Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial

Abstract

BackgroundIn cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR).MethodsWe performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).Results160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.ConclusionsProlonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.Current Controlled Trials numberISRCTN: ISRCTN84413719

Tranexamic acid–associated seizures: Causes and treatment

“…However, observational clinical trials and case reports have shown that TXA, and to a lesser extent EACA, but not aprotinin, are associated with seizures 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34. Most TXA‐associated seizures occur in patients who have undergone cardiac procedures 16, 17, 18, 20, 21, 24, 25, 26, 30, 31, 32, 34. However, several case reports indicate that TXA‐associated seizures also occur in nonsurgical patients 10, 22, 27.…”

Tranexamic Acid Use in Prehospital Uncontrolled Hemorrhage

“…TXA was shown to have anti-inflammatory effects in a randomized, double-blinded study of patients undergoing cardiopulmonary bypass (CPB) in a 2011 Jimenez et al study. 49 The study compared single-dose TXA group (given before CPB) and a double-dose group (given an additional TXA dose after CPB). An inflammatory reaction (IR) was defined as temperature > 38 °C, systemic vascular resistance index < 1600 dyne.sec/cm 5 per m 2 , and cardiac index > 3.5 L/min per m 2 .…”

Tranexamic acid: a clinical review

“…Patients receiving TXA had reduced incidences of inflammatory response and vasoplegic shock, fewer mean hours of norepinephrine use (1.2 vs 25.4 h) and fewer hours of mechanical ventilation (6.5 vs 12 h) in intensive care after CPB. In a larger RCT, IL-6 had a direct relationship with temperature, D-dimer, troponin I, CK, and lactic acid after CPB [15]. Furthermore, giving additional post-CPB TXA significantly reduced the relative risk (RR 2.5) of inflammatory response compared to pre-CPB TXA dosing alone.…”

“…Given the link between inflammatory response and coagulation-fibrinolysis systems and the likely attenuation of inflammatory response by TXA in CPB [14,15], clinicians ought to identify at-risk patients who may benefit from its treatment.…”