Milrinone Inhaled in Cardiac Surgery - Full Text View

Purpose

Pulmonary hypertension is an important morbidity factor in patients having to undergo cardiac surgery with cardiopulmonary bypass (ECC). Milrinone used in inhalation, shows evidence of being a pulmonary vasodilator able to possibly contribute to the reduction of pressure on the pulmonary artery.

Condition	Intervention	Phase
Valvular Stenosis Valvular Insufficiency Hypertension, Pulmonary Coronary Artery Disease	Drug: Milrinone Drug: Normal saline	Phase 2


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	2- Inhaled Milrinone Prevents the Increase in Pulmonary Artery Pressure After CPB

Resource links provided by NLM:

MedlinePlus related topics: Heart Surgery Pulmonary Hypertension

Drug Information available for: Milrinone Milrinone lactate

U.S. FDA Resources

Further study details as provided by Montreal Heart Institute:

Primary Outcome Measures:

To demonstrate that inhaled milrinone administered before CPB is superior to placebo in reducing the severity of difficult separation from bypass [ Time Frame: End of CPB ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Reduction in morbidity and mortality post-op [ Time Frame: At discharge, 3 months, 6 months and 1 year by telephone ] [ Designated as safety issue: Yes ]
Reduction in pulmonary artery pressure [ Time Frame: Same day before and after CPB ] [ Designated as safety issue: Yes ]
Right ventricular function measured using transthoracic echocardiography (TTE) and TEE [ Time Frame: Same day before and after the CPB ] [ Designated as safety issue: Yes ]
Serum levels of milrinone in relation with the pharmacodynamic marker [ Time Frame: Same day pre CPB per CPB and post CPB ] [ Designated as safety issue: Yes ]
reduction of the composite index of hemodynamic complications (defined as hospital death, vasoactive drugs > 24 hours and post-op cardiac arrest), [ Time Frame: 24 hrs post op and hospital discharge ] [ Designated as safety issue: Yes ]


Estimated Enrollment:	124
Study Start Date:	February 2009
Study Completion Date:	December 2012
Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: Normal saline Normal saline by inhalation over 15 min	Drug: Normal saline 5 ml normal saline by inhalation over 15 min Other Names: Placebo Comparator
Active Comparator: Milrinone Inhaled milrinone 5 mg(as for the injectable solution)	Drug: Milrinone inhaled milrinone 5 mg (as for the injectable solution) Other Names: Milrinone Cardiac Surgery Milrinone inhaled Inhaled milrinone reduces pulmonary artery pressure

Detailed Description:

This controlled, randomized, double-blind study will aim at confirming the efficiency as well as the security of Milrinone, used in inhalation, to diminish the degree of pulmonary hypertension before the cardiopulmonary bypass (ECC) circulation. In addition, the pharmacokinetic and echo graphic repercussions of administering the medication will be analysed. At the present time, there is no data on the pharmacokinetics of the medication when it's administered through inhalation. For this reason, we would like to study the serous rate of the medication in the minutes following its administration through inhalation.

Eligibility


Ages Eligible for Study:	18 Years to 90 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Adult patients scheduled for elective valvular or complex (2 or more valves or
valve and revascularization) cardiac surgery under CPB with preoperative PHT defined as mean pulmonary artery pressure (MPAP) over 30 mmHg or
systolic pulmonary artery pressure (SPAP) over 40 mmHg (using preoperative right-sided catheterization or estimated by echocardiography).

Exclusion Criteria:

Cardiac surgery not requiring CPB, contraindication to TEE (esophageal pathology or unstable cervical spine) and emergency surgery.
Patients will be recruited the day before surgery and randomized using computerized cards by the pharmacy department

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00819377

Locations


Canada, Quebec
Montreal Heart Institute
Montreal, Quebec, Canada, H1T 1C8

Sponsors and Collaborators

Andre Denault

Heart and stoke fondation of Quebec

Organon

Canadian Anesthesiologists' Society

Investigators


Principal Investigator:	Denault André, MD FRCPC	Montreal Heart Institute

More Information

Publications:

Baim DS, McDowell AV, Cherniles J, Monrad ES, Parker JA, Edelson J, Braunwald E, Grossman W. Evaluation of a new bipyridine inotropic agent--milrinone--in patients with severe congestive heart failure. N Engl J Med. 1983 Sep 29;309(13):748-56.

Denault AY, Lamarche Y, Couture P, Haddad F, Lambert J, Tardif JC, Perrault LP. Inhaled milrinone: a new alternative in cardiac surgery? Semin Cardiothorac Vasc Anesth. 2006 Dec;10(4):346-60. Review.

Omae T, Kakihana Y, Mastunaga A, Tsuneyoshi I, Kawasaki K, Kanmura Y, Sakata R. Hemodynamic changes during off-pump coronary artery bypass anastomosis in patients with coexisting mitral regurgitation: improvement with milrinone. Anesth Analg. 2005 Jul;101(1):2-8, table of contents.

Kikura M, Levy JH, Michelsen LG, Shanewise JS, Bailey JM, Sadel SM, Szlam F. The effect of milrinone on hemodynamics and left ventricular function after emergence from cardiopulmonary bypass. Anesth Analg. 1997 Jul;85(1):16-22.

Lobato EB, Florete O Jr, Bingham HL. A single dose of milrinone facilitates separation from cardiopulmonary bypass in patients with pre-existing left ventricular dysfunction. Br J Anaesth. 1998 Nov;81(5):782-4.

Iwagaki T, Irie J, Ijichi K, Uratsuji Y. [The effects of milrinone on hemodynamics in patients undergoing cardiac surgery]. Masui. 2001 Apr;50(4):360-4. Japanese.

Shibata T, Suehiro S, Sasaki Y, Hosono M, Nishi S, Kinoshita H. Slow induction of milrinone after coronary artery bypass grafting. Ann Thorac Cardiovasc Surg. 2001 Feb;7(1):23-7.

Kim JH, Ham BM, Kim YL, Bahk JH, Ryu HG, Jeon YS, Kim KB. Prophylactic milrinone during OPCAB of posterior vessels: implication in angina patients taking beta-blockers. Eur J Cardiothorac Surg. 2003 Nov;24(5):770-6.

Hoffman TM, Wernovsky G, Atz AM, Kulik TJ, Nelson DP, Chang AC, Bailey JM, Akbary A, Kocsis JF, Kaczmarek R, Spray TL, Wessel DL. Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease. Circulation. 2003 Feb 25;107(7):996-1002.

Maslow AD, Regan MM, Schwartz C, Bert A, Singh A. Inotropes improve right heart function in patients undergoing aortic valve replacement for aortic stenosis. Anesth Analg. 2004 Apr;98(4):891-902, table of contents.

Doolan LA, Jones EF, Kalman J, Buxton BF, Tonkin AM. A placebo-controlled trial verifying the efficacy of milrinone in weaning high-risk patients from cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 1997 Feb;11(1):37-41.

Yamada T, Takeda J, Katori N, Tsuzaki K, Ochiai R. Hemodynamic effects of milrinone during weaning from cardiopulmonary bypass: comparison of patients with a low and high prebypass cardiac index. J Cardiothorac Vasc Anesth. 2000 Aug;14(4):367-73.

Solina A, Papp D, Ginsberg S, Krause T, Grubb W, Scholz P, Pena LL, Cody R. A comparison of inhaled nitric oxide and milrinone for the treatment of pulmonary hypertension in adult cardiac surgery patients. J Cardiothorac Vasc Anesth. 2000 Feb;14(1):12-7.

Denault AY, Chaput M, Couture P, Hébert Y, Haddad F, Tardif JC. Dynamic right ventricular outflow tract obstruction in cardiac surgery. J Thorac Cardiovasc Surg. 2006 Jul;132(1):43-9.

Couture P, Denault AY, Pellerin M, Tardif JC. Milrinone enhances systolic, but not diastolic function during coronary artery bypass grafting surgery. Can J Anaesth. 2007 Jul;54(7):509-22.

Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991 Nov 21;325(21):1468-75.

Cuffe MS, Califf RM, Adams KF Jr, Benza R, Bourge R, Colucci WS, Massie BM, O'Connor CM, Pina I, Quigg R, Silver MA, Gheorghiade M; Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA. 2002 Mar 27;287(12):1541-7.

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.

Haraldsson s A, Kieler-Jensen N, Ricksten SE. The additive pulmonary vasodilatory effects of inhaled prostacyclin and inhaled milrinone in postcardiac surgical patients with pulmonary hypertension. Anesth Analg. 2001 Dec;93(6):1439-45, table of contents.

Sablotzki A, Starzmann W, Scheubel R, Grond S, Czeslick EG. Selective pulmonary vasodilation with inhaled aerosolized milrinone in heart transplant candidates. Can J Anaesth. 2005 Dec;52(10):1076-82.

Bernstein AD, Parsonnet V. Bedside estimation of risk as an aid for decision-making in cardiac surgery. Ann Thorac Surg. 2000 Mar;69(3):823-8.

Lamarche Y, Perrault LP, Maltais S, Tétreault K, Lambert J, Denault AY. Preliminary experience with inhaled milrinone in cardiac surgery. Eur J Cardiothorac Surg. 2007 Jun;31(6):1081-7. Epub 2007 Apr 2.

Robitaille A, Denault AY, Couture P, Bélisle S, Fortier A, Guertin MC, Carrier M, Martineau R. Importance of relative pulmonary hypertension in cardiac surgery: the mean systemic-to-pulmonary artery pressure ratio. J Cardiothorac Vasc Anesth. 2006 Jun;20(3):331-9. Epub 2006 Apr 19.

Lindsay CA, Barton P, Lawless S, Kitchen L, Zorka A, Garcia J, Kouatli A, Giroir B. Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock. J Pediatr. 1998 Feb;132(2):329-34.

Oddie CJ, Jackman GP, Bobik A. Analysis of milrinone in plasma using solid-phase extraction and high-performance liquid chromatography. J Chromatogr. 1986 Jan 10;374(1):209-14.

Hudson RJ, Thomson IR, Jassal R. Effects of cardiopulmonary bypass on sufentanil pharmacokinetics in patients undergoing coronary artery bypass surgery. Anesthesiology. 2004 Oct;101(4):862-71.

Fiset P, Mathers L, Engstrom R, Fitzgerald D, Brand SC, Hsu F, Shafer SL. Pharmacokinetics of computer-controlled alfentanil administration in children undergoing cardiac surgery. Anesthesiology. 1995 Nov;83(5):944-55.


Responsible Party:	Andre Denault, MD FRCPC ABIM-CCM, Montreal Heart Institute
ClinicalTrials.gov Identifier:	NCT00819377 History of Changes
Other Study ID Numbers:	08-1004
Study First Received:	January 8, 2009
Last Updated:	October 23, 2013
Health Authority:	Canada: Ethics Review Committee

Keywords provided by Montreal Heart Institute:


Valvular surgery pulmonary artery pressure

Additional relevant MeSH terms:


Coronary Artery Disease Myocardial Ischemia Coronary Disease Hypertension, Pulmonary Heart Diseases Cardiovascular Diseases Arteriosclerosis Arterial Occlusive Diseases Vascular Diseases Lung Diseases Respiratory Tract Diseases	Milrinone Cardiotonic Agents Platelet Aggregation Inhibitors Vasodilator Agents Phosphodiesterase 3 Inhibitors Phosphodiesterase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Protective Agents Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 23, 2016