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Ann Thorac Surg 2002;74:733-738
© 2002 The Society of Thoracic Surgeons
a Department of Anesthesia, Holon, Israel
b Department of Cardiothoracic Surgery, The Edith Wolfson Medical Center, Holon, Israel
Accepted for publication May 13, 2002.
* Address reprint requests to Dr Medalion, Department of Cardiothoracic Surgery, The Edith Wolfson Medical Center, POB 5, Holon, 58100, Israel
e-mail: dawn{at}wolfson.health.gov.il
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and methodsResultsCommentReferences |
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Methods. Fifty patients undergoing primary coronary artery bypass grafting were randomly assigned to receive either placebo (0.9% NaCl; n = 25) or 10 mg/kg TA followed by infusion of 1 mg/kg per hour during the operation (n = 25). Data measured included blood loss, transfusion, reoperation, fibrinogen level, fibrinogen split products, platelet size, and platelet function. Measurements were made after induction of anesthesia, after heparin administration, during patient warming, after skin closure, and 24 hours after operation.
Results. Patients in the TA study group weighed less. Other demographic characteristics were similar between groups. Postoperative bleeding was less in the TA group (194 ± 135 mL versus 488 ± 238 mL, p < 0.001), whereas blood requirement was higher in the control group (1.68 ± 1 versus 0.52 ± 0.9 U of packed cells per patient, p < 0.001). The percent of patients exposed to blood products was significantly less in the TA group (36% versus 100%, p < 0.001). Fibrinogen split products were lower in the TA group during bypass (p < 0.001). Fibrinogen levels fell in both groups during cardiopulmonary bypass. Platelet number and function were reduced equally in both groups by cardiopulmonary bypass. Other test results were not different between groups.
Conclusions. The use of low-dose TA during coronary artery bypass grafting significantly reduced the coagulopathy-induced postoperative bleeding and allogeneic blood products requirement. The low levels of fibrinogen split products during bypass in the study group reflect the inhibiting effect of TA in fibrinolysis. Tranexamic acid had no effect on platelet function during cardiopulmonary bypass.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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-amino-n-caproic acid (EACA) given before CPB have been shown to reduce mediastinal bleeding after such procedures when compared with placebo [3–7]. The antifibrinolytic drugs have been shown to be equally effective as aprotinin in reducing bleeding and the use of allogeneic blood products, both in high-risk patients and routine patient populations undergoing cardiac operations [8, 9]. Because antifibrinolytic drugs are much cheaper than aprotinin, and equally effective in reducing bleeding during cardiac operations [9], we studied a homogeneous patient population undergoing elective or urgent CABG to estimate the influence of intraoperative administration of TA on perioperative bleeding, need for allogeneic transfusion, and its effect on platelet number and function and fibrinolysis.
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Material and methods |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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The operation was performed through a median sternotomy. The left internal mammary artery was harvested as a thin pedicle with its venous tributaries. The left radial artery was harvested simultaneously with the saphenous vein when needed. Cardiopulmonary bypass was achieved with aortic and single venous cannulas. The patients were uniformly cooled to 32°C. The oxygenator used was a COBE Optima XP Hollow Fiber Sealed System (COBE Cardiovascular, Inc., Arvada, CO). Cardioplegia was achieved with antegrade and retrograde sanguinous cardioplegia with repeated doses every 20 minutes. All distal anastomoses were performed first and proximal anastomoses were performed during the same cross-clamp while perfusing the heart with warm blood. The mediastinum and left chest were routinely drained, and the right chest was drained only when the right pleura was opened. Arterial blood samples were repeatedly analyzed for gases, chemistry, and coagulation tests. Group 1 (TA) received 10 mg/kg TA intravenously for more than 15 minutes, in a volume of 10 mL, after induction of anesthesia, followed by a continuous infusion of 1 mg/kg per hour in a volume of 10 mL for the duration of the procedure. The placebo group received a 10-mL bolus of 0.9% saline solution followed by a continuous infusion of saline (10 mL/h). The surgeon was blinded with respect to whether TA or placebo was infused. Blood samples were taken after induction of anesthesia, after heparin administration, during CPB, during patient warming, after skin closure, and 24 hours after operation. The blood samples were analyzed for hemoglobin (Hb) concentration, platelet number, size, and function, activated clotting time (ACT), fibrinogen split products (FSP), fibrinogen concentration, prothrombin time, partial thromboplastin time, and kidney (creatinine, blood urea nitrogen) and liver function tests (liver enzymes, bilirubin, prothrombin time). Platelet function, as determined by the HemoStatus Platelet Function Test (Medtronic; Parker, CO), assesses acceleration of kaolin ACT exposed to different concentrations of platelet-activating factor. The value is expressed as a ratio of a platelet-activating factor-accelerated ACT to control ACT [10, 11]. Before being placed on CPB, the patient received 3 mg/kg heparin (porcine intestinal heparin sodium; Kamada, Beit Kama, Israel) through a central vein. The ACT values were kept between 500 to 600 seconds during the bypass period by administering additional doses of heparin as necessary. Also, 10,000 U of heparin was added to the extracorporeal circuit. When coming off CPB, patients received platelets as necessary (see Discussion for transfusion criteria). Patients received packed red blood cells for Hb less than 10 g/dL (see Discussion for transfusion criteria). For the first 24 hours, the following clinical data were recorded for each patient: amount of blood loss for 24 hours, percentage of patients exposed to blood products in the first 24 hours, the type and amount of blood products infused during the first 24 hours, reoperation for bleeding within 24 hours, evidence of myocardial infarction (by electrocardiogram, troponin level), evidence of gross neurologic event (ie, stroke), and death.
Normally distributed continuous variables are expressed as mean ± standard deviation. Abnormally distributed variables are expressed as median. Noncontinuous data are expressed as number of events and percentage. For statistical analysis, the two-tailed Student’s t test was used for normally distributed continuous variables and the Mann-Whitney U test for abnormally distributed variables. Noncontinuous variables were compared by 
2 or Fisher’s exact test as appropriate. Differences were considered significant with a p 
0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Comment |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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Meta-analysis of multiple studies has shown aprotinin and antifibrinolytics to reduce mediastinal chest tube drainage by 30% versus placebo [13]. Although delivery protocols were uniform for aprotinin, they still vary widely for TA and EACA [13]. Whereas the effect of TA and aprotinin on reducing blood loss after cardiac operations is clear [12, 14], a meta-analysis of randomized studies of EACA versus placebo could not show a significant effect in reducing transfusion requirements [15]. Tranexamic acid has been shown as effective as aprotinin in reducing coagulopathy-caused bleeding after CPB and cheaper than aprotinin [12]. As TA is emerging as the presently available drug of choice to reduce coagulopathy-caused bleeding, we designed our study to glean knowledge about the benefit of using low-dose TA in terms of reducing blood loss and allogeneic transfusion and its effect on various coagulation factors.
In a low-risk patient population, TA was shown to decrease mediastinal bleeding after cardiac operation as early as 1990 [6]. A similar result was found in studies by Karski and associates from Toronto [16]. The first significant study of a uniform patient population undergoing coronary operation was reported by Rousou and colleagues [17]. They retrospectively studied 415 patients undergoing CABG excluding emergency and redo operations. The first 209 patients were operated on without TA and the subsequent 206 with a 2-g bolus of TA followed by 8 g during the procedure. Chest tube drainage in the control group was 1,114 mL versus 803 mL in the study group. A double-blind randomized placebo-controlled study was reported from Brook Army Medical Center [2] on patients undergoing primary coronary artery operation. The dose of TA was 15 mg/kg started before CPB and 1 mg/kg continued for 5 hours. The bleeding was reduced from 1,202 mL in the control group versus 1,020 mL in the TA group. Since then, multiple studies have shown the efficacy of TA in prospective studies comparing patients receiving TA to groups receiving aprotinin or EACA [9, 18, 19]. These studies mostly included patient populations that were at high risk for bleeding mixed with those of primary myocardial revascularization. The few studies since 1998 that had a placebo group with primary myocardial revascularization used high-dose TA [18, 19] or administration of TA well into the postoperative period. With improved CPB and surgical techniques, blood loss is small after routine primary CABG even without the use of antifibrinolytics [18–20]. Therefore it is a valid question to ask whether the addition of low-dose TA as given in our study is beneficial. From our findings, TA is beneficial even in this setting. Although control patients only bled 488 mL in 24 hours, the use of TA significantly reduced this even further to 194 mL. The low amount of bleeding in the TA group is compatible with recently published reports [9, 19]. Our institutional policy is to maintain the Hb at more than 10 g/dL in the postoperative setting. This is based on recommendations of the American Society of Anesthesiologists [21] to keep the Hb greater than 10 g/dL in patients with limited cardiac reserves. We included in this group patients suffering from coronary disease and recently weaned from CPB. Using this philosophy, the use of TA reduced the amount of blood transfused to the patients even in this low-risk group. Further, after disconnection from bypass, the patients received platelets and fresh-frozen plasma according to a recent report of the American Society of Anesthesiologists Task Force 2 [21], which states that patients at risk of surgical bleeding or those with platelet dysfunction may require platelet transfusion. Thus, the increased platelet transfusions in the control group most probably represents more oozing after disconnection from bypass in the control group whereas the lower percentage of platelet transfusion in the study group is probably not related to any effect of TA on platelet number and function. This increased platelet transfusion in the control group explains the high platelet count in the control group at 24 hours after the operation and the larger size of platelets in the study group, reflecting younger platelets secondary to bone marrow production.
Extracorporeal circulation causes fibrinolysis by plasmin activation [2, 17, 19, 20]. Tranexamic acid is a competitive inhibitor of plasminogen and, at higher doses, acts as a noncompetitive inhibitor of plasmin [2, 17, 19]. In early studies, doses of TA administered to inhibit fibrinolysis were very high, exceeding 20 mg/kg, and in some cases as much as 20 g [3]. In 1995, Horrow and coworkers [3] performed a preoperative randomized double-blind study to evaluate the proper dose of TA. They showed that 10 mg/kg loading dose followed by 1 mg/kg per hour maintenance dose for 12 hours after operation is equally effective in reducing bleeding as twice or four times the dose [3]. The effectiveness of this regimen was reinforced by Misfield and associates [19] on a low-risk patient population undergoing primary myocardial revascularization. Despite this however, high doses of TA continued to be used to inhibit fibrinolysis during CPB [9, 17, 18, 22], both in bolus form and continuous drip. Our study reinforces the studies by Harrow and colleagues [3] and Misfield and coworkers [19]. At the small dose of 10 mg/kg bolus and 1 mg/kg per hour, bleeding and blood product transfusion were significantly reduced. Further, FSP, a measure of fibrinolysis, did not change in the study group from pre-CPB values throughout CPB and the postoperative period. This was in clear contrast to the control group, in which FSP was elevated during bypass and continued to rise as the time of CPB increased (Table 3). We speculate that the initial dose followed by the immediate infusion does not allow the initial formation of plasmin and, therefore, allows TA to reduce fibrinolysis by acting as a competitive inhibitor of plasminogen rather than act as a noncompetitive inhibitor of plasma that requires a higher dose [17, 22]. The reason for higher levels of fibrinogen in our control group is not clear. This finding may explain the lack of difference between fibrinogen levels of the two groups, 24 hours after operation, in spite of the higher level of fibrinolysis in the control group as expressed by higher FSP levels.
The timing of TA administration to reduce postoperative blood loss is unclear. It is both logical and established that TA should be given before CPB as an initial dose [2]. Whether to continue the TA after the operation is controversial. Tranexamic acid has been used effectively when given up to 12 hours after an operation [3, 19] and when only given during the operation [2]. A study by Katoh and associates [22] showed that giving a second bolus of TA after CPB is effective to further reduce blood loss after cardiac operations. These authors gave an initial bolus of 100 mg/kg and no continuous infusion. They postulated that because the half-life of TA is 80 minutes, a second bolus would prevent fibrinolysis after the operation [22]. A recent study failed to prove the efficacy of postoperative administration of TA [23].
With our regimen, FSP were unchanged from preoperative levels throughout the procedure and the first 24 hours postoperatively. Blood loss in the first 24 hours after operation was very low. Again, if given in bolus form as CPB time increases, TA levels will fall and plasmin will be formed later during bypass, necessitating an additional bolus with TA or continuing TA infusion after operation. However, the question of whether it is necessary to continue TA into the postoperative period was not addressed by our present study.
The effect of TA on plasmin-mediated fibrinolysis during CPB is clearly demonstrated in this paper and others [2, 3, 19]. Whether TA can help reduce platelet dysfunction after CPB is controversial [2, 3, 24]. Inasmuch as TA inhibits the formation of plasmin, one would expect TA to inhibit plasmin-induced platelet activation, consequently preserving platelet function [2, 3]. Whether this is a clinical phenomenon or a theoretical consideration is unclear. Despite the obvious effect of TA on reducing fibrinolysis (Table 3), platelet number and function as measured by the accelerated ACT were reduced during CPB equally in both the control and study groups. Whether a higher dose of TA will reduce platelet dysfunction during CPB remains to be studied. We believe that more-specific tests can provide evidence for the protective effects of TA on platelets.
Our study suffers from a number of limitations. First, we only studied one dose of TA. It may be that higher doses of TA would have produced even greater beneficial effects, particularly in preserving platelet function. Second, we did not include one arm of the study that included TA administered after CPB to determine whether any additional benefit would come from this regimen. Third, we only performed one type of platelet function test. It may be that an effect of TA on preserving platelet function during CPB can be demonstrated with more-exhaustive testing.
With these limitations in mind, we conclude that administering a low dose of 10 mg/kg of TA followed by 1 mg/kg per hour as a continuous infusion is associated with decreased fibrinolysis during CPB. This effect has positive clinical results in terms of bleeding and transfusion in patients undergoing primary CABG. We have also found that the administration of TA at this dose has no clinical effect on platelet function during CPB.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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References |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentReferences |
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-aminocaproic acid in primary cardiac surgery. Ann Thorac Surg 1999;68:2252-2256.This article has been cited by other articles:
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  M. M Maddali and M. C Rajakumar Tranexamic Acid and Primary Coronary Artery Bypass Surgery: a Prospective Study Asian Cardiovasc Thorac Ann, August 1, 2007; 15(4): 313 - 319. [Abstract] [Full Text] [PDF]
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 The Society of Thoracic Surgeons Blood Conservatio, V. A. Ferraris, S. P. Ferraris, S. P. Saha, E. A. Hessel II, C. K. Haan, B. D. Royston, C. R. Bridges, R. S.D. Higgins, G. Despotis, et al. Perioperative Blood Transfusion and Blood Conservation in Cardiac Surgery: The Society of Thoracic Surgeons and The Society of Cardiovascular Anesthesiologists Clinical Practice Guideline Ann. Thorac. Surg., May 1, 2007; 83(5_Supplement): S27 - S86. [Abstract] [Full Text] [PDF]
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 J. J. Andreasen and C. Nielsen Prophylactic tranexamic acid in elective, primary coronary artery bypass surgery using cardiopulmonary bypass Eur. J. Cardiothorac. Surg., August 1, 2004; 26(2): 311 - 317. [Abstract] [Full Text] [PDF]
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