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

• 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.

• 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 measured daily, cardiac rhythm will be monitored continuously for 48 hours, renal function will be monitored daily, and liver transaminases will be monitored 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.

The purpose of this pilot study is to determine a safe dose of milrinone to use in a larger study of babies with persistent pulmonary hypertension of the newborn (PPHN).

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.

• Experimental: high dose
  50 mcg/kg load followed by 0.5 mcg/kg/min infusion
  Intervention: Drug: milrinone lactate
• Experimental: low dose
  20 mcg/kg load followed by 0.2 mcg/kg/min infusion
  Intervention: Drug: milrinone lactate

Inclusion Criteria:

• Gestational age > 34 weeks
• Post-natal age < 10 days
• Hypoxemia defined by: Oxygenation Index (OI) >15 (Mean Airway Pressure x Fraction of Inspired Oxygen x 100 /PaO2) as drawn from two post-ductal arterial blood gas samples (in-dwelling arterial catheter) taken at least 15 minutes apart. OR mechanically ventilated and with >75% FiO2 for >6 hours while on iNO
• Absence of congenital heart disease based on a two-dimensional echocardiogram and/or clinical assessment
• An in-dwelling arterial catheter to facilitate painless sampling
• Currently on iNO or plan to start iNO before enrollment

Exclusion Criteria:

• Lethal non-cardiac congenital anomalies including diaphragmatic hernia
• Clinically apparent bleeding; thrombocytopenia <30,000 or other laboratory evidence of coagulopathy
• Currently on ECMO or plan to initiate ECMO within 2 hours of enrollment

• University of Pennsylvania
• Bedford Pharmaceuticals
• American Medical Association
• Thrasher Research Fund