Evaluating the efficacy and safety of milrinone for prevention of post-patent ductus arteriosus closure syndrome (the MIDAS trial) in extremely preterm infants: a multicentre, double-masked, randomised, placebo-controlled trial

Abstract

Introduction: Post-ligation cardiac syndrome (PLCS) represents a state of severe post-intervention cardiopulmonary instability, seen in up to 50% of extremely premature infants after surgical closure of the patent ductus arteriosus (PDA); yet an evidence-based approach to treatment of this condition does not exist. The objective of this study is to determine the efficacy and safety of prophylactic milrinone in reducing incidence of PLCS and/or mortality within the first 7 days following PDA closure. The central hypothesis is that administration of intravenous milrinone will reduce the incidence of PLCS or death within 7 days of PDA closure either by percutaneous device (PCD) closure or surgical ligation (SL).

Methods and analysis: MIDAS (MIlrinone for prevention of post-patent Ductus Arteriosus closure Syndrome) is a multicentre, double-masked, randomised, placebo-controlled trial conducted across 19 neonatal intensive care units (NICUs) in the USA with an anticipated enrolment of 316 infants over 2 years. Prior to PDA closure (PCD or SL), infants will be randomised to either of two interventions that will be started after a 30-min period of stability and within 90 min following PDA closure: Group A (milrinone): milrinone infusion at an initial dose of 0.33 mcg/kg/min accompanied by a slow intravenous bolus of 10 mL/kg of 0.9% NaCl; Group B (placebo): 0.9% saline infusion of equivalent volume. Infants will be eligible if (1) gestational age at birth ≤27 weeks and 6 days and postnatal age ≤90 days at intervention; (2) haemodynamically significant PDA with minimum transductal diameter ≥1.0 mm prior to PDA closure or classified as at least small; (3) decision by clinical team to proceed with PDA closure via SL or PCD based on clinical and echocardiography features of haemodynamic significance; (4) invasive or non-invasive positive pressure respiratory support (does not include low-flow (<2.0 L/min) nasal cannula) for at least 2 days prior to PDA closure. The primary outcome is a composite of PLCS or death within 7 days of PDA closure. An intent to treat analysis will be applied using robust Poisson or logistic regression with generalised estimating equations (GEE) to account for centre effects and randomisation stratification factors.

Ethics and dissemination: The study has been approved by the University of Utah single Research Ethics Board (#00185742). Results will be disseminated through conferences, peer-reviewed publications, contributing to the enhancement of knowledge in post-PDA closure management and safety and efficacy of milrinone in preterm infants.

Trial registration number: NCT06679855.

Keywords: Cardiovascular Disease; Heart failure; NEONATOLOGY.

Figure 1. Outline of randomisation process for treatment allocation.

Figure 2. MIDAS trial patient journey timeline. MIDAS, MIlrinone for prevention of post-patent Ductus Arteriosus closure Syndrome.