Milrinone for Prevention of Post-ligation Cardiac Syndrome Trial

The goal of this Phase 3, randomized, masked clinical trial is to is to find out whether milrinone, when given to infants after PDA closure, will help the heart work better by supplying oxygen to the lungs and tissues. The main questions it aims to answer are: 1. to determine if milrinone decreases the risk of death or PLCS within 7 days of the procedure, compared to standard treatment; and 2. to determine the effects of milrinone on two-year survival and neurodevelopmental outcome.

Researchers will compare milrinone to a placebo saline solution to see if it helps the heart work better by supplying oxygen to the lungs and tissues. After randomization the following will happen in both the control and treatment groups: * Infant will start receiving either a low dose (0.33 μg/kg/min) of milrinone in the treatment group, OR saline solution in the control group through an intravenous (IV) line. The study drug will be started within 2 hours of the PDA closure procedure. * For the first 2 to 4 hours, the study team will monitor very closely to see if there are any major side effects from the study drug. * If the infant continues to have high blood pressure, which places an added stress on the heart, the dose will go up to 0.66 μg/kg/min. One more increase will be allowed to 0.75 μg/kg/min. The study drug will then stay at this dose. No more changes will happen to the dose. If there are side effects, then the study drug will be stopped and will not be started again. * The study drug will be stopped after 24 hours if the infant only required the lowest drug and remains well. If the required higher doses of milrinone, it will take longer to wean them off the medication. Some infants may receive milrinone for 3-5 days. If the infant's heart starts to work better by using less oxygen from the breathing machine (ventilator), the study drug may be stopped before 3 days. * Information will be collected from the infant's medical record including demographic information, gestational age, blood pressures, heart rates, respiratory rates, information about his or her breathing, medications, details of medical treatment for PDA, medical procedures including echocardiograms (ultrasound of the baby's heart), details of PDA closure (by surgery or transcatheter closure), head ultrasounds, and diagnoses. The investigators will also be collecting information from the maternal medical record including ultrasounds that may be relevant to the infant's course. * Right after the study drug is stopped (which could be 5 days or less) the doctor may decide to give the infant the drug milrinone. This is a decision that will be made by the infant's doctor. * After the infant goes home from the hospital, they will be scheduled for follow-up exams in the clinic. The follow-up visit will be done when the infant is about 2 years old. The visit will take about two hours to do. During the follow-up visit the investigators will test the infant's movement, behavior, and development. The investigators will also check the infant to make sure they do not have high blood pressure or any evidence of kidney disease.

Inclusion Criteria: * Gestational age at birth ≤27 weeks (and 6 days) and postnatal age \< 3 months at intervention * Invasive or non-invasive positive pressure respiratory support (does not include low flow nasal cannula) * Hemodynamically significant PDA with minimum transductal diameter ≥1.0 mm within 2 days of intervention * Decision by clinical team to proceed with PDA closure via surgical ligation or percutaneous cardiac catheterization based on clinical and echocardiography features of hemodynamic significance. Exclusion Criteria: * Any major congenital malformation * Congenital heart disease (except small (≤1mm) muscular ventricular septal defects, or small/moderate (\<3mm) atrial septal defect) * Acute renal failure defined by urine output \< 0.5 mL/kg/hour OR rise of serum creatinine by 0.3 mg/dL within 48 hours OR rise of serum creatinine more than 40% above baseline serum creatinine within prior 72 hours. * Systemic administration of vasodilator/inodilator agents * Prior history of arrhythmia