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

Study Overview
=================
Brief 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.

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.

Official Title
-----------------
Inhaled Milrinone and Epoprostenol for the Prevention of Difficult Cardiac Pulmonary Bypass Separation: A Randomized, Double-blind, Controlled Trial

Conditions
-----------------
Right Heart Failure, Right Ventricular Dysfunction

Intervention / Treatment
-----------------
* Drug: Combined Epoprostenol Sodium & Milrinone
* Drug: Normal saline


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: - Only patients undergoing cardiac surgery with CPB and aged 18 years and older will be included in this study. Exclusion Criteria: 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Normal Saline<br>The control group will receive a saline solution (8mL) as a placebo, before CPB start. | Drug: Normal saline<br>* 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.<br>|
| Active Comparator: Combination of inhaled Epoprostenol and Milrinone<br>The experimental group will receive simultaneously 4mg of Milrinone (1mg/mL, 4mL) and 60 mcg of Epoprostenol (15 mcg/mL, 4mL) before CPB initiation. | Drug: Combined Epoprostenol Sodium & Milrinone<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiac Surgery, Right Ventricular Dysfunction, Cardiopulmonary Bypass, Inhaled Therapy