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

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

Study Overview

• Status: Completed
• Conditions: Right Ventricular Dysfunction; End Stage Heart Disease
• Intervention / Treatment: Drug: Inhaled, nebulized, Milrinone; Drug: inhaled nebulized milrinone

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Nebraska
    • Omaha, Nebraska, United States, 68198-2265
      • University of Nebraska Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. For BTT candidates:

   • Must be an approved candidate for heart transplantation according to institutional policy

2. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: inhaled nebulized Milrinone; 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; 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.; Other Names: Primacor; Drug: inhaled nebulized milrinone; 0.5 mg/ml inhaled nebulized milrinone deliver at 12 ml/hr continuously until either 24 hours or extubated.; Other Names: Primacor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence of Arrhythmias, Hypotension and Hypersensitivity Reaction	Arrhythmias:AtrialVentricular; '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

Collaborators and Investigators

• Sponsor: University of Nebraska
• Collaborators: Thoratec Corporation
• Investigators: Principal Investigator: Nicholas A Haglund, MD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): April 5, 2012
• Primary Completion (Actual): February 1, 2013
• Study Completion (Actual): February 21, 2014

Study Registration Dates

• First Submitted: May 6, 2011
• First Submitted That Met QC Criteria: April 2, 2012
• First Posted (Estimated): April 4, 2012

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 30, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: mechanical circulatory assist device
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Ventricular Dysfunction; Ventricular Dysfunction, Right; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: 0195-11-FB