Milrinone in Congenital Diaphragmatic Hernia

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

66 participants

Study Classification

INTERVENTIONAL

Study Start Date

2017-10-24

Study Completion Date

2025-05-19

Brief Summary

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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.

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Detailed Description

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This is a pilot trial to determine if milrinone infusion in neonates ≥ 36 weeks' postmenstrual age (PMA) at birth with CDH would lead to an increase in PaO2 with a corresponding decrease in OI by itself or in conjunction with other pulmonary vasodilators such as iNO at 24 h post-infusion.

Conditions

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

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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Milrinone

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 Type EXPERIMENTAL

Milrinone

Intervention Type DRUG

The study intervention is an intravenous infusion of milrinone or placebo

5% dextrose (D5W)

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

Group Type PLACEBO_COMPARATOR

Placebo (5% Dextrose)

Intervention Type DRUG

The study intervention is an intravenous infusion of milrinone or placebo

Interventions

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Milrinone

The study intervention is an intravenous infusion of milrinone or placebo

Intervention Type DRUG

Placebo (5% Dextrose)

The study intervention is an intravenous infusion of milrinone or placebo

Intervention Type DRUG

Other Intervention Names

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Milrinone Lactate Injection Primacor D5W

Eligibility Criteria

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Inclusion Criteria

* ≥ 36 0/7 weeks PMA by best obstetric estimate AND birth weight of ≥ 2000g
* postnatal age ≤7 days (168 hours of age)
* invasive mechanical ventilation (defined as ventilation with an endotracheal tube) and
* one arterial blood gas with an OI ≥ 10 (after tracheal tube obstruction and other easily resolvable mechanical causes for increased OI are ruled out) on the most recent arterial blood gas within 12 hours prior to the time of randomization.
* if an arterial blood gas is not available at the time of randomization, a preductal OSI of ≥ 5 can be used as an inclusion criterion instead of OI ≥ 10; (the OSI should be based on the most recent preductal pulse oximetry recording and must be within 12 hours of randomization)
* postnatal blood gas with PCO2 ≤ 80 mmHg (arterial, capillary or venous blood gas) on the most recent blood gas sample obtained within 12 hours prior to randomization Note: Criteria (iv) to (vi) must be met at the most recent analysis within 12 hours prior to randomization.

Exclusion Criteria

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
* Periventricular hemorrhagic infarction
* Posterior fossa hemorrhage
* Cerebellar hemorrhage
* persistent thrombocytopenia (platelet count \< 80,000/mm3) despite blood product administration on the most recent blood draw prior to randomization
* coagulopathy (PT INR \> 1.7) despite blood product administration on the most recent blood draw (if checked - there is no reason to check PT for the purpose of this study)
* aneuploidy associated with short life span (such as trisomy 13 or 18) will not be included in the study (infants with trisomy 21 can be included in the study)
* elevated arterial, venous or capillary PCO2 \> 80 mmHg in spite of maximal ventilator support (including high frequency ventilation) on the most recent blood gas obtained within 12 hours prior to randomization
* use of milrinone infusion prior to randomization (the use of other inhaled pulmonary vasodilators such as iNO, inhaled epoprosternol, inhaled PGE1 and oral such as endothelin receptor antagonists is permitted - Note: it is unlikely to be on oral pulmonary vasodilators early in the course of CDH)
* ongoing therapy with parenteral (intravenous or subcutaneous) pulmonary vasodilators such as IV/SQ prostacyclin analogs (Epoprostenol - Flolan or Treprostinil - Remodulin or PGE1 - Alprostadil) or IV phosphodiesterase 5 inhibitors (sildenafil - Revatio) at the time of randomization. In addition, initiation of therapy with these two classes of parenteral medications during the first 24 hours of study drug initiation is not permitted and will be considered a protocol deviation. The risk of systemic hypotension is high during the first 24 hours of study-drug (milrinone) infusion and hence parenteral administration of other pulmonary vasodilators is avoided to minimize risk of hypotension.
* Subjects already on ECMO or patients who are being actively considered for ECMO by the neonatal or surgical team
* attending (neonatal, critical care or surgical) refusal for participation in the trial (including concern about presence of hemodynamic instability)

Minimum Eligible Age

0 Hours

Maximum Eligible Age

168 Hours

Eligible Sex

ALL

Accepts Healthy Volunteers

No