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 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 is 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 sixteen 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 to significantly 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 and 22.8 L/70-kg, respectively. Inter-individual variability was between 94–142% for all parameters and residual variability was 29%. Conclusions The clearance of etomidate is lower in neonates and infants with congenital heart disease compared to published values for older children without congenital heart disease. In addition, etomidate pharmacokinetics is highly variable in this pediatric cardiac population.

Theophylline Population Pharmacokinetics and Dosing in Children Following Congenital Heart Surgery With Cardiopulmonary Bypass

“…More sensitive and specific measures of cardiac physiology, organ perfusion, and/or organ function are likely needed for such a complex and heterogeneous population. Further, our findings are in line with previous studies, which have also shown that marked alterations in drug clearance and/or volume are common in children undergoing cardiac surgery requiring CPB …”

“…Further, our findings are in line with previous studies, which have also shown that marked alterations in drug clearance and/or volume are common in children undergoing cardiac surgery requiring CPB. [25][26][27] Because of this markedly reduced clearance in children after cardiac surgery requiring CPB, typical recommended aminophylline doses for children will be inappropriate. The predicted steady-state serum concentration using the FDA-recommended continuous infusion rate of 1 mg/kg/h in a 2-year-old after cardiac surgery requiring CPB is 31 mg/L, which is potentially toxic.…”

“…Cardiac disease, surgery, and CPB can all impact drug pharmacokinetics. [25][26][27] In addition, optimizing theophylline exposure is important because theophylline has a narrow therapeutic index, and toxicities including cardiac arrhythmias and seizures can be seen at higher exposures (ie, concentrations >20 mg/L). 28 The objectives of the current study were (1) to evaluate the pharmacokinetics of theophylline in children after cardiac surgery requiring CPB using a population-based approach and (2) to identify an empiric aminophylline dosing strategy that optimizes achievement of target serum drug concentrations.…”

“…However, the pharmacokinetics in infants and children undergoing cardiac surgery with CPB has not been reported. Cardiac disease, surgery, and CPB can all impact drug pharmacokinetics . In addition, optimizing theophylline exposure is important because theophylline has a narrow therapeutic index, and toxicities including cardiac arrhythmias and seizures can be seen at higher exposures (ie, concentrations >20 mg/L) .…”

Etomidate in pediatric anesthesiology: Where are we now?

“…However, more recent pharmacokinetic data provide support for the use of a larger dose in pediatric patients with the general conclusions that due to enhanced clearance and increased central compartment volume, younger children will require a higher etomidate bolus dose than older children to achieve equivalent plasma concentrations. [ 11 12 ]…”