Milrinone in Congenital Diaphragmatic Hernia

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 othereasily resolvable mechanical causes for increased OI are ruled out) on the mostrecent 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 preductalOSI of ≥ 5 can be used as an inclusion criterion instead of OI ≥ 10; (the OSI shouldbe based on the most recent preductal pulse oximetry recording and must be within 12hours of randomization)

• postnatal blood gas with PCO2 ≤ 80 mmHg (arterial, capillary or venous blood gas) onthe most recent blood gas sample obtained within 12 hours prior to randomizationNote: Criteria (iv) to (vi) must be met at the most recent analysis within 12 hoursprior 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 beincluded as long as there is no evidence of obstruction to left ventricularoutflow tract on echocardiogram,

• Note 2: infants with other acyanotic congenital heart disease (CHD) and CDH maybe included in the study and will be a predetermined subgroup for analysis)

• cyanotic CHD - transposition of great arteries (TGA), total anomalous pulmonaryvenous return (TAPVR), partial anomalous pulmonary venous return (PAPVR), truncusarteriosus (TA), tetralogy of Fallot (TOF), single ventricle physiology -hypoplastic left heart syndrome (HLHS), tricuspid atresia, critical pulmonicstenosis or atresia etc.,

• enrolled in conflicting clinical trials (such as a randomized controlled blindedtrial of another pulmonary vasodilator therapy); Note: mothers enrolled in fetaltracheal occlusion studies such as FETO may be enrolled if permitted byinvestigators of the fetal tracheal occlusion study; [FETO refers to fetoscopicendoluminal tracheal occlusion and involves occlusion of fetal trachea with aballoon 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) orsevere oligohydramnios associated with renal dysfunction at randomization; renaldysfunction may be secondary to renal anomalies or medical conditions such as acutetubular necrosis

• severe systemic hypotension (mean blood pressure < 35 mm Hg for at least 2 h with avasoactive 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 productadministration on the most recent blood draw prior to randomization

• coagulopathy (PT INR > 1.7) despite blood product administration on the most recentblood draw (if checked - there is no reason to check PT for the purpose of thisstudy)

• aneuploidy associated with short life span (such as trisomy 13 or 18) will not beincluded 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 ventilatorsupport (including high frequency ventilation) on the most recent blood gas obtainedwithin 12 hours prior to randomization

• use of milrinone infusion prior to randomization (the use of other inhaled pulmonaryvasodilators such as iNO, inhaled epoprosternol, inhaled PGE1 and oral such asendothelin receptor antagonists is permitted - Note: it is unlikely to be on oralpulmonary vasodilators early in the course of CDH)

• ongoing therapy with parenteral (intravenous or subcutaneous) pulmonary vasodilatorssuch 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 thesetwo classes of parenteral medications during the first 24 hours of study druginitiation is not permitted and will be considered a protocol deviation. The risk ofsystemic hypotension is high during the first 24 hours of study-drug (milrinone)infusion and hence parenteral administration of other pulmonary vasodilators isavoided to minimize risk of hypotension.

• Subjects already on ECMO or patients who are being actively considered for ECMO bythe neonatal or surgical team

• attending (neonatal, critical care or surgical) refusal for participation in thetrial (including concern about presence of hemodynamic instability)