Pharmacology of Milrinone in Neonates With Persistent Pulmonary Hypertension of the Newborn and Suboptimal Response to Inhaled Nitric Oxide

Objectives: Persistent pulmonary hypertension of the newborn is a common problem with significant morbidity and mortality. Inhaled nitric oxide is the standard care, but up to 40% of neonates are nonresponders. Milrinone is a phosphodiesterase III inhibitor which increases the bioavailability of cyclic adenosine monophosphate and has been shown to improve pulmonary hemodynamics in animal experimental models. The primary objective was to investigate the pharmacological profile of milrinone in persistent pulmonary hypertension of the newborn. Secondary objectives were to delineate short-term outcomes and safety profile. Subjects and Methods: An open label study of milrinone in neonates with persistent pulmonary hypertension of the newborn was conducted. Patients received an intravenous loading dose of milrinone (50 mu g/kg) over 60 mins followed by a maintenance infusion (0.33-0.99 mu g/kg/min) for 24-72 hrs. Physiologic indices of cardiorespiratory stability and details of cointerventions were recorded. Serial blood milrinone levels were collected after the bolus, following initiation of the maintenance infusion to determine steady state levels, and following discontinuation of the drug to determine clearance. Echocardiography was performed before and after (1, 12 hrs) milrinone initiation. Interventions: Milrinone. Measurements and Main Results: Eleven neonates with a diagnosis of persistent pulmonary hypertension of the newborn who met eligibility criteria were studied. The median (SD) gestational age and weight at birth were 39.2 +/- 1.3 wks and 3481 +/- 603 g. The mean (+/-SD) half-life, total body clearance, volume of distribution, andsteady state concentration of milrinone were 4.1 +/- 1.1 hrs, 0.11 +/- 0.01 L/kg/hr, 0.56 +/- 0.19 L/kg, and 290.9 +/- 77.7 ng/mL. The initiation of milrinone led to an improvement in PaO2 (p = 0.002) and a sustained reduction in FIO2 (p < 0.001), oxygenation index (p < 0.001), mean airway pressure (p = 0.03), and inhaled nitric oxide dose (p < 0.001). Although a transient reduction in systolic arterial pressure (p < 0.001) was seen following the bolus, there was overall improvement in base deficit (p = 0.01) and plasma lactate (p = 0.04) with a trend towards lower inotrope score. Serial echocardiography revealed lower pulmonary artery pressure, improved right and left ventricular output, and reduced bidirectional or right-left shunting (p < 0.05) after milrinone treatment. Conclusions: The pharmacokinetics of milrinone in persistent pulmonary hypertension of the newborn is consistent with published data. The administration of intravenous milrinone led to better oxygenation and improvements in pulmonary and systemic hemodynamics in patients with suboptimal response to inhaled nitric oxide. These data support the need for a randomized controlled trial in neonates. (Pediatr Crit Care Med 2013; 14:74-84)