1/2 Milrinone for Prevention of Post-Patent Ductus Arteriosus Closure Syndrome in Extremely Preterm Infants (MIDAS Trial) – CCC - PROJECT SUMMARY Significance: Prematurity a major health problem in the United States, with more than 385,000 babies born preterm annually. The economic cost is more than $50 billion, mostly in extremely low birth weight infants (ELBW, born<1000g). Patent ductus arteriosus (PDA) is the most common cardiovascular problem and requires interventional closure in 16% of cases. Intervention is complicated by Post-Ligation Cardiac Syndrome (PLCS), characterized by low or high blood pressure and respiratory instability, with highest incidence in the most immature patients. Both PDA surgery and PLCS are independently associated with increased risk of adverse respiratory outcomes and neuro-developmental disabilities. Of surviving ELBW infants after PDA closure, 50% had neurodevelopmental impairment including severe handicaps. Postprocedural instability is decreased by early milrinone use, a vasodilator drug which enhances heart function. Avoiding postprocedural instability and establishing the safety of milrinone are considered important outcomes by parents. Investigators and Prior Work: Prospective observational mechanistic data demonstrates that PLCS relates to inability of the immature myocardium to tolerate the change in left ventricular loading conditions. Preliminary data demonstrates the efficacy of milrinone in reducing the incidence of PLCS through optimizing heart function. The Clinical Coordinating Center MPI Dr. Patrick McNamara, a world leading hemodynamics scientist, conducted the original mechanistic studies which characterized the biological mechanisms of PLCS and the pharmacology of milrinone. Dr Edward Bell (MPI) has an extensive record in leading multicenter clinical trials and the Data Coordinating Center (DCC) PI Dr. Abhik Das has led several NHLBI funded trials. Innovation: In most centers PLCS is recognized late, when hypotension is severe, and prompts use of vasopressor drugs which impair heart function. There are no prior randomized clinical trials of milrinone after PDA closure; therefore, neither treatment efficacy nor long-term safety is known. We propose a randomized controlled trial (RCT) to evaluate the immediate benefits of milrinone in decreasing the rate of PLCS and 7-day mortality. The need to assess long-term outcomes of RCTs is compelling to ensure treatment safety. Approach: We will perform a RCT in preterm infants born less than 28 weeks’ gestation asking: “Does routine use of intravenous milrinone lower the risk of PLCS or mortality within 7 days of intervention and is treatment safe?” The question is relevant to the mission of NHLBI and aligns with parental values to minimize postprocedural risk. In addition, it represents a paradigm shift in Neonatology to conduct clinical trials of treatments that offer biologic plausibility in illnesses that have been mechanistically characterized. Environment: We have partnered with the NICHD Neonatal Research Network (NRN), which includes 15 clinical centers, and have added 4 additional sites to maximize enrollment capabilities. We believe this trial is both feasible and achievable based on the prior track record of NRN in completing meaningful clinical trials.
