Phenobarbital for neonatal seizures in hypoxic ischemic encephalopathy: a pharmacokinetic study during whole body hypothermia

Abstract

Purpose: Therapeutic hypothermia has recently been introduced to treat term newborns with hypoxic-ischemic encephalopathy, of whom more than half have seizures. Phenobarbital is widely used to treat neonatal seizures, but it is unknown whether its pharmacokinetics is affected by hypothermia. We evaluated the influence of hypothermia on phenobarbital pharmacokinetics in asphyxiated newborns.

Methods: Nineteen term asphyxiated newborns treated with mild whole body hypothermia, started within 6 h after birth and protracted for 72 h, received phenobarbital for clinical seizures. Treatment schedule consisted of a loading dose of 20 mg/kg, titrated to response, up to a maximum dose of 40 mg/kg, followed by a maintenance dose of 2.5 or 1.5 mg/kg every 12 h. Phenobarbital concentrations were measured on 28 dried blood spots in each newborn.

Key findings: Eighteen newborns showed plasma concentrations within the reference range after receiving a loading dose of 20 mg/kg. In the remaining newborn, who had received a loading dose of 35 mg/kg, phenobarbital concentrations exceeded the upper reference limit. Phenobarbital concentrations reached a virtual steady state in all newborns. Pharmacokinetic parameters were then calculated. Minimum and maximum concentration (24.7 ± 8.8 and 30.63 ± 10.3 mg/L), average plasma concentration (27.37 ± 9.4 mg/L), and half-life (173.9 ± 62.5 h) were considerably higher than reported in literature for normothermic newborns. Pharmacokinetic parameters did not differ significantly between infants receiving different maintenance doses.

Significance: Phenobarbital administered to newborns under whole body hypothermia results in higher plasma concentrations and longer half-lives than expected in normothermic newborns.