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J Thorac Cardiovasc Surg 1994;107:1215-1221
© 1994 Mosby, Inc.

CARDIOPULMONARY BYPASS, MYOCARDIAL MANAGEMENT, AND SUPPORT TECHNIQUES

Influence of aprotinin on the thrombomodulin/ protein C system in pediatric cardiac operations

Giessen, Germany

Received for publication May 28, 1993. Accepted for publication Sept. 27, 1993. Address for reprints: Joachim Boldt, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikstr. 29, Justus-Liebig-University Giessen, 35392 Giessen, Germany.

Abstract

Thirty consecutive children scheduled for pediatric cardiac operation with cardiopulmonary bypass were included in the study. Before the operation, the patients were randomly divided into two groups: with aprotinin (n = 15, 30,000 U/kg after induction of anesthesia, 30,000 U/kg added to the prime of the cardiopulmonary bypass system followed by additional 30,000 U/kg every hour until the end of cardiopulmonary bypass or without aprotinin (n = 15). Thrombomodulin, (free) protein S, protein C, and thrombin/antithrombin III complex were measured from arterial blood samples taken after induction of anesthesia (at baseline, before aprotinin) and before, during, and after cardiopulmonary bypass until the first postoperative day. Standard coagulation parameters (antithrombin III, fibrinogen, platelet count, and partial thromboplastin time) were without differences between the groups. Thrombomodulin plasma concentrations were within normal range (<40µg/L) and were similar in both groups at baseline. During cardiopulmonary bypass and until 5 hours after cardiopulmonary bypass, however, thrombomodulin plasma levels were significantly lower in the children treated with aprotinin. No further differences were observed on the first postoperative day. Protein C and protein S plasma levels did not differ between the two groups. Thrombin/antithrombin III–complex plasma concentrations increased significantly during cardiopulmonary bypass, however, without showing differences between children with (225 ± 49µg/L) and without (149 ± 31µg/L) aprotinin treatment. Blood loss and the need for homologous blood and blood products did not differ significantly between the two groups. We concluded that administration of aprotinin resulted in reduced thrombomodulin plasma levels in pediatric patients undergoing cardiac operation without altering protein C/protein S plasma concentration. The exact role of aprotinin in endothelium-derived coagulation should be further studied. (J THORAC CARDIOVASC SURG 1994;107:1215-21)

Bleeding after cardiopulmonary bypass (CPB) continues to be a problem in congenital cardiac operations. ¹ One major reason for this appears to be the contact of blood with the synthetic, nonendothelial surfaces of the extracorporeal circulation equipment. ^2-4 Moreover, in young children concentration of some of the coagulation factors and hemostatic inhibitors are different from those of adults. ^5,6 Besides platelet and plasmatic associated hemostasis, it has become obvious in recent years that the endothelium appears to play an important role in the regulation of anticoagulant and procoagulant pathways. ⁷ The procoagulant tissue factor can initiate thrombin formation; however, the endothelium produces anticoagulant cofactors, such as plasmin activators and heparin-like enzymes. ⁸ Thrombomodulin (TM) is one of these endothelial cell products which are involved in the regulation of coagulation. ⁸ Thrombin binds to TM, and this endothelium-activated thrombin-TM complex activates protein C, which, together with protein S, degrades factors Va and VIIIa. These factors are responsible for inhibition of the perpetuation of thrombin generation. ^10,11 Thus, substances expressed on or released by the endothelium, such as TM, may modify the activation of coagulation. ¹²

Several pharmacologic and nonpharmacologic interventions have been done to reduce the risk of extensive bleeding. The proteinase inhibitor, aprotinin, has been enthusiastically recommended in adult cardiac operations for significantly reducing the need of homologous blood after bypass. ^13,14 Thus far, however, it is not yet been shown exactly how aprotinin works. ¹⁵ There are only few studies dealing with aprotinin in pediatric cardiac surgery, and the results were not uniform. ^16,17 The aim of the present study was to investigate the influence of aprotinin on endothelium-related coagulation in children undergoing cardiac operations with CPB.

METHODS

Patients
After informed consent had been obtained from parents according to the guidelines of the ethic committee of the hospital, 30 consecutive children undergoing corrective or palliative operation of congenital heart disease with CPB were studied. Exclusion criteria were a reoperation, kidney or liver insufficiency, and therapy with heparin or cyclooxygenase inhibitors within 7 days before the operation. Before the operation, the children were randomly distributed to one of the following two groups: in group 1 (n = 15), aprotinin 30,000 U/kg was administered after induction of anesthesia and added to the prime (30,000 U/kg), and the same dose was given every hour during CPB; group 2 (n = 15), operation and CPB were carried out without aprotinin.

Induction and maintenance of anesthesia, consisting of weight-related doses of fentanyl, midazolam, and pancuronium bromide, were comparable for both groups. All children were supported by controlled mechanical ventilation until the end of the operation and spent at least the next 5 hours in the pediatric intensive care unit.

CPB
Five minutes before the start of CPB, bovine heparin 300 U/kg was administered for anticoagulation. Additional heparin was given when necessary to achieve an activated clotting time (ACT; measured by Hemochron device [International Technidyne Corporation, Edison, N.J.] with the use of celite diatomaceous earth) of more than 400 seconds. CPB was performed with a COBE VPCMLplus membrane oxygenator (Cobe Laboratories, Lakewood, Colo.) and a flow of 2.4 L/min per square meter. Priming of the extracorporeal circuit consisted of 500 ml of Ringer's solution, 250 ml of 5% human albumin, 50 ml of 20% human albumin, weight-related doses of electrolytes, and aprotinin in group 1. Packed red cells (PRC) were added to the prime in relation to the child's weight and preoperative hemoglobin value. Ringer's solution was added to keep up the filling of the circuit. When the hemoglobin value was less than 7 gm/dl, PRC were given. After the patient was weaned from bypass, the blood remaining in the extracorporeal oxygenation equipment was salvaged by a centrifugation device (Cell Saver III, Haemonetics, Braintree, Mass.), and the prepared autologous blood was retransfused in the postbypass period. Heparin was neutralized by protamine chloride in a ratio of 1:1 to the initial dose of heparin. All children underwent operated with the same surgical team, which was blinded to the grouping.

Measured parameters and data points
Hemoglobin and hematocrit levels, platelet count, blood gas variables, and ACT were measured from arterial blood samples. TM plasma levels were measured by a one-step sandwich enzyme-linked immunosorbent assay with the use of polyclonal antibody (Diagnostica Stago, Asnieres, France) against human TM. ¹⁸ Protein C and protein S plasma concentrations were also assessed by enzyme-linked immunosorbent assay (Boehringer-Mannheim, Mannheim, Germany). Protein S was quantified as free protein S after bound protein S was removed from the plasma by precipitation with polyethylene. Normal values of TM in healthy volunteers assessed by this method were reported to be less than 40 ng/ml. ¹⁹ Protein C normally ranged between 70% and 100%, and free protein S is normally greater than 30%. Thrombin/antithrombin III complex (TAT) were also measured by enzyme-linked immunosorbent assay (Behringwerke, Marburg, Germany) (normal values <30 µg/L). All data from enzyme-linked immunosorbent assay represented the means of duplicate measurements.

Blood samples were taken after induction of anesthesia (baseline values), before start of CPB (before anticoagulation with heparin), 20 minutes after onset of CPB, after weaning from CPB (before infusion of protamine), at the end of the operation, 5 hours after the end of CPB, and on the morning of the first postoperative day.

Fluid balances (input and output), blood loss from postbypass suction and from postoperative chest tube drainage were also documented. During the patients' stay in the pediatric intensive care unit, PRC were given when hemoglobin was less than 9.0 gm/dl; fresh frozen plasma was given when bleeding exceeded 5 ml/kg per hour and platelet count was greater than 50,000/ ml (ACT < 200 sec). Platelet concentrates were administered when bleeding exceeded 5 ml/kg per hour and platelet count was less than 50,000/ml and ACT was less than 200 sec. All volume therapy and blood transfusions were indicated by anesthesiologists and pediatric intensivists who were not involved in the study.

Statistics
Before the study, power analysis has been done to evaluate the number of patients that would be necessary to avoid type II errors in the statistical interpretation. Mean values ± standard deviation were calculated from all parameters. For statistical interpretation, one- and two-factorial analyses of variance (including multivariate analyses of variance) followed by Scheffé's test were carried out. ² Tests were used to analyze differences in the use of homologous blood, and p values of less than 0.05 were considered statistically significant.

RESULTS

The two groups did not differ significantly with regard to demographic data, type of operation, and CPB procedure (Tables I and II). The total amount of heparin was also similar in both groups (Table I). Hemoglobin (Table III), electrolytes, and blood gases were without group differences. Also standard coagulation parameters (fibrinogen and AT-III plasma concentration, PTT, platelet count) were comparable between the two groups (Table III). TM plasma levels were similar and within normal range at baseline and before start of CPB (Fig. 1). Twenty minutes after beginning of CPB, TM plasma concentration was significantly lower in the children treated with aprotinin (5 ± 4 ng/ml) than in those without aprotinin (20 ± 9 ng/ml). At the end of the operation until 5 hours after the end of CPB, TM plasma level remained lower in the patients treated with aprotinin (p < 0.05). On the first postoperative day, no more statistical differences could be seen.

View larger version (26K): [in this window] [in a new window]   Fig. 1. Thrombomodulin plasma levels in the two groups (normal range, 30 to 40 µg/L). p.o., Postoperative day.

View larger version (23K): [in this window] [in a new window]   Fig. 2. Protein C (normal range, 70% to 100%) and free protein S (normal value >30%) plasma concentrations. p.o., Postoperative day.

View larger version (23K): [in this window] [in a new window]   Fig. 3. TAT in the two groups (normal value 30 µg/L). p.o., Postoperative day.

DISCUSSION

CPB is associated with several alterations in the coagulation cascade. ²⁰ These include platelet dysfunction, hyperfibrino(geno)lysis, and endothelial defects. ^3,4,20 Pharmacologic interventions, such as the use of protease inhibitor aprotinin, are aimed at limiting the negative effects of CPB on the coagulation system. ¹³ The exact mechanism by which aprotinin reduces postbypass bleeding tendency has not yet been fully elucidated. ¹⁵ Fibrinolysis is said to be inhibited by aprotinin, leading to fewer fibrin split products ²¹; however, some researchers deny that CPB is associated with marked fibrinolysis and claim that the contribution of fibrinolysis to postoperative bleeding remains unclear. ² Particularly in high doses, aprotinin attenuates kallikrein activation and the contact activation of coagulation. ^13,20 Other researchers claim that the kallekrein system for activation of coagulation is unimportant. ²² Another main effect of aprotinin appears to be related to its platelet preservation properties. ²³

The endothelium presents another important dimension in the regulation of hemostasis. ¹¹ TM is one of the substances produced by the endothelium. It is mainly expressed on the endothelial cell, but soluble TM is also present in plasma and urine. TM binds to thrombin and initiates the antithrombotic protein C/protein S pathway. ¹² TM is not only a cofactor for protein C activation but also has direct antithrombin properties. Normal values with the use of the assay in the present study are reported to be less than 40 ng/ml. ¹⁹ Other authors using different assays for TM measurement found values of less than 10 ng/ml as normal. ^24,25

Serine protease inhibitors are important controllers of the coagulation system. Aprotinin, being a serine protease inhibitor, may thus influence plasmatic or endothelium-associated natural inhibitors. As shown by the present results, children treated with aprotinin showed lower TM plasma concentrations than did those without treatment. The significant reduction of TM during and after CPB in both groups appears to be due to hemodilution in this situation, which was similar for both groups. The lower TM plasma levels in group 1 may be due to a direct or indirect suppression of endothelial TM expression by aprotinin. In a study of adults who underwent cardiac operation, TM, as well as protein C and protein S, decreased significantly during CPB, which was assumed to be due to activation and consumption of the TM/protein C system in response to generated thrombin. ²⁶

The alterations of TM expression on the endothelial cell surface may be of importance for the development of coagulation disorders in critically ill patients (e.g., those with disseminated intravascular coagulation, inflammation, and sepsis). ^10,27 This development may be caused by either an increased TM expression or a split of the TM from the endothelial surface and a consecutive release into the circulating blood. In adult respiratory distress syndrome and inflammatory syndrome, proteases released from leukocytes may affect the expression of TM ^25,27; endotoxin and interleukin-1 have been shown to down-regulate the expression of TM. ^10,27

The reasons for the lower TM plasma concentrations in the children treated with aprotinin in the present study can only be assumed at the moment. We have not measured thrombin, which appears to be one stimulus for an increased TM expression. However, TAT was comparable for both groups, and therefore differences in thrombin generation are unlikely to be responsible for the differences in TM plasma levels.

It is widely accepted that CPB results in an increase in proinflammatory mediators. The interactions between these mediators with hemostasis and particularly with the endothelial cell are not completely understood. TM is assumed to be a good marker of endothelial damage. ¹⁹ Several years ago, aprotinin was used to prevent the deleterious consequences of severe trauma and sepsis. It can only be speculated whether by surpressing the negative consequences of some of these mediators, aprotinin contributes to preserve endothelial function during CPB indicated by less TM release or whether aprotinin directly inhibits expression (e.g., by modifying ribonucleic acid transcription) or release of TM. Nevertheless, increasing TM plasma levels may possibly result in a less thrombogenic endothelial surface and vice versa. Whether the reduction in TM plasma concentration by aprotinin may explain the often published reduction in bleeding tendency (and the sometimes postulated early graft thrombosis in patients who undergo coronary artery bypass) warrants further studies. It is important to stress that baseline values of TM were high in our study, and in none of the children treated with aprotinin were TM plasma levels markedly altered after the operation. However, the critical level of TM plasma concentration is not yet known.

In the present study, protein C was lower than normal in both groups already at baseline, which is in accordance with other studies of children. ⁵ In a study of pediatric cardiac operations, protein C and protein S plasma levels were not significantly changed after the operation. ²⁸ Baseline values, although within normal values, were approximately half of the concentration measured in children undergoing major noncardiac operations. By contrast, in adult cardiac operations, Knöbl and associates ²⁹ found an increase in protein S soon after beginning of CPB. Protein C then significantly decreased during CPB and remained low after CPB, thus being a possible reason for the well known bleeding tendency of patients undergoing cardiac operation in this situation.

The increase in TAT provides strong evidence that heparinization was not able to completely inhibit formation of thrombin and its function. ²⁹ During CPB, TAT was also increased in the children treated with aprotinin and significantly exceeded normal values. This is in accordance with results from Mössinger and associates, ³⁰ who also found increased TAT plasma concentrations in pediatric patients treated with aprotinin for cardiac operations. At the end of the operation, TAT plasma levels were similar with regard to baseline values in the two groups, which indicates the wide range of compensation and clearance in these patients.

Whether our results depend on the doses of aprotinin cannot be answered at the moment, and the correct dose of aprotinin is still an unsolved question. According to the most widely used Royston scheme, ¹³ high-dose aprotinin is defined as the administration of 2,000,000 U of aprotinin after induction of anesthesia as a loading dose, followed by a continuous infusion of 500,000 U until the end of the operation, and an additional 2,000,000 U added to the prime of the CPB circuit. This dose is independent of patient weight (i.e., a patient weighing 50 kg receives the same dose as a patient weighing 110 kg). Several recent studies have reported that a significant reduction in blood loss and a need for homologous blood use is also possible when aprotinin is given in a much lower dose or only once. ³¹ Moreover, in patients with low riskundergoing aorta–coronary artery bypass grafting, 3 x 10 ⁶ U of aprotinin given once immediately before CPB significantly lowered concentration of split products of cross-linked fibrin (D dimers) compared with a nontreated control group. ³² By contrast, in a study with sophisticated platelet- and plasmatic-associated coagulation parameters, Vandenvelde, Fondu, and Dubois-Primo ³³ did not find any differences between patients who did and did not receive aprotinin added to the prime. The correct dose for pediatric patients undergoing operation is even more difficult to establish because of the varying pharmacologic conditions in these two categories of patients, and adult doses are not applicable to infants or children.

In the present study, aprotinin did not reduce bleeding or the use of homologous blood or blood products. Other studies have also shown that careful perioperative management of the patient undergoing cardiac operation is more successful than the use of aprotinin. Some authors favor aprotinin because it keeps the hemostatic system in a more physiologic state after CPB. ^21,30 However, pediatric and adult patients may differ significantly in their physiologic (plasmatic-, platelet-, and endothelium-related) hemostasis. As shown by various reports, the use of aprotinin is not without potential risks. ^34,35 Anaphylactic response has been shown in approximately 1% of patients. ³⁶ This risk appears to increase markedly whenever there is a second exposure to the substance. Last but not least, cost/benefit ratio has not been definitely elucidated either.

We conclude that the endothelial aspect of coagulation has been widely neglected, particularly in pediatric cardiac surgery. The imbalance in procoagulant and anticoagulant factors may result in bleeding diathesis or thrombus formation. Children treated with aprotinin showed a lower TM plasma concentration, but there was no influence on the protein C/protein S pathway. Bleeding and the use of homologous blood were similar in children treated with and without aprotinin. Before recommending aprotinin for first-case pediatric cardiac operations, additional study is required to elucidate the exact role of aprotinin on plasmatic-, platelet-, and endothelium-related coagulation in this situation.

Footnotes

From the Departments of Anesthesiology and Intensive Care Medicine^a and Cardiovascular Surgery,^b Justus-Liebig-University Giessen, Germany.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boldt, J. Articles by Hempelmann, G. Search for Related Content PubMed PubMed Citation Articles by Boldt, J. Articles by Hempelmann, G.