Inhaled Versus Intravenous Milrinone for Patients Undergoing Mitral Valve Replacement Surgery

This prospective open-label randomized study aims to compare the effect of inhaled versus intravenous milrinone on the pulmonary vascular resistance in patients undergoing mitral valve replacement surgery.

The primary outcome is to determine change in pulmonary artery pressure. The secondary outcomes include,

• Incidence of systemic hypotension.
• Hemodynamic affection and need of vasopressors and inotropes.
• Change in pulmonary vascular resistance versus systemic vascular resistance.
• Right ventricular function.
• Duration of mechanical ventilation.
• Need for mechanical circulatory support devices.
• Urine output
• Length of intensive care (ICU) in stay.

As the investigators hypothesize that inhaled milrinone has a selective pulmonary vasodilator effect devoid of the systemic hypotension with the intravenous administration.

Study Overview

• Status: Completed
• Conditions: Pulmonary Hypertension; Mitral Valve Replacement; Inhaled Milrinone; Intravenous Milrinone
• Intervention / Treatment: Drug: Inhaled Milrinone; Drug: IV Milrinone

Detailed Description

All patients underwent standard preoperative cardiac surgery assessment. Premedication included bromazepam and ranitidine, given the night before and 2 hours prior to arrival to OT. On arrival, IV access and arterial cannula were inserted under local anesthesia, along with routine monitoring electrocardiogram (ECG), pulse oximetery (SpO2), and IBP.

Anesthesia was induced with midazolam, fentanyl, and cis-atracurium. After tracheal intubation, ultrasound (US) guided- central venous catheter (CVC) was inserted and TEE also applied and then anesthesia maintained with morphine, cis-atracurium infusions, and sevoflurane. Mechanical ventilation was set to maintain end-tidal carbon dioxide (etco2) in the range of 30-40 mmHg using lung protective ventilation strategies.

During CPB, flow of 2.2 L.min-1.m-2, a custodiol cardioplegia was given, temperature kept at 28-32℃ and anesthesia maintained by sevoflurane- through a vaporizer mounted on CPB machine-.

A senior consultant certified cardiac anesthetist conducted a baseline TEE using Philips EPIQ CVxi echocardiography machine. Baseline measures included left ventricular ejection fraction (LVEF), and RV function represented by tricuspid annulus plane systolic excursion (TAPSE), fractional area changes (FAC), and right ventricular systolic pressure (RVSP) by doppler also, PVR and systemic vascular resistance (SVR) was calculated, plus patients hemodynamics (mean arterial blood pressure (MAP), heart rate (HR)), all measures were recorded.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Egypt
  • Menoufia
    • Shibīn Al Kawm, Menoufia, Egypt
      • Menoufia University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Severe mitral regurgitation and moderate or severe pulmonary hypertension

• Scheduled for mitral valve replacement surgery

  # Criteria of severe mitral regurgitation:

• Central jet MR >40% LA or holosystolic eccentric jet MR
• Vena contracta ≥ 0.7 cm
• Regurgitant volume ≥60 ml
• Regurgitant fraction ≥50%

• EROA ≥0.40 cm2

  # Criteria of moderate and severe pulmonary hypertension:

• Moderate pulmonary hypertension; mean pulmonary artery pressure > 41 mmHg while, severe pulmonary hypertension; mean pulmonary artery pressure > 55 mmHg
• Mean pulmonary artery pressure > 40% of mean systemic blood pressure.
• Mean pulmonary artery pressure approximated from estimated systolic pulmonary artery pressure as following; mPAP= (estimated sPAP X 0.61) ± 2

Exclusion Criteria:

• Patients with aortic valvular lesions or pulmonary stenosis.
• Hemodynamic instability in the preoperative time (defined as acute requirement for vasoactive support or mechanical device).
• Contraindication to transesophageal echocardiography; esophageal stricture, tumor or diverticulum or active upper gastrointestinal bleeding
• Patients with hepatic or renal dysfunction.
• Patients with coagulopathy.
• Emergency surgeries.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A (iMil); Patients will receive 2 doses of inhaled milrinone at the following time points (after sternotomy and after aortic cross clamp off) at dosage of 50 mcg/kg by nebulization, inhaled milrinone will be administered through Aerogen solo with Pro-X controller - continuous mode- attached to ventilator circuit distal to viral/ bacterial heat and moisture exchange filter. Then pulmonary vascular resistance and systemic vascular resistance will be calculated after first dose ended by 2 minutes and after second dose ended by 15 minutes till stabilization of post CPB other variables like temperature and acid-base status, both measurements will be done while using inspired oxygen of 0.80.	Drug: Inhaled Milrinone; Patients will receive 2 doses of inhaled milrinone at the following time points (after sternotomy and after aortic cross clamp off) at dosage of 50 mcg/kg by nebulization, inhaled milrinone will be administered through Aerogen solo with Pro-X controller - continuous mode- attached to ventilator circuit distal to viral/ bacterial heat and moisture exchange filter.
Active Comparator: Group B (IvMil); Patients will receive intravenous milrinone - started after induction of anesthesia - infusion at dosage of 0.3 - 0.75 mcg/kg/min after loading dose of 50 mic/kg over 10 min. After cross clamp off and temperature of 32 degree, Pulmonary vascular resistance and systemic vascular resistance will be calculated at the same corresponding time points to group A.	Drug: IV Milrinone; Patients will receive intravenous milrinone infusion at dosage of 0.3 - 0.75 mcg/kg/min with loading dose of 50 mcg/kg over 10 min. After cross clamp off and temperature of 32 degree, Pulmonary vascular resistance and systemic vascular resistance will be calculated at the same corresponding time points to group A.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in pulmonary artery pressure	Intraoperative

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of systemic hypotension		Intraoperative
Hemodynamic affection and need of vasopressors and inotropes.		Intraoperative
Pulmonary vascular resistance versus systemic vascular resistance	Systemic vascular resistance: (MAP-CVP) x 80 / CO Pulmonary vascular resistance = (MPAP-PAWP) X 80 / CO	Intraoperative
Right ventricular function	Measured by tricuspid annulus plane systolic excursion, fractional area changes, and right ventricular systolic pressure by doppler	Intraoperative
Duration of mechanical ventilation		Postoperative in ICU (up to 24 hours)
Need for mechanical circulatory support devices		Intraoperative
Urine output		Intraoperative

Collaborators and Investigators

• Sponsor: Menoufia University
• Investigators: Study Chair: Ghada A Hassan, Professor, Faculty of Medicine - Menoufia University; Study Chair: Mohamed A Salem, A. Professor, Faculty of Medicine - Menoufia University; Study Chair: Khaled M Gaballah, A. Professor, Faculty of Medicine - Menoufia University; Study Director: Mohammed O El Gouhary, Lecturer, Faculty of Medicine - Ain Shams university

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Actual): January 1, 2025
• Study Completion (Actual): January 1, 2025

Study Registration Dates

• First Submitted: April 6, 2023
• First Submitted That Met QC Criteria: April 19, 2023
• First Posted (Actual): May 3, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 9, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Milrinone
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Hypertension; Respiratory Aspiration; Hypertension, Pulmonary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Vasodilator Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: 2/2023 ANET 60

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No