Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation

Summary

In cardiac surgery, the presence of pulmonary hypertension (PH) is a prognostic factor associated with increased mortality and morbidity. In this context, one of the main causes of PH is related to reperfusion ischemia during weaning from extracorporeal circulation (CPB). One of the consequences of PH is right ventricular dysfunction. During weaning from CPB, the development of a right ventricular dysfunction is associated with increased requirements for vasopressor and inotropic agents, duration of mechanical ventilation, prolonged intensive care and hospital stay, and increased mortality compared with patients with left ventricular (LV) dysfunction. The management of patients with PH with or without right ventricular (RV) dysfunction relies on several strategies such as the administration of intravenous and inhaled agents, or mechanical ventricular support. Among those agents, the administration of inotropes or pulmonary vasodilators such as epoprostenol, milrinone and nitric oxide are among the most widely used treatments recommended by the Canadian Cardiovascular Society. At the Montreal Heart Institute, inhaled epoprostenol and milrinone are routinely administered to patients with PH or LV dysfunction in the perioperative setting. Despite the frequent use of inhaled epoprostenol and milrinone, Health Canada has not yet approved the use of these molecules. The primary objective of this multicenter, double-blind, randomized clinical trial is to evaluate the clinical efficacy of the combined administration of inhaled epoprostenol and milrinone in a cardiac surgery setting. This trial will compare the clinical outcome of 71 patients who will receive inhaled epoprostenol and milrinone before the start of bypass surgery to 71 patients who will receive a placebo before the start of the CPB. The primary clinical outcome is the proportion of patients with an "unsuccessful" CPB weaning defined by the use of an inotrope +/- vasopressor agent or the use of mechanical circulatory support or a return to bypass grafting for hemodynamic reasons. This clinical trial will evaluate the clinical efficacy of the combination of inhaled agents in a cardiac surgery setting. Therefore, if the results of this study are positive, the combination of inhaled epoprostenol and milrinone will optimize the management of patients with pulmonary hypertension with or without a right ventricular dysfunction.

Timeline

Start

2025-12-10

Primary completion

2028-05-01

Completion

2028-12-01

Publications

• Background Denault AY, Bussieres JS, Arellano R, Finegan B, Gavra P, Haddad F, Nguyen AQN, Varin F, Fortier A, Levesque S, Shi Y, Elmi-Sarabi M, Tardif JC, Perrault LP, Lambert J. A multicentre randomized-controlled trial of inhaled milrinone in high-risk cardiac surgical patients. Can J Anaesth. 2016 Oct;63(10):1140-1153. doi: 10.1007/s12630-016-0709-8. Epub 2016 Jul 28.
• Results Davila-Roman VG, Waggoner AD, Hopkins WE, Barzilai B. Right ventricular dysfunction in low output syndrome after cardiac operations: assessment by transesophageal echocardiography. Ann Thorac Surg. 1995 Oct;60(4):1081-6. doi: 10.1016/0003-4975(95)00526-q.
• Results Authors/Task Force Members; Kunst G, Milojevic M, Boer C, De Somer FMJJ, Gudbjartsson T, van den Goor J, Jones TJ, Lomivorotov V, Merkle F, Ranucci M, Puis L, Wahba A; EACTS/EACTA/EBCP Committee Reviewers; Alston P, Fitzgerald D, Nikolic A, Onorati F, Rasmussen BS, Svenmarker S. 2019 EACTS/EACTA/EBCP guidelines on cardiopulmonary bypass in adult cardiac surgery. Br J Anaesth. 2019 Dec;123(6):713-757. doi: 10.1016/j.bja.2019.09.012. Epub 2019 Oct 2. No abstract available.
• Results El Kebir D, Hubert B, Taha R, Troncy E, Wang T, Gauvin D, Gangal M, Blaise G. Effects of inhaled nitric oxide on inflammation and apoptosis after cardiopulmonary bypass. Chest. 2005 Oct;128(4):2910-7. doi: 10.1378/chest.128.4.2910.
• Results McMullan DM, Bekker JM, Parry AJ, Johengen MJ, Kon A, Heidersbach RS, Black SM, Fineman JR. Alterations in endogenous nitric oxide production after cardiopulmonary bypass in lambs with normal and increased pulmonary blood flow. Circulation. 2000 Nov 7;102(19 Suppl 3):III172-8. doi: 10.1161/01.cir.102.suppl_3.iii-172.
• Results Seghaye MC, Duchateau J, Bruniaux J, Demontoux S, Detruit H, Bosson C, Lecronier G, Mokhfi E, Serraf A, Planche C. Endogenous nitric oxide production and atrial natriuretic peptide biological activity in infants undergoing cardiac operations. Crit Care Med. 1997 Jun;25(6):1063-70. doi: 10.1097/00003246-199706000-00026.
• Results Lamarche Y, Malo O, Thorin E, Denault A, Carrier M, Roy J, Perrault LP. Inhaled but not intravenous milrinone prevents pulmonary endothelial dysfunction after cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005 Jul;130(1):83-92. doi: 10.1016/j.jtcvs.2004.09.011.
• Results Lamarche Y, Perrault LP, Maltais S, Tetreault K, Lambert J, Denault AY. Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg. 2007 Jun;31(6):1081-7. doi: 10.1016/j.ejcts.2007.02.019. Epub 2007 Apr 2.
• Results Haddad F, Denault AY, Couture P, Cartier R, Pellerin M, Levesque S, Lambert J, Tardif JC. Right ventricular myocardial performance index predicts perioperative mortality or circulatory failure in high-risk valvular surgery. J Am Soc Echocardiogr. 2007 Sep;20(9):1065-72. doi: 10.1016/j.echo.2007.02.017. Epub 2007 Jun 12.
• Results Maslow AD, Regan MM, Panzica P, Heindel S, Mashikian J, Comunale ME. Precardiopulmonary bypass right ventricular function is associated with poor outcome after coronary artery bypass grafting in patients with severe left ventricular systolic dysfunction. Anesth Analg. 2002 Dec;95(6):1507-18, table of contents. doi: 10.1097/00000539-200212000-00009.
• Results Haddad F, Doyle R, Murphy DJ, Hunt SA. Right ventricular function in cardiovascular disease, part II: pathophysiology, clinical importance, and management of right ventricular failure. Circulation. 2008 Apr 1;117(13):1717-31. doi: 10.1161/CIRCULATIONAHA.107.653584. No abstract available.
• Results Denault AY, Tardif JC, Mazer CD, Lambert J; BART Investigators. Difficult and complex separation from cardiopulmonary bypass in high-risk cardiac surgical patients: a multicenter study. J Cardiothorac Vasc Anesth. 2012 Aug;26(4):608-16. doi: 10.1053/j.jvca.2012.03.031. Epub 2012 May 11.
• Results Hirani N, Brunner NW, Kapasi A, Chandy G, Rudski L, Paterson I, Langleben D, Mehta S, Mielniczuk L; CCS/CTS Pulmonary Hypertension Committee. Canadian Cardiovascular Society/Canadian Thoracic Society Position Statement on Pulmonary Hypertension. Can J Cardiol. 2020 Jul;36(7):977-992. doi: 10.1016/j.cjca.2019.11.041.
• Results Haj RM, Cinco JE, Mazer CD. Treatment of pulmonary hypertension with selective pulmonary vasodilators. Curr Opin Anaesthesiol. 2006 Feb;19(1):88-95. doi: 10.1097/01.aco.0000192765.27453.5a.
• Results Elmi-Sarabi M, Deschamps A, Delisle S, Ased H, Haddad F, Lamarche Y, Perrault LP, Lambert J, Turgeon AF, Denault AY. Aerosolized Vasodilators for the Treatment of Pulmonary Hypertension in Cardiac Surgical Patients: A Systematic Review and Meta-analysis. Anesth Analg. 2017 Aug;125(2):393-402. doi: 10.1213/ANE.0000000000002138.
• Results Green JB, Hart B, Cornett EM, Kaye AD, Salehi A, Fox CJ. Pulmonary Vasodilators and Anesthesia Considerations. Anesthesiol Clin. 2017 Jun;35(2):221-232. doi: 10.1016/j.anclin.2017.01.008. Epub 2017 Apr 14.
• Results Fox BD, Shtraichman O, Langleben D, Shimony A, Kramer MR. Combination Therapy for Pulmonary Arterial Hypertension: A Systematic Review and Meta-analysis. Can J Cardiol. 2016 Dec;32(12):1520-1530. doi: 10.1016/j.cjca.2016.03.004. Epub 2016 Mar 17.
• Results Hache M, Denault AY, Belisle S, Couture P, Babin D, Tetrault F, Guimond JG. Inhaled prostacyclin (PGI2) is an effective addition to the treatment of pulmonary hypertension and hypoxia in the operating room and intensive care unit. Can J Anaesth. 2001 Oct;48(9):924-9. doi: 10.1007/BF03017361.
• Results Hardy JF, Belisle S. Inotropic support of the heart that fails to successfully wean from cardiopulmonary bypass: the Montreal Heart Institute experience. J Cardiothorac Vasc Anesth. 1993 Aug;7(4 Suppl 2):33-9. doi: 10.1016/1053-0770(93)90095-3.
• Results Blaise G, Langleben D, Hubert B. Pulmonary arterial hypertension: pathophysiology and anesthetic approach. Anesthesiology. 2003 Dec;99(6):1415-32. doi: 10.1097/00000542-200312000-00027. No abstract available.
• Results Gaies MG, Gurney JG, Yen AH, Napoli ML, Gajarski RJ, Ohye RG, Charpie JR, Hirsch JC. Vasoactive-inotropic score as a predictor of morbidity and mortality in infants after cardiopulmonary bypass. Pediatr Crit Care Med. 2010 Mar;11(2):234-8. doi: 10.1097/PCC.0b013e3181b806fc.
• Results Shahian DM, O'Brien SM, Filardo G, Ferraris VA, Haan CK, Rich JB, Normand SL, DeLong ER, Shewan CM, Dokholyan RS, Peterson ED, Edwards FH, Anderson RP; Society of Thoracic Surgeons Quality Measurement Task Force. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: part 1--coronary artery bypass grafting surgery. Ann Thorac Surg. 2009 Jul;88(1 Suppl):S2-22. doi: 10.1016/j.athoracsur.2009.05.053.
• Results van Heerden PV, Gibbs NM, Michalopoulos N. Effect of low concentrations of prostacyclin on platelet function in vitro. Anaesth Intensive Care. 1997 Aug;25(4):343-6. doi: 10.1177/0310057X9702500402.

Drugs

Indications