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

Critical Care, Nov 2007

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.

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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

Critical Care Vol11No6 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 Juan J Jimenez 2 Jose L Iribarren 2 Leonardo Lorente 2 Jose M Rodriguez 1 Domingo Hernandez 0 Ibrahim Nassar 4 Rosalia Perez 2 Maitane Brouard 2 Antonio Milena 3 Rafael Martinez 4 Maria L Mora 2 0 Research Unit, Hospital Universitario de Canarias , Ofra s/n La Cuesta, La Laguna, 38320 , Spain 1 Hematology Department, Hospital Universitario de Canarias , Ofra s/n La Cuesta, La Laguna, 38320 , Spain 2 Intensive Care Department, Hospital Universitario de Canarias , Ofra s/n La Cuesta, La Laguna, 38320 , Spain 3 Biochemistry and Central Laboratories, Hospital Universitario de Canarias , Ofra s/n La Cuesta, La Laguna, 38320 , Spain 4 Cardiac Surgery Department, Hospital Universitario de Canarias , Ofra s/n La Cuesta, La Laguna, 38320 , Spain 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 - Introduction Cardiopulmonary bypass (CPB) may activate an inflammatory response (IR) involving contact system, complement, cytokine, 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. and coagulation-fibrinolytic cascades, among others. The coagulation-fibrinolytic cascades and the IR, though in many respects separate processes, are closely interconnected [1]. Several preoperative and perioperative risk factors for IR have CI = confidence interval; CPB = cardiopulmonary bypass; ICU = intensive care unit; IL-6 = interleukin-6; IR = inflammatory response; OR = odds ratio; PAI-1 = plasminogen activator inhibitor 1; PT = prothrombin time; STNFR = soluble tumor necrosis factor receptor; TA = tranexamic acid; VS = vasoplegic shock. been proposed [2,3]. The incidence of vasoplegic shock (VS), the most severe presentation of IR, may be as high as 10% [4]. Numerous strategies to reduce IR and bleeding in high-risk patients exist, among which is the use of aprotinin [5]. Like aprotinin, tranexamic acid (TA) inhibits fibrinolysis (that is, plasmin activity and D-dimer formation), but its effect on IR remains unclear. Additionally, there is evidence that fibrinolysis is a marker for the onset of systemic inflammation. [6]. This paper describes a study in two parts. First, we performed a case control study to determine risk factors associated with IR in patients who underwent CPB. Second, we carried out a randomized, double-blind, placebo-controlled study to test the hypothesis that inhibition of excessive fibrinolysis by TA could reduce the incidence of IR and VS after CPB. The second study was interrupted because of the high incidence of adverse effects observed in the placebo group. Thus, we present data of an interim analysis. Materials and methods The study was approved by the institutional ethics committee of the University Hospital of the Canary Islands (La Laguna, Spain) and was conducted according to the Declaration of Helsinki. The study consisted of two parts. Part 1: Assessment of postoperative incidence and protective/risk factors for inflammatory response after cardiopulmonary bypass After obtaining informed written consent, we prospectively enrolled 191 consecutive Caucasian adult patients scheduled for cardiac surgery wit (...truncated)


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Juan J Jimenez, Jose L Iribarren, Leonardo Lorente, Jose M Rodriguez, Domingo Hernandez, Ibrahim Nassar, Rosalia Perez, Maitane Brouard, Antonio Milena, Rafael Martinez, Maria L Mora. 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, Critical Care, 2007, pp. R117, 11, DOI: 10.1186/cc6173