Clinical Trial: Milrinone in Congenital Diaphragmatic Hernia

Study Status: Not yet recruiting
Recruit Status: Not yet recruiting
Study Type: Interventional

Official Title: Milrinone in Congenital Diaphragmatic Hernia

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.

Detailed Summary: 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.
Sponsor: NICHD Neonatal Research Network

Current Primary Outcome: Oxygenation Response [ Time Frame: 24 h after initiation of study drug ]

The primary outcome is the oxygenation response, as determined by change in OI (or OSI) at 24 h after initiation of study drug. The last OI (or OSI) prior to initiation of ECMO or death will be used for analysis if infant requires ECMO or dies within 24 h of initiation of the study drug.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • Oxygenation Response at 48 and 72 h [ Time Frame: 48 and 72 h after initiation of study drug ]
    Oxygenation index at 48 and 72 h (or OI at the time of initiation of ECMO or immediately prior to death, for infants placed on ECMO or died before these time points)
  • Changes in estimated systolic pulmonary arterial pressure on echocardiogram [ Time Frame: Prior to initiation of study drug to between 24 and 72 hours after initiation of study drug ]
    Changes in echocardiogram to assess pulmonary arterial pressure (as defined by protocol) between pre-study drug echocardiogram and echocardiogram obtained between 24 and 72 h after starting the study drug. The outcome will be available only for those infants who have a pre-study drug echocardiogram and a second echocardiogram between 24 and 72 hours after initiation of study drug performed for clinical reasons.
  • Vasoactive Inotrope Score and Systemic Blood Pressure [ Time Frame: 72 hours after initiation of study drug ]
    Vasoactive Inotrope Score is a quantitative assessment of the degree of therapeutic support required by the patient to maintain adequate perfusion and/or blood pressure.
  • Area Under the Curve for Inspired Oxygen [ Time Frame: 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) ]
    Area under the curve for inspired oxygen after initiation of the study drug (inspired oxygen and ventilator data from 4 time points per day - every 6 hours will be recorded to calculate area under the curve)
  • Oxygenation Response to Additional Inotropes or Pulmonary Vasodilators [ Time Frame: Through 24 h post study drug initiation ]
    If subsequent to the study drug, any additional inotrope or pulmonary vasodilator is used (such as iNO), we will evaluate the oxygenation response to these agents. If inotropes or vasodilators were used prior to the initiation of study drug, similar values will be recorded. The OI and PaO2/ FiO2 ratio prior to at least 30 min after initiation of the inotrope / vasodilator are recorded. The change in OI and PaO2/ FiO2 ratio in response to these agents is evaluated as a continuous variable and arbitrarily classified into responders, partial responders and non-responders
  • Supplemental Continuous Oxygen [ Time Frame: 28 days and 56 days postnatal age (or discharge whichever comes first) ]
    The use of supplemental oxygen at 28 d will be used to calculate the incidence of chronic lung disease. Chronic lung disease severity will be classified similar to the BPD classification in preterm infants at > 32 week gestation.
  • Survival to discharge without ECMO [ Time Frame: Measured by no ECMO at time of hospital discharge or at the time the infant reaches 120 days of life and remains in the hospital, whichever comes earlier ]
  • Clinical status (Pulmonary and Nutritional) [ Time Frame: All clinical status measures (as defined by protocol) will be obtained just prior to the infants discharge from the hospital and again at 12 months of age. ]
    Clinical status - pulmonary (use of supplemental oxygen or respiratory medications - diuretics, methylxanthines, steroids, inhaled or nebulized steroids or bronchodilators) and nutritional (weight, length, head circumference, use of anti-reflux medications)
  • Feasibility and sample size calculation to Perform a Definitive Trial (primary outcome - improvement in survival without ECMO [ Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years ]
  • Feasibility to perform a definitive trial (incidence of systemic hypotension) [ Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years ]
  • Feasibility to perform a definitive trial (incidence of intracranial bleeding) [ Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years ]
  • Feasibility to perform a definitive trial (incidence of arrhythmias) [ Time Frame: From initial recruitment: 16 patients enrolled per month to complete the trial in 4 years ]
  • Adjusted Oxygen Response [ Time Frame: 24 h after initiation of study drug ]


Original Secondary Outcome: Same as current

Information By: NICHD Neonatal Research Network

Dates:
Date Received: October 14, 2016
Date Started: June 1, 2017
Date Completion: February 2021
Last Updated: May 9, 2017
Last Verified: May 2017