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J Thorac Cardiovasc Surg 1996;112:1098-1107
© 1996 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
Received for publication Jan. 22, 1996 Revisions requested March 13, 1996; revisions received April 23, 1996 Accepted for publication June 4, 1996. Address for reprints: Thomas J. Vander Salm, MD, Department of Surgery, University of Massachusetts Medical School, 55 Lake Avenue, N. Worcester, MA 01655-0333.
Abstract
Excessive postoperative bleeding after heart operations continues to be a source of morbidity. This prospective double-blind study evaluated epsilon-aminocaproic acid as an agent to reduce postoperative bleeding and investigated its mode of action. One hundred three patients were randomly assigned to receive either 30 gm epsilon-aminocaproic acid (51 patients) or an equivalent volume of placebo (52 patients). In a subset of these patients (14 epsilon-aminocaproic acid, 12 placebo), tests of platelet function and fibrinolysis were performed.Results: By multivariate analysis, three factors were associated with decreased blood loss in the first 24 hours after operation: epsilon-aminocaproic acid versus placebo (647 ml versus 839 ml, p = 0.004), surgeon 1 versus all other surgeons (582 ml versus 978 ml,p = 0.002), and no intraaortic balloon versus intraaortic balloon pump use (664 ml versus 1410 ml,p = 0.02). No significant differences in platelet function could be demonstrated between the two groups. Inhibited fibrinolysis, as reflected by less depression of the euglobulin clot lysis and no rise in d-dimer levels, was significant in the epsilon-aminocaproic acid group compared with the placebo group.Conclusion: The intraoperative use of epsilon-aminocaproic acid reduces postoperative cardiac surgical bleeding. (J THORAC CARDIOVASC SURG 1996;112:1098-107)
Bleeding after heart operations continues to be a concern for cardiac surgeons. Treatment during the operation with aprotinin reduces bleeding, but that drug is expensive and may cause such complications as renal failure, coronary graft occlusion, myocardial infarction, and allergic reaction.
1-4 Treatment of bleeding after heart operations with epsilon-aminocaproic acid (EACA) was reported in 1967 by Sterns and Lillehei. 5 Several other authors have since confirmed EACA's effectiveness, but the drug appears to be regarded as secondary in importance to aprotinin. 6-10 In our previous investigation of the use of low-dose EACA, we found that it diminished bleeding after cardiac operations. 11 We and others have since begun prophylactic use of the drug in larger doses. 10 This randomized, prospective double-blind study compared patients receiving high-dose EACA with a control group of patients receiving a placebo and investigated the mechanism of action of EACA during cardiopulmonary bypass (CPB).
Material and methods
After protocol approval by the Human Subjects Research Committee of the University of Massachusetts Medical Center, informed consent was obtained from 103 patients. Consenting patients were then prospectively randomly assigned to receive EACA (Amicar; Lederle Laboratories, Pearl River, N.Y.; 51 patients) or a similar volume of 0.9% saline solution (52 patients) in a double-blind study. Random assignment by means of a random number table and drug preparation were performed by the hospital pharmacy. Surgeons, perfusionists, anesthesiologists, and all laboratory personnel were unaware whether each patient received placebo or EACA. Patients in the treatment group received a total of 30 gm EACA: 10 gm intravenously before skin incision. 10 gm intravenously after heparin administration, and 10 gm intravenously at the discontinuation of CPB but before protamine administration. Patients in the control arm group received saline solution in the same volumes and with the same timing. Heparin was administered per protocol at 400 U/kg, and incremental doses were given during the operation to maintain the activated clotting time at greater than 400 seconds. Protamine for heparin neutralization was administered per protocol at 1 mg/100 U total heparin dose. Patients requiring emergency operations, those with abnormal results of preoperative bleeding studies, and those who were pregnant were excluded from the study; no other exclusion criteria were used. Eligible patients included those needing coronary bypass or valve operations. Closure time was defined as the time from termination of CPB to the application of the dressing. The dose of EACA was chosen on the basis of our previous study, 11 in which a total of 11 gm EACA was administered, and on the larger 30 gm dose administered by Daily and colleagues. 10 Patient body surface areas in the study population ranged 1.40 to 2.78 m2 (mean 1.96 m2). Postoperative chest tube drainage was not reinfused. The trigger for postoperative transfusion was a hematocrit lower than 25%.
For all patients, routine preoperative and postoperative hematologic and coagulation studies performed consisted of complete blood cell count, prothrombin time, partial thromboplastin time, bleeding time, and thrombin time. Postoperative blood loss, as measured by chest tube drainage, and blood component therapy were recorded. In a subset of 26 patients (14 EACA, 12 control), various hemostatic tests were performed. These tests were of two types, those evaluating platelet function and those measuring fibrinolysis. These included fibrinogen level, antiplasmin level, d-dimer level, euglobulin lysis time, antithrombin III level, and platelet count measured before operation, after heparin administration, 45 minutes after initiation of CPB, 5 minutes after protamine administration, 2 hours after operation, and 24 hours after operation. Bleeding time was measured before operation and 2 hours after operation. These assays were all performed as described elsewhere. 12 After the Swan-Ganz catheter (Baxter Healthcare Corp., Edwards Div., Irvine, Calif.) had been placed, 5 ml blood was withdrawn from it before blood samples were drawn.
In addition and at the same time intervals, whole blood flow cytometry (performed as described elsewhere 13) was used to measure the expression of platelet surface glycoprotein (GP) Ib, GPIIb-IIIa complex, fibrinogen binding to the GPIIb-IIIa complex, and P-selectin. The following monoclonal antibodies were used in these studies: S12 (Centocor, Inc., Malvern, Pa.) is directed against P-selectin, 14,15 a component of the 
-granule membrane of resting platelets that is expressed on the platelet surface membrane only after platelet degranulation and secretion. 14,16 6D1 (provided by Barry S. Coller, Mount Sinai Medical Center, N.Y.) is directed against the von Willebrand factor binding site on the amino terminal domain of platelet membrane GP Ib. 17,18 Y2/51 (DAKO Corp., Carpenteria, Calif.) is directed against platelet membrane GPIIIa. 19 7E3 (also provided by Coller) is directed at the fibrinogen binding site on the GPIIb-IIIa complex. 20 F26 (provided by Harvey Gralnick, National Institutes of Health Clinical Center, Bethesda, Md.) is directed against a conformational change in fibrinogen bound to the GPIIb-IIIa complex. 21,22 S12, 6D1, 7E3, and F26 were biotinylated as described elsewhere. 13,23 Fluorescein isothiocyanate–conjugated Y2/51 was purchased from DAKO.
In a pilot study we compared preoperative blood obtained by peripheral venipuncture with preoperative blood obtained through the Swan-Ganz catheter and found no statistical difference in the binding of monoclonal antibodies S12, 6D1, 7E3, and F26 (n = 9). Drawing the blood through the Swan-Ganz catheter did not result in platelet activation or other platelet surface changes, so blood was obtained from the Swan-Ganz catheter in all subsequent studies.
Statistical methods
The primary outcome variable was blood loss through the chest tubes at 24 hours. Baseline characteristics and operative data for the control and EACA groups were compared by an unpaired t test for continuous variables and by 
2 tests for association of categoric variables. A multivariate analysis was used to adjust for confounding factors in the blood loss correlation and to determine the factors independently predictive of blood loss. Because of skewed (nonnormal) distribution of blood loss and large, unequal variances, the natural log of blood loss, rather than the actual blood loss, was used for the calculation of statistical significance. Differences were considered significant at a 95% confidence level ( = 0.05).
Results
Preoperative patient variables did not differ significantly between the EACA and control groups with respect to age, sex, reoperations, or preoperative clotting factors; all of which were normal in both groups (Table I). The following operative variables also did not differ significantly between the two groups: surgeon, cardioplegia temperature, operation performed, and use of internal mammary grafts (Table II). CPB time, however, was significantly longer in the EACA group (148 minutes EACA vs 129 minutes control, p = 0.02), as was crossclamp time (85 minutes EACA vs 73 minutes control, p = 0.04). Mean closure time was 58 minutes in the EACA group and 54 minutes in the control group (p = 0.2) Closure time for surgeon 1 was 55 minutes; for the other surgeons it was 58 minutes (p = 0.3).
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21,22 F26 binds only to activated, not resting, platelets. 21,22 Fig. 3 demonstrates the effects of the combination of 20 mmol/L adenosine diphosphate (ADP) with 20 mmol/L epinephrine on the platelet surface binding of monoclonal antibody F26, as determined by whole blood flow cytometry. In the absence of ADP and epinephrine, there was little binding of F26 and therefore little platelet activation. This finding demonstrates that CPB did not result in circulating activated platelets, regardless of whether the patient received EACA. After the ex vivo addition of ADP and epinephrine, there was a marked increase in the platelet surface binding of F26. This finding demonstrates that the reactivity of platelets (as determined by their ability to bind fibrinogen in response to ADP and epinephrine) was unaffected by CPB and was not significantly affected by whether the patient received EACA. Finally, the platelet surface expression of P-selectin was minimal irrespective of whether EACA was used (Fig. 4).
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(Table III). At 12 hours, blood retrieved from the chest tubes was 425 ml in the EACA group and 565 ml in the control group (p < 0.004). At 24 hours, blood retrieved from the chest tubes was 647 ml in the EACA group and 839 ml in the control group (p = 0.002). No significant difference, however, was observed in the number of packed red blood cells administered to the two groups during the first 24 hours (0.94 units in the EACA group and 1.12 units in the control group). Neither did any significant difference exist with respect to other blood products (cryoprecipate and fresh-frozen plasma) administered to the two groups. Postoperative hematocrit at discharge and immediate postoperative clotting studies were also similar in the two groups (Table III).
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(Table IV). In addition to the use of EACA, surgeon 1 was associated with less bleeding than the other surgeons taken in aggregate (582 vs 978 ml, p = 0.002). Patients with intraaortic balloon pump (IABP) use had increased blood loss compared with patients not requiring an IABP (1410 vs 664 ml, p = 0.02). Despite the fact that a disproportionate number of the patients in the control group were performed by the surgeon with the lowest bleeding rate, the EACA group had less bleeding. Although CPB time and crossclamp time were longer in the EACA group by univariate analysis, by multivariate analysis, these factors were not found to be associated with postoperative bleeding.
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(Table V). Men received a mean of 0.78 units of packed red cells compared with women, who received 1.68 units (p = 0.0001). When normalized for body surface area, the packed red cells were 0.41 per patient/m2 for men and 0.98 per patient/m2 for women. Patients undergoing primary operation received 0.84 units, compared with 2.42 units for patients undergoing reoperation (p = 0.005). To assess the possibility that smaller preoperative red cell mass in the women led to a greater proportion of red cell mass lost and therefore a greater transfusion requirement, a metric was constructed that measured the relative proportion of the red cell mass lost. This metric was calculated by dividing the 24 hour blood loss by the product of the preoperative hematocrit and body weight. This relative measure was 0.24 in men and 0.25 in women. The difference in red cell transfusions between men and women cannot be explained by a difference in the proportion of the preoperative red cell mass lost.
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Other than the decreased bleeding in the EACA group, no differences in complications were observed between control and EACA groups. Although a trend toward higher increased prevalence of electrocardiographically diagnosed myocardial infarction (new Q waves or loss of R waves) in the EACA group than in the control group (5 of 51 vs 2 of 52; p = 0.08) was observed, this difference was not statistically significant. Furthermore, no differences in postoperative creatine kinase level or creatine kinase index were seen between the two groups. No cerebrovascular accidents occurred in the EACA group; two occurred in the control group (p = 0.33). One patient in the EACA group and three in the control group required reexploration for postoperative bleeding (p = 0.6).
Discussion
Multiple factors contribute to the bleeding diathesis seen after cardiac operations performed with CPB. Not all are understood, and there is disagreement regarding their relative importance. The two major hematologic abnormalities leading to increased postoperative hemorrhage are decreased platelet function and increased fibrinolysis. 24-26 Bleeding time increases during and after CPB. This was long considered to reflect an intrinsic platelet defect caused by the nonphysiologic nature of CPB, but Kestin and associates 27 have proposed that the platelet defect occurs because of an antagonistic external force, such as cold, or lack of availability of platelet agonists. Previous studies that used whole blood flow cytometry failed to show any loss of platelet membrane receptors, 27 but studies of platelet-rich plasma or washed platelets do show such alterations. 28,29 This difference is likely to be the result of artifactual in vitro changes in platelet membrane receptors caused by the separation procedures required for the preparation of platelet-rich plasma and washed platelets.
The mechanism of the fibrinolysis is more clearly understood. 24,26,30 Blood coming into contact with foreign surfaces in the CPB circuit initiates the contact phase of coagulation and generates kallikrein. This in turn stimulates bradykinin release, and both molecules activate tissue plasminogen activator, which converts plasminogen to plasmin, a potent fibrinolytic and fibrinogenolytic agent. Heparin also directly increases plasmin activity. Further consequences of CPB are a reduction in circulating 2-antiplasmin and an increase in circulating plasminogen activator inhibitor–1. 31
Aprotinin has been shown by numerous studies to reduce bleeding after cardiac operations. 1,2,32 It interrupts several steps in the cascade of hematologic changes during CPB that lead to the bleeding diathesis. 26,33-38 These salutary effects occur at least in part as a result of aprotinin's direct antiplasmin activity, its inhibition of kallikrein, its inhibition of urokinase, and its preservation of normal levels of 2-antiplasmin. Aprotinin has also been reported to preserve platelet function, 1,29 although other reports suggest that its role in platelet preservation is absent or minimal compared with its interruption of fibrinolysis. 39,40 Although it is of unquestioned value in reducing blood loss, aprotinin is expensive. Questions have also been raised about its safety. Suggestions that aprotinin causes abnormal intravascular clotting, leading to organ dysfunction, have been made by several investigators. 2-4 For these two reasons we investigated the ability of EACA to reduce postoperative bleeding and also the mechanism of its action. EACA exerts its antifibrinolytic effect by binding with plasminogen and plasmin, displacing them from fibrin. 24 It also inhibits tissue plasminogen activator activity. 6 Because plasmin reduces the platelet GPIb receptors 41 and thus reduces platelet adhesion, and because the fibrin degradation products of fibrinolysis also inhibit platelet function, we measured the effect of EACA on platelet function in 26 patients by means of detailed hematologic testing.
In this study, the platelet surface expressions of P-selectin, GPIb, the GPIIb-IIIa complex, and fibrinogen binding to platelet surface GPIIb-IIIa were all unaffected by the administration of EACA to patients during CPB. Each of these antigens is of functional importance. P-selectin, an -granule membrane protein that is expressed on the platelet surface only after degranulation, 14,16 mediates adhesion of activated platelets to neutrophils and monocytes. 42,43 GPIb, a receptor for von Willebrand factor, is critical for platelet adhesion to damaged blood vessel walls. 44 The GPIIb-IIIa complex, a receptor for fibrinogen, von Willebrand factor, and fibronectin, is critical for platelet aggregation. 45 The lack of any effect of EACA on P-selectin, GPIb, the GPIIb-IIIa complex, and fibrinogen binding to the GPIIb-IIIa complex strongly suggests that the EACA-dependent decrease in CPB-associated blood loss is not mediated through a platelet-dependent mechanism.
We examined the fibrinolytic system in the same subset of the study population. In the control group, evidence of increased fibrinolysis was seen. This has been previously reported during CPB. 26 We found a marked increase in plasma d-dimer concentrations and a corresponding drop in euglobulin lysis time in the control group; in the EACA group no change occurred in D-dimer concentrations, and although the euglobulin clot lysis time fell slightly, it did so to a lesser extent than in the control group.
The major end point of the study was postoperative bleeding. At both 12 hours and 24 hours after operation, univariate and multivariate analyses demonstrated a significant reduction in blood loss in the EACA group. This is consistent with our previous study and several other studies, which showedreduced bleeding as a result of EACA use. 6,7,9-11 We assessed bleeding by directly measuring chest tube effluent. When these measurements were normalized for body surface area, the conclusions did not change.
In our previous study of EACA, 11 we limited the patient population to those patients undergoing elective coronary artery bypass operations, as did Daily and colleagues 10 in their recent publication. Because the difference in bleeding at 12 hours between the control (332 ml) and EACA (272 ml) groups in our earlier study was statistically significant but clinically insubstantial, we broadened the inclusion group in the current study. All patients undergoing coronary bypass operations, valve operations, or a combination of the two were included. Pregnant women, patients with known bleeding disorders, and patients requiring emergency operation were excluded.
Bleeding after heart operations is a problem of such magnitude that it is curious that little recognition or importance seems to have been given to reports demonstrating the efficacy of EACA published during the infancy of cardiac surgery. In 1967, Sterns and Lillehei 5 almost halved postoperative bleeding by giving EACA at the conclusion of CPB. In 1976, Lambert and colleagues 8 showed prompt resolution of established postoperative bleeding after EACA treatment. The interest in aprotinin therapy may have rekindled interest in EACA.
This rekindled interest assumes greater significance as a result of the current focus on medical costs. Purchased through our hospital pharmacy, the commonly used high-dose aprotinin regimen (20 x 106 kIU before bypass, 20 x 106 kIU in heart-lung pump, and 5 x 106 kIU/hr after 1 hour for the duration of the operation) costs our hospital $150 per 10 x 106 kIU, or about $785 per patient. A 30 gm dosage of EACA (the total dose used in this study) costs our hospital $6.96—a difference between the two drugs of about $778 per patient. This cost differential places aprotinin at a considerable disadvantage in the choice between the two drugs on the basis of a cost-benefit analysis.
As in our previous investigation of EACA, 11 we found no morbidity associated with the drug. Other studies have also shown no increase in complications from EACA use. 7,9,10 Because of the statistically insignificant increase in perioperative myocardial infarctions in the treatment group, however, this question must still be considered unanswered. With only 103 enrolled patients, it is possible that the study lacked sufficient statistical power to detect other differences in complication rates between the two groups.
Increased attention to control of bleeding in the terminal stages of the operation may be one cause of decreased postoperative bleeding. Although such increased attention cannot be measured directly, the operative time spent after the patient has been weaned from CPB and all the cardiac portions of the operation have been completed could be used as a surrogate measure. There was no difference in closure time (termination of CPB to dressing application) between the EACA and control groups. An unexpected and unexplained finding in this study was that the patients of one surgeon (surgeon 1) had significantly less bleeding than did those of the other surgeons. We have since discovered that this result parallels that in our total patient database extending back several years. In this study, the closure time for surgeon 1 was slightly but not significantly less than for the aggregate of the other surgeons. We therefore could not conclude that extra time (or care) in closing contributed to the difference in bleeding.
We conclude that EACA reduces postoperative bleeding after heart operations at far less expense than aprotinin and with no detectable morbidity. The EACA-dependent decrease in the CPB-associated blood loss is mediated by inhibition of the fibrinolytic system, not by a platelet-dependent mechanism.
Acknowledgments
We thank Drs. Barry S. Coller and Harvey Gralnick for generously providing monoclonal antibodies, Drs. Anne M. Stoddard and Frederick A. Anderson, Jr., for performing the statistical evaluation, and Marc Barnard, MS, and Hollace MacGregor, BS, for performing the hematologic and fibrinolytic analyses.
Footnotes
From the Division of Cardiothoracic Surgery,a Department of Pediatrics,d and Department of Anesthesia,b University of Massachusetts Medical Center, Worcester, Mass., and the Naval Blood Research Laboratory,c Boston University School of Medicine, Boston, Mass. 
References
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