Asian Cardiovasc Thorac Ann 2007;15:49-53
© 2007 Asia Publishing EXchange Ltd
Effects of Tranexamic Acid and Autotransfusion in Coronary Artery Bypass
Aflatoon Mehr-Aein, MD,
Saeed Davoodi, MD1,2,
Manouchehr Madani-Civi, MD1,2
Department of Anesthesiology, Shariati Hospital
1 Research Department, Tehran Heart Center, Tehran University of Medical Sciences
2 Department of Cardiac Surgery, National Iranian Oil Company Central Hospital, Tehran, Iran
For reprint information contact: Manouchehr Madani-Civi, MD Tel: 98 21 6672 6520 Fax: 98 21 8802 9256 Email: madani_68{at}yahoo.com, P.O. Box 16765-3156, Tehran, Iran.
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ABSTRACT
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The aim of this study was to compare the effects of intraoperative autotransfusion and tranexamic acid on postoperative bleeding and the need for allogeneic transfusion. In a prospective randomized study, 200 patients undergoing coronary artery bypass were divided into two groups: 100 patients received 1–2 units of autologous blood after termination of cardiopulmonary bypass; and 100 patients were given tranexamic acid 15 mg·kg–1 before injection of heparin and again before injection of protamine. Postoperative bleeding was significantly lower in the tranexamic acid group (600 mL) than the autotransfusion group (1,100 mL). The percentage of patients transfused in the autotransfusion and tranexamic acid groups was 70% and 65%, respectively. Patients in the autotransfusion group received significantly more whole blood (2.82 vs 1.93 units). Intensive care and hospital stays were shorter in the tranexamic acid group. There was no hospital mortality and no difference in thrombotic complications between groups. Tranexamic acid was more effective than autotransfusion in reducing postoperative blood loss and allogeneic transfusions after coronary bypass.
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INTRODUCTION
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Defective hemostasis following cardiopulmonary bypass (CPB) is a serious complication that results in increased bleeding and a greater requirement for allogeneic blood transfusion. Excessive bleeding has been reported in 5%–25% of patients undergoing CPB; however, only 3%–5% of all patients require re-operation for bleeding, and 50%–80% do not have an identifiable surgical bleeding source.1 The mechanisms of bleeding during and after CPB are hemodilution, heparin administration, impaired platelet function, and increased fibrinolytic activity.2 Fibrinolysis has been reported to cause 25%–45% of significant post-bypass bleeding. The use of allogeneic blood products increases the rate of transmission of infectious diseases, modulates the immune response, and increases the risk of postoperative infection. These risks increase in proportion to the number of donors to which the recipient is exposed. The risks of blood transfusion with high donor-exposure levels have focused attention on blood conservation as a priority in reducing complications after cardiac operations.
Hemostatic defects are induced during the operation. Two principal therapeutic approaches to this complex problem have evolved, which may be used complementarily. One is autotransfusion (AT), especially acute normovolemic hemodilution (ANH), and the other is hemostatic drug therapy, including antifibrinolytic agents such as epsilon-aminocaproic acid or tranexamic acid (TX), platelet-preserving agents (prostacyclin, dipyridamole), desmopressin, and aprotinin.3–8 Tranexamic acid, a serine protease inhibitor, has been demonstrated to decrease allogeneic blood transfusion requirements in patients undergoing coronary artery surgery.9,10 Intraoperative blood salvage is widely used in cardiac surgery, but there is still controversy regarding the efficacy of ANH in decreasing allogeneic blood needs. The aim of this study was to assess the efficacy of TX in comparison to ANH in reducing postoperative bleeding and the need for allogeneic transfusion in a prospective randomized trial.
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PATIENTS AND METHODS
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The study was approved by the Ethical Committee of the hospital and informed consent was obtained from all patients. Two hundred patients undergoing conventional coronary artery bypass grafting (CABG) were randomly divided into two groups. In the AT group, after induction of anesthesia and before heparin injection, 1–2 units of blood (300–450 mL) was drawn and Ringer’s lactate solution (in a 3:1 ratio to blood drawn) or Ringer’s albumin (2:1 ratio) was infused simultaneously into another vein. In the TX group, all patients received tranexamic acid 15 mg·kg–1 before injection of heparin, and 15 mg·kg–1 after termination of CPB, before heparin reversal. Standard preoperative data were collected prospectively for every patient undergoing CABG at our institution. The datasets were filled in consecutively by the anesthetist, surgeon, perfusionist, and nurses. Inclusion criteria were primary CABG, age 70 years or less, ejection fraction 35% or more, body mass index 25 or less, no administration of acetylsalicylic acid in the 7 days before surgery, and no heparin infusion before the operation. Exclusion criteria were redo operation, emergency CABG, off-pump CABG, hemoglobin < 10 g·dL–1, platelet count < 100 K·µL–1, a known coagulopathy disorder, and renal insufficiency.
All operations were carried out by one team of cardiac surgeons. Anesthesia was standardized in all patients. Anesthetic induction consisted of fentanyl 3 µg·kg–1 followed by diazepam 0.1 mg·kg–1 and sodium thiopental 2 mg·kg–1. Intubation was carried out after administration of succinylcholine 3 mg·kg–1. In patients with systolic hypertension > 140 mm Hg, lidocaine 1 mg·kg–1 was injected before intubation. During surgery, halothane 0.5% with fentanyl 1–3 µg·kg–1·min–1 was used. Muscle relaxation was maintained with pancuronium 2 mg·hr–1. The surgeon was blinded to the randomization. Routine CPB was instituted with mild hypothermia (32°C nasopharyngeal) using a membrane oxygenator and a roller pump. Myocardial viability was preserved with topical hypothermia and antegrade cold hyperkalemic crystalloid cardioplegia. Adequacy of tissue perfusion was monitored by the arteriovenous difference in partial pressure of CO2, the lactate level, urine output, and base deficit. Patients were heparinized fully according to body weight with 300 unit·kg–1. After sternotomy, the internal mammary artery was harvested and if a vein graft was needed, the saphenous vein was harvested also. After discontinuation of antegrade CPB, heparin was reversed with protamine in a ratio of 1.3:1. After weaning from CBP, 3 chest tubes were inserted in the pericardium, mediastinum, and left pleural space. The amount of bleeding from the tubes was recorded and this drainage was not re-transfused into patients by cell salvage techniques.
On arrival in the intensive care unit (ICU), patients were placed on mechanical ventilation. All patients were evaluated for extubation every hour. Hemodynamically stable patients without excessive drainage and good arterial blood gases were extubated. Oxygen saturation and respiratory rate were monitored continuously. Arterial blood gases were obtained 1, 2, and 6 hr after extubation. If drainage was < 100 mL in 6 hr, the chest tubes were withdrawn. In the ICU, blood glucose, hemoglobin (Hb), hematocrit, prothrombin time, platelet count, electrolytes, and serum creatinine were measured routinely. Chest radiography was performed every day. We aimed to discharge all patients from the ICU within 18–24 hr, and to discharge them from the hospital on the 5th or 6th postoperative day. All patients had 48 hr electrocardiographic monitoring for myocardial ischemia in the ICU. If a myocardial infarction was suspected, the levels of creatine kinase MB-isoenzyme and troponin I were measured. Patients were examined every day for neurologic and pulmonary embolic events by specialists. If the patient was medically unfit on day 6, further investigations were carried out, depending on the clinical status.
Blood loss was recorded at 1, 4, 8, 16, and 24 hr postoperatively. If drainage was > 500 mL in the first hour or 800 mL in the 2 hours after the operation, the patient underwent re-operation. The indication for blood transfusion was decided in each individual patient on the basis of age, hematocrit, Hb, and hemodynamic parameters. Generally, the indications for whole blood transfusion were hematocrit < 20% and/or Hb < 7 g·dL–1 during the operation and hematocrit < 28% and/or Hb < 9 g·dL–1 in the ICU and post-ICU. The indications for fresh frozen plasma infusion were prolonged prothrombin time (more than 1.5 times normal) and blood loss > 200 mL·hr–1. The indications for platelet transfusion were platelet count < 75/µL and bleeding > 200 mL for longer than 2 hours. Central venous pressure readings were used to determine the need for intravascular volume replacement; when needed, patients received allogeneic blood products.
All measurements are expressed as mean ± the standard error of the mean. Statistical analyses were performed with SPSS for Windows version 11.0 software (SPSS, Inc., Chicago, IL, USA). Comparisons of results between groups were carried out by the two-sample t test for each normally distributed variable. The nonparametric Mann-Whitney U test was used to analyze intraoperative and postoperative blood loss. A p value of less than 0.05 was considered to indicate a significant difference.
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RESULTS
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The patients’ clinical characteristics are listed in Table 1
. There were no differences between the 2 groups with respect to demographics, risk factors, preoperative medication, heart rate, or blood pressure. Intraoperative and postoperative variables (Table 2) were similar in both groups, but ICU and hospital stays were significantly longer in the AT group. Table 3 compares blood loss between the two groups after the operation. There was a significantly greater blood loss and longer total drainage time in the AT group. The greatest amount of bleeding occurred in the first 8 hours. Transfusion requirements for the two groups are compared in Figure 1. Patients in the AT group received more units per patient of whole blood (2.82 vs 1.93, p < 0.01), fresh frozen plasma (3.08 vs 2.38, p < 0.01), and platelets (0.8 vs 0.2, p < 0.01) than the TX group. The percentage of patients who received no allogeneic blood products during or after the operation was higher ( p < 0.01) in the TX group (35%) than the AT group (30%). Postoperative myocardial infarction was not seen in either group. Re-exploration was required in 2 patients in the AT group and none in the TX group. Renal failure occurred in 2 patients in the AT group and none in the TX group. There was no difference between the 2 groups in terms of neurological dysfunction and coagulopathies. There was no hospital mortality (up to 7 days postoperatively and before discharge) in either group.
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Figure 1. Transfusion of allogeneic blood products (intraoperative and postoperative) in units per patient. AT = autotransfusion, FFP = fresh frozen plasma, TX = tranexamic acid.
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DISCUSSION
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In this study, we compared the hemostatic effects of AT and TX in patients undergoing CABG under CPB. The results of this controlled randomized study in cardiac surgical patients meeting predetermined inclusion criteria, demonstrate limited benefit of preoperative ANH to attenuate perioperative blood loss or reduce allogeneic blood transfusion. Hemostatic defects encountered during CPB cause increased blood loss during and after the operation, a greater need for allogeneic blood transfusion, more re-operations, and higher morbidity. Significant post-CPB hemorrhage has been reported in 6% to 25% of patients postoperatively.11 The most important factors that cause hemostatic defects after CABG surgery are: inadequate surgical hemostasis, incomplete heparin reversal, complement activation, platelet dysfunction, and hyperfibrinolysis. Chest incision and cardiac surgery increase the concentration and activity of tissue plasminogen, which converts plasminogen to plasmin and inactivates fibrin. However, platelet dysfunction was found to be another important factor: contact with a synthetic surface results in 
-granule release, with subsequent reduced aggregation and adhesiveness of platelets.1,12
Recently, there has been a trend towards reducing blood loss and the need for blood transfusion. In this regard, the use of AT and antifibrinolytic drugs has been recommended. In the 1980s, because of the fear of viral transmission during allogeneic blood transfusion, there was a trend towards autologous blood transfusion and reduction in the need for allogeneic blood products. There are 3 methods of autotransfusion: preoperative blood donation, acute normovolemic hemodilution, and blood salvage techniques. In our study, ANH was used because of the presence of fresh platelets and an adequate amount of coagulation factors in transfused blood. There is no rise in K+, and a decrease in 2,3-diphosphoglycerate in transfused blood. This method needs careful monitoring; therefore, it is inappropriate in emergency surgery and patients with a hepatic disorder. Previous studies on the efficacy of ANH in cardiac surgery have resulted in conflicting reports.12 Sherman and colleagues13 showed no difference in blood loss with ANH, the requirement for allogeneic blood actually being greater in their ANH group than in the group of patients serving as controls. Pliam and colleagues14 showed that the requirements of allogeneic blood tended to be even greater after ANH (although the difference did not reach statistical significance). The reason for the discrepancy in the results is probably related to the fact that most of the reports on this topic included only small numbers of patients, were not randomized, or had no predefined criteria.15
The effect of TX in reducing the need for allogeneic blood has been proven in many studies. In the 1990s, the pathophysiology of the fibrinolytic system during CABG became better defined. Many investigators have demonstrated activation of the fibrinolytic system during CPB.10,16 Thus, the use of antifibrinolytic drugs such as aprotinin, 
-aminocaproic acid, desmopressin, and recently TX, has increased. Tranexamic acid is a synthetic antifibrinolytic drug that is 10 times more potent than -aminocaproic acid. Horrow and colleagues17 first reported the use of TX in cardiac surgery in 1990. The antifibrinolytic effect of TX is due to suppression of tissue plasminogen activator with consequent inhibition of secondary fibrinolysis. Tranexamic acid had no effects on plasmin neutralization and plasminogen activator inhibitor-1. However, TX stabilizes adenosine diphosphate granules in platelets and inhibits platelet dysfunction. The effect of TX on blood loss after CPB in this series agrees with other studies.18 Tranexamic acid has no effect on perioperative thrombotic complications.18 The potential for hypercoagulability with the use of antifibrinolytic agents, as suggested by Cosgrove and colleagues19 was taken into account in this study. The possibility of thromboembolic complications and, in particular, graft occlusion with myocardial infarction caused by TX, must be considered when giving this drug to patients.
In a recent study, vein graft patency was assessed with magnetic resonance imaging 5 to 30 days after surgery.20 It was found that administration of TX before CPB did not compromise early venous graft patency rates. We found no evidence of hypercoagulability such as increased incidence of cerebrovascular accidents, deep venous thrombosis, or pulmonary emboli. A long-term study with larger numbers of patients may be necessary to clarify the issue of hypercoagulability. Mortality and other clinical outcomes were similar in the two groups, except for bleeding and transfusion requirements. Our results showed that patients in the TX group bled less after surgery and had a smaller volume of blood retransfused than those in the AT group. There may have been a postoperative relative allogeneic over-transfusion in ANH patients because of a dilution phenomenon associated with the strict hematocrit trigger criterion for transfusion. Postoperative hematocrit may indeed have been relatively lower in ANH patients. It was concluded that TX, which is inexpensive and readily available, significantly reduced blood loss and blood product transfusion requirements in patients undergoing CABG. No increased incidence of thrombotic complications as a result of its use could be demonstrated.
Presented at The 11th Annual Meeting of the Asian Society for Cardiovascular Surgery, Kuala Lumpur, Malaysia, February 12–15, 2003.
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ABSTRACT
INTRODUCTION
