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Ann Thorac Surg 1997;63:497-503
© 1997 The Society of Thoracic Surgeons
Cardiothoracic Unit, Great Ormond Street Hospital for Children NHS Trust, London; Research Haematology, Heart Science Centre, Harefield Hospital, Middlesex; and Clinical Research, Bayer PLC, Bayer House, Strawberry Hill, Newbury, United Kingdom
Accepted for publication September 19, 1996.
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Abstract |
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 TopFootnotes Abstract IntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Forty-two patients were randomly assigned to receive either high-dose aprotinin or placebo. Aprotinin efficacy was assessed using time from protamine administration to skin closure, postoperative blood loss and hemoglobin loss, and postoperative transfusion requirements. Measures of fibrinolysis (fibrin degradation product titers) and platelet preservation (ß-thromboglobulin levels) were also assessed.
Results. There were no statistically significant differ-ences between groups in any of the blood loss or transfusion parameters. Fibrin degradation product levels, measured 4 hours postoperatively, had increased significantly for control patients, but remained unchanged for the aprotinin group (p < 0.02). ß-Thromboglobulin levels increased more rapidly during cardiopulmonary bypass in the control group (p = 0.03).
Conclusions. Aprotinin appears to provide no clinical benefit in routine pediatric cardiac operations. A reduction in fibrinolysis, with perhaps an early preservation of platelet structure, is seen in the aprotinin group.
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Introduction |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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Aprotinin is a basic polypeptide, 58 amino acid residues long and of bovine origin, that inhibits a wide variety of serum proteases. The main mechanism of action of aprotinin is probably as an inhibitor of plasmin. The high-dose aprotinin regimen also inhibits kallikrein, produced from prekallikrein during activation of factor XII by the artificial surfaces of the bypass equipment and the exposed surfaces of surgically cut vessels [8]. The antiplasmin action of aprotinin coupled with inhibition of kallikrein-mediated activation of plasminogen provides a significant antifibrinolytic effect [9]. By inhibiting kallikrein, aprotinin reduces the activation of complement, the angiotensin system, and bradykinin. It also acts as a weak anticoagulant by inhibiting the positive feedback of kallikrein on the activation of factor XII, thus reducing production of coagulation factors and it prolongs the activated partial thromboplastin time [10, 11].
There are few published data concerning the use of aprotinin in children. In 1982 Papov-Cenik and colleagues [6] suggested that aprotinin given perioperatively may reduce perioperative bleeding in pediatric patients and studies [7, 12] have indicated that aprotinin may reduce hemorrhage in patients at high risk of hemorrhage. Boldt and associates [13], however, recently published a prospective, randomized study that used a low-dose aprotinin regimen (less than 35,000 kallikrein inhibiting units [KIU]/kg [4.9 mg/kg]) and showed no reduction in perioperative bleeding. Davis and Whittington [14] published a recent review of aprotinin administration in cardiac operations and suggested that more studies were required to investigate its use in the pediatric population. Our group has published results from a pilot study in pediatric cardiac operations using a high-dose aprotinin regimen (dosage adjusted for body surface area in a similar manner to Royston's study in adults) and comparing with historical controls [15]. This suggested that although the aprotinin did not reduce postoperative hemorrhage or transfusion requirement in children undergoing the arterial switch operation, the drug may be effective in reducing the time from protamine administration to skin closure after CPB. This time is normally spent in obtaining surgical hemostasis before closing the chest and may be important in morbidity and mortality. Certainly, it has been shown that increasing surgical operating time is associated with a postoperative decline of left ventricular function [16]. Children who are returned quickly to the intensive care unit are likely not to have suffered from so much handling of delicate tissues, and therefore, cardiac function may be better preserved in the immediate postoperative period.
As a result of this pilot study [15], and with power calculations based on its data, we have conducted a prospective, randomized, double-blind, placebo-controlled study in children less than 16 years of age undergoing open heart operations with CPB. The study was designed to assess the efficacy of aprotinin in reducing postoperative blood loss and the time of operation, as well as to investigate changes in areas of the coagulation scheme.
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Patients and Methods |
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Any child at this center under the age of 16 years undergoing open heart operation with CPB was considered eligible for entry into the study. Patients prospectively excluded from the study included children with a known bleeding disorder; those taking aspirin, dipyridamole, or anticoagulants 7 days before operation; those with a known metabolic disorder, sepsis, or renal failure; patients previously exposed to aprotinin or with a known allergy to aprotinin; and patients with a hemoglobin level of more than 19 g/dL. In addition, during the period in which this study was conducted, two of three staff surgeons thought that the benefits of aprotinin in patients undergoing the arterial switch operation was such that the majority of these patients, who were otherwise eligible for the study, received aprotinin; therefore, they were excluded from the study.
The study population was stratified into three groups as defined: group I included children 1 year of age or less undergoing a major open heart operation with hypothermic (<22°C), low-flow (<1.3 L • m-2 • min-1), nonpulsatile CPB. Group II included children between 1 and 5 years of age and undergoing a major reconstructive open heart operation (eg, repair of tetralogy of Fallot, with or without pulmonary artery reconstruction, or the Fontan procedure) with hypothermia, intermittent low-flow, nonpulsatile CPB. Group III included children more than 1 year of age and undergoing a redo open heart operation using a median sternotomy.
Within each of the groups defined above (I, II, and III) patients were allocated to receive either aprotinin or placebo using a predetermined computer-generated randomization protocol.
Dosages and Duration of Treatment
For children with a body surface area of 1.16 m2 or less, aprotinin was administered after induction of anesthesia. A loading dose of 140 KIU/m2 was given as an intravenous bolus over 20 minutes, with a pump priming dose of 240 KIU/m2 and a continuous central venous infusion of 56 KIU • m-2 • h-1 from the beginning of operation until skin closure at the end of operation. Control (placebo) patients were given an equivalent volume protocol of 0.9% saline solution.
For children with a body surface area of more than 1.16 m2, aprotinin was administered as a loading dose of 250 KIU/m2 given as an intravenous bolus over 20 minutes, with a pump priming dose of 280 KIU/m2, and a continuous central venous infusion of 70 KIU • m-2 • h-1 (9.8 mg • m-2 • h-1) from the beginning of operation until skin closure at the end of operation. Again, control patients were given an equivalent volume protocol of 0.9% saline solution.
Premedication, anesthetics, and perfusion techniques were similar for all patients. Pethidine-Co, (pethidine, 25 mg, plus promethazine, 6.25 mg, plus chlorpromazine, 6.25 mg/mL) at a dose of 0.07 mL/kg body weight and atropine, 0.3 mg, were given intramuscularly. Induction of anesthesia used cyclopropane and oxygen followed by intubation after paralysis with a mixture of suxamethonium, 1 mg/kg, and pancuronium bromide, 0.1 mg/kg. Anesthesia was maintained during cardiopulmonary bypass using nitrous oxide and oxygen together with intermittent doses of pancuronium bromide, 0.1 mg/kg, and incremental doses of fentanyl to a maximum of 20 µg/kg or morphine to a maximum dose of 0.1 mg/kg.
The bypass machine was primed with a mixture of fresh (less than 5 days old), whole, cytomegalovirus-free citrate-phosphate-dextrose blood, mixed with crystalloid to achieve a predicted hematocrit of 20% to 25% in the patients undergoing deep hypothermic CPB, 25% in patients undergoing moderate hypothermia, and 30% in patients undergoing bypass at 32°C. The crystalloid component of the prime was Plasmalyte 148 (Travenol, UK) with added heparin (2,500 IU per unit of blood, and 1,500 IU per 500 mL of crystalloid), sodium bicarbonate (8.4% at 60 mL/L of prime), and 20% mannitol (2.5 mL/kg).
Perfusion techniques were standardized and the patient core temperature was lowered to the appropriate level using arteriovenous cooling on bypass. Flow rates were maintained at 2.4 L • m-2 • min-1 using a nonpulsatile roller occlusive pump. The activated clotting time was maintained at more than 400 seconds by intermittent bolus doses of heparin in the control group. Those receiving high-dose aprotinin had the activated clotting time maintained at more than 750 seconds by the anesthetist. The surgeons remained blinded to the activated clotting time levels throughout the study, and ultrafiltration was not used.
Perioperatively the patients received prophylactic antibiotics (gentamicin and flucloxacillin) and some required cardiosupportive drugs (dopamine and nitroprusside). To standardize the blood transfusion regimen postoperatively, blood was transfused to maintain the patients' hematocrit at more than 35%.
Time from protamine administration to skin closure (hours) was measured. Surgeons were asked for a subjective impression of the status of the operative field as "very dry," "dry," "normal," or "wet." Over the first 24 hours postoperatively, total blood drainage loss (mL/kg), total hemoglobin loss (g/kg), and total amount of fluid, blood, and blood products given (mL) were measured.
Blood samples were taken preoperatively and at the times given below to compare renal function (serum levels of urea, creatinine, lactate, sodium, and potassium), liver function (alkaline phosphatase, alanine transferase, bilirubin, and total protein), and hematologic functions (hemoglobin, hematocrit, white cell count and differential, platelet count, fibrinogen, prothrombin time, activated partial thromboplastin time, fibrin(ogen) degradation product titers, and ß-thromboglobulin). Sequential blood samples were taken in the ratio of 9:1 into 3.8% sodium citrate at the following times: (A) after anesthesia, (B) before heparin administration, (C) before starting bypass, (D) while on bypass, (E) at the beginning of the rewarming period, (F) at the end of the rewarming period, (G) after protamine administration, (H) 4 hours postoperatively, (I) 12 hours postoperatively, and (J) 24 hours postoperatively.
Adverse events recorded during this study were classified as "early" if they occurred within 24 hours of operation and "delayed" if they occurred more than 24 hours after operation.
Statistical Analysis
Descriptive statistics were applied to data from the treatment and nontreatment groups and compared using Wilcoxon two-sample tests, Fisher's exact test and analysis of variance as appropriate. Results are given as median values with interquartile range or as mean ± 1 standard deviation. Statistical significance has been taken as a probability of 0.05 or less.
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Results |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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. There were no statistically significant differences in age, weight, or body surface area within the groups (I, II, and III), but obvious differences between groups.
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Operative details are summarized in Table 2. The most common surgical procedure to occur in group I was closure of ventricular septal defect. In group II the most common procedure was repair of tetralogy of Fallot. In group III the most common procedure was redo valve replacement and repair.
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There were nine "delayed" adverse effects in the aprotinin group (53%). Three patients (18%) were in heart failure, 2 patients (12%) had pulmonary edema, and 1 patient (6%) was recorded in each for acidosis, complete heart block, hypoxia, and tachycardia. There were six "delayed" adverse events in the placebo group (27%). These were 2 patients (9%) who had pleural effusions and 1 patient (5%) was recorded in each with pulmonary edema, heart failure, paralysis, and tachycardia. None of these adverse events were considered by the investigators to be related to the study drug.
There were no statistically significant differences between treatment groups for any of the measures of renal, hepatic, or basic hematologic function (see below).
Efficacy of Aprotinin
There were no statistical differences in any of the three surgical groups (I, II, and III) in timing from administration of protamine to skin closure (Table 3).
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summarizes the drainage losses in the first 24 hours after operation. There were no differences in the drainage loss between controls and the aprotinin-treated groups. However, there was a statistically significant difference between surgical groups in drainage volume loss. Group III, the redo operation group, had a significantly lower drainage volume in the first 24 hours postoperatively than either group I or group II.
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. Although the aprotinin groups tended toward a lower hemoglobin loss, there were no statistically significant differences either within or between groups. This was particularly the case in the redo operation group who received aprotinin (0.26 ± 0.16 g • kg-1 • 24 h-1) compared with the redo patients who did not receive aprotinin (0.69 ± 0.32 g • kg-1 • 24 h-1). However, because of the low numbers (5 patients in each group) this failed to reach statistical significance (p = 0.06).
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. Patients who received a blood transfusion often received both whole blood and packed red cells, depending on availability. Eleven patients in the aprotinin group (65%) and 10 patients in the placebo group (45%) received whole blood. Seven patients (42%) in the aprotinin group and 11 patients (50%) in the placebo group received packed red blood cells.
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Subjective assessment of the surgical field by the surgeon is summarized in Table 7. There was a trend toward a drier surgical field assessment in the aprotinin group, and a greater tendency toward the surgical field being "wet" in the placebo group than in the aprotinin group. The surgeons commented that in 2 patients in the control group closure was delayed by bleeding. Both of these patients were in group III, the redo operation group. No patients in the aprotinin group had closure delayed by bleeding.
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). The median level had not changed in the aprotinin group, whereas the median level in the placebo group had risen by 100% to 250 µg/mL (interquartile range, 250 to 500 µg/mL; p < 0.02). There was also a statistically significant difference between treatment groups in the change of ß-thromboglobulin from postanesthesia levels (A) to the levels during cardiopulmonary bypass (D) (Fig 2). Median levels increased to 18.6 IU/mL (14.3 to 44.3 IU/mL) for the aprotinin group and increased to 43.3 IU/mL (30.0 to 53.0 IU/mL) for the placebo group during the early bypass period (p = 0.03). This difference, however, lost significance during the period of CPB (Fig 2).
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Comment |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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). However, when hemoglobin loss was assessed a clinically significant reduction was seen in those patients receiving aprotinin (Table 5). This failed to reach statistical significance, possibly because of the small size of the group. A larger study group would help to investigate this further.
The results of this study are at odds with those generated from studies in adults [3, 9, 14, 17, 18]. The reasons for this are uncertain. First, it may be that there is less postoperative bleeding in children because they are returned to the intensive care unit only after obsessional hemostasis [15]. Second, perhaps the study size was too small. In surgical group I, some patients were excluded from randomization because of the reluctance of two surgeons to perform the arterial switch operation without aprotinin. This may explain why the results were also at odds with the results of our pilot study that concentrated on the effects of aprotinin in neonatal switches, and found a decrease in the time taken to close the chest [15]. Unfortunately, because of the strong suggestion from this earlier pilot study, the policy of this unit is to use aprotinin in the arterial switch operation. We were unable to investigate this finding further. Third, a child's hemostatic balance is different from that of an adult in that children have high levels of nonspecific inhibitors. Aprotinin is thought to reduce perioperative bleeding in adults by acting as an antifibrinolytic agent, but there are no studies of fibrinolysis in children to suggest that their hemostatic function perioperatively is the same as in adults. The mechanism of aprotinin has been extensively debated. Current opinion is that the main mode of action is as an antiplasmin agent. The failure of fibrin degradation product titers to increase in the aprotinin group (see Fig 1) confirms that in children high-dose aprotinin decreases fibrinolytic activity. There were also significantly lower plasma levels of ß-thromboglobulin, a product of platelet activation, during cardiopulmonary bypass in the aprotinin group (see Fig 2), suggesting that it may have an effect on platelet function at least at the beginning of bypass. This, however, contrasts with the lack of effect of aprotinin on platelet aggregation in children undergoing CPB [13] and the recent evidence in adults [19]. A larger study in a pediatric population would help to elucidate this further.
Our study has also given contrasting results compared with the study by Herynkopf and associates [7] in children, which showed a reduction in blood transfusion and increased diuresis in the aprotinin-treated group, but like our study showed no significant difference in drainage loss. This may be because of differences in the threshold for blood transfusion between the centers. Our results, however, are similar to those of Boldt and colleagues [13], who showed no significant differences in blood loss when compared with controls.
Some studies have suggested that aprotinin may contribute to renal failure [5, 20]. Our data do not substantiate the concerns regarding the effects of aprotinin on renal function in pediatric patients.
In conclusion, this study has demonstrated no benefit in the routine use of aprotinin in pediatric cardiac operations. Our policy is now to restrict the use of aprotinin to redo operations, because of the strong clinical suggestion of reduced hemoglobin loss in this group (see Table 5), to those patients undergoing first time arterial switch operation [15], and to those patients judged to be especially vulnerable to hemorrhage. Further studies are required to examine perioperative hematologic changes in children undergoing CPB and in the use of high-dose aprotinin in other areas of pediatric cardiac surgery, such as transplantation.
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Acknowledgments |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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This study was funded by Bayer Diagnostics, Bayer PLC, Evans House, Basingstoke, United Kingdom.
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Footnotes |
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TopFootnotesAbstractIntroductionPatients and MethodsResultsCommentAcknowledgmentsReferences |
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