Milrinone in Congenital Diaphragmatic Hernia

NCT02951130 | Completed Phase 2 Results DMC FDA Drug

• 17 other identifiers: NICHD-NRN-0057UG1HD034216UG1HD027904UG1HD021364UG1HD027853UG1HD040689UG1HD040492UG1HD027851UG1HD087229UG1HD053109UG1HD068278UG1HD068244UG1HD068263UG1HD027880UG1HD053089UG1HD087226U10HD036790
• Study Type: interventional
• Target: 66
• Locations: 1 country
• Sites: 19

Brief Summary

Infants with congenital diaphragmatic hernia (CDH) usually have pulmonary hypoplasia and persistent pulmonary hypertension of the newborn (PPHN) leading to hypoxemic respiratory failure (HRF). Pulmonary hypertension associated with CDH is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO). Increased pulmonary vascular resistance (PVR) can lead to right ventricular overload and dysfunction. In patients with CDH, left ventricular dysfunction, either caused by right ventricular overload or a relative underdevelopment of the left ventricle, is associated with poor prognosis. Milrinone is an intravenous inotrope and lusitrope (enhances cardiac systolic contraction and diastolic relaxation respectively) with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PPHN. Milrinone is commonly used during the management of CDH although no randomized trials have been performed to test its efficacy. Thirty percent of infants with CDH in the Children's Hospital Neonatal Database (CHND) and 22% of late-preterm and term infants with CDH in the Pediatrix database received milrinone. In the recently published VICI trial, 84% of patients with CDH received a vasoactive medication. In the current pilot trial, neonates with an antenatal or postnatal diagnosis of CDH will be randomized to receive milrinone or placebo to establish safety of this medication in CDH and test its efficacy in improving oxygenation.

Conditions

Congenital Diaphragmatic Hernia; Persistent Pulmonary Hypertension of the Newborn; Hypoxemic Respiratory Failure; Pulmonary Hypoplasia

Keywords

CDH; PPHN; HRF

Outcome Measures

Primary Outcomes (1)

• Oxygenation Response

  The primary outcome of this study is change in oxygenation from baseline (prior to study drug infusion) to 24 hours after initiation of study drug infusion. Oxygenation is assessed by oxygenation index (OI = mean airway pressure x oxygen concentration in % / PaO2 in mmHg). Oxygen saturation index (OSI = mean airway pressure x oxygen concentration in % / oxygen saturation in %) values were converted to OI values for this measure. Data are presented as OI at 24 hours minus OI at baseline. A negative value indicates improvement in oxygenation. A positive value indicates deterioration in oxygenation.

  24 h after initiation of study drug

Secondary Outcomes (13)

• Oxygenation Response at 48 and 72 h

  48 and 72 h after initiation of study drug

• Changes in Estimated Systolic Pulmonary Arterial Pressure on Echocardiogram

  Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug

• Vasoactive Inotrope Score and Systemic Blood Pressure

  72 hours after initiation of study drug

• Area Under the Curve for Inspired Oxygen

  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)

• Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators

  Through 24 h post study drug initiation

Study Arms (2)

Milrinone

EXPERIMENTAL

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.

Drug: Milrinone

5% dextrose (D5W)

PLACEBO COMPARATOR

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

Drug: Placebo (5% Dextrose)

Interventions

Milrinone DRUG

The study intervention is an intravenous infusion of milrinone or placebo

Also known as: Milrinone Lactate Injection, Primacor

Milrinone

Placebo (5% Dextrose) DRUG

The study intervention is an intravenous infusion of milrinone or placebo

Also known as: D5W

5% dextrose (D5W)

Eligibility Criteria

• Age: 0 Hours - 168 Hours
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may not qualify if:

• Infants are ineligible if they meet any of the following criteria:
• known hypertrophic cardiomyopathy
• Note 1: infants of diabetic mothers with asymmetric septal hypertrophy can be included as long as there is no evidence of obstruction to left ventricular outflow tract on echocardiogram,
• Note 2: infants with other acyanotic congenital heart disease (CHD) and CDH may be included in the study and will be a predetermined subgroup for analysis)
• cyanotic CHD - 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.,
• enrolled in conflicting clinical trials (such as a randomized controlled blinded trial of another pulmonary vasodilator therapy); Note: mothers enrolled in fetal tracheal occlusion studies such as FETO may be enrolled if permitted by investigators of the fetal tracheal occlusion study; \[FETO refers to fetoscopic endoluminal tracheal occlusion and involves occlusion of fetal trachea with a balloon device at mid-gestation and subsequent removal in later gestation\]
• infants with bilateral CDH
• o Note 3: infants with anterior and central defects are included in the study
• associated abnormalities of the trachea or esophagus (trachea-esophageal fistula, esophageal atresia, laryngeal web, tracheal agenesis)
• renal dysfunction (with serum creatinine \> 2 mg/dL not due to maternal factors) or severe oligohydramnios associated with renal dysfunction at randomization; renal dysfunction may be secondary to renal anomalies or medical conditions such as acute tubular necrosis
• severe systemic hypotension (mean blood pressure \< 35 mm Hg for at least 2 h with a vasoactive inotrope score of \> 30)
• decision is made to provide comfort/ palliative care and not full treatment
• Intracranial bleed (including the following findings on the cranial ultrasound)
• Cerebral parenchymal hemorrhage
• Blood/echodensity in the ventricle with distension of the ventricle

Sponsors & Collaborators

• NICHD Neonatal Research Network: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (19)

University of Alabama at Birmingham

Birmingham, Alabama, 35233, United States

Location

Stanford University

Palo Alto, California, 94304, United States

Location

Emory University

Atlanta, Georgia, 30303, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Children's Mercy

Kansas City, Missouri, 64108, United States

Location

University of New Mexico

Albuquerque, New Mexico, 87131, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

RTI International

Durham, North Carolina, 27709, United States

Location

Duke University

Durham, North Carolina, 27710, United States

Location

Cincinnati Children's Medical Center

Cincinnati, Ohio, 45267, United States

Location

Case Western Reserve University, Rainbow Babies and Children's Hospital

Cleveland, Ohio, 44106, United States

Location

Research Institute at Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Brown University, Women & Infants Hospital of Rhode Island

Providence, Rhode Island, 02905, United States

Location

University of Texas Southwestern Medical Center at Dallas

Dallas, Texas, 75235, United States

Location

University of Texas Health Science Center at Houston

Houston, Texas, 77030, United States

Location

University of Utah

Salt Lake City, Utah, 84108, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• Lakshminrusimha S, Keszler M, Kirpalani H, Van Meurs K, Chess P, Ambalavanan N, Yoder B, Fraga MV, Hedrick H, Lally KP, Nelin L, Cotten M, Klein J, Guilford S, Williams A, Chaudhary A, Gantz M, Gabrio J, Chowdhury D, Zaterka-Baxter K, Das A, Higgins RD. Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices. Matern Health Neonatol Perinatol. 2017 Nov 27;3:27. doi: 10.1186/s40748-017-0066-9. eCollection 2017.

  PMID: 29209510 DERIVED

MeSH Terms

Conditions

Hernias, Diaphragmatic, Congenital; Persistent Fetal Circulation Syndrome; Respiratory Insufficiency

Interventions

Milrinone; Glucose

Condition Hierarchy (Ancestors)

Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hernia, Diaphragmatic; Internal Hernia; Hernia; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Infant, Newborn, Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Amrinone; Aminopyridines; Amines; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hexoses; Monosaccharides; Sugars; Carbohydrates

Results Point of Contact

• Title: Satyan Lakshminrusimha
• Organization: UC Davis School of Medicine

slakshmi@health.ucdavis.edu

916 734 5178

Study Officials

• Satyan Lakshminrusimha, M.D.

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 14, 2016
• First Posted: November 1, 2016
• Study Start: October 24, 2017
• Primary Completion: September 30, 2024
• Study Completion: May 19, 2025
• Last Updated: November 6, 2025
• Results First Posted: November 6, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share

Locations

US (19)