Project Summary Infants born preterm are exposed to an array of morbidities. The most common cardiovascular problem observed in this population is patent ductus arteriosus (PDA). Following surgical closure of a PDA, infants can develop Post-Ligation Cardiac Syndrome (PLCS), a serious complication which represents a state of severe postoperative cardiopulmonary instability. PLCS can be observed in up to 50% of extremely premature infants after surgical closure of the PDA. Recognition and treatment of PLCS often occurs late and treatment is variable across hospitals. To date, there have been no randomized controlled clinical trials (RCTs) of cardiovascular drugs to either prevent or treat PLCS in preterm infants. Given the variance in treatment of PLCS, the potential use of harmful treatments amid suboptimal evidence or scientifically proven justification for use, a masked, multicenter randomized trial is essential. Preliminary data suggest that milrinone, a commonly used cardiovascular medication, reduces the risk of PLCS in neonates requiring surgical ligation for PDA. The proposed Milrinone for Prevention of Post-ligation Cardiac Syndrome (MIDAS) trial aims to move preliminary research forward by designing and implementing an RCT to obtain additional data to determine efficacy of prophylactic milrinone at reducing the incidence of PLCS and improving neonatal outcomes. We will apply the experience and rigor of the Neonatal Research Network infrastructure in performing randomized placebo-controlled trials in union with RTI’s leadership in statistical design and analysis and numerous prior successes in the development and implementation of RCTs. The specific aims for the MIDAS trial are: • Specific Aim #1: Determine the efficacy of prophylactic milrinone on decreasing PLCS and mortality in extremely preterm infants, born at gestational age <27 weeks and 6 days, after PDA closure by surgical ligation or percutaneous cardiac catheterization. • Subsidiary Aim: Determine the effects of prophylactic milrinone on 2-year survival and incidence of adverse neurodevelopmental outcomes in extremely preterm infants treated with PDA ligation. With successful execution of these planned experimental aims, the DCC will be able to contribute toward identification of an evidence-based approach (demonstrative of external validity and reproducibility) for the safe prevention and treatment of PCLS in preterm infants.