Pilot study of milrinone for low systemic blood flow in very preterm infants

Objectives

To examine the hemodynamic effects of milrinone given prophylactically to very preterm infants at high risk of low superior vena cava (SVC) flow and to investigate the preliminary efficacy and safety of an optimal dose.

Study design

This was a prospective, open-label study in two stages. The first involved dose escalation in two cohorts. Milrinone infusions of 0.25 μg/kg per minute (n = 8) and then 0.5 μg/kg per minute (n = 11) were administered from 3 to 24 hours of age. Population pharmacokinetic modeling was used to develop an optimized dose regimen. Ten infants then were loaded with 0.75 μg/kg per minute for 3 hours, followed by 0.2 μg/kg per minute maintenance until 18 hours of age. Infants were monitored for blood pressure, serial echocardiograms, and blood milrinone levels. The primary outcome was maintenance of SVC flow greater than 45 mL/kg per minute through the first 24 hours.

Results

Low SVC flow developed in 36% of babies at both 0.25 μg/kg per minute and 0.5 μg/kg per minute of milrinone. Blood levels on these two regimens were slow to reach the target range and accumulated above this range by 24 hours. At 0.75 to 0.2 μg/kg per minute, no infant had SVC flow below 45 mL/kg per minute, compared with 61% in historic control subjects. Four infants needed an additional inotrope to support blood pressure. Blood levels were within the target range in 9 of 10 babies.

Conclusions

We used population pharmacokinetic modeling to develop an optimal dosing regimen for milrinone. The efficacy and safety in this novel preventative approach to circulatory support is encouraging but inconclusive. We do not recommend the use of milrinone in preterm infants outside a research setting.

Abbreviations:  LCOS, Low cardiac output syndrome , MBP, Mean blood pressure , MCA, Middle cerebral artery , P/IVH, Peri/intraventricular hemorrhage , RVO, Right ventricular output , SVC, Superior vena cava