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, Jose L Iribarren, Leonardo Lorente, Jose M Rodriguez, Domingo Hernandez, Ibrahim Nassar, Rosalia Perez, Maitane Brouard, Antonio Milena, Rafael Martinez, Maria L Mora, 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

Abstract

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.

Figures

Figure 1
Figure 1
Levels of interleukin-6 (IL-6) at 4 hours between inflammatory response (IR) patients and non-IR patients. ICU, intensive care unit.
Figure 2
Figure 2
Relationship between 24-hour chest tube bleeding and inflammatory response. Horizontal lines represent the median, boxes encompass the 25th to 75th percentile, and error bars encompass the 10th to 90th percentile.
Figure 3
Figure 3
Randomized control trial flow diagram.
Figure 4
Figure 4
Twenty-four-hour chest tube bleeding between tranexamic acid and placebo groups. Horizontal lines represent the median, boxes encompass the 25th to 75th percentile, and error bars encompass the 10th to 90th percentile.
Figure 5
Figure 5
Differences between tranexamic acid (TA) (solid line) and placebo (dotted line) in D-dimer levels. ICU, intensive care unit.

References

    1. Laffey JG, Boylan JF, Cheng DC. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97:215–252. doi: 10.1097/00000542-200207000-00030.
    1. Taneja R, Yared JP, Hammel J, O'Connor MS, Insler S, Starr NJ. Hyperdynamic circulation following cardiopulmonary bypass predisposes to postoperative bleeding. Critical Care. 2001;5(Suppl 1):P110. (2 March 2001)
    1. Tuman KJ, McCarthy RJ, O'Connor CJ, Holm WE, Ivankovich AD. Angiotensin-converting enzyme inhibitors increase vasoconstrictor requirements after cardiopulmonary bypass. Anesth Analg. 1995;80:473–479. doi: 10.1097/00000539-199503000-00007.
    1. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, Haverich A, Schlag G, Borst HG. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg. 1996;61:1714–1720. doi: 10.1016/0003-4975(96)00055-0.
    1. Greilich PE, Brouse CF, Whitten CW, Chi L, Dimaio JM, Jessen ME. Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin. J Thorac Cardiovasc Surg. 2003;126:1498–1503. doi: 10.1016/S0022-5223(03)00946-2.
    1. Cvachovec K, Horacek M, Vislocky I. A retrospective survey of fibrinolysis as an indicator of poor outcome after cardiopulmonary bypass and a possible early sign of systemic inflammation syndrome. Eur J Anaesthesiol. 2000;17:173–176. doi: 10.1046/j.1365-2346.2000.00643.x.
    1. Gomes WJ, Carvalho AC, Palma JH, Teles CA, Branco JN, Silas MG, Buffolo E. Vasoplegic syndrome after open heart surgery. J Cardiovasc Surg (Torino) 1998;39:619–623.
    1. Kristof AS, Magder S. Low systemic vascular resistance state in patients undergoing cardiopulmonary bypass. Crit Care Med. 1999;27:1121–1127. doi: 10.1097/00003246-199906000-00033.
    1. Johnson MR. Low systemic vascular resistance after cardiopulmonary bypass: are we any closer to understanding the enigma? Crit Care Med. 1999;27:1048–1050. doi: 10.1097/00003246-199906000-00008.
    1. Vincent JL. Dear SIRS, I'm sorry to say that I don't like you. Crit Care Med. 1997;25:372–374. doi: 10.1097/00003246-199702000-00029.
    1. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31:1250–1256. doi: 10.1097/01.CCM.0000050454.01978.3B.
    1. Kilger E, Weis F, Briegel J, Frey L, Goetz AE, Reuter D, Nagy A, Schuetz A, Lamm P, Knoll A, et al. Stress doses of hydrocortisone reduce severe systemic inflammatory response syndrome and improve early outcome in a risk group of patients after cardiac surgery. Crit Care Med. 2003;31:1068–1074. doi: 10.1097/01.CCM.0000059646.89546.98.
    1. Hauser GJ, Ben-Ari J, Colvin MP, Dalton HJ, Hertzog JH, Bearb M, Hopkins RA, Walker SM. Interleukin-6 levels in serum and lung lavage fluid of children undergoing open heart surgery correlate with postoperative morbidity. Intensive Care Med. 1998;24:481–486. doi: 10.1007/s001340050600.
    1. Despotis GJ, Avidan MS, Hogue CW., Jr Mechanisms and attenuation of hemostatic activation during extracorporeal circulation. Ann Thorac Surg. 2001;72:S1821–S1831. doi: 10.1016/S0003-4975(01)03211-8.
    1. Baufreton C, Corbeau JJ, Pinaud F. [Inflammatory response and haematological disorders in cardiac surgery: toward a more physiological cardiopulmonary bypass] Ann Fr Anesth Reanim. 2006;25:510–520. doi: 10.1016/j.annfar.2005.12.002.
    1. Iribarren J, Jimenez J, Brouard M, Lorenzo J, Perez R, Lorente L, Nuñez C, Henry C, Martinez R, Mora ML. Vasoplegic syndrome after cardiopulmonary bypass surgery associated factors and clinical outcomes: a nested case-control study. Crit Care. 2007;11(Suppl 2):P254. doi: 10.1186/cc5414. (22 March 2007)
    1. Syrovets T, Jendrach M, Rohwedder A, Schule A, Simmet T. Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKbeta-mediated NF-kappaB activation. Blood. 2001;97:3941–3950. doi: 10.1182/blood.V97.12.3941.
    1. Robson SC, Shephard EG, Kirsch RE. Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1 beta, IL-6 and plasminogen activator inhibitors from monocytes in vitro. Br J Haematol. 1994;86:322–326.
    1. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs. 1999;57:1005–1032. doi: 10.2165/00003495-199957060-00017.
    1. Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, Wijeysundera DN, Fedorko L, Yau TM. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion. 2006;46:327–338. doi: 10.1111/j.1537-2995.2006.00724.x.
    1. Diprose P, Herbertson MJ, O'Shaughnessy D, Deakin CD, Gill RS. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth. 2005;94:271–278. doi: 10.1093/bja/aei044.
    1. Asehnoune K, Dehoux M, Lecon-Malas V, Toueg ML, Gonieaux MH, Omnes L, Desmonts JM, Durand G, Philip I. Differential effects of aprotinin and tranexamic acid on endotoxin desensitization of blood cells induced by circulation through an isolated extracorporeal circuit. J Cardiothorac Vasc Anesth. 2002;16:447–451. doi: 10.1053/jcan.2002.125145.
    1. Marano CW, Garulacan LA, Laughlin KV, Igidbashian L, Trace C, Goldman SM, Sutter FP, Reichard GA, Jr, Mullin JM. Plasma concentrations of soluble tumor necrosis factor receptor I and tumor necrosis factor during cardiopulmonary bypass. Ann Thorac Surg. 2000;70:1313–1318. doi: 10.1016/S0003-4975(00)01932-9.
    1. el-Barbary M, Khabar KS. Soluble tumor necrosis factor receptor p55 predicts cytokinemia and systemic inflammatory response after cardiopulmonary bypass. Crit Care Med. 2002;30:1712–1716. doi: 10.1097/00003246-200208000-00006.
    1. Casati V, Della Valle P, Benussi S, Franco A, Gerli C, Baili P, Alfieri O, D'Angelo A. Effects of tranexamic acid on postoperative bleeding and related hematochemical variables in coronary surgery: comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg. 2004;128:83–91. doi: 10.1016/j.jtcvs.2003.10.034.
    1. Jimenez JJ, Iribaren JL, Raya JM, Nassar I, Lorente L, Perez R, Brouard M, Lorenzo JM, Alarco B, Martinez R, et al. Factors associated with excessive bleeding in cardiopulmonary bypass patients: a nested case-control study. J Cardiothorac Surg. 2007;2:17. doi: 10.1186/1749-8090-2-17.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere