Inhaled Versus Intravenous Milrinone for Patients Undergoing Mitral Valve Replacement Surgery

This prospective double blinded 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: Active, not recruiting
• Conditions: Pulmonary Hypertension; Mitral Valve Replacement; Inhaled Milrinone; Intravenous Milrinone
• Intervention / Treatment: Drug: Inhaled Milrinone; Drug: IV Milrinone

Detailed Description

Standard preoperative assessment for cardiac surgery will be done for all patients. Premedication will be given according to standard protocol in our university hospitals as follow bromazepam 3mg oral and ranitidine 150 mg orally in the night-before then another dose of ranitidine 150 mg 2 hours before arrival in operating theatre by small sips of clear liquid.

On arrival to induction room wide bore IV access will be inserted using local anesthetic then arterial cannula in radial artery will be inserted the same manner using local anesthetic then in operating room routine monitoring including a five-lead electrocardiogram, pulse oximeter and invasive blood pressure will be attached.

Anesthesia will be induced with midazolam 0.02 mg/kg and fentanyl 2-5 mcg/kg and muscle relaxation will be achieved by cis-atracurium 0.15 mg/kg. After tracheal intubation, central venous line and transesophageal echocardiography will be inserted, then anesthesia will be maintained throughout the procedure with morphine 20 mcg/kg/min, cis-atracurium 2 mcg/kg/min and sevoflurane 0.4% - 2% MAC. Ventilation will be adjusted to maintain end-tidal carbon dioxide in the range of 30-40 mmHg.

During cardiopulmonary bypass, flow of 2.2 l/min/m2 will be achieved, 20 ml/kg cold blood cardioplegia will be given manually and pressure controlled at 20 - 30 min interval along with hot shot at start of weaning from CPB, temperature will be maintained at 32-34℃ and propofol 1% infusion at rate of 8 - 12ml/hr.

In initial TEE study, baseline measures will be taken assessing left ventricular ejection fraction, and right ventricular hemodynamics represented by right ventricular function measured by [tricuspid annulus plane systolic excursion, fractional area changes, and right ventricular systolic pressure by doppler] also, pulmonary vascular resistance and systemic vascular resistance will be calculated, plus patients hemodynamics (mean arterial blood pressure, heart rate) and inotropic score all measures will be recorded.

• Study Type: Interventional
• Enrollment (Estimated): 116
• 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 multiple valve diseases -other than mitral valve-.
• 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: Double

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 (21-23), 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 0.5 mcg/kg/min without loading dose (24), 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 - started after induction of anesthesia - infusion at dosage of 0.5 mcg/kg/min without loading dose (24), 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 and postoperative in ICU (up to 24 hours)
Hemodynamic affection and need of vasopressors and inotropes.		Intraoperative and postoperative in ICU (up to 24 hours)
Pulmonary vascular resistance versus systemic vascular resistance	Systemic vascular resistance: (MAP-CVP) x 80 / CO Pulmonary vascular resistance = (MPAP-LAP) X 80 / CO	Intraoperative and postoperative in ICU (up to 24 hours)
Right ventricular function	Measured by tricuspid annulus plane systolic excursion, fractional area changes, and right ventricular systolic pressure by doppler	Intraoperative and postoperative in ICU (up to 24 hours)
Duration of mechanical ventilation		Intraoperative and postoperative in ICU (up to 24 hours)
Need for mechanical circulatory support devices		Intraoperative and postoperative in ICU (up to 24 hours)
Urine output		Intraoperative and postoperative in ICU (up to 24 hours)
Length of intensive care (ICU) in stay		Intraoperative and postoperative in ICU (up to 24 hours)

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 (Estimated): October 1, 2024
• Study Completion (Estimated): March 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 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Milrinone
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Respiration Disorders; Lung Diseases; Hypertension; Respiratory Aspiration; Hypertension, Pulmonary; 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: 2/2023 ANET 60

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No