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133 Pilot Study of Milrinone for Prevention of Low Systemic Blood Flow in Very Preterm Infants

Background: Low systemic blood flow as measured by superior vena cava (SVC) flow is common in very preterm infants. It is strongly associated with IVH and disability and may be caused by poor cardiac adaptation to high vascular resistance (VR)[1]. Because of limited efficacy of therapeutic circulatory support using traditional inotropes[2], we are exploring a preventative approach using Milrinone, an inodilator that increases contractility and reduces VR. The aim of this study was to examine the safety and pharmaco-kinetics (PK) of Milrinone infusion given prophylactically from 3 hours to very preterm infants (median GA 26w) at risk of low blood flow.Methods: A dose escalation and PK study was undertaken, starting with low dose infusion (0.25mcg/kg/min) followed by a higher dose (0.5mcg/kg/min) from 3 until 24 hours of age. Monitoring was with serial echocardiography and head ultrasound (HUS). Serial blood Milrinone levels were taken for PK analysis. Using this data, a population modelling and simulation approach established an optimal dosing profile that fulfilled our preventative aim and achieved target drug levels. This regimen was to load with 0.75mcg/kg/min for 3 hours and maintain with 0.2mcg/kg/min until 18 hours of age. The primary outcome was maintenance of SVC flow >45ml/kg/min in the absence of severe hypotension. Secondary outcomes included intraventricular haemorrhage (IVH). Exit criteria: BP >24mmHg for over 30 mins unresponsive to inotropes.Results: At both infusion rates in the dose escalation phase of study, target blood levels were not achieved quickly enough, only 64% of babies maintained SVC flow and Milrinone levels were high by 24 hrs. Ten infants were then studied using the optimised regimen. All maintained SVC flow >45 ml/kg/min (compared to 40% in an historical cohort) and had drug concentrations within the target therapeutic range. No infant met exit criteria. No immediate adverse effects attributable to Milrinone were noted. There were 3 late deaths attributable to severe respiratory failure and NEC and one from late diagnosis of lethal congenital malformation.Conclusion: Population PK modelling in the preterm infant has been able to establish an optimal dose regimen for Milrinone that fulfils preventative aims. These encouraging results are currently being investigated for therapeutic efficacy within a pilot RCT.