Effect of ulinastatin on post-operative blood loss and allogeneic transfusion in patients receiving cardiac surgery with cardiopulmonary bypass: a prospective randomized controlled study with 10-year follow-up

Peng Zhang, Hong Lv, Xia Qi, Wenjing Xiao, Qinghua Xue, Lei Zhang, Lihuan Li, Jia Shi, Peng Zhang, Hong Lv, Xia Qi, Wenjing Xiao, Qinghua Xue, Lei Zhang, Lihuan Li, Jia Shi

Abstract

Background: Major bleeding and allogeneic transfusion leads to negative outcomes in patients receiving cardiac surgery with cardiopulmonary bypass (CPB). Ulinastatin, a urine trypsin inhibitor, relieves systemic inflammation and improves coagulation profiles with however sparse evidence of its effects on blood loss and allogeneic transfusion in this specific population.

Methods: In this prospective randomized controlled trial, 426 consecutive patients receiving open heart surgery with CPB were randomly assigned into three groups to receive ulinastatin (group U, n = 142), tranexamic acid (group T, n = 143) or normal saline (group C, n = 141). The primary outcome was the total volume of post-operative bleeding and the secondary outcome included the volume and exposure of allogeneic transfusion, the incidence of stroke, post-operative myocardial infarction, renal failure, respiratory failure and all-cause mortality. A ten-year follow-up was carried on to evaluate long-term safety.

Results: Compared with placebo, ulinastatin significantly reduced the volume of post-operative blood loss within 24 h (688.39 ± 393.55 ml vs 854.33 ± 434.03 ml MD - 165.95 ml, 95%CI - 262.88 ml to - 69.01 ml, p < 0.001) and the volume of allogeneic erythrocyte transfusion (2.57 ± 3.15 unit vs 3.73 ± 4.21 unit, MD-1.16 unit, 95%CI - 2.06 units to - 0.26 units, p = 0.002). The bleeding and transfusion outcomes were comparable between the ulinastatin group and the tranexamic acid group. In-hospital outcomes and 10-year follow-up showed no statistical difference in mortality and major morbidity among groups.

Conclusions: Ulinastatin reduced post-operative blood loss and allogeneic erythrocyte transfusion in heart surgery with CPB. The mortality and major morbidity was comparable among the groups shown by the 10-year follow-up.

Trial registration: The trial was retrospectively registered on February 2, 2010.

Trial registration number: https://www.clinicaltrials.gov Identifier: NCT01060189.

Keywords: Blood conservation; Cardiopulmonary bypass; Tranexamic acid; Ulinastatin.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
CONSROT flow chart
Fig. 2
Fig. 2
Long-term survival (10-year follow-up). There was no significant difference among three groups in long-term survival. (log-rank test, p = 0.844). (Group T = tranexamic acid group; Group U = ulinastatin group; Group C = placebo group)

References

    1. Brown JR, Birkmeyer NJ, O'Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation. 2007;115(22):2801–2813.
    1. Levi M, Cromheecke ME, de Jonge E, Prins MH, de Mol BJ, Briet E, et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet. 1999;354(9194):1940–1947.
    1. Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002;74(4):1180–1186.
    1. Cremer J, Martin M, Redl H, Bahrami S, Abraham C, Graeter T, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg. 1996;61(6):1714–1720.
    1. Doguet F, Litzler PY, Tamion F, Richard V, Hellot MF, Thuillez C, et al. Changes in mesenteric vascular reactivity and inflammatory response after cardiopulmonary bypass in a rat model. Ann Thorac Surg. 2004;77(6):2130–2137.
    1. Murphy GJ, Angelini GD. Side effects of cardiopulmonary bypass: what is the reality? J Card Surg. 2004;19(6):481–488.
    1. Schwartz SM, Duffy JY, Pearl JM, Nelson DP. Cellular and molecular aspects of myocardial dysfunction. Crit Care Med. 2001;29(10 Suppl):S214–S219.
    1. Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation. 1995;91(6):1872–1885.
    1. Kopec M, Bykowska K, Lopaciuk S, Jelenska M, Kaczanowska J, Sopata I, et al. Effects of neutral proteases from human leukocytes on structure and biological properties of human factor VIII. Thromb Haemost. 1980;43(3):211–217.
    1. Taki M, Miura T, Inagaki M, Tomita Y, Saito N, Okada Y, et al. Influence of granulocyte elastase-like proteinase (ELP) on platelet functions. Thromb Res. 1986;41(6):837–846.
    1. Bjork P, Axelsson L, Bergenfeldt M, Ohlsson K. Influence of plasma protease inhibitors and the secretory leucocyte protease inhibitor on leucocyte elastase-induced consumption of selected plasma proteins in vitro in man. Scand J Clin Lab Invest. 1988;48(2):205–211.
    1. Manfredi AA, Rovere-Querini P, Maugeri N. Dangerous connections: neutrophils and the phagocytic clearance of activated platelets. Curr Opin Hematol. 2010;17(1):3–8.
    1. Muramatu M, Mori S, Matsuzawa Y, Horiguchi Y, Nakanishi Y, Tanaka M. Purification and characterization of urinary trypsin inhibitor, UTI68, from normal human urine, and its cleavage by human uropepsin. J Biochem. 1980;88(5):1317–1329.
    1. Ogawa M, Nishibe S, Mori T, Neumann S. Effect of human urinary trypsin inhibitor on granulocyte elastase activity. Res Commun Chem Pathol Pharmacol. 1987;55(2):271–274.
    1. Ohnishi H, Suzuki K, Niho T, Ito C, Yamaguchi K. Protective effects of urinary trypsin inhibitor in experimental shock. Jpn J Pharmacol. 1985;39(2):137–144.
    1. Okida M, Masako O, Maruya H, Higashi T, Yukaya H. Intraoperative changes in blood coagulation and the effectiveness of ulinastatin during liver resection. J Anesth. 1991;5(1):43–47.
    1. Ji HW, Chen L. Effects of ulinastatin on coagulation and platelet function in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Zhonghua Yi Xue Za Zhi. 2009;89(3):175–178.
    1. Park JB, Kim SH, Lee SA, Chung JW, Kim JS, Chee HK. Effects of ulinastatin on postoperative blood loss and hemostasis in atrioventricular valve surgery with cardiopulmonary bypass. Korean J Thorac Cardiovasc Surg. 2013;46(3):185–191.
    1. Song JE, Kang WS, Kim DK, Yoon TG, Kim TY, Bang YS, et al. The effect of ulinastatin on postoperative blood loss in patients undergoing open heart surgery with cardiopulmonary bypass. J Int Med Res. 2011;39(4):1201–1210.
    1. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. Bmj. 2012;344:e3054.
    1. Myles PS, Smith JA, Forbes A, Silbert B, Jayarajah M, Painter T, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017;376(2):136–148.
    1. Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011;1:CD001886.
    1. Mangano DT, Tudor IC, Dietzel C. Multicenter study of perioperative ischemia research G, ischemia R, education F. the risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006;354(4):353–365.
    1. Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomised and large matched observational studies. Eur J Cardiothorac Surg. 2010;37(6):1375–1383.
    1. Bingyang J, Jinping L, Mingzheng L, Guyan W, Zhengyi F. Effects of urinary protease inhibitor on inflammatory response during on-pump coronary revascularisation. Effect of ulinastatin on inflammatory response. J Cardiovasc Surg. 2007;48(4):497–503.
    1. Cao ZL, Okazaki Y, Naito K, Ueno T, Natsuaki M, Itoh T. Ulinastatin attenuates reperfusion injury in the isolated blood-perfused rabbit heart. Ann Thorac Surg. 2000;69(4):1121–1126.
    1. He QL, Zhong F, Ye F, Wei M, Liu WF, Li MN, et al. Does intraoperative ulinastatin improve postoperative clinical outcomes in patients undergoing cardiac surgery: a meta-analysis of randomized controlled trials. Biomed Res Int. 2014;2014:630835.
    1. Kawamura T, Inada K, Akasaka N, Wakusawa R. Ulinastatin reduces elevation of cytokines and soluble adhesion molecules during cardiac surgery. Can J Anaesth. 1996;43(5 Pt 1):456–460.
    1. Kawamura T, Shimoda Y, Wakusawa R. The effects of urinastatin on the plasma levels of granulocyte elastase during open heart surgery under simple deep hypothermia. J Anesth. 1992;6(3):269–276.
    1. Nakanishi K, Takeda S, Sakamoto A, Kitamura A. Effects of ulinastatin treatment on the cardiopulmonary bypass-induced hemodynamic instability and pulmonary dysfunction. Crit Care Med. 2006;34(5):1351–1357.
    1. Sato Y, Ishikawa S, Otaki A, Takahashi T, Hasegawa Y, Suzuki M, et al. Induction of acute-phase reactive substances during open-heart surgery and efficacy of ulinastatin. Inhibiting cytokines and postoperative organ injury. Jpn J Thorac Cardiovasc Surg. 2000;48(7):428–434.
    1. Shibata T, Yamamoto F, Suehiro S, Kinoshita H. Effects of protease inhibitors on postischemic recovery of the heart. Cardiovasc Drugs Ther. 1997;11(4):547–556.
    1. Sugita T, Watarida S, Katsuyama K, Nakajima Y, Yamamoto R, Mori A. Effect of a human urinary protease inhibitor (Ulinastatin) on respiratory function in pediatric patients undergoing cardiopulmonary bypass. J Cardiovasc Surg. 2002;43(4):437–440.
    1. Levin R, Degrange M, Del Mazo C, Tanus E, Porcile R. Preoperative levosimendan decreases mortality and the development of low cardiac output in high-risk patients with severe left ventricular dysfunction undergoing coronary artery bypass grafting with cardiopulmonary bypass. Exp Clin Cardiol. 2012;17(3):125–130.

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