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1 Aprotinin in Pediatric Cardiac Operations: Platelet Function, Blood Loss, and Use of Homologous Blood Joachim Boldt, MD, Christoph Knothe, MD, Bernfried Zickmann, MD, Niels Wege, Friedhelm Dapper, MD, and Gunter Hempelmann, MD Deuartment of Anesthesioloev and Intensive Care Medicine and Department of Cardiovascular Surgery, Justus-Liebig-University u, Giessen, Giessen, Germany Excessive hemorrhage secondary to cardiopulmonary bypass may be encountered after pediatric cardiac operations. Platelet dysfunction appears to be especially responsible for this problem. The proteinase inhibitor aprotinin is suggested to possess platelet preservation properties and reduce blood loss in this situation. The effects of aprotinin (5,000 U/kg after induction of anesthesia, 5,000 U/kg added to the prime, 5,000 U/kg every hour of cardiopulmonary bypass) on platelet function were randomly studied in children with a weight of less than 0 kg (group ) and children weighing more than 0 kg (group 4), who were compared with two groups of children without aprotinin (group, <lo kg; group 3, >0 kg). Twelve children undergoing major vessel operations without cardiopulmonary bypass and aprotinin served as a control. Platelet function was assessed using aggregometry (turbidometric technique with adenosine diphosphate,.0 pmol/l; collagen, 4 pg/ml; epinephrine, 5 pmol/l; NaCl [control]). Platelet function was not altered in the control patients within the entire investigation period. Maximum aggregation in the small children was already lower at baseline in comparison with that of the children >0 kg. Cardiopulmonary bypass was followed by a significant reduction in platelet aggregation in all groups. Treatment with aprotinin did not improve platelet function (maximum aggregation and maximum gradient of aggregation) in any group. On the first postoperative day, maximum aggregation in the small children exceeded baseline values, whereas in both groups of children >0 kg baseline values had almost been established. Postoperative blood loss was not reduced by treatment with aprotinin. On the first postoperative day, blood loss in group 3 (>lo kg, with aprotinin) was highest. Total use of packed red cells and fresh frozen plasma was higher in both aprotinin-treated groups. We conclude that aprotinin was without positive influence on platelet aggregation and postoperative blood loss in small and in bigger children undergoing cardiac operations. The reasons for the reduced platelet function in the small children need further investigation. (Ann Thoruc Surg 993;55:460-6) ediatric cardiac surgery has been extended to early P childhood, and the ability to correct even complicated congenital heart diseases has improved considerably. Bleeding can still be a problem in these small patients, and several attempts have been made to reduce blood loss including the use of warm fresh blood and routine transfusion of platelet concentrates. This has become unpopular in recent years due to the awareness of the risks associated with the transfusion of homologous blood or blood products [l,. However, hemodynamic instability due to enhanced and prolonged bleeding after cardiopulmonary bypass (CPB) can adversely affect the patients outcome. In cardiac operations on adults, use of the proteinase inhibitor aprotinin has been demonstrated to reduce postoperative bleeding significantly [3-6. It was reported that aprotinin possesses important plateletpreserving effects, thus leading to an improvement in Accepted for publication Sep 0, 99. Address reprint requests to Prof Dr Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikstr. 9, Justus-Liebig-University Giessen, D-6300 Giessen, Germany. postbypass hemostasis and contributing to a reduction in blood loss and blood requirements [7-9. However, there are very few reports of the use of aprotinin in pediatric cardiac operations [lo]. The present study was designed to investigate the effects of aprotinin, particularly on changes in platelet function assessed by aggregometry and on blood loss, use of homologous blood, and blood derivatives, in children undergoing cardiac operations. Material and Methods Patients and Grouping Sixty consecutive children undergoing cardiac surgical procedures were investigated. Informed consent was obtained from the parents before the operation according to the protocol of the Ethic Study Board of the hospital. All patients suffered from congenital heart disease. None of the patients underwent circulatory arrest with deep hypothermia. Redo operations were excluded from the study. Operation procedures are listed in Table. Five different groups were studied: group (n = ), children weighing less than 30 kg undergoing cardiac by The Society of Thoracic Surgeons /93/$6.00

2 Ann Thorac Surg 993; BOLDT ET AL 46 APROTlNlN IN PEDIATRIC CARDIAC OPERATIONS Table. Operative Procedures in the Groups (-) (+I (- (+) Aprotinin Aprotinin Aprotinin Aprotinin Procedure <0kg 40kg >lokg >lokg Fallot repair TGA Replacement of aortic arch Truncus arteriosus ASD + VSD repair PSt + ASD repair fit + VSD repair Aorto-pulmonary shunt Mitral valve replacement AV canal repair ASD = atrial septal defect; AV = atrioventricular; PSt = pulmonary artery stenosis; TGA = transposition of the great arteries; VSD = ventricular septal defect. operations using CPB; group (n = ), children weighing less than 0 kg receiving aprotinin (5,000 U/kg after induction of anesthesia, 5,000 U/kg added to the prime of the CPB circuit, 5,000 U/kg administered every 60 minutes of CPB); group 3 (n = ), children weighing more than 0 kg and without aprotinin; group 4 (n = ), children weighing more than 0 kg undergoing CPB and receiving the aprotinin regimen used in group ; and group 5 (n = ), children undergoing major vessel operations (ductus arteriosus, subclavian flap, shunt operation) without CPB and without aprotinin (control group). Aprotinin was administered with regard to a randomized sequence. Anesthesia and Cardiopulmonary Bypass Induction and maintenance of anesthesia consisted of weight-related doses of fentanyl, midazolam, and pancuronium bromide. All children were on controlled mechanical ventilation until the end of the operation and during the first hours in the pediatric intensive care unit. Anticoagulation was achieved by 300 U/kg bovine heparin given 5 minutes before the start of CPB. Additional heparin was given to achieve an activated clotting time greater than 400 seconds. Cardiopulmonary bypass was carried out using a COBE VPCMLplus membrane oxygenator (Cobe Laboratories, Lakewood, CO) and a flow of.4 L/min - m. When hypothermia was performed during the operation (rectal temperature < 4"C), perfusion flow was reduced to half of the initial flow. Priming of the extracorporeal circuit consisted of 500 ml of Ringer's solution, 50 ml of human albumin 5%, and 50 ml of human albumin 0%. One unit of packed red cells was added to the prime in all children weighing less than 0 kg. In the groups of children weighing more than 0 kg, packed red cells were added with regard to the preoperative hematocrit value (<0.3). Additional packed red cells were given when the hematocrit was less than 0.8. After weaning from bypass, blood remaining in the circuit was salvaged using a Cell Saver device (Cell Saver, Haemonetics, Munich, FRG). This autologous blood was retransfused in the postbypass period. Protamine was given in a :l ratio with regard to the initially administered heparin (activated clotting time < 00 seconds). All patients were operated on by the same surgeon, who was not informed of the grouping of the patients. All blood and blood derivatives (fresh frozen plasma, platelet concentrates) were given by anesthesiologists and intensivists blinded to the grouping. Packed red cells were given when the hematocrit was less than 0.35 in the children weighing less than 0 kg and less than 0.30 in the children weighing more than 0 kg. Fresh frozen plasma was indicated when bleeding exceeded 5 ml * kg-' - h-' and the platelet count was more than 50,000/mL (activated clotting time < 00 seconds). Platelet concentrates were administered when bleeding exceeded 5 ml - kg-' - h-' and the platelet count was less than 50,000/mL (activated clotting time < 00 seconds). Measured Parameters and Data Points Platelet aggregation was measured from arterial blood samples by the turbidimetric method [ll] using a doublechannel APACT-aggregometer (LAbor, Ahrensburg, FRG). The following inductors were used: adenosine diphosphate (ADP;.0 FmoYL), collagen (4 pg/ml), epinephrine (5 pmol/l), and NaCl (control). Maximum aggregation was defined as the maximum of increase in light transmission after addition of the aggregating agent (read as percentage increase). Maximum gradient of aggregation was defined as the maximum increase per minute (read as percentage increase per minute). All measurements were performed in duplicate, always by the same investigator. In addition to aggregometry, hematocrit, platelet count, blood gas variables, and activated clotting time were monitored. Rectal, esophageal, and blood (in the oxygenator) temperatures were also measured. Measurements were camed out after induction of anesthesia (baseline values), 0 minutes after the onset of CPB, after weaning from CPB (before infusion of protamine), at the end of the operation, 5 hours after the end of the operation, and on the morning of the first postoperative day. Blood samples in the control children (without CPB) were taken at comparable time intervals. Moreover, fluid balances (input and output), blood loss from postbypass suction and blood loss from postoperative chest tube drainage, and the use of fresh frozen plasma, platelets, and packed red cells were also documented. Statistics Power analyses were done before starting the study to evaluate the number of patients that would be necessary to protect from type I errors in the statistical interpretation. All data are expressed as mean values f standard deviation. For statistical interpretation, one- and two-

3 46 BOLDT ET AL Ann Thorac Surg 993;55:460-6 Table. Biometric Data and Data From Cardiopulmonary Bypass (-) (+I (-) (+) Aprobnin Aprotinin Aprotmin Aprotinin Variable 4 0 kg <0 kg >0 kg >0 kg Control Age (mo) 6.4 f f f. 3.4 f f 5.4 Weight (kg) 5.0 f f f. 6.3 f.7.6 f 6.9 CPB (min) 9 f 33 0 f 9 5 f 5 9 f 7 - Ischemia (min) 55 f 5 57 f 6 63 f 9 67 f 0 - Total heparin (Uikg) 475 f f f f 50 - PRC added to the prime (units) Lowest temperature ( C) Rectal 9.3 f. 8.7 f * f f. Esophageal 8. f f f k f.0 Blood 7.0 f f f.6 7. f CPB = cardiopulmonary bypass; Ischemia = period of aortic cross-clamping; PRC = packed red cells. factorial analyses of variance (including multivariate analyses of variance) followed by Scheffps test were used. Correlation between two variables was assessed by analysis of covariance. Percentage changes were additionally investigated by H test (KruskaWallis). Values of p less than 0.05 were considered statistically significant. Results Demographic and perioperative data of the children are listed in Table. The nature of the operation was comparable for the two pairs of groups (groups and ; groups 3 and 4), and the pairs of groups did not differ with regard to cyanotic and acyanotic heart failure. Time from end of CPB to the end of the operation (closing procedure) was also similar in the two pairs of groups (45 5 minutes). The patients age in groups and (<lo kg) ranged from 3 days to 6 months; their body weight ranged from 3.0 to 8.0 kg (no group differences). The patients age in groups 3 and 4 (>lo kg) ranged from month to 70 months, and their weight ranged from 3 to 9 kg (no group differences). Control patients were aged from to 9 months. Heparin given to achieve anticoagulation in groups through 4 and lowest temperatures were without differences between the groups (see Table ). Hematocrit and platelet count measured at the six data points were similar in the two pairs of groups (group l/group ; group 3/group 4) (Table 3). Compared with baseline values, no significant changes in aggregometry (maximum aggregation as well as maximum gradient of aggregation) were noticed in the control group throughout the entire investigation period; these values are therefore not illustrated in the figures. At baseline, maximum aggregation was already significantly lower in the children weighing less than 0 kg than in the children weighing more than 0 kg (all three inductors) (Figs -3). Cardiopulmonary bypass resulted in a significant reduction in maximum aggregation in all groups for all inductors (ranging from -0% to -49% relative to baseline values). Platelet aggregation in the postbypass period recovered, and on the first postoperative day maximum platelet aggregation in all small children (<lo kg, groups l and ) exceeded baseline values (+lo% to +40% relative to baseline) without showing differences between aprotinin-treated and nontreated children. In the children weighing more than 0 kg, Table 3. Platelet Count and Hematocrit After End of 5 h After st Postoperative Variable Induction CPB End of CPB Operation Operation Dav Hematocrit Group Group Group 3 Group 4 Platelet count (i09/l) Group Group Group 3 Group f f f f f f 56 7 f 4 7 f f f f f 5 95 f 9 30 f 49 3 f * f f f f 5 93 f f * f f f f f 53 5 f 36 f f f f f f f 49 0 f 0 06 f 0.39 f f f f 0.04 f 37 f 5 7 f 7 06 f 4 CPB = cardiopulmonary bypass; group = <lo kg without aprotinin; group = <lo kg with aprotinin; group 3 = >0 kg without aprotinin; group 4 = >I0 kg with aprotinin.

4 Ann Thorac Surg 993;55:460-6 BOLDT ET AL 463 6o max. aggregation ADP.0 pmol/l (X) H < 0 kg without aprotinin CF-0 < 0 kg with aprotinin.* 8. M > 0 kg without aprotinin 0--0 > 0 kg with oprotinin R f SD (p < 0.0); and platelet concentrates, 350 ml (70 ml/kg) in group and 360 ml (66 ml/kg) in group (Fig 5). Use of homologous blood and blood products in groups 3 and 4 until the first postoperative day was as follows (without prime, which was similar for both groups): packed red cells, 600 ml (35 ml/kg) in group 3 and,00 ml (63 ml/kg) in group 4 (p < 0.05); fresh frozen plasma,,50 ml (67 ml/kg) in group 3 and,050 ml (8 ml/kg) in group 4 (p < 0.05); and platelet concentrates, 300 ml (7 ml/kg) in group 3 and 400 ml (4 ml/kg) in group 4 (see Fig 5). Comment Hemorrhagic complications after pediatric cardiac operations appear to have multifactorial genesis. Abnormalities in platelet function seem to be the most predictable defect, resulting both from the interactions between platelets and the synthetic surfaces of the extracorporeal oxygenation equipment and from the physical forces (ie, shear stress) produced by the suction and the pump system [-5. Thus, enhanced bleeding appears to be related to platelet abnormalities secondary to CPB rather than to deficiency of coagulation factors [6]. These changes in platelet function include a reduction in platelet count, a decreased I I I I I I OftU cm oftr end of 5 h oftn st p.0. induction CPB opuotion opuotion day Fig. Changes in maximum platelet aggregation induced by.0 FmollL adenosine triphosphate (ADP). (CPB = cardiopulmonary bypass; p.0. = postoperative; %? SD = mean? standard deviation; * p < 0.05 versus baseline values; ** p < 0.05 versus children <0 kg.) H < 0 kg without aprotinin 0--0 < 0 kg with oprotinin 8 - I maximum aggregation had almost reached baseline values on the first postoperative day (no group differences). Maximum gradient of platelet aggregation had a course comparable with that of maximum platelet aggregation. Reduction of maximum gradient of aggregation during CPB was even more pronounced than that of maximum platelet aggregation (ranging from -3% to -80% relative to baseline). Moreover, maximum gradient recovered less sufficiently in the postoperative course than did maximum aggregation values. No differences in aprotinintreated and nontreated children were seen with regard to maximum gradient of platelet aggregation within the entire investigation period. Blood loss until 5 hours after the operation and until the first postoperative day did not differ among the two pairs of groups (Fig 4). On the first postoperative day, patients in group 4 (>lo kg with aprotinin) had the highest blood loss (p < 0.05). Until the first postoperative day, use of packed red cells (without addition to the prime, which was comparable for the two groups) added to a total of 690 ml (38 ml/kg) in group and 830 ml (55 ml/kg) in group (p < 0.05); fresh frozen plasma, 730 ml (46 ml/kg) in group and,460 ml (70 ml/kg) in group Xf SD ----c3- / 4 - / / F. 8 I I I I I I oftn CPE after and of 5 h oft- ht p.0. blduction CPB oprolion oprotion doy Fig. Changes in maximum platelet aggregation induced by epinephrine. (CPB = cardiopulmonary bypass; p.0. = postoperative; jz SD = mean? standard deviation; * p < 0.05 versus baseline values; ** p < 0.05 versus children <I0 kg.)

5 464 BOLDT ET AL Ann Thorac Surg 993;55:460-6 adhesiveness, alteration in membrane receptors of the platelets, a-granule release, and a change of in vitro response to ADP and collagen [4, 7, 8. In several centers, fresh whole blood is given in pediatric cardiac operations to optimize coagulation after bypass [9]. In a study of children aged less than years, Manno and associates [9] reported on the great benefit when whole blood that was less than 48 hours old was transfused. In contrast to this, in children aged more than years, the regimen of postbypass blood donation (components or fresh whole blood) was without differences with regard to bleeding and coagulation abnormalities. As the risk of transmitting viral diseases is particularly high with this transfusion regimen, other centers use blood components (fresh frozen plasma, platelet concentrates) rather than fresh whole blood [0]. Pharmacological manipulations to reduce blood loss and thus the need for blood transfusion in the adult include the use of desmopressin, dipyridamole, prostacyclin, and aprotinin [Zl-3. In pediatric cardiac surgery there are only a few reports of the use of these agents. Desmopressin, for example, has failed to reduce blood loss in children undergoing cardiac operations [4]. One of the most important effects of aprotinin appears to be a direct or indirect (via its antifibrinolytic action) protection of the platelets at the molecular level: aprotinin 50 max. aggregation collagen (%) )--I < 0 kg without aprotinin < 0 kg with aprotinin. blood loss (ml/kg) end of operation st p.0. day Fig 4. Postoperative blood loss from chest tubes. (p.0. = postoperative; % SD = mean * stundard deviation; * p < 0.05 for the difference between groups 3 and 4.) seems to preserve membrane-bound glycoprotein receptors, which are of main importance for platelet aggregation [8, 5. Because quantitative as well as qualitative changes in platelets occur in cardiac surgical defects, this.800 homologous blood and blood products (mi) * 0 J.. 60 TT i,,t-: M > 0 kg without aprotinin > 0 kg with aprotinin. T * I' 0 J. I I I I I ofbr CPB afta end of 5 h aft- st p.0. induction CF'E cpaation aprotion day Fig 3. Changes in maximum platelet aggregation induced by collagen. (CPB = cardiopulmonary bypass; p.0. = postoperative; % SD = mean standard deviation; * p < 0.05 versus baseline values; ** p < 0.05 versus children <0 kg.) > lokg wimout aprotinin >lokg with aprotinin Fig 5. Total use of homologous blood and blood products until the first postoperative day. (FFP = fresh frozen plasma; PRC = packed red cells [with addition to the priming, which was comparable for the two pairs of groups &oup Ilgroup ; group dlgroup 4} * p < 0.05 intergroup diflerence [group llgroup ; group 3grOUp 4.)

6 Ann Thorac Surg 993; BOLDT ET AL 465 seems to be a promising attempt to counteract the risk of postoperative bleeding. In the present study, aggregometry was performed because platelet dysfunction can be expressed as decreased adhesion and a diminished sensibility to triggering agonists such as ADP, collagen, and epinephrine [7, 6,7. As shown by several studies, the most important consequence of postbypass bleeding appears to be the loss of aggregability [4,8. A control group without CPB was selected in the present study to exclude that anesthetics, surgical procedure, and other factors rather than CPB were responsible for changes in platelet function. One of the major results was that small children already showed a reduced response to ADP, collagen, and epinephrine at baseline. The reason for the significant differences in aggregometry between children weighing less than 0 kg and those weighing more than 0 kg after induction of anesthesia may be a reduction in or damage to platelet membrane receptors or a reduction in sensitivity to aggregating stimuli such as ADP, collagen, and epinephrine. The mechanism for the impairment in platelet aggregation in these children remains unclear. The decreased sensitivity to ADP may reflect chronic endogenous activation of platelets. Bleeding diathesis appears to be more common in cyanotic than in acyanotic heart failure; in a study in 97 it was reported that children with cyanotic heart disease are prone to excessive hemorrhage after corrective operations [B]. However, much has changed in cardiac surgery since those days. In contrast to this, others have more recently demonstrated that bleeding tendency appears to be independent of preexistent cyanosis [lo]. Another important result was that platelet function assessed by aggregometry in children who received aprotinin did not differ from that of those without aprotinin application. Moreover, aprotinin-treated children had a greater blood loss (>lo kg) and a more pronounced need for blood and blood products. This appears to be confusing, because so far aprotinin has never been reported in the adult to cause a deterioration of coagulation. One explanation for this phenomenon may be that during closure of the chest the operative field in the aprotinintreated patients appears to be drier than in the nontreated children. Thus, blood stanching may be carried out more One problem with the present study is whether the dosage of aprotinin was sufficient. However, not only the exact mechanism of action of aprotinin is uncertain [30, 3, the correct dosage even in adult cardiac operations is also controversial [3, 33. The use of "high-dose" aprotinin in adult cardiac operations does not differ between patients weighing 50 or 00 kg. In one of the few studies with aprotinin in pediatric cardiac operations, aprotinin administration was already started on the day before operation [lo]. The loading dose and the priming dose used in the present study were similar to those in adult cardiac operations, which is reported to be approximately million units and which is without relation to body weight [5, 5, 33]! There are some studies investigating whether this "high dose" of aprotinin is really necessary [3, 33. Moreover, it is well known that doses in adults cannot be transferred uncritically to infants and children because of the varying pharmacological conditions in these two categories of patients. In the few studies that report the effects of aprotinin in pediatric operations, the loading dose ranged between 0,000 U/kg and more than 50,000 U/kg, which represents approximately a total loading dose of 4 million U in the adult, and which is much more than usually given [lo, 34. We conclude that CPB results in several changes in the hemostatic system. Acquired platelet dysfunction appears to be one of the most important alterations secondary to CPB procedures. With regard to pediatric operations, the following conclusion can be drawn from the present study: () Platelet function assessed by aggregometry was already reduced in small children (< 0 kg) before the start of CPB. () Treatment with aprotinin did not lead to an improvement in platelet function, nor did it reduce blood loss or the need for blood and blood products in comparison with nontreated children. This was independent of the weight and age of the children. As long as the exact mechanism, the concrete (weight/ age-related) dosage regimen, and the riskhenefit ratio [ of aprotinin are not fully elucidated, aprotinin cannot be recommended for routine use in pediatric cardiac operations at present. References accurately in these nontreated patients. In the further. Miller RD, Bove JR. Acquired immune deficiency syndrome and blood products. Anesthesiology 983;58: postoperative course, the children rewarmed and hemo-. Peterman TA. Transfusion associated acquired immunodynamics further improved with the risk of increased deficiency syndrome. World J Surg 987;: (microcapillary) bleeding. 3. Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass Mostly, platelet dysfunction was reported to be only with high dose aprotinin (Trasylol). J Thorac Cardiovasc Surg transient and reversed within a few hours after CPB [6, 989; Also, in the children in this study, platelet function 4. Royston D, Bidstrup BP, Taylor KM, Stapsford RN. Effect of recovered in the postbypass period, and aggregation in aprotinin on need for blood transfusion after repeat openthe small children reached baseline values or was even heart surgery. Lancet 987;: Dietrich w, Spannagel M, Jochum M, et al. Influence of beyond baseline values. Normally, the platelet population high-dose aprotinin treatment on blood loss and coagulation is very heterogeneous, consisting of old (hypoaggregat- patterns in patients undergoing myocardial revascularizaing), normal, and young (hyperaggregating) platelets tion. Anesthesiology 990;73: 9-6. []. It is not clearly known whether restoration of platelet 6- GD* GJt Lamarra Mr A. Unorthodox use of aprotinin to control life-threatening bleeding after function after CPB results from the recovery of previously cardiopulmonary bypass. Lancet 990;335: inhibited Platelets or from the of newt Young 7. Reuter HD. 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