Milrinone Pharmacokinetics and Pharmacodynamics in Neonates with Persistent Pulmonary Hypertension of the Newborn

Abstract

To describe the pharmacokinetics and pharmacodynamics of milrinone in infants with persistent pulmonary hypertension of the newborn (PPHN) and to explore the impact of age on milrinone disposition. Randomized, open label pilot study. Multicenter; level 3 and level 4 neonatal intensive care units. Six infants ≥34 weeks' gestational age and10 days of life with persistent hypoxemia receiving inhaled nitric oxide. Intravenous milrinone lactate in one of two dosing regimens: (1) low dose, 20 mcg/kg bolus followed by 0.2 mcg/kg/minute, and (2) standard dose, 50 mcg/kg bolus followed by 0.5 mcg/kg/minute. The final structural model was a two-compartment disposition model with interindividual variability estimated on clearance (CL). The estimated value of CL is 7.65 mL/minute/3.4 kg (3.05 mL/minute/kg). The addition of age improved the precision of the CL estimate, and CL increased with chronological age in days. The oxygenation index was highly variable within each participant and improved with time. There were no observed safety concerns in either dosing group. The CL of milrinone in newborns with PPHN is reduced and increases with age. In this pilot study, we did not see significant pharmacodynamic or safety effects associated with drug exposure.

Comprehensive Echocardiographic Assessment of Ventricular Function and Pulmonary Pressure in the Neonatal Omphalocele Population

“…36 There is currently lack of data in the newborn population, but this agent may become an interesting avenue to address patients with severe PH and underlying RV dysfunction leading to mortality. [36][37][38] Long-term evolution of PH in newborns with omphalocele remains unknown. Although some have suggested that PH resolves, 2 late PH has been described in some graduates of the NICU.…”

The Use of Cardiotonic Drugs in Neonates

“…The use of milrinone has increased significantly in the NICU 97 , primarily in the setting of PPHN. Although there are a number of case reports and case series, there are no randomized controlled trials addressing the use of milrinone in the setting of PPHN [98][99][100] . There is currently one small pilot trial enrolling and a larger planned study of milrinone in the setting of congenital diaphragmatic hernia.…”

Treating Hypotension in Preterm Neonates With Vasoactive Medications

“…Milrinone has a half-life of approximately 4 h in neonates, thus rendering a slow onset of action ( 97 , 98 ). Giaccone et al recently found that renal clearance was increased in relation to gestational and chronological age in term neonates (up to 10 days) ( 99 ). Therefore, the dosage of milrinone needs to be adjusted in renal impairment, prematurity, or early chronologic age to avoid drug accumulation and thus side effects including thrombocytopenia ( 90 , 91 , 99 ).…”