Right Heart FailurePhase 2MILANNCT05450328
Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation
A Phase 2 study testing Combined Epoprostenol Sodium & Milrinone and Normal saline in people with Right Heart Failure and Right Ventricular Dysfunction, run by Montreal Heart Institute at 1 site in Canada.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Right Heart Failure, Right Ventricular Dysfunction
- What is being tested?
- Combined Epoprostenol Sodium & Milrinone and Normal saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 141 participants
- Where
- 1 siteCanada
- Study dates
- 10 Dec 2025to 1 Dec 2028
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Only patients undergoing cardiac surgery with CPB and aged 18 years and older will be included in this study.
Who cannot join
- The presence of congenital cardiomyopathy, which the correction is the primary objective of the proposed surgery. For example, a patient who requires surgery for atrial septal defect closure only would not be eligible for the study. On the other hand, a patient who undergoes this same surgery in addition to a valve replacement, for example, would be eligible to participate in the study.
- Heart transplant or ventricular assist device surgery
- Urgent surgery including hemodynamic instability requiring vasopressor agents upon arrival in the operating room
- A contraindication to transesophageal ultrasound monitoring or the presence of an unstable cervical spine.
- Presence of a contraindication related to Epoprostenol or Milrinone administration such as a documented left ventricular or right ventricular outflow tract obstruction, a severe unaddressed aortic stenosis, or a documented allergy to either of these two molecules.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Canada1 site, 1 recruiting
- Recruiting
Montreal Heart Institute
Montreal, Quebec, H1T 1C8
Leah Elisheva Soto, PhD (c), 4385304636, leah.elisheva.soto@umontreal.ca
Abir Attia, Msc, 5143763330 ext. 2385, abir.attia@icm-mhi.org
About this study
Official title: Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation: A Randomized, Double-blind, Controlled Trial
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.
Read the detailed description
Hypothesis: Based on the knowledge gained from previous work, the administration of inhaled Milrinone and Epoprostenol therapy prior to the initiation of cardiopulmonary bypass (CPB) is superior in terms of favourable clinical outcomes. The combined administration of these agents improves right ventricular performance while reducing myocardial and pulmonary ischemia-reperfusion injury secondary to weaning from bypass surgery. For these reasons, we hypothesize that administration of combination therapy before the start of CPB may provide better hemodynamic stability throughout the surgery and favourable postoperative clinical outcomes.
Objective:
Primary Objective To determine whether the use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB, decreases the occurrence of difficult CPB weaning compared to placebo administration.
Secondary Objectives To determine the effect of combined use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB on hemodynamic and perioperative parameters.
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on postoperative clinical outcomes.
Design: The proposed study is a randomized, double-blind, controlled trial to determine the efficacy of the combined use of inhaled Epoprostenol and Milrinone prior to the initiation of CPB compared with the use of a placebo in a cardiac surgery setting. The clinical outcome of interest is the incidence of a difficult weaning from CPB. A difficult weaning is defined as the use of an inotrope with or without a vasopressor agent or the use of mechanical circulatory support or a return on CPB for hemodynamic reasons.
Patients/Participants:
Inclusion Criteria Only patients undergoing cardiac surgery with CPB and aged 18 years and older will be included in this study.
Interventions:
We will randomly assign the 142 patients in a 1:1 allocation scheme to receive a combination of inhaled Epoprostenol and Milrinone or a placebo after induction of general anesthesia, i.e. before CPB initiation. Free and informed consent to participate in this research project will be obtained the day before surgery by the anesthesiologist in charge of the case or by a member of the research team.
In both study groups, the anesthetic procedure will be performed according to Canadian practice standards and is left to the discretion of the clinician. In both groups, the procedure will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions.
The experimental group will receive simultaneously 4mg of Milrinone (1mg/mL, 4mL) and 60 mcg of Epoprostenol (15 mcg/mL, 4mL) before CPB initiation. The control group will receive a saline solution (8mL) as a placebo, before CPB start. For each patient, 2 syringes of 4mL will be prepared on the morning of surgery, depending on the allocation group, to ensure drug stability. For example, for patients in the experimental group, one syringe containing 4mg of milrinone (1mg/mL, 4mL) and one syringe containing 60 mcg of epoprostenol (15 mcg/mL, 4mL) will be prepared. For the control group, two syringes containing 4mL of 0.9% physiological saline will be prepared.
Expected outcomes:
The administration of this combination therapy prior to the start CPB may decrease the proportion of patients presenting a difficult CPB weaning, in addition to better hemodynamic stability during surgery. Also, we believe that patients who have received the combined therapy will have favourable postoperative clinical outcomes, such as less vasoactive and inotropic agents and a reduction in the duration of postoperative organ dysfunction.
This randomized, double-blind, multicenter, controlled clinical trial will evaluate the clinical efficacy of the combination of inhaled agents in cardiac surgery setting intraoperatively and postoperatively. 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 right ventricular dysfunction.
- Conditions
- Right Heart Failure, Right Ventricular Dysfunction
- Being tested
- Combined Epoprostenol Sodium & Milrinone, Normal saline
- Keywords
- Cardiac Surgery, Right Ventricular Dysfunction, Cardiopulmonary Bypass, Inhaled Therapy
- Medical subject headings
- Heart Failure, Ventricular Dysfunction, Right
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Combined Epoprostenol Sodium & MilrinoneDrug
One syringe containing 4mg of milrinone (1mg/mL, 4mL) and one syringe containing 60 mcg of epoprostenol (15 mcg/mL, 4mL).
The drugs will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions.
Normal salineDrug
The control group will receive two syringes of 4mL of Normal Saline, before CPB start.
The placebo will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions.
| Study group | Role | What they receive |
|---|---|---|
| Normal Saline | Placebo comparator | The control group will receive a saline solution (8mL) as a placebo, before CPB start. Receives: Drug: Normal saline |
| Combination of inhaled Epoprostenol and Milrinone | Active comparator | The experimental group will receive simultaneously 4mg of Milrinone (1mg/mL, 4mL) and 60 mcg of Epoprostenol (15 mcg/mL, 4mL) before CPB initiation. Receives: Drug: Combined Epoprostenol Sodium & Milrinone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients who have a difficult CPB weaning in both groups
To determine whether the use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB, decreases the occurrence of difficult CPB weaning compared to placebo administration.
Measured: 1 year
Secondary outcomes (14)
Correlation between the variation of central venous pressure and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB on central venous pressure.
Measured: 1 year
Correlation between the variation of cardiac output and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on cardiac output.
Measured: 1 year
Correlation between the variation of arterial pressure and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on arterial pressure.
Measured: 1 year
Correlation between the right ventricular curve etiology (normal, square root, oblique) and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on right ventricular curve etiology.
Measured: 1 year
Correlation between the PAM/ PAPM ratio taken at T0 and T1 and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on PAM/PAPM ratio.
Measured: 1 year
Correlation between the cardiac index taken at T0 and T1 and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on cardiac index.
Measured: 1 year
Correlation between right ventricular contractility and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on the dp/dt calculated from the right ventricular waveform.
Measured: 1 year
Correlation between right ventricular outflow tract obstruction and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on right ventricular systolic pressure and systolic pulmonary artery pressure variation.
Measured: 1 year
Correlation between cerebral saturation and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on the cerebral saturation quantified by the near infrared spectroscopy.
Measured: 1 year
Correlation between fluid administration during surgery and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on fluid administration during surgery such as crystalloid, colloid and blood transfusion.
Measured: 1 year
Correlation between the vasoactive and inotropic score and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on the vasoactive and inotropic score quantified on the patient arrival in the ICU.
Measured: 1 year
Correlation between the time of persistent organ dysfunction (TPOD) and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on the TPOD.
Measured: 1 year
Correlation between the ICU stay and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on the ICU stay.
Measured: 1 year
Correlation between the post-operative complications and patients who received the treatment
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on post-operative complications defined by the Society of Thoracic Surgeons and patients who received the treatment.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jul 2022
- Study start10 Dec 2025
- Primary completion1 May 2028 (estimated)
- Study completion1 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (23)Papers the sponsor has linked to this study.
- Other trials for Right Heart FailureStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 141 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Montreal Heart Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- André Denault, MD, PhD, Principal investigator, Montreal Heart Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05450328
- Sponsor's protocol ID
- ICM 2022-3026
- Acronym
- MILAN
- Status last verified
- Jun 2026
- First submitted
- 16 May 2022
- Last updated
- 25 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 27470232Davila-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.
PubMed 7574953Authors/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.
PubMed 31585674El 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.
PubMed 16236968McMullan 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.
PubMed 11082382Seghaye 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.
PubMed 9201062Lamarche 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.
PubMed 15999045Lamarche 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.
PubMed 17400468Haddad 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.
PubMed 17566702Maslow 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.
PubMed 12456409Haddad 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.
PubMed 18378625Denault 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.
PubMed 22578975Hirani 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.
PubMed 32682511Haj 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.
PubMed 16547439Elmi-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.
PubMed 28598920
Study at a glance
From the registry record, last updated by the sponsor on 25 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation: A Randomized, Double-blind, Controlled Trial
- ClinicalTrials.gov ID
- NCT05450328
- Acronym / sponsor ID
- MILAN / ICM 2022-3026
- Conditions
- Right Heart Failure, Right Ventricular Dysfunction
- Keywords
- Cardiac Surgery, Right Ventricular Dysfunction, Cardiopulmonary Bypass, Inhaled Therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 141 participants (estimated)
- Lead sponsor
- Montreal Heart InstituteUniversity, hospital or other
- Study start
- 10 Dec 2025 (actual)
- Primary completion
- 1 May 2028 (estimated)
- Study completion
- 1 Dec 2028 (estimated)
- First posted
- 8 Jul 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
Hypothesis: Based on the knowledge gained from previous work, the administration of inhaled Milrinone and Epoprostenol therapy prior to the initiation of cardiopulmonary bypass (CPB) is superior in terms of favourable clinical outcomes. The combined administration of these agents improves right ventricular performance while reducing myocardial and pulmonary ischemia-reperfusion injury secondary to weaning from bypass surgery. For these reasons, we hypothesize that administration of combination therapy before the start of CPB may provide better hemodynamic stability throughout the surgery and favourable postoperative clinical outcomes.
Objective:
Primary Objective To determine whether the use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB, decreases the occurrence of difficult CPB weaning compared to placebo administration.
Secondary Objectives To determine the effect of combined use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB on hemodynamic and perioperative parameters.
To determine the effect of combined use of inhaled Epoprostenol and milrinone, prior to the initiation of CPB on postoperative clinical outcomes.
Design: The proposed study is a randomized, double-blind, controlled trial to determine the efficacy of the combined use of inhaled Epoprostenol and Milrinone prior to the initiation of CPB compared with the use of a placebo in a cardiac surgery setting. The clinical outcome of interest is the incidence of a difficult weaning from CPB. A difficult weaning is defined as the use of an inotrope with or without a vasopressor agent or the use of mechanical circulatory support or a return on CPB for hemodynamic reasons.
Patients/Participants:
Inclusion Criteria Only patients undergoing cardiac surgery with CPB and aged 18 years and older will be included in this study.
Interventions:
We will randomly assign the 142 patients in a 1:1 allocation scheme to receive a combination of inhaled Epoprostenol and Milrinone or a placebo after induction of general anesthesia, i.e. before CPB initiation. Free and informed consent to participate in this research project will be obtained the day before surgery by the anesthesiologist in charge of the case or by a member of the research team.
In both study groups, the anesthetic procedure will be performed according to Canadian practice standards and is left to the discretion of the clinician. In both groups, the procedure will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions.
The experimental group will receive simultaneously 4mg of Milrinone (1mg/mL, 4mL) and 60 mcg of Epoprostenol (15 mcg/mL, 4mL) before CPB initiation. The control group will receive a saline solution (8mL) as a placebo, before CPB start. For each patient, 2 syringes of 4mL will be prepared on the morning of surgery, depending on the allocation group, to ensure drug stability. For example, for patients in the experimental group, one syringe containing 4mg of milrinone (1mg/mL, 4mL) and one syringe containing 60 mcg of epoprostenol (15 mcg/mL, 4mL) will be prepared. For the control group, two syringes containing 4mL of 0.9% physiological saline will be prepared.
Expected outcomes:
The administration of this combination therapy prior to the start CPB may decrease the proportion of patients presenting a difficult CPB weaning, in addition to better hemodynamic stability during surgery. Also, we believe that patients who have received the combined therapy will have favourable postoperative clinical outcomes, such as less vasoactive and inotropic agents and a reduction in the duration of postoperative organ dysfunction.
This randomized, double-blind, multicenter, controlled clinical trial will evaluate the clinical efficacy of the combination of inhaled agents in cardiac surgery setting intraoperatively and postoperatively. 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 right ventricular dysfunction.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Normal Saline | Placebo comparator | Drug: Normal salineThe control group will receive a saline solution (8mL) as a placebo, before CPB start. |
| Combination of inhaled Epoprostenol and Milrinone | Active comparator | Drug: Combined Epoprostenol Sodium & MilrinoneThe experimental group will receive simultaneously 4mg of Milrinone (1mg/mL, 4mL) and 60 mcg of Epoprostenol (15 mcg/mL, 4mL) before CPB initiation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Only patients undergoing cardiac surgery with CPB and aged 18 years and older will be included in this study.
Key exclusion criteria (5 listed)
- The presence of congenital cardiomyopathy, which the correction is the primary objective of the proposed surgery. For example, a patient who requires surgery for atrial septal defect closure only would not be eligible for the study. On the other hand, a patient who undergoes this same surgery in addition to a valve replacement, for example, would be eligible to participate in the study.
- Heart transplant or ventricular assist device surgery
- Urgent surgery including hemodynamic instability requiring vasopressor agents upon arrival in the operating room
- A contraindication to transesophageal ultrasound monitoring or the presence of an unstable cervical spine.
- Presence of a contraindication related to Epoprostenol or Milrinone administration such as a documented left ventricular or right ventricular outflow tract obstruction, a severe unaddressed aortic stenosis, or a documented allergy to either of these two molecules.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Combined Epoprostenol Sodium & MilrinoneOne syringe containing 4mg of milrinone (1mg/mL, 4mL) and one syringe containing 60 mcg of epoprostenol (15 mcg/mL, 4mL). The drugs will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions. | Drug | Combination of inhaled Epoprostenol and Milrinone |
| Normal salineThe control group will receive two syringes of 4mL of Normal Saline, before CPB start. The placebo will be administered via an ultrasonic nebulizer (Aeroneb Professional Nebulizer System, Aerogen Ltd, Galway, Ireland, registration number: 66728) over a period of 20 minutes. This type of nebulizer is used routinely at the Montreal Heart Institute and can hold a maximum of 8 mL of solutions. | Drug | Normal Saline |
Primary outcome
Proportion of patients who have a difficult CPB weaning in both groups
Time frame: 1 year
To determine whether the use of inhaled Epoprostenol and Milrinone, prior to the initiation of CPB, decreases the occurrence of difficult CPB weaning compared to placebo administration.
14 secondary outcomes
Correlation between the variation of central venous pressure and patients who received the treatment
Time frame: 1 year
Correlation between the variation of cardiac output and patients who received the treatment
Time frame: 1 year
Correlation between the variation of arterial pressure and patients who received the treatment
Time frame: 1 year
Correlation between the right ventricular curve etiology (normal, square root, oblique) and patients who received the treatment
Time frame: 1 year
Correlation between the PAM/ PAPM ratio taken at T0 and T1 and patients who received the treatment
Time frame: 1 year
Correlation between the cardiac index taken at T0 and T1 and patients who received the treatment
Time frame: 1 year
Correlation between right ventricular contractility and patients who received the treatment
Time frame: 1 year
Correlation between right ventricular outflow tract obstruction and patients who received the treatment
Time frame: 1 year
Correlation between cerebral saturation and patients who received the treatment
Time frame: 1 year
Correlation between fluid administration during surgery and patients who received the treatment
Time frame: 1 year
Correlation between the vasoactive and inotropic score and patients who received the treatment
Time frame: 1 year
Correlation between the time of persistent organ dysfunction (TPOD) and patients who received the treatment
Time frame: 1 year
Correlation between the ICU stay and patients who received the treatment
Time frame: 1 year
Correlation between the post-operative complications and patients who received the treatment
Time frame: 1 year
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Jun 2026.
- Background: PubMed 27470232Denault 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 publication: PubMed 7574953Davila-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 publication: PubMed 31585674Authors/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 publication: PubMed 16236968El 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 publication: PubMed 11082382McMullan 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 publication: PubMed 9201062Seghaye 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 publication: PubMed 15999045Lamarche 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 publication: PubMed 17400468Lamarche 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 publication: PubMed 17566702Haddad 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 publication: PubMed 12456409Maslow 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 publication: PubMed 18378625Haddad 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 publication: PubMed 22578975Denault 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
André Denault, MD, PhD principal investigator
Montreal Heart Institute
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Combined Epoprostenol Sodium & Milrinone and Normal saline in people with Right Heart Failure and Right Ventricular Dysfunction, run by Montreal Heart Institute at 1 site in Canada.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 25 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Stephanie Jarry, PhD (c) (5149289258, stephanie.jarry.1@umontreal.ca), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients who have a difficult CPB weaning in both groups (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05450328, which also lists 23 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Jun 2026.