Population pharmacokinetics of etomidate in neonates and infants with congenital heart disease

Abstract

Background Etomidate is a rapid-onset, short-acting hypnotic medication administered for the induction of anesthesia. It is currently approved by the Food and Drug Administration for use in older children and adults. Pharmacokinetic data to help guide dosing in neonates and infants are lacking. Objective The aim of this study was to determine the pharmacokinetics of etomidate in neonates and infants with congenital heart disease undergoing cardiac surgery. Methods Four neonates and 16 infants, postnatal age 0.3-11.7 months, requiring open-heart surgery received 0.3 mg/kg of etomidate administered as a single intravenous dose prior to surgery. Blood sampling for plasma etomidate concentration occurred immediately following etomidate administration until the initiation of cardiopulmonary bypass. A population pharmacokinetic approach using nonlinear mixed-effects modeling was applied to characterize etomidate pharmacokinetics. Results The pharmacokinetics of etomidate was described by a two-compartment model with first-order elimination. An allometric weight-based model was applied to scale results to a 70 kg adult. Covariates including age and cardiac physiology were not found significantly to impact etomidate pharmacokinetics. The study population was found to have a central and intercompartmental clearance of 0.624 l/min/70 kg and 0.44 l/min/70 kg, respectively; central and peripheral distribution volume of 9.47 l/70 kgand 22.8 l/70 kg, respectively. Inter-individual variability was 94-142% for all parameters and the residual variability was 29%. Conclusions The clearance of etomidate is lower in neonates and infants with congenital heart disease compared with published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population.