Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial

INTRODUCTION: Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study. METHODS: A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes. RESULTS: In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB. CONCLUSION: The use of TA attenuates the development of IR and VS after CPB. TRIAL REGISTRATION NUMBER: ISRCTN05718824

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

<p>Abstract</p> <p>Background</p> <p>In 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).</p> <p>Methods</p> <p>We 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).</p> <p>Results</p> <p>160 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; <it>P </it>= 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), (<it>P </it>= 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; <it>P </it>= 0.01 corrected-<it>P </it>significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; <it>P </it>= 0.01 corrected-<it>P </it>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; <it>P </it>= 0.014 corrected-<it>P </it>significant].</p> <p>We found a significant direct relationship between IL-6 and temperature (rho = 0.26; <it>P </it>< 0.01), D-dimer (rho = 0.24; <it>P </it>< 0.01), norepinephrine (rho = 0.33; <it>P </it>< 0.01), troponin I (rho = 0.37; <it>P </it>< 0.01), Creatine-Kinase (rho = 0.37; <it>P </it>< 0.01), Creatine Kinase-MB (rho = 0.33; <it>P </it>< 0.01) and lactic acid (rho = 0.46; <it>P </it>< 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.</p> <p>Conclusions</p> <p>Prolonged 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.</p> <p>Current Controlled Trials number</p> <p>ISRCTN: <a href="http://www.controlled-trials.com/ISRCTN84413719">ISRCTN84413719</a></p

Relative adrenal insufficiency and hemodynamic status in cardiopulmonary bypass surgery patients. A prospective cohort study

<p>Abstract</p> <p>Background</p> <p>The objectives of this study were to determine the risk factors for relative adrenal insufficiency in cardiopulmonary bypass patients and the impact on postoperative vasopressor requirements.</p> <p>Methods</p> <p>Prospective cohort study on cardiopulmonary bypass patients who received etomidate or not during anesthetic induction. Relative adrenal insufficiency was defined as a rise in serum cortisol ≤ 9 μg/dl after the administration of 250 μg of consyntropin. Plasma cortisol levels were measured preoperatively, immediately before, 30, 60, and 90 minutes after the administration of cosyntropin, and at 24 hours after surgery.</p> <p>Results</p> <p>120 elective cardiopulmonary bypass patients were included. Relative adrenal insufficiency (Δcortisol ≤9 μg/dl) incidence was 77.5%. 78 patients received etomidate and 69 (88%) of them developed relative adrenal insufficiency, (<it>P </it>< 0.001). Controlling for clinical characteristics with a propensity analysis, etomidate was the only independent risk factor associated with relative adrenal insufficiency (OR 6.55, CI 95%: 2.47-17.4; <it>P </it>< 0.001). Relative adrenal insufficiency patients showed more vasopressor requirements just after surgery (<it>P </it>= 0.04), and at 4 hours after surgery (<it>P </it>= 0.01). Pre and post-test plasma cortisol levels were inversely associated with maximum norepinephrine dose (ρ = -0.22, <it>P </it>= 0.02; ρ = -0.18, <it>P </it>= 0.05; ρ = -0.21, <it>P </it>= 0.02; and ρ = -0.22, <it>P </it>= 0.02, respectively).</p> <p>Conclusions</p> <p>Relative adrenal insufficiency in elective cardiopulmonary bypass patients may induce postoperative vasopressor dependency. Use of etomidate in these patients is a modifiable risk factor for the development of relative adrenal insufficiency that should be avoided.</p

Factors associated with excessive bleeding in cardiopulmonary bypass patients: a nested case-control study

<p>Abstract</p> <p>Introduction</p> <p>Excessive bleeding (EB) after cardiopulmonary bypass (CPB) may lead to increased mortality, morbidity, transfusion requirements and re-intervention. Less than 50% of patients undergoing re-intervention exhibit surgical sources of bleeding. We studied clinical and genetic factors associated with EB.</p> <p>Methods</p> <p>We performed a nested case-control study of 26 patients who did not receive antifibrinolytic prophylaxis. Variables were collected preoperatively, at intensive care unit (ICU) admission, at 4 and 24 hours post-CPB. EB was defined as 24-hour blood loss of >1 l post-CPB. Associations of EB with genetic, demographic, and clinical factors were analyzed, using SPSS-12.2 for statistical purposes.</p> <p>Results</p> <p>EB incidence was 50%, associated with body mass index (BMI)< 26.4 (25–28) Kg/m², (<it>P </it>= 0.03), lower preoperative levels of plasminogen activator inhibitor-1 (PAI-1) (<it>P </it>= 0.01), lower body temperature during CPB (<it>P </it>= 0.037) and at ICU admission (<it>P </it>= 0.029), and internal mammary artery graft (<it>P </it>= 0.03) in bypass surgery. We found a significant association between EB and 5G homozygotes for PAI-1, after adjusting for BMI (F = 6.07; <it>P </it>= 0.02) and temperature during CPB (F = 8.84; <it>P </it>= 0.007). EB patients showed higher consumption of complement, coagulation, fibrinolysis and hemoderivatives, with significantly lower leptin levels at all postoperative time points (<it>P </it>= 0.01, <it>P </it>< 0.01 and <it>P </it>< 0.01).</p> <p>Conclusion</p> <p>Excessive postoperative bleeding in CPB patients was associated with demographics, particularly less pronounced BMI, and surgical factors together with serine protease activation.</p

Differences between tranexamic acid (TA) (solid line) and placebo (dotted line) in D-dimer levels

<p><b>Copyright information:</b></p><p>Taken from "Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial"</p><p>http://ccforum.com/content/11/6/R117</p><p>Critical Care 2007;11(6):R117-R117.</p><p>Published online 7 Nov 2007</p><p>PMCID:PMC2246206.</p><p></p> ICU, intensive care unit

Levels of interleukin-6 (IL-6) at 4 hours between inflammatory response (IR) patients and non-IR patients

<p><b>Copyright information:</b></p><p>Taken from "Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial"</p><p>http://ccforum.com/content/11/6/R117</p><p>Critical Care 2007;11(6):R117-R117.</p><p>Published online 7 Nov 2007</p><p>PMCID:PMC2246206.</p><p></p> ICU, intensive care unit