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 µg/kg) over 60 mins followed by a maintenance infusion (0.33-0.99 µg/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, and steady 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.

Patent ductus arteriosus ligation is associated with impaired left ventricular systolic performance in premature infants weighing less than 1000 g.

OBJECTIVE: Patent ductus arteriosus ligation is often complicated by systemic hypotension and oxygenation failure. The ability of the immature myocardium to compensate for altered afterload is poorly understood. The aim of this study was to characterize the effects of patent ductus arteriosus ligation on myocardial performance in preterm infants. METHODS: Serial echocardiographic analysis was performed before and after patent ductus arteriosus ligation. Characteristics of the patent ductus arteriosus, myocardial performance (fractional shortening, mean velocity of circumferential fiber shortening, and left ventricular output) and left ventricular afterload (end-systolic wall stress) were assessed. The stress-velocity relationship was measured as a preload-independent, afterload-adjusted measure of myocardial contractility. RESULTS: Forty-six preterm infants were assessed at 28.5 +/- 11.3 days and a weight of 1058 +/- 272 g. Patent ductus arteriosus ligation was followed by increased left ventricular exposed vascular resistance temporally coinciding with reduced left ventricular preload, decreased left ventricular contractility, and low left ventricular output. Neonates weighing 1000 g or less had a higher rate of low fractional shortening (<25%) or low left ventricular output (<170 mL x kg(-1) x h(-1)) and increased need for cardiotropes and demonstrated a trend toward an impaired stress-velocity relationship. Neonates with impaired left ventricular systolic performance were more likely to require cardiotropes and have low systolic arterial pressure, increased heart rate, and abnormal base deficit. CONCLUSION: Patent ductus arteriosus ligation is sometimes associated with impaired left ventricular systolic performance, which is most likely attributable to altered loading conditions. Neonates weighing 1000 g or less are at increased risk of impaired left ventricular systolic performance, which might relate to maturational differences and decreased tolerance to altered loading conditions.