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Ann Thorac Surg 2000;69:452-456
© 2000 The Society of Thoracic Surgeons

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Original Articles

Low-dose aprotinin is ineffective to treat excessive bleeding after cardiopulmonary bypass

^a Department of Anesthesia, Montreal Heart Institute, Montreal, Quebec, Canada

Address reprint requests to Dr Hardy, Department of Anesthesia, Montreal Heart Institute, 5000 Belanger St E, Montreal, PQ H1T 1C8, Canada
e-mail: hardy{at}icm.umontreal.ca

	Abstract

Top Abstract Introduction Material and methods Results Comment Appendix References

 
Background. Uncontrolled clinical experience at our institution suggested that low-dose aprotinin could control excessive bleeding after cardiopulmonary bypass (CPB). A randomized clinical trial was conducted to determine the efficacy of low-dose aprotinin in the treatment of hemorrhage after cardiac surgery.

Methods. One hundred seventy-one patients undergoing cardiac surgery with CPB were included. Forty-four patients (26%) bled significantly in the intensive care unit (>100 mL/h) and received either aprotinin (200,000 KIU bolus + 100,000 KIU/h for 8 hours) or placebo in addition to our standard management of excessive bleeding.

Results. Median bleeding before study drug administration was not different between aprotinin (200 mL) and placebo (212.5 mL) groups. Bleeding decreased significantly with time and similarly in both groups. Ninety-five percent of patients required transfusions in both groups. Median blood products transfused were 13 and 8 units per patient in the aprotinin and placebo groups respectively (p = NS).

Conclusions. Routine administration of low-dose aprotinin as part of the treatment protocol to control hemorrhage after CPB does not reduce bleeding or transfusion requirements and, therefore, cannot be recommended.

	Introduction

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Disturbances of the hemostatic system are a major complication of cardiopulmonary bypass (CPB), leading ultimately to postoperative hemorrhage [1, 2]. Excessive postoperative mediastinal drainage is seen in 5% to 20% of patients undergoing CPB [3]. Aprotinin, a serine protease inhibitor, modulates the action of many enzymes involved in inflammation, fibrinolysis, and hemostasis. Numerous studies have confirmed its ability to decrease postoperative bleeding and transfusion requirements, when administered prophylactically before exposure to CPB [4–8]. However, recent studies have questioned its risk:benefit ratio, when used in this fashion [9, 10]. Adverse effects on coronary artery bypass graft (CABG) patency, renal impairment, anaphylactic reactions upon reexposure, and disseminated intravascular coagulation after profound hypothermia have been ascribed to the systemic use of aprotinin [11, 12]. The prophylactic administration of aprotinin implies exposure of all patients to the risks and cost of the drug, when only a proportion of these patients will benefit from its administration.

Considering these limitations, it may be advised to use aprotinin as a therapeutic, rather than a prophylactic tool, once excessive bleeding is confirmed. Few studies have tried to determine the effect of postoperative aprotinin on blood loss and transfusion requirements in patients undergoing cardiac surgery. Angelini and colleagues [13] described the use of high-dose aprotinin to control life-threatening bleeding and decrease transfusions after CPB in 6 patients. Despite this initial favorable report, Kallis and colleagues [14], in a double-blind randomized study, failed to show a significant decrease in transfusion requirements, using a similar 2 x 10⁶ KIU bolus of aprotinin followed by an infusion of 0.5 x 10⁶ KIU · h for 4 hours.

Preliminary, uncontrolled clinical experience at our institution suggested that low doses of aprotinin could control excessive bleeding after CPB. The present prospective, randomized, placebo-controlled study was designed to validate our clinical experience with low-dose aprotinin in the intensive care unit (ICU) to treat postoperative hemorrhage and reduce the need for transfusion of allogeneic blood products (ABPs).

	Material and methods

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One hundred and seventy-one patients undergoing cardiac surgery with CPB were enrolled in this prospective randomized, double-blind, placebo-controlled study approved by the institutional review board of the Montreal Heart Institute. Patients receiving antiplatelet drugs within 7 days of operation, anticoagulants, or presenting a preoperative bleeding diathesis were excluded from the study.

Study groups
Patients were allocated to the treatment during the first 3 hours after arrival in ICU. Excessive mediastinal drainage was defined as a blood loss of greater than 100 mL · h. Patients meeting our criterion for excessive postoperative bleeding were randomized into two groups. The aprotinin group immediately received a total dose of 1 x 10⁶ kallikrein inhibiting units (KIU), consisting of a 2 x 10⁵ KIU bolus, followed by an infusion of 1 x 10⁵ KIU · h for 8 hours. The placebo group received a bolus of normal saline solution followed by an infusion. Aprotinin or placebo were added to our standard management protocol, as described in the Appendix.

Operative details
Anesthesia and surgical techniques were left to the discretion of the anesthesiologist and surgeon except the management of anticoagulation and CPB. Heparin 300 UI · kg was administered initially and, during CPB, the activated coagulation time (ACT, with the Hemochron 801 device; International Technidyne Corporation, Edison, NJ) was maintained at a value more than 480 seconds with additional heparin as required. A membrane oxygenator (Bentley Laboratories Inc, Irvine, CA) was primed with 1,500 to 2,000 mL of lactated Ringer’s solution containing 5,000 units of heparin. Colloids (human albumin or pentastarch) were added to the pump prime at the discretion of the attending anesthesiologist. Flows of 2.4 L · min^-1 · m^-2 were obtained with a Sarns roller pump (Sarns Inc, Ann Arbor, MI). Mild systemic hypothermia (between 32° and 34°C urinary bladder temperature) was maintained during aortic cross-clamping, and the myocardium was preserved by the intermittent infusion of blood cardioplegia into the aortic root. After separation from CPB, anticoagulation was reversed with protamine sulfate (3 mg · kg). Blood remaining in the CPB circuit after separation was collected and infused to the patient. Postoperative mediastinal shed blood was not retransfused.

Data compared
Clinical data compared between groups included basic demographic data, type of operation, duration of CPB, duration of surgery, and incidence of surgical reexploration for excessive mediastinal bleeding. Blood loss during the operation was evaluated by the attending anesthesiologist. Mediastinal blood shed before the introduction of the study drug, and during the first, second, and third hour after initiation of the drug, and the total 24 hour blood loss after operation were measured by the ICU nurses. The percentage of patients receiving a transfusion and the number of units of packed red blood cells (PRBC), platelets, fresh frozen plasma, and cryoprecipitates administered were recorded.

Hemoglobin concentrations after induction of anesthesia, during CPB (nadir concentration), and at the time of discharge from the hospital were measured in the two groups. A routine coagulation profile including thrombin time, international normalized ratio of the prothrombin time (INR), activated partial thromboplastin time (aPTT), and fibrinogen concentration was drawn in all patients preoperatively and upon arrival in the ICU.

Statistical analysis
All normally distributed data are expressed as the mean ± standard deviation. Analysis of categorical variables was performed using ² tests with Yate’s correction for continuity. Mean values between groups were compared using a Student’s t test or analysis of variance for normally distributed variables. Nonparametric Mann-Whitney tests were used to analyze intraoperative and postoperative blood losses, as these do not distribute normally.

Blood exposure and transfusion requirements were analyzed according to a two-step procedure. First, the proportion of patients transfused was compared between the aprotinin and the placebo groups. Second, the total number of units of ABPs administered in those patients receiving transfusions was compared. Analysis was performed for each type of ABP separately (Mann-Whitney tests). A p value less than 0.05 was considered statistically significant.

	Results

Top Abstract Introduction Material and methods Results Comment Appendix References

 
Forty-four of the 171 patients (26%) initially included in this study bled more than 100 mL · h and received either aprotinin (n = 22) or placebo (n = 22) as part of their treatment for excessive postoperative mediastinal drainage.

Comparisons of perioperative characteristics of the control and aprotinin group are presented in Table 1. Age, sex, weight, height, duration of CPB, and duration of surgery were not different between groups. In the aprotinin group, 50% of patients underwent CABG surgery, 36% a valve surgery, and 14% a combined procedure (valve plus CABG). Surgical procedures were similar in the placebo group, in which 50% of patients underwent CABG, 23% a valve surgery, and 27% a combined operation (p = NS). The proportion of reoperative surgery was higher in the aprotinin than in the placebo group (9.1% versus 0%), but the difference was not significant (p = 0.48).

View larger version (21K): [in this window] [in a new window]   Fig 1. Evolution of percentage of patients bleeding excessively (> 100 mL · h) in aprotinin and control groups, after study drug administration.

	Comment

Top Abstract Introduction Material and methods Results Comment Appendix References

Postoperative aprotinin did not reduce blood losses, incidence of transfusion, nor median exposure to ABPs. Mediastinal bleeding decreased similarly in both groups, and stopped after the third hour, irrespective of study drug administration, except in 8 patients. These 8 patients required reexploration for hemostasis. This reexploration rate, 4.6% (8 of 171), is comparable to those previously described in the literature [15].

In this selected group of patients presenting excessive mediastinal drainage, the inefficacy of our "therapeutic" aprotinin regimen may have several explanations. First, the aprotinin dosage may have been too low. Kallis and colleagues [14] studied high-dose aprotinin in patients bleeding excessively after cardiac surgery with CPB. Decreased tissue plasminogen activator levels and increased fibrinogen levels were observed in the aprotinin group, as well as a significant decrease of mediastinal blood shed. However, they failed to show a decrease in transfusion requirements. Angelini and colleagues [13] reported 6 patients in whom similar doses of aprotinin were administered successfully several hours after CPB (6 to 14 hours after termination of CPB) in an attempt to control life-threatening bleeding. Aprotinin decreased mean blood loss and transfusion requirements during the next 10 hours. One may question the doses used in the present study, but this regimen is recommended to treat hyperfibrinolytic states and results in effective (between 40 to 50 KIU · mL) antifibrinolytic plasma concentrations of aprotinin [16].

Time and mode of administration are also two major determinants of drug efficacy. In a previous study, we showed that a prophylactic ultra-low dose aprotinin regimen (1 x 10⁶ KIU) could reduce transfusions in patients undergoing repeat operations or complex procedures when given in the pump prime [17]. However, the same dose of aprotinin administered as a bolus (200,000 KIU) followed by a continuous infusion (100,000 KIU · h) failed to demonstrate any clinical usefulness [18]. Prophylactic aprotinin (2 x 10⁶ KIU), administered immediately at the end of the procedure, significantly reduced the percentage of patients transfused compared to placebo (36% versus 60% respectively, p < 0.01) in the study by Cicek and colleagues [10]. Thus, the late administration of aprotinin in the present trial, in addition to the use of low doses, could explain the inefficacy of this therapeutic approach.

In retrospect, our initial successful experience with postoperative low-dose aprotinin was probably because of the treatment of a systemic hyperfibrinolytic state, well documented by the hematologist. Failure of the systematic use of aprotinin in patients presenting excessive mediastinal drainage to show a clinical benefit suggests that systemic hyperfibrinolysis might not be the primary cause of a bleeding diathesis in most patients. However, Pelletier and colleagues reported recently that fibrinolytic activity could be extremely high in the mediastinum, despite a low systemic fibrinolytic activity [19]. The benefit of reexploration, even when no surgically correctable cause is evidenced, is supported by our observations. Mediastinal lavage and clot removal appear to reduce fibrinolysis locally and, subsequently, to decrease mediastinal drainage. Low-dose aprotinin infusion may be inadequate to treat this intense, localized hyperfibrinolysis.

Another possible explanation for the clinical inefficacy of our therapeutic approach may lie in the various causes of excessive bleeding after CPB. Postbypass bleeding is generally thought to be secondary to the activation, consumption and dilution of several constituents of the hemostatic response, including defects of platelet structure or function [20, 21]. The effectiveness of aprotinin to prevent post-bypass platelet dysfunction is generally accepted [22, 23] but, to our knowledge, it has never been demonstrated that aprotinin could correct an established platelet defect. Expression of platelet GPIb membrane receptors and the percentage of activated platelets have been shown to recuperate after CPB, both parameters returning to baseline between the second and the fourth postbypass hour [24]. Considering mediastinal bleeding decreased and stopped after the fourth postbypass hour in the majority of our patients, we may hypothesize that bleeding stopped when platelet function recovered spontaneously. However, transfusion of blood products, including platelets, may also have contributed to recovery of the hemostatic system, and our study cannot discriminate between the respective contributions of these two factors.

In summary, routine administration of low-dose aprotinin as part of the treatment protocol to control hemorrhage after CPB does not reduce bleeding or transfusion requirements and, therefore, cannot be recommended. However, our study cannot exclude the efficacy of this approach in cases where systemic hyperactivity of the fibrinolytic system has been demonstrated.

	Appendix

Top Abstract Introduction Material and methods Results Comment Appendix References

 
Protocol for transfusion of allogeneic blood products during and after cardiopulmonary bypass at the Montreal Heart Institute
Our usual practice is to maintain a hemoglobin concentration of approximately 70 g · L during CPB, and hemoglobin concentrations as low as 80 g · L are tolerated after CPB as long as hemodynamic stability is maintained. Human albumin (not plasma) is used when volume expansion alone is desired. When bleeding is excessive (> 100 mL · h) coagulopathy is treated as follows:

1. with additional protamine if the activated coagulation time is prolonged > 10% compared to baseline;
   
2. with 2 to 4 units of fresh frozen plasma if the international normalized ratio of the prothrombin time is > 1.8 or if the activated partial thromboplastin time is > 50 seconds;
   
3. with 8 units of platelet concentrates if the platelet count is < 80,000 x 10⁹ L;
   
4. with 8 units of cryoprecipitate if the fibrinogen concentration is < 1.0 g · L.
   

	References

Top Abstract Introduction Material and methods Results Comment Appendix References

 

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