytic agents. Potential advantages and disadvantages of the dierent blood products and pharmacological agents must be considered in managing the pediatric cardiac surgery patient. Ó 1999 Elsevier Science Ltd. All rights reserved. Keywords: Congenital heart defects; Cardiac surgery; Cardiopulmonary bypass; Blood transfusion; Hemostasis; Anti®brinolytic agents
1. Introduction Congenital heart defects have been reported to occur in approximately 1% of live births. From the ®rst palliative shunts oered by Blalock and Taussig in the 1940s [1], pediatric cardiac surgical technology has advanced tremendously, and today complex corrective procedures are performed on the tiniest of patients. Blood transfusion is integral to the support of most children who require openheart surgery and meeting blood transfusion requirements has become quite challenging. Perioperative blood requirements may exceed 100 ml/kg and are in¯uenced by hemostatic abnormalities related to factors intrinsic to the patient, including
age and underlying cardiac disease, as well as to the surgical procedure itself. Optimal transfusion support of the pediatric cardiac surgery patient must address these issues. Blood transfusion practices vary widely in the context of pediatric cardiac surgery and no one approach has received broad acceptance. Recent advances have included widespread use of hemoconcentration and bypass circuits appropriate for pediatric blood volumes, decreasing the amount of transfusion required to support individual surgical procedures. Newer adjunctive pharmacological therapies have also in¯uenced the use of blood products. This paper will provide a review of several approaches with regard to transfusion. 1.1. Pediatric cardiac surgery ± overview
* Corresponding author. Tel.: +215-590-2263; fax: +215-5903171; e-mail: [email protected] 1 Correspondence address.
With progress in the ®eld of congenital heart surgery, smaller patients are now undergoing
0955-3886/99/$ ± see front matter Ó 1999 Published by Elsevier Science Ltd. All rights reserved. PII: S 0 9 5 5 - 3 8 8 6 ( 9 9 ) 0 0 0 6 6 - 1
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cardiac surgical procedures. In North America, infants constitute approximately 50% of the pediatric cardiac surgical population [2]. Pediatric cardiac surgeries can be categorized as simple, intermediate, and complex (Table 1). In general, blood product requirements increase with greater Table 1 Classi®cation of operative procedures Simple Aortic valvuloplasty ASD patch repair (closure of ASD) Blalock±Taussing shunta Repair partial anomalous pulmonary venous return Resection subaortic membrane Intermediate Closure of primum ASD with mitral valve replacement ASD repair with mitral valve replacement ASD/VSD patch repair Incomplete AV canal repair Complete AV canal repair Pulmonary valvotomy RV out¯ow tract augmentation; repair total anomalous pulmonary venous return Senning procedureb Patch closure of VSD VSD patch repair with resection of coarctation of aorta Complex Arterial switch Fontan procedure for various forms of single ventricle physiologyc Modi®ed Glenn shuntd Separation of aorta and pulmonary artery with VSD patch repair (Truncus arteriosus repair) Stage I palliation for hypoplastic left heart syndromee a
Subclavian to pulmonary artery anastomosis. An operation used in children with transposition of the great vessels that redirects the venous return using an intra-atrial bae of autologous tissue. The bae directs the pulmonary venous blood across the tricuspid valve into the right ventricle and to the aorta; the systemic venous blood is directed across the mitral valve into the left ventricle and to the pulmonary artery. c An operation used in children with a single ventricle that separates the pulmonary from the systemic circulation. This procedure is based on the principle that the right atrial pressure is adequate to drive blood through the lung, making a ventricle unnecessary. d Superior vena cava to right pulmonary artery anastomosis. e Palliative procedure consisting of (1) transection of main pulmonary artery, (2) creation of neoaorta, and (3) creation of systemic to pulmonary artery shunt. Reprinted with permission from [4]. b
complexity of the surgical procedure [3,4]. Infants may undergo palliative shunting procedures followed by later de®nitive surgical repair. Repeat cardiac procedures are associated with an increased need for blood products [3], due to a propensity to bleed from scar tissue. Newer techniques including transcatheter therapy may limit the need for blood product support in the treatment of congenital heart disease. Transcatheter procedures can now be used in certain instances for repair of lesions including valvular stenosis, coarctation of the aorta, patent ductus arteriosus, and atrial septal defect [5]. Finally, the ®eld of pediatric cardiac transplantation has greatly expanded over the past two decades, and over half of pediatric heart recipients are less than ®ve years old [6]. 2. The problem of hemostasis 2.1. Patient age The coagulation system is immature at birth and continues to develop until late childhood. Neonates have low levels of factors II, VII, IX± XII, prekallikrein, and high molecular weight kininogen [7]. The protime (PT) and activated partial thromboplastin time (aPTT) are also mildly prolonged in newborns, re¯ecting a slower rate of thrombin generation [7]. These dierences are even more pronounced in premature infants. Many of the coagulation factor levels remain signi®cantly lower than adult values until late childhood [8]. Although these hemostatic alterations are physiological in normal infants and children, they may become clinically signi®cant in pediatric cardiac surgery patients when exacerbated by illness or dilution from cardiopulmonary bypass (CPB). Levels of naturally occurring coagulation inhibitors are also altered in neonates. Protein C, protein S, antithrombin III, and heparin cofactor II are decreased [7], and levels of protein C and heparin cofactor II remain signi®cantly lower than adult values until late childhood [8]. Conversely, a2 macroglobulin levels are elevated until adolescence [8]. Altered levels of coagulation inhibitors may make adequate anticoagulation necessary for CPB dicult.
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2.2. Congenital heart disease A variety of hemostatic abnormalities have been described in children with congenital heart disease. Thrombocytopenia may be present, the severity of which inversely correlates with hemoglobin level, and patient age [9]. This may re¯ect shortened platelet survival, which has been demonstrated in thrombocytopenic as well as nonthrombocytopenic patients with cyanotic congenital heart disease [10]. The platelets may also be dysfunctional with prolonged bleeding times and impaired platelet aggregation in vitro reported in children with congenital heart disease [11]. Perioperative medications such as prostaglandins and amiodarone also may adversely aect platelet function. An acquired reduction of the largest von Willebrand factor multimers has also been demonstrated in some children with congenital heart defects [12]. Additionally, coagulation factor levels, including factors V, VIII, and ®brinogen, are often reduced in congenital heart disease [13], which may re¯ect the presence of chronic disseminated intravascular coagulation [14,15]. The combination of such coagulation abnormalities may impair adequate perioperative hemostasis and must be considered when choosing appropriate transfusion support. 2.3. Cardiopulmonary bypass The incidence of severe bleeding associated with CPB in adults has been estimated to be 3±5% [16]. CPB causes hemostatic alterations through a variety of mechanisms [17]. Hemodilution related to the volume of non-blood solutions necessary to prime the pump results in a signi®cant reduction in coagulation factor levels [13,18,19]. This decline is also exacerbated by increased consumption of coagulation factors as a result of activation of the contact system upon exposure of blood to the extracorporeal circuit [13,20]. In adults, factor levels usually do not fall below that needed for adequate hemostasis. This phenomenon is more dramatic in infants in whom the prime volume may be two or three times larger than their blood volume and in whom the foreign surface area exposure is proportionately greater than in older children and adults.
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CPB causes thrombocytopenia related to dilution as well as to platelet activation and consumption. The resultant aberration of platelet function causes a prolongation of the bleeding time, decreased adhesiveness [21], and impaired platelet aggregation in response to agonists such as epinephrine and adenosine diphosphate [16]. Lowered levels of platelet surface antigens including glycoprotein IIb/IIIa, ®brinogen receptors [22], and platelet a2 adrenergic receptors [16], have been reported in association with CPB which may contribute to the pathogenesis. A more recent study found no abnormalities in these surface antigens and suggested that a factor extrinsic to the platelet may instead be causative [23]. Excessive or inadequate amounts of protamine used to reverse heparinization can also cause platelet dysfunction. Finally, deep hypothermia employed in many cardiac procedures alters both platelet function and coagulation parameters [24]. In a study of 22 children older than one year of age who underwent CPB, [19] plasma levels of coagulation factors decreased by an average 56% at the initiation of CPB related to hemodilution and levels of ®brinogen and Factors II, V, and VII continued to decline during CPB. Levels of some of the coagulation factors fell to values less than the minimum necessary for hemostasis. Platelet counts also decreased signi®cantly after CPB to a mean of 117 ´ 109 /l and bleeding times signi®cantly increased. A similar study in 30 neonates undergoing CPB demonstrated comparable reductions of coagulation factor levels [13]. Approximately half of the patients had reduced coagulation factor levels prior to the initiation of CPB, and in these infants, factor levels were reduced to an even greater extent. In particular, ®brinogen values remained low (<1 g/l) throughout the procedure. Platelet levels also fell to 30% of pre-CPB values. 3. Blood product selection 3.1. Whole blood The use of whole blood to meet transfusion requirements can simultaneously address the numerous hemostatic defects in the pediatric cardiac
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surgery patient and may result in fewer donor exposures. A potential disadvantage is the limited availability of the product. Whole blood is often employed in the CPB pump priming mixture as well as to meet transfusion needs during CPB [3]. At the authorsÕ institution, for small infants, the CPB pump is primed with a balanced electrolyte solution such as Plasma-lyte A (Baxter Hyland Healthcare, Glendale, CA) and whole blood to produce a ®nal hematocrit of 25% during cardiopulmonary bypass. We generally use a bloodless prime solution for non-anemic children who weigh more than approximately 7 kg. Whole blood that was recently collected has also been shown to be bene®cial in meeting the post-surgical blood product requirements in certain groups of patients. In a study of 161 children who underwent open-heart surgery, transfusion of fresh whole blood in the early postoperative period was compared with the use of individual blood components reconstituted as whole blood [4]. The use of less than 48 h old whole blood resulted in signi®cantly less blood loss in children less than two years old undergoing complex procedures. There was no signi®cant dierence in postoperative hemorrhage in children greater than two years of age receiving whole blood or blood components, but small numbers may have limited the analysis. Very fresh whole blood (less than 6 h old) conferred no signi®cant advantage over 24±48 h old whole blood. The hemostatic advantage of fresh whole blood is likely related to better preservation of platelet function. Centrifugation of blood for separation of random donor platelet units is associated with platelet loss and activation. In the previous study, platelet aggregation studies were more abnormal in the children who received blood component therapy compared to those who received whole blood [4]. Similarly, in a study of adult cardiac surgery patients, transfusion of six units of platelets were required to attain a rise in platelet count equivalent to one unit of fresh whole blood [25]. Furthermore, eight units of platelets were needed to restore the normal platelet aggregation provided by one unit of whole blood [25]. The platelets in whole blood that is 24±48 h old presumably are less functional than those of whole blood less than
6 h old because storage at 4°C is known to impair platelet function. Nonetheless, the hemostatic ef®cacy of the two products was similar. Transfusion of 24±48 h old whole blood is preferable to very fresh whole blood because it allows time for pre-transfusion testing and transport of the unit without compromising hemostasis. However, newer testing and preparation techniques may not be feasible with 24±48 h old whole blood. Nucleic acid testing (NAT) of blood products for human immunode®ciency virus (HIV) and hepatitis C virus (HCV) has been introduced on an experimental basis in the United States. Because this testing currently requires a minimum of ®ve days, it cannot be completed on fresh whole blood or platelets prior to administration. Universal leukoreduction has also been recommended by the Blood Products and Advisory Committee of the Food and Drug Administration, although this has not been uniformly accepted in the United States. Since the currently available whole blood leukoreduction ®lters also remove platelets, leukoreduction of whole blood is not performed at this time. It is the authorsÕ policy to provide 24±48 h old blood to meet the early postoperative transfusion requirements of all pediatric cardiac surgery patients. Others restrict the use of such fresh whole blood to patients less than two years old in whom a clear bene®t has been demonstrated. During the period of time that NAT is investigational, the hemostatic bene®ts of using 24±48 h old whole blood in pediatric cardiac surgery will have to be weighed against the very small viral safety advantage provided by NAT. It must be emphasized that whole blood that is stored for more than 48 h cannot be expected to be as ecacious as fresh whole blood due to deterioration in platelet function and diminution of levels of coagulation factors. 3.2. Blood components Intraoperative and postoperative transfusion requirements may also be met with the use of individual blood components. Blood components are more readily available than whole blood, but potential disadvantages include less functional
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platelets and increased number of donor exposures. Uniform criteria for postoperative transfusion management of the pediatric cardiac surgery patient have not been established. Practice varies according to the preference of individual surgeons and anesthesiologists and may vary from case to case. Packed red blood cell transfusions have been used by some to maintain a hemoglobin level greater than 10 g/dL [3,26], and to a higher level of 12±13 g/dL in neonates [27] and patients with residual shunts and cyanosis [26,27]. Lower hemoglobin levels of 8 g/dL are acceptable to others [28]. Transfusion of large amounts of additive solutions may cause electrolyte disturbances particularly in small infants. When the equivalent of two blood volumes or more must be transfused, it is often recommended to centrifuge the red blood cell unit and remove the additive solution, although this has not been studied extensively in the pediatric cardiac surgery population. The use of platelet concentrates has been recommended by some to keep the platelet count greater than 100 ´ 109 /L3 routinely on the ®rst postoperative day [3] or in the presence of active bleeding. With active bleeding, platelet concentrates may be bene®cial even in the presence of a normal platelet count due to the platelet dysfunction induced by CPB. Fresh frozen plasma is often used to manage postoperative hemorrhage in the presence of altered coagulation tests [3,26]. The use of cryoprecipitate, instead, has been suggested for neonates due to the high proportion of patients with low ®brinogen levels [13]. In practice, transfusion support must be tailored to the individual patient. 3.3. Estimating blood product requirements A reasonable estimate of the blood product requirement for a given surgical procedure can help tailor preoperative blood product orders to decrease the number of emergent units as well as the cost of unnecessary crossmatching of units. Overall blood product requirements increase with increasing complexity of the cardiac procedure [3,4]. In a retrospective analysis, the average use of blood components in patients less than 12 years old undergoing open-heart surgery was deter-
67
mined [3]. Seventy-eight % of the blood products were transfused intra-operatively, and 22% were used postoperatively. The average number of components needed for complex procedures was 6.3 units compared with 2.3 units for simple procedures. The authors were able to extrapolate standard preoperative blood orders for repair of atrial septal defect, ventricular septal defect, tetralogy of Fallot, and single-ventricle defect based on their estimates. 3.4. Blood product testing and preparation 3.4.1. Infectious disease All blood products transfused to pediatric cardiac surgery patients should undergo complete routine infectious disease testing for HIV-1 and 2, HTLV I/II, hepatitis B surface antigen, hepatitis B core antibody, antibody to hepatitis C virus, and syphilis. Fresh whole blood that is 24±48 h old allows sucient time for full screening to be accomplished. 3.4.2. Antibody screening Routine blood typing and antibody screening should be performed. The identi®cation of coldreacting antibody in the patientÕs serum, such as anti-M or anti-P1 elicits concern about potential hemolysis of antigen-positive blood products during deep hypothermia. This area has not been studied extensively. A report of two adult patients with anti-M IgM antibodies demonstrated normal survival of M-positive transfused red blood cells and no transfusion reactions at blood temperatures of 16±28°C [29]. However, there exist anecdotal reports of agglutination and hemolysis of Mpositive red blood cells in the presence of anti-M antibody. Therefore, it is authorsÕ policy to provide M-negative blood to patients with anti-M antibody. We do not routinely prepare P1 or Lewis a or b negative blood for patients with these antibodies. 3.4.3. Irradiation Several indications exist for irradiation of cellular blood products for pediatric cardiac surgery patients due to a risk of developing transfusionassociated graft versus host disease. Cellular blood
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products donated from biological relatives should be irradiated due to a possibility of transfusion of HLA-homozygous lymphocytes into an HLAheterozygous recipient. Additionally, all heart transplant recipients should receive irradiated blood because they will be maintained on immunosuppressive therapy. Certain congenital heart defects may be found in association with the DiGeorge anomaly (Table 2). In addition to cardiac defects, the DiGeorge anomaly consists of absence or hypoplasia of the thymus and parathyroid glands with persistent hypocalcemia, and frequently, dysmorphic facial features [30,31]. It is often associated with deletions involving chromosome 22. Importantly, thymic hypoplasia with impaired cell-mediated immunity places the patient at risk for developing transfusion-associated graft versus host disease. Evaluation of children with cardiac lesions found in association with the DiGeorge anomaly includes serum parathyroid levels, serum calcium levels, chromosome studies, and T cell studies [31]. We routinely irradiate blood for children with the DiGeorge anomaly, or with cardiac lesions found in association with this anomaly unless the DiGeorge anomaly has been de®nitively excluded. 4. Limiting blood product usage The majority of pediatric patients who undergo open-heart surgery require perioperative transfusion support. Decreasing the amount of transfusions is desirable due to the risk of infectious disease transmission. Approaches to limiting the number of donor exposures include newer surgical Table 2 Cardiac defects associated with the DiGeorge anomaly [30,31] Tetralogy of Fallot Interrupted aortic arch type B Truncus arteriosus Right aortic arch Pulmonary atresia Double outlet right ventricle Transposition of the great arteries Hypoplastic left heart syndrome Aberrant left subclavian artery
and cardiopulmonary bypass techniques to limit blood loss, the use of autologous and salvaged blood, and the use of pharmacological agents such as anti-®brinolytics. With some of these modi®cations, and by accepting lower hemoglobin values, pediatric cardiac surgery with CPB has been successfully accomplished without the use of blood products in some pediatric patients whose parents are of the JehovahÕs Witness faith [32]. 4.1. Cardiopulmonary bypass ± modi®ed ultra®ltration Hemodilution during CPB increases blood product requirements in small cardiac surgery patients. Techniques to reduce the extent of hemodilution can decrease transfusion requirements. Since the blood oxygenator comprises the largest portion of the extracorporeal system, reducing its size can substantially decrease the prime volume. Newer oxygenator designs such as the reversephase hollow-®ber membrane oxygenator have enabled priming volumes as low as 80 ml [2]. Another approach to reducing the need for blood transfusions is to reverse the hemodilution caused by CPB. Ultra®ltration is a technique whereby water, electrolytes, and low molecular weight substances are removed as blood passes through a ®lter, resulting in hemoconcentration. Conventional ultra®ltration occurs during CPB and has been shown to increase coagulation factor levels signi®cantly. Modi®ed ultra®ltration is a newer technique that is performed for 10±15 min after weaning from CPB. Multiple studies have demonstrated that modi®ed ultra®ltration results in signi®cantly less blood loss and fewer postoperative transfusions [33±36]. The greatest bene®t may be observed in neonates, patients with preoperative pulmonary hypertension, and those who require extended CPB times of greater than 2 hours [27]. Modi®ed ultra®ltration is now used routinely in many pediatric cardiac surgery centers. 4.2. Directed blood donation Families often request the use of directed blood donations to provide for transfusion needs of pe-
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diatric patients. However, there are no data to suggest that the use of such directed donors decreases infectious disease transmission over properly tested products from the blood supply. The number of donor exposures may be limited by using dedicated donors, a small number of donors to supply all of the patientÕs transfusion needs. Directed donations may be used to provide 48 h old whole blood for pediatric cardiac surgery patients. Special ``rapid turnaround'' directed donor cards are used to identify these units. From a practical perspective, we estimate that for every two units of blood that are donated, one unit will actually become available to the patient due to the possibility of positive infection screening or lack of ABO speci®city in directed donor units. 4.3. Autologous blood transfusion Transfusion of autologous blood is another means of reducing donor exposure. An additional bene®t is a decreased risk of alloantibody production. Autologous blood may be obtained by preoperative blood donation with or without the use of erythropoietin, or autologous blood can be salvaged during the cardiac procedure and returned to the patient postoperatively. Most experience with preoperative autologous blood donation comes from adult patients. The feasibility of this process may be limited in pediatric patients because of their small blood volume. Additionally, patients with preoperative anemia, hypoxemia, or cardiovascular instability may not be candidates. A recent retrospective analysis demonstrated the ecacy of autologous blood transfusions in pediatric cardiac surgery [37]. Eighty children, including 20 under the age of ®ve years and children as small as 12.3 kg, underwent preoperative blood donation prior to surgical correction of anomalies including atrial and ventricular septal defects, complex cardiac defects, endocardial cushion defects, and valve replacements. Patients underwent sequential blood donations and an average total of 735 ml of blood was stored per patient. Adverse events were few and included mild vasovagal reactions and rescheduling of blood draws due to inadequate intravenous access. With supplemental oral iron
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therapy, the hemoglobin level remained stable in most patients. The transfusion of autologous packed red cells resulted in a marked decrease in homologous donor exposure. Ninety-four % of patients did not require homologous blood transfusion compared with only 16% in a similar group of patients who did not receive autologous transfusion. Preoperative autologous blood donations have also resulted in decreased homologous blood use in other pediatric surgical procedures [38]. Therefore, autologous blood collected preoperatively appears to be ecacious and well tolerated in selected children undergoing open-heart surgery. Autologous blood may also be salvaged from the CPB system and used for postoperative transfusion. A prospective study addressed the feasibility of this method in pediatric cardiac surgery patients [39]. Blood recovered from the CPB circuit was stored at room temperature for up to 18 h prior to transfusion. Despite the known hemostatic alterations induced by CPB, transfusion of salvaged blood did not result in increased bleeding compared with patients who did not receive autologous blood. Total blood product requirements were similar between the two groups. Bacterial contamination occurred at a rate of approximately 2% of stored autologous units. Free hemoglobin levels were higher in children who received salvaged blood, but remained in an acceptable range. Thus, the use of salvaged blood may be another feasible adjunct to homologous transfusion in pediatric cardiac surgery patients. The risks of transfusion of salvaged blood stored at 22°C for 18 h must be weighed against the known risks of properly stored blood components. 4.4. Adjunctive pharmacological therapy 4.4.1. Aprotinin A number of pharmacological agents have been employed in an attempt to decrease blood product requirements related to cardiac surgery. One of the most extensively studied medications is aprotinin, a non-speci®c protease inhibitor. Its mechanisms of action include inhibition of plasmin and kallikrein, anti-in¯ammatory eects, and preservation of platelet function [40]. The use of high-dose
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aprotinin in adult patients undergoing open-heart surgery has been shown to reduce blood loss and transfusion requirements [41]. Studies on the bene®t of aprotinin for pediatric cardiac surgery have been more con¯icting. Some have shown decreased blood loss and postoperative transfusion requirements with aprotinin [42±44], while others have not demonstrated any improvement [40]. Pediatric patients with complex cardiac malformations [42] or who are having repeat cardiac surgical procedures [44] appear to derive the greatest hemostatic bene®t from aprotinin, likely because of the higher incidence of bleeding in these patient groups. Allergic reactions may occur with re-exposure to aprotinin because it is derived from a bovine source. The risk of allergic reactions following reexposure to aprotinin has been reported to be as high as 6% [45]. A recent report found a lower incidence of 1.2% in pediatric patients, but most had been pretreated with dexamethasone [46]. Since patients undergoing reoperations may derive the most bene®t from the drug, determining an individual patientÕs risk of allergic reaction upon re-exposure is important. The incidence of allergic reactions appears to be highest when repeat exposures occur within 200 days of the prior treatment [46]. Therefore, it is advisable to delay repeat surgical procedures if possible. Administering a test dose of aprotinin and appropriate monitoring for anaphylaxis is recommended for all repeat exposures [46]. Premedication with steroids or antihistamines has also been used prophylactically to decrease the risk of anaphylaxis. 4.4.2. Tranexamic acid Tranexamic acid inhibits ®brinolysis through competitive inhibition of plasmin and plasminogen. Several studies in adult cardiac surgery patients have demonstrated decreased blood loss and transfusion requirements associated with its use [47,48]. In children, the data are less clear because there are few studies and the doses and methods of administration are not comparable. One study found that only children with cyanotic heart defects had decreased postoperative blood loss with the use of a single 50 mg/kg dose of tranexamic acid [49]. Another report, using a larger bolus dose of tranexamic followed by a
continuous infusion of the medication showed decreased blood loss and transfusion requirements in children undergoing repeat cardiac surgeries [50]. Further studies are needed to demonstrate the ecacy of this medication in the pediatric cardiac surgery population. 5. Conclusion Although tremendous progress has been observed in the ®eld of pediatric cardiac surgery in the past 20 years, blood transfusions are still required to support the majority of young patients who require open-heart surgery with cardiopulmonary bypass. Transfusion practices vary widely and are a re¯ection not only of individual preference based on training and experience, but also of blood product availability. Widespread use of ultra®ltration and intraoperative blood salvage for autologous transfusion will continue to reduce the need for allogeneic transfusion in the future. Other approaches to reducing transfusion requirements for infants and children may include the use of pharmacological agents that have already been demonstrated to reduce blood loss in adults. The theoretical bene®ts of such agents must be carefully assessed in children before widespread acceptance occurs. References [1] Blalock A, Taussig HE. The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. JAMA 1945;128:189±202. [2] Groom RC, Akl BF, Albus R, Lefrak EA. Pediatric cardiopulmonary bypass: a review of current practice. Internat Anesthes Clin 1996;34:141±63. [3] Chambers LA, Cohen DM, Davis JT. Transfusion patterns in pediatric open heart surgery. Transfusion 1996;36:150±4. [4] Manno CS, Hedberg KW, Kim HC, Bunin GR, Nicolson S, Jobes D, et al. Comparison of the hemostatic eects of fresh whole blood, stored whole blood, and components after open heart surgery in children. Blood 1991;77:930±6. [5] Mendelsohn AM, Shim D. Inroads in transcatheter therapy for congenital heart disease. J Pediatr 1998;133:324±33. [6] Addonizio LJ. Current status of cardiac transplantation in children. Curr Opin Pediatr 1996;8:520±6.
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