Milrinone in congenital diaphragmatic hernia - a randomized pilot trial: study protocol, review of literature and survey of current practices

Abstract

Background: Congenital diaphragmatic hernia (CDH) is commonly associated with pulmonary hypoplasia and pulmonary hypertension (PH). PH associated with CDH (CDH-PH) is frequently resistant to conventional pulmonary vasodilator therapy including inhaled nitric oxide (iNO) possibly due to right and left ventricular dysfunction. Milrinone is an intravenous inotrope and lusitrope with pulmonary vasodilator properties and has been shown anecdotally to improve oxygenation in PH. We developed this pilot study to determine if milrinone infusion would improve oxygenation in neonates ≥36 weeks postmenstrual age (PMA) with CDH.

Methods/design: Data on pulmonary vasodilator management and outcome of CDH patients was collected from 18 university NICUs affiliated with the Neonatal Research Network (NRN) from 2011 to 2012. The proposed pilot will be a masked, placebo-controlled, multicenter, randomized trial of 66 infants with CDH with an oxygenation index (OI) ≥10 or oxygen saturation index (OSI) ≥5. The primary outcome is the oxygenation response, as determined by change in OI at 24 h after initiation of study drug. As secondary outcomes, we will determine oxygenation at 48 h and 72 h post-infusion, right ventricular pressures on echocardiogram and the incidence of systemic hypotension, arrhythmias, intracranial hemorrhage, survival without extracorporeal membrane oxygenation, and chronic lung disease (oxygen need at 28 days postnatal age). Finally, we will evaluate the pulmonary and nutritional status at 4, 8 and 12 months of age using a phone questionnaire.

Results: Three hundred thirty-seven infants with CDH were admitted to NRN NICUs in 2011 and 2012 of which 275 were ≥36 weeks PMA and were exposed to the following pulmonary vasodilators: iNO (39%), sildenafil (17%), milrinone (17%), inhaled epoprostenol (6%), intravenous epoprostenol (3%), and intravenous PGE1 (1%). ECMO was required in 36% of patients. Survival to discharge was 71%.

Discussion: CDH is an orphan disease with high mortality with few randomized trials evaluating postnatal management. Intravenous milrinone is a commonly used medication in neonatal/pediatric intensive care units and is currently used in 17% of patients with CDH within the NRN. This pilot study will provide data and enable further studies evaluating pulmonary vasodilator therapy in CDH.

Trial registration: ClinicalTrials.gov; NCT02951130; registered 14 October 2016.

Keywords: Extracorporeal membrane oxygenation; Oxygen; Persistent pulmonary hypertension; Phosphodiesterase; Pulmonary hypertension.

Fig. 1

Patients with left sided CDH may have left ventricular hypoplasia and dysfunction. Such dysfunction may be associated with elevated left atrial pressure, pulmonary venous hypertension and poor LV output. The systemic circulation may be dependent on right to left ductal flow due to elevated PVR. Pulmonary vasodilators such as inhaled NO may result in pulmonary arterial dilation and exacerbate pulmonary edema in the presence of pulmonary venous hypertension and decrease ductal-dependent systemic flow (“ductal steal”). IV PGE1 maintains ductal patency leading to reduced RV afterload and support systemic circulation. Milrinone, by improving left ventricular diastolic and systolic function reduces left atrial pressure and also dilates pulmonary vasculature resulting in improved oxygenation in CDH. The presence of hypoplastic lungs with remodeled pulmonary vasculature and volutrauma, barotrauma and oxygen toxicity contribute to poor response to pulmonary vasodilator therapy. We hypothesize that a combination of milrinone with “gentle” ventilation will improve oxygenation and response to pulmonary vasodilator therapy in CDH. RVH – right ventricular hypertrophy; RA – right atrium; LA – left atrium; LV – left ventricle: PVR – pulmonary vascular resistance; NO – nitric oxide; PA – pulmonary artery; PV – pulmonary vein; IV PGE1 – intravenous prostaglandin E1 (alprostadil)

Fig. 2

Study design – please see text for details. * In the presence of an indwelling arterial catheter, or if there is an arterial blood gas drawn by arterial stick, oxygenation index (OI) values are preferred for making decisions regarding study drug therapy over oxygen saturation index (OSI) values

Fig. 3

Optional guidelines for “optimal” management of a neonate with congenital diaphragmatic hernia in the preoperative period. A nasogastric or orogastric suction tube is placed to decompress the stomach in the delivery room. Respiratory management includes intubation and positive pressure ventilation with care to avoid high PIP. The target of respiratory management is to maintain preductal oxygen saturations in the 85–95% range and PaCO₂ between 45 and 70 mmHg with a pH > 7.20. If PaCO₂ of ≤70 mmHg cannot be achieved with conventional ventilation (maximum PIP of 28 cm H₂O and a maximum rate of 60/min), high frequency ventilation (high frequency oscillator – HFOV or jet ventilator – HFJV) may be required. Blood pressure is maintained to achieve adequate perfusion and avoid lactic acidosis and oliguria. Monitoring chest X-rays to maintain contralateral lung expansion to 8 to 9 ribs may avoid baro/volutrama. A trial of inhaled NO may be considered when oxygenation index exceeds 15 with clinical or echocardiographic evidence of pulmonary hypertension. CMV – conventional mechanical ventilation. Modified from Chandrasekharan et al. [48]

Fig. 4

Protocol for the milrinone CDH study. Parents are approached for consent during either the antenatal period or the first 7 postnatal days. Once eligibility is determined based on presence of hypoxemic respiratory failure and meeting all the inclusion criteria and absence of any of the exclusion criteria, subjects are randomized to milrinone or placebo. Details of other modalities of treatment (alkalosis, surfactant), medications administered (including pulmonary vasodilator therapy, vasopressor therapy and postnatal steroids) are recorded. A baseline cranial ultrasound (#1) is obtained either prior to or within 4 h of study drug initiation. Randomization is performed within 12 h of establishing eligibility. The study drug should be initiated within 5 h of randomization. Maximum duration of study drug therapy is 72 h. Patient is monitored for adverse events (AE) 24 h after cessation of study drug. The criteria for triggering study drug wean/discontinuation are two oxygenation indices (OI) < 7 at least an hour or maximum 12 h apart. If arterial access is not available, oxygen saturation index (OSI) will be used to assess hypoxemia. Once weaning/discontinuation criteria are met, study drug should be weaned within 4 h. Open label milrinone can be initiated any time after completion of the study drug. Status form (including data on surgical details) will be collected at the end of the hospital course or at 120 days of postnatal age or death (whichever is earlier)

Fig. 5

Protocol for initiation, escalation, weaning and discontinuation of study drug. The study drug (milrinone or placebo – D5W) is initiated after documentation of hypoxemia (oxygenation index – OI ≥ 10 or oxygen saturation index – OSI ≥ 5), in the absence of hypotension and other exclusion criteria. A fluid bolus (10 ml/kg of lactated Ringers solution or normal saline) is recommended prior to study drug initiation. The starting dose is 0.33 μg/kg/min. After 2–4 h of therapy at this dose, study drug is escalated to 0.66 μg/kg/min in the absence of hypotension (mean systemic BP ≥ 35 mmHg and vasoactive inotrope score ≤ 30). The maximum duration of therapy is 72 h. Study drug is weaned to 0.33 μg/kg/min when study discontinuation criteria are met (two OIs < 7 or two OSIs <3.5 at least an hour apart). After 2 h of study drug infusion at 0.33 μg/kg/min, study drug can be discontinued. The presence of any severe and life threatening serious adverse events (SAE) necessitates immediate cessation of study drug. Open label milrinone is permitted after cessation of study drug