Milrinone in Congenital Diaphragmatic Hernia


Trial ID: NCT02951130


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.

Official Title

Milrinone in Congenital Diaphragmatic Hernia

Stanford Investigator(s)


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

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)


drug: Milrinone

drug: Placebo (5% Dextrose)


Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Krisa P Van Meurs, MD