Bleeding after cardiopulmonary bypass is a frequent complication of perioperative patient care. To determine whether prophylactic treatment with epsilon-aminocaproic acid (EACA) minimizes bleeding after cardiopulmonary bypass, a retrospective cohort of patients (n = 350) undergoing coronary artery bypass graft (CABG) or valve replacement surgery were evaluated for intraoperative and postoperative allogeneic blood component therapy. We selected EACA as the drug for prophylaxis in order to provide short-term competitive inhibition of the plasmin-mediated conversion of fibrinogen and fibrin to their respective degradation products. Because existing data show that excessive fibrinolytic activity represents a substantial factor in the hemorrhage tendency that follows cardiopulmonary bypass [1-3], we hypothesized that prebypass EACA administration would be a useful adjunct to existing blood conservation techniques.
After the appropriate institutional consent, a cohort of 350 adult patients for CABG or valvular replacement surgery were studied. All cases were performed between February 1992 and September 1993. Reoperations and transplants were excluded from study. EACA administration was given at the discretion of the surgeon.
Anesthesia was induced. After administration of heparin, and once an activated clotting time (ACT) of more than 400 s was achieved, patients selected or chosen to receive EACA prophylaxis were given an intravenous bolus dose of 10 g. Anticoagulation during bypass was maintained by heparin to keep the ACT greater than 400 s. Nonpulsatile flow (2.0-2.4 L centered dot min-1 centered dot m-2) and mean arterial pressures between 60 and 85 mm Hg were maintained during bypass. Protamine sulfate (1 mg/100 U) of previously administered heparin was used to neutralize heparin after cardiopulmonary bypass. An ACT within 15 s of baseline demonstrated adequate neutralization of heparin by protamine. We gave additional protamine to fulfill this criteria.
Our cohort of patients (n = 350) was subdivided into no-EACA (n = 149) and EACA (n = 201) groups. The efficacy of drug administration was determined by transfusion requirements of red cell mass and blood component therapy, operative time after separation from bypass, and requirements for reexploration. The retrospective nature of the study precluded the establishment of rigid criteria for determining the need to transfuse and the type of blood product to administer during the perioperative course. The hospital course of each patient was evaluated to detect potential complications, such as pulmonary embolization, deep vein thrombosis, stroke, myocardial infarction, or other coagulation related events. No-EACA and EACA differences were determined by chi squared analysis. A significance level of P < 0.05 was used.
The distribution of operative procedures and the demographics of our cohort groups were similar for age, bypass time, crystalloid administration, salvage blood transfusions, heparin or protamine doses, hemodynamic data and hematocrits on admission to the intensive care unit, or the number and distribution of CABG or valve procedures.
We observed that EACA administration dramatically reduced the percent of patients who received packed red blood cells by 53%, the number of packed red blood cells units used per patient by 57%, the percent of patients receiving platelets by 66%, and the number of platelet units administered per patient by 68% Table 1.
In addition, we observed that the time period from termination of cardiopulmonary bypass to completion of surgery was approximately 30 min longer in patients not receiving EACA, and, reoperation occurrences for bleeding was almost four times higher in the no drug group Table 1.
Our data show that prophylactic treatment with EACA decreased allogeneic blood product replacement, substantially reduced the operative time after separation from bypass, and minimized the number of patients who required reexplorations for bleeding after cardiopulmonary bypass surgery. DelRossi et al.  observed a 50% decrement in the number of blood transfusions required in patients who had received EACA as compared to a control group. Likewise, in a double-blind study, Vander Salm et al.  showed decreased bleeding in the EACA group during the time period from termination of cardiopulmonary bypass to completion of the operation. Ovrum et al.  studied 200 elective CABG patients in whom half received antifibrinolytic therapy with the plasmin inhibitor tranexamic acid. In this study, drug administration reduced autotransfusions and the amount of shed blood. These studies demonstrate that pharmacologic methods may be effectively used to aid in the conservation of blood products.
Because of the increased risks of adverse drug reactions and perioperative complications, many have suggested that the routine use of prophylactic antifibrinolytic drugs during cardiopulmonary bypass is not defensible . The possible risks include thrombosis of saphenous vein bypass grafts and other thromboembolic conditions, such as pulmonary embolism and glomerular thrombosis . For instance, Horrow et al.  reports on one patient given tranexamic acid who subsequently developed acute thrombosis of all grafts and the adjacent native coronary arteries. With the exception of a few anecdotal experiences involving glomerular thrombosis, there are no substantiated reports on the use of EACA [10-12]. In fact, DelRossi et al.  report EACA patients had fewer myocardial infarctions, cerebrovascular accidents, and reoperations for bleeding. Vander Salm et al.  reports the development of deep venous thrombosis in only 3.3% of patients receiving EACA and 8% in the control group. These studies report no incidence of a proposed hyperthrombotic state or any other clinical side effects from EACA.
In the present study, patients were neither randomized nor were investigators blinded. The patient groups were homogenous in both demographics and perioperative management, and all patients were treated by the same surgical and anesthesia teams under the same management guidelines. Our computerized database, in which data was recorded on site and in a prospective manner, allowed us to retrieve a complete analysis of the variables described in both control and EACA subjects including demographics, exposure to drug, and patient intra- and postoperative course. End-points of study in those exposed to drug therapy and controls were uniform, systematically recorded, and easily obtainable.
In conclusion, our data demonstrates that prophylactic EACA administration minimizes blood replacement therapy and is a useful intraoperative adjunct to existing blood salvage and conservation techniques. Our data suggest that the benefits of routine EACA prophylaxis for bypass far outweigh the risk of possible adverse reactions or complications.
1. Gomes MM, McGoon DC. Bleeding patterns after open-heart surgery. J Thorac Cardiovasc Surg 1970;60:87-97.
2. Lambert CJ, Marengo-Rowe AJ, Leveson JE, et al. The treatment of postperfusion bleeding using epsilon-aminocaproic acid, cryoprecipitate, fresh-frozen plasma, and protamine sulfate. Ann Thorac Surg 1978;28:440-4.
3. Garcia JB, Paicrashi BC, Mary DA, et al. Postoperative blood loss after extracorporeal circulation for heart valve surgery. J Thorac Cardiovasc Surg 1973;65:487-96.
4. DelRossi M, Cernaianu AC, Botros S, et al. Prophylactic treatment of postperfusion bleeding using EACA. Chest 1989;96:27-30.
5. Vander Salm TJ, Ansell JE, Okike ON, et al. The role of epsilonaminocaproic acid in reducing bleeding after cardiac operation: a double-blind randomized study. J Thorac Cardiovasc Surg 1988;95:538-40.
6. Ovrum E, Holen EA, Abdelnoor M, et al. Tranexamic acid (cyklokapron) is not necessary to reduce blood loss after coronary artery bypass operations. J Thorac Cardiovasc Surg 1993;105:78-83.
7. Gravlee GP, D'Ambra MN. Point/counterpoint: should antifibrinolytics be used routinely during cardiopulmonary bypass. Issues Cardiovasc Anesth 1993;1:1-5.
8. Gralnick HR, Greipp P. Thrombosis with epsilon aminocaproic acid therapy. Am J Clin Pathol 1970;56:151-4.
9. Horrow JC, Hlavacek J, Strong MD, et al. Prophylactic tranexamic acid decreased bleeding after cardiac operations. J Thorac Cardiovasc Surg 1990;99:70-4.
10. Charytan C, Purtilo D. Glomerular capillary thrombosis and acute renal failure after epsilon aminocaproic acid therapy. N Engl J Med 1969;280:1102-4.
11. Ratnoff OD. Epsilon aminocaproic acid: a dangerous weapon [editorial]. N Engl J Med 1969;280:1124-5.
12. Horrow JC, Van Riper DF, Strong MD, et al. Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery. Circulation 1991;84:2063-70.