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

Study Overview
=================
Brief Summary
-----------------
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).

Detailed Description
-----------------
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.

Official Title
-----------------
Milrinone Pharmacokinetics and Pharmacodynamics in Newborns With Persistent Pulmonary Hypertension of the Newborn - a Pilot Study to Enable a Randomized Trial of Intervention

Conditions
-----------------
Persistent Fetal Circulation Syndrome

Intervention / Treatment
-----------------
* Drug: Milrinone Lactate


Participation Criteria
=================
Eligibility Criteria
-----------------
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 (FiO2) 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 extracorporeal membrane oxygenation (ECMO)or plan to initiate ECMO within 2 hours of enrollment

Ages Eligible for Study
-----------------
Maximum Age: 10 Days

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Dose Milrinone<br>Subjects will receive a bolus intravenous (IV) infusion of 50 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.5 mcg/kg/min milrinone lactate over 24 hours. After completion of infusion, subjects will be monitored for an additional 24 hours. | Drug: Milrinone Lactate<br>* Milrinone lactate will be given first as an IV bolus over one hour at the assigned dose level, followed by a 24 hour IV infusion at the assigned dose level.<br>* Other names: Milrinone;|
| Experimental: Low Dose Milrinone<br>Subjects will receive a bolus intravenous (IV) infusion of 20 mcg/kg/min of milrinone lactate over 1 hour followed by a continuous IV infusion of 0.2 mcg/kg/min milrinone lactate over 24 hours. After completion of infusion, subjects will be monitored for an additional 24 hours. | Drug: Milrinone Lactate<br>* Milrinone lactate will be given first as an IV bolus over one hour at the assigned dose level, followed by a 24 hour IV infusion at the assigned dose level.<br>* Other names: Milrinone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) | The schedule of milrinone pharmacokinetic (PK) sampling varied by weight to minimize blood sampling. For babies weighing less than 3kg, samples were drawn at the end of the bolus, 15 minutes prior to the end of infusion (EOI) and 20 minutes, 1, 2, 6 and 12 hours after EOI. For babies weighing 3kg or more, samples were drawn at the end of the bolus, 6 hours after start of infusion, 15 minutes prior to the EOI and 30 minutes, 1, 3, 9 and 15 hours after EOI. Milrinone plasma concentrations were determined using a validated high-performance mass spectrometry assay. | End of bolus dose, 15 minutes prior to end of infusion (EOI), at four time points after EOI with final sample at 12-15 hours after EOI (timing based on infant's weight) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | Oxygenation Index (mean airway pressure*Fraction of Inspired Oxygen/Partial Pressure of Oxygen in the blood) was calculated at baseline and every 6 hours after start of infusion until 12-24 hours after initiation of milrinone infusion. | for up to 24 hours after start of infusion | 
| Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | An echocardiogram obtained while on milrinone was obtained with the goal of attempting to look for improvements in parameters associated with pulmonary hypertension. The primary parameter measured was the myocardial performance index (MPI). An Echocardiogram was performed at baseline (pre-infusion) and repeated 12-24 hours ater the initiation of the Milrinone infusion. Also known as the Tei index, the MPI is an index that incorporates both systolic and diastolic time intervals in expressing global systolic and diastolic ventricular function. Systolic dysfunction prolongs preejection (isovolumic contraction time, IVCT) and a shortening of the ejection time (ET). Both systolic and diastolic dysfunction result in abnormality in myocardial relaxation which prolongs the relaxation period (isovolumic relaxation time, IVRT). Normal value for MPI is 0.39+/-0.05 with dilated cardiomyopathy value of MPI at 0.59+/-0.10 (both units on a scale) | Up to 24 hours after start of infusion | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Persistent pulmonary hypertension of newborn, PPHN, Persistent pulmonary hypertension, Pulmonary hypertension, Pulmonary hypertension of newborn