Inhaled Milrinone Use in Patients Receiving HeartMate II LVAD: A Pilot Study

Study Overview
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Brief Summary
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Right ventricular (RV) failure occurs in an estimated 5-41% of cases involving left ventricular assist device (LVAD) implantation and has been shown to adversely affect peri-operative morbidity and mortality. Current therapies to improve RV dysfunction pre and post-operatively are limited. Inhaled milrinone has been shown in several small human studies to be safely tolerated and provide favorable effects on pulmonary hemodynamics. Study Hypothesis: Delivery of inhaled milrinone, a phosphodiesterase III inhibitor, may provide pulmonary artery vasodilation and therefore improved RV function in patients with end stage heart failure receiving HeartMate II LVAD as a bridge to cardiac transplantation or as destination therapy. Specifically, we aim to: demonstrate safety of inhaled milrinone in this patient cohort demonstrate efficacy of inhaled milrinone in this patient cohort

Detailed Description
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Right ventricular (RV) failure occurs in an estimated 5-41% of cases involving left ventricular assist device (LVAD) implantation and has been shown to adversely affect peri-operative morbidity and mortality. Current therapies to improve RV dysfunction pre and post-operatively are limited. Inhaled milrinone has been shown in several small human studies to be safely tolerated and provide favorable effects on pulmonary hemodynamics. Study Hypothesis: Delivery of inhaled milrinone, a phosphodiesterase III inhibitor, may provide pulmonary artery vasodilation and therefore improved RV function in patients with end stage heart failure receiving HeartMate II LVAD as a bridge to cardiac transplantation or as destination therapy. Specifically, the aims are: demonstrate safety of inhaled milrinone in this patient cohort demonstrate efficacy of inhaled milrinone in this patient cohort

Official Title
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Inhaled Milrinone Use in Patients Receiving HeartMate II LVAD: A Pilot Study

Conditions
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End Stage Heart Disease, Right Ventricular Dysfunction

Intervention / Treatment
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* Drug: Inhaled, nebulized, Milrinone
* Drug: inhaled nebulized milrinone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For BTT candidates: Must be an approved candidate for heart transplantation according to institutional policy For DT candidates: Patients with New York Heart Association (NYHA) class IV symptoms that have failed to respond to maximal medical therapy including beta blocker and angiotensin converting enzyme inhibitors if tolerated for at least 45 of 60 days, OR dependence on continuous inotropic therapy for 14 days OR dependence on intra-aortic balloon pump (IABP) for 7 days Left ventricular ejection fraction (LVEF) < 25% Patients with functional limitations on cardiopulmonary stress testing with a peak oxygen consumption of ≤ 14 ml/kg/min unless balloon pump or inotrope dependent or physically unable to perform the test. Patients not deemed to be a heart transplant candidate after evaluation Must have mean PAP > 25 mmHg by pulmonary catheter indices pre-operatively (within 72 hrs) and/or a PVR > 3 Woods units (WU). Age ≥ 19 years old (in the state of Nebraska, an individual must be ≥ 19 years old to legally provide consent as compared to age ≥ 18 in most other states) Signed informed consent Exclusion Criteria: Age < 19 years old Pregnancy or current breast feeding Undergoing cardiac transplantation without implantation of mechanical assist device Documented medical allergy to milrinone Failure to meet inclusion criteria for LVAD implantation for BTT or DT indications

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: inhaled nebulized Milrinone<br>Drug: Inhaled, nebulized, Milrinone 1 mg/ml milrinone (dissolved in dextrose) and diluted in 0.9% normal saline in a 1:1 ratio to final drug concentration of 0.5mg/ml will be delivered via an IV pump at a fixed dose of 12 ml/hour which will run into a vibrating mesh nebulizer reservoir, connected to the mechanical ventilator circuit. Inhaled milrinone will begin at time of resumption of mechanical ventilation when initiating wean from cardiopulmonary bypass after LVAD implantation in the operating room, and run continuously for a total maximum duration of 24 hours OR until the patient is extubated whichever occurs first. Plasma milrinone levels will be assessed to determine if systemic milrinone absorption occurs after prolonged milrinone inhalation. | Drug: Inhaled, nebulized, Milrinone<br>* 1 mg/ml milrinone (dissolved in dextrose) and diluted in 0.9% normal saline in a 1:1 ratio to final drug concentration of 0.5mg/ml will be delivered via an IV pump at a fixed dose of 12 ml/hour which will run into a vibrating mesh nebulizer reservoir, connected to the mechanical ventilator circuit. Inhaled milrinone will begin at time of resumption of mechanical ventilation when initiating wean from cardiopulmonary bypass after LVAD implantation in the operating room, and run continuously for a total maximum duration of 24 hours OR until the patient is extubated whichever occurs first. Plasma milrinone levels will be assessed to determine if systemic milrinone absorption occurs after prolonged milrinone inhalation.<br>* Other names: Primacor;Drug: inhaled nebulized milrinone<br>* 0.5 mg/ml inhaled nebulized milrinone deliver at 12 ml/hr continuously until either 24 hours or extubated.<br>* Other names: Primacor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Incidence of Arrhythmias, Hypotension and Hypersensitivity Reaction | Arrhythmias: Atrial Ventricular 'Sustained' hypotension Hypersensitivity reaction to milrinone | 12 and 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy - Hemodynamic | Invasive Hemodynamic pulmonary catheter: PAS, PAD, mPAP, RA pressures, PCWP, CI, RVSWi (calculated), TPG, PVR, and SvO2 | 30, 60 minutes, then every 4 hours thereafter | 
| Efficacy - Echocardiographic | Echocardiographic RV dimensions RV systolic functional assessment Tricuspid valve regurgitation Pulmonary Vascular resistance | Pre-op Echocardiography, intraoperative TEE (before and after inhaled milrinone) and postoperative Echocardiography within 48 hours of milrinone initiation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mechanical circulatory assist device