Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation.

Abstract

Gentamicin pharmacokinetics may be altered in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO). Description of gentamicin pharmacokinetics and relevant variables can improve dosing. A retrospective population pharmacokinetic study was designed, and pediatric patients who received gentamicin while undergoing ECMO therapy over a period of 6 1/2 years were included. Data collection included the following: patient demographics, serum creatinine, albumin, hematocrit, gentamicin dosing and serum concentrations, urine output, and ECMO circuit parameters. Descriptive statistics were used to characterize the patient population. Population pharmacokinetic analysis was performed with NONMEM, and simulation was performed to identify empiric doses to achieve therapeutic serum concentrations. A total of 37 patients met study criteria (75.7% male patients), with a median age of 0.17 [interquartile range (IQR) 0.12-0.82] years. Primary indications for ECMO included the following: congenital diaphragmatic hernia (n = 17), persistent pulmonary hypertension (n = 5), and septic shock (n = 4). Patients received a total of 117 gentamicin doses [median 1.8 (IQR 1.4-2.9) mg/kg/dose] and had 125 serum concentrations measured at a median of 22.8 (IQR 15.8-25.5) hours after a dose. Population pharmacokinetic analysis identified a 2-compartment model with additive error as the best fit. Covariates included the following: allometrically scaled fat-free mass on clearance, central and peripheral volume of distribution (VDcentral and VDperipheral), and intercompartmental clearance; serum creatinine on clearance; ultrafiltration rate on central volume of distribution. Simulation identified dosage of 4-5 mg/kg/dose every 24 hours for neonates and infants as an acceptable empiric dosing regimen. Children and adolescents had elevated trough concentrations when dosed according to traditional dosing methods. Fat-free mass should be used to dose gentamicin in pediatric ECMO patients. Serum creatinine is a marker of gentamicin clearance and should be used to adjust gentamicin dosing in pediatric ECMO patients.