What side effects are associated with this type of intervention?

Common treatments for Pulmonary Hypertension, particularly those similar to Milrinone, include phosphodiesterase inhibitors, endothelin receptor antagonists, prostacyclin analogs, and soluble guanylate cyclase stimulators. Milrinone can cause hypotension, ventricular arrhythmias, and torsade de pointes. PDE-5 inhibitors like sildenafil and tadalafil may lead to headaches, flushing, dyspepsia, and visual disturbances. Endothelin receptor antagonists such as bosentan and macitentan can cause liver function abnormalities and fluid retention. Prostacyclin analogs like epoprostenol often result in jaw pain, nausea, and infusion site pain. Soluble guanylate cyclase stimulators like riociguat may cause hypotension and gastrointestinal symptoms.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of Pulmonary Hypertension (PH) that have properties similar to Milrinone, which is an inotrope and lusitrope with pulmonary vasodilator effects. Notable approvals include PDE-5 inhibitors such as sildenafil and tadalafil, which improve pulmonary hemodynamics and exercise capacity. Endothelin receptor antagonists like bosentan have also been approved, although they come with warnings about potential fluid retention. These drugs, like Milrinone, aim to enhance cardiac function and reduce pulmonary vascular resistance, thereby improving oxygenation and overall patient outcomes.

What other types of research exist?

Promising alternatives to Milrinone for pulmonary hypertension patients include: <ol> <li>R 80122 - A selective phosphodiesterase III inhibitor with positive inotropic and lusitropic effects, and moderate vasodilating properties.</li> <li></li> </ol> E-1020 (Loprinone Hydrochloride) - A PDE III inhibitor with positive inotropic and vasodilating effects. 3. Sildenafil - A PDE-5 inhibitor that improves pulmonary hemodynamics and exercise capacity. 4. Tadalafil - Another PDE-5 inhibitor that increases exercise capacity and delays clinical worsening. 5. Riociguat - A soluble guanylate cyclase stimulator that may improve exercise capacity and quality of life.

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Inotrope and Lusitrope

Milrinone for Congenital Diaphragmatic Hernia

Q: What is the mechanism of action of this treatment?

Common treatments for Pulmonary Hypertension (PH) include phosphodiesterase inhibitors (PDE5Is) such as Sildenafil, endothelin receptor antagonists (ERAs), and soluble guanylate cyclase stimulants like Riociguat. PDE5Is work by inhibiting the enzyme phosphodiesterase type 5, leading to relaxation of pulmonary vascular smooth muscle and reduced pulmonary arterial pressure. ERAs block endothelin receptors, reducing vasoconstriction and vascular remodeling. Riociguat stimulates soluble guanylate cyclase, enhancing nitric oxide signaling and leading to vasodilation. Milrinone, an inotrope and lusitrope with pulmonary vasodilator properties, increases cardiac contractility and promotes myocardial relaxation while reducing pulmonary vascular resistance. These mechanisms are crucial for PH patients as they help lower pulmonary pressures, improve cardiac output, and enhance overall cardiovascular function, thereby alleviating symptoms and improving quality of life.

Phase 2

Waitlist Available

Led By Satyan Lakshminrusimha, M.D.

Research Sponsored by NICHD Neonatal Research Network

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Infants must be ≥ 36 0/7 weeks PMA by best obstetric estimate AND have a birth weight of ≥ 2000g

Must be on invasive mechanical ventilation (defined as ventilation with an endotracheal tube)

Must not have

Infants on ongoing therapy with specific parenteral pulmonary vasodilators or ECMO

Infants with cyanotic congenital heart disease (CHD) such as transposition of great arteries (TGA), total anomalous pulmonary venous return (TAPVR), partial anomalous pulmonary venous return (PAPVR), truncus arteriosus (TA), tetralogy of Fallot (TOF), single ventricle physiology - hypoplastic left heart syndrome (HLHS), tricuspid atresia, critical pulmonic stenosis or atresia etc.

Timeline

Screening 3 weeks

Treatment Varies

Follow Up after initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first)

Summary

This trial is testing if milrinone, a medicine that helps the heart and lungs, can improve oxygen levels in newborns with severe lung and heart problems due to CDH. These babies often don't get better with usual treatments. The goal is to see if milrinone can safely help these babies breathe easier. Milrinone is used in up to 30% of CDH infants across the United States, but no studies have tested its effectiveness or safety in these newborns.

Who is the study for?

This trial is for newborns over 36 weeks gestation, weighing at least 2000g, diagnosed with congenital diaphragmatic hernia (CDH), experiencing severe lung and heart issues due to the hernia. They must be on mechanical ventilation but stable enough not to require certain emergency treatments or have specific heart conditions, bleeding in the brain, or genetic disorders that shorten life span.

What is being tested?

The study tests Milrinone's safety and effectiveness in improving oxygen levels in infants with CDH compared to a placebo. Infants will be randomly assigned to receive either Milrinone or a placebo solution intravenously while their oxygenation status is monitored.

What are the potential side effects?

Milrinone may cause changes in blood pressure or heart rhythm, headaches, nausea or vomiting. It can also potentially lead to an increased risk of infection due to its effects on the immune system.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My baby was born at or after 36 weeks of pregnancy and weighed at least 2000g.

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I am on a breathing machine through a tube in my windpipe.

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My latest blood gas test shows PCO2 levels at or below 80 mmHg.

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My baby is 7 days old or younger.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My infant is on special medication for lung blood vessel issues or is on ECMO.

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My infant has a specific type of heart defect present from birth.

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My infant has a birth defect in both sides of the diaphragm.

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My infant has a birth defect involving the throat or food pipe.

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My infant has kidney issues not caused by maternal factors, or severe low amniotic fluid due to kidney problems.

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My infant has had very low blood pressure for at least 2 hours despite strong medication.

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My infant has a blood clotting issue not improved by blood products.

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My infant has high CO2 levels despite maximum support from a ventilator.

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My infant has low platelet counts despite receiving blood products.

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My infant has a genetic condition known to shorten life span.

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My infant has been diagnosed with thickened heart muscles.

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My infant is receiving comfort care instead of full treatment.

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My infant has had a brain bleed confirmed by ultrasound.

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My infant is not enrolled in any other clinical trials for lung treatments.

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My infant is on milrinone treatment before being assigned to a study group.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ after initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~after initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first)

This trial's timeline: 3 weeks for screening, Varies for treatment, and after initiation of the study drug at 4 time points per day - every 6 hours x 72 hours or discontinuation of study drug (whichever comes first) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Oxygenation Response

Secondary study objectives

Oxygen

Changes in estimated systolic pulmonary arterial pressure on echocardiogram

Clinical status (Pulmonary and Nutritional)

+4 more

Side effects data

From 2017 Phase 2 trial • 72 Patients • NCT02232399

18%

Junctional ectopic tachycardia

11%

Inotropic score > 20

Closure of another small VSD + tricuspid valve plasty + permanent pacemaker due to total AV-block

Readmission for pericardal fluid drainage

Verified bacterial sepsis

Arrhythmia

Pericardial fluid and sepsis

Pericard effusion

100%

80%

60%

40%

20%

Study treatment Arm

Milrinone

Levosimendan

Trial Design

2Treatment groups

Experimental Treatment

Placebo Group

Group I: MilrinoneExperimental Treatment1 Intervention

Milrinone infusion at 0.33µg/kg/min. The dose of the study drug will be increased to 0.66 µg/kg/min if oxygenation index (OI) remains ≥ 10 without any evidence of hypotension (as defined by the protocol) two hours after initiation of study drug. Infusion will be continued until the OI decreases to \< 7. The maximum duration of study drug infusion is 72 hours.

Group II: 5% dextrose (D5W)Placebo Group1 Intervention

An equivalent volume of 5% dextrose (D5W) will be used for infants randomized to the placebo arm.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Milrinone

2023

Completed Phase 4

~23040

0 / 19Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Common treatments for Pulmonary Hypertension (PH) include phosphodiesterase inhibitors (PDE5Is) such as Sildenafil, endothelin receptor antagonists (ERAs), and soluble guanylate cyclase stimulants like Riociguat. PDE5Is work by inhibiting the enzyme phosphodiesterase type 5, leading to relaxation of pulmonary vascular smooth muscle and reduced pulmonary arterial pressure. ERAs block endothelin receptors, reducing vasoconstriction and vascular remodeling. Riociguat stimulates soluble guanylate cyclase, enhancing nitric oxide signaling and leading to vasodilation. Milrinone, an inotrope and lusitrope with pulmonary vasodilator properties, increases cardiac contractility and promotes myocardial relaxation while reducing pulmonary vascular resistance. These mechanisms are crucial for PH patients as they help lower pulmonary pressures, improve cardiac output, and enhance overall cardiovascular function, thereby alleviating symptoms and improving quality of life.

Global myocardial function is compromised in infants with pulmonary hypertension.Additive effects of inhaled nitric oxide and intravenous milrinone in experimental pulmonary hypertension.