Pharmacokinetic Study of Milrinone in Babies With Persistent Pulmonary Hypertension of the Newborn

• Pharmacokinetic profile of milrinone in newborns with PPHN [ Time Frame: according to weight (see below) ] [ Designated as safety issue: No ]
  For infants <3 kg, samples will be collected at end of bolus, 15min prior to end of infusion (EOI), and after EOI at 20min, 1hr, 2hr, 6hr, & 12 hr. For infants >3 kg, samples will be collected at end of bolus, 6 hours after start of infusion, 15min prior to end of infusion (EOI), and after EOI at 30min, 1hr, 3hr, 9hr, & 15 hr. Samples will be stored at -70C and milrinone plasma concentrations measured by modification of a high-pressure liquid chromatography assay in laboratory of Clinical Pharmacology and Therapeutics at CHOP.
  
  

• Oxygenation index [ Time Frame: every 6 hours for 48 hours ] [ Designated as safety issue: No ]
  Oxygenation index (mean airway pressure*FiO2/PaO2) will be calculated every 6 hours.
  
  
• Echocardiographic signs of pulmonary hypertension [ Time Frame: 12-24 hours ] [ Designated as safety issue: No ]
  An echocardiogram obtained while on milrinone will look for improvements in parameters associated with pulmonary hypertension. Parameters measured will be: myocardial performance index (MPI) of LV and RV, cardiac output of LV, tricuspid regurgitation (trivial, mild, moderate, severe), RV systolic pressure, mitral regurgitation (trivial, mild, moderate, severe), presence or absence of patent foramen ovale (PFO) with peak and mean pressure gradient, and presence or absence of patent ductus arteriosus (PDA) with peak and mean pressure gradient.
  
  
• Safety profile [ Time Frame: 24-48 hours ] [ Designated as safety issue: Yes ]
  Safety analysis will be performed as follows: blood pressure will be monitored hourly for 48 hours, platelet count will be recorded daily, cardiac rhythm will be monitored continuously for 48 hours, renal function will be recorded daily, and liver transaminases will be recorded within a week. All adverse events will be included in the safety analysis. Interim safety analyses will be performed after 1/3 and 2/3 of subjects have been enrolled. A data safety monitoring committee will meet monthly to discuss adverse events and interim analyses.
  
  

Persistent pulmonary hypertension of the newborn (PPHN) is a condition in which the pulmonary vasculature fails to relax after birth resulting in severe hypoxemia. This condition has a high rate of mortality and morbidity. The current standard of care is treatment with inhaled nitric oxide (iNO). However, for many babies this treatment does not provide sufficient improvement in oxygenation.

In this study, subjects already receiving nitric oxide will be randomized to one of two dosing regimens of milrinone. They will receive milrinone IV for 24 hours and will be monitored for 24 hours afterwards. During this time, milrinone assays will be performed by blood sampling. Echocardiograms will also be performed to explore the pharmacodynamics of milrinone. Safety monitoring will be performed.