Purpose

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

Eligibility

Eligible Ages
Under 168 Hours
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


Eligibility criteria:

Infants are eligible if they meet all of the following 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)

Study Design

Phase
Phase 2
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
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.
  • Drug: Milrinone
    The study intervention is an intravenous infusion of milrinone or placebo
    Other names:
    • Milrinone Lactate Injection
    • Primacor
Placebo Comparator
5% dextrose (D5W)
An equivalent volume of 5% dextrose (D5W) will be used for infants randomized to the placebo arm.
  • Drug: Placebo (5% Dextrose)
    The study intervention is an intravenous infusion of milrinone or placebo
    Other names:
    • D5W

Recruiting Locations

University of Texas Health Science Center at Houston
Houston, Texas 77030
Contact:
Kathleen A Kennedy, MD MPH

More Details

Status
Recruiting
Sponsor
NICHD Neonatal Research Network

Study Contact

Satyan Lakshminrusimha, M.D.
716-878-7673
slakshmi@buffalo.edu

Detailed Description

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.