Persistent Fetal Circulation Syndrome
Conditions
Keywords
Persistent pulmonary hypertension of newborn, PPHN, Persistent pulmonary hypertension, Pulmonary hypertension, Pulmonary hypertension of newborn
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.
Interventions
DRUGMilrinone Lactate
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.
Sponsors
University of Pennsylvania
Bedford Pharmaceuticals
American Medical Association
Thrasher Research Fund
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 10 Days
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | for up to 24 hours after start of 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. |
| Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | Up to 24 hours after start of 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) |
Countries
United States
Participant flow
Recruitment details
Recruitment began in June 2010 at three large academic medical centers. The study was closed to enrollment at all sites in November 2013.
Participants by arm
| Arm | Count |
|---|---|
| High Dose Milrinone Subjects received a 50mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.5mcg/kg over 24 hours | 7 |
| Low Dose Milrinone Subjects received a 20mcg/kg loading dose of milrinone lactate given intravenously (IV) over 1 hour followed by an IV infusion of 0.2mcg/kg over 24 hours | 5 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Excluded prior to receiving drug | 1 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Req. Extracorporeal membrane oxygenation | 1 | 1 |
Baseline characteristics
| Characteristic | High Dose Milrinone | Low Dose Milrinone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 7 Participants | 5 Participants | 12 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) White | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment United States | 7 participants | 5 participants | 12 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 3 / 5 |
| serious Total, serious adverse events | 0 / 7 | 0 / 5 |
Outcome results
Primary
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.
Time frame: 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)
Population: The pharmacokinetic analysis, including the primary outcome parameter, Clearance, was planned a priori to include all the participants pooled together. A PK analysis by arm wouldn't be appropriate. The randomization arms were only created to explore the secondary clinical and pharmacodynamic outcomes.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Milrinone | Define Plasma Concentration-time Profile of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn (PPHN) - Clearance (CL, mL/Min) | 7.65 mL/min/3.4 kg | Standard Error 18.8 |
Secondary
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)
Time frame: Up to 24 hours after start of infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Milrinone | Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | -.12 units on a scale | Standard Deviation 0.29 |
| Low Dose Milrinone | Change in Myocardial Performance Index (MPI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | -.09 units on a scale | Standard Deviation 0 |
Secondary
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.
Time frame: for up to 24 hours after start of infusion
Population: OI was calculated every 6 hours after start of infusion for 24 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Milrinone | Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | 4.9 units on a scale | Standard Deviation 11.5 |
| Low Dose Milrinone | Change in Oxygenation Index (OI) From Baseline to up to 24 Hours After Start of Milrinone Infusion | 36.5 units on a scale | Standard Deviation 27 |