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Population Pharmacokinetic Analysis of Gentamicin in Pediatric Extracorporeal Membrane Oxygenation
Brady S Moffett1,2, Jennifer Morris1,2, Marianne Galati3
1Department of Pharmacy, Texas Children's Hospital.
Insights
Optimizing gentamicin dosing in pediatric patients on extracorporeal membrane oxygenation (ECMO) is crucial. Fat-free mass and serum creatinine are key variables for accurate gentamicin dosing in these critically ill children.
Area of Science:
- Pharmacology
- Pediatric Critical Care
- Extracorporeal Life Support
Background:
- Gentamicin pharmacokinetics can be significantly altered in pediatric patients requiring extracorporeal membrane oxygenation (ECMO).
- Understanding these altered pharmacokinetics is essential for optimizing gentamicin dosing strategies.
- Improved dosing can enhance therapeutic efficacy and minimize toxicity in this vulnerable population.
Purpose of the Study:
- To describe gentamicin pharmacokinetics in pediatric patients undergoing ECMO.
- To identify key patient and circuit variables influencing gentamicin dosing.
- To develop evidence-based empiric dosing recommendations for gentamicin in pediatric ECMO patients.
Main Methods:
- A retrospective population pharmacokinetic study included pediatric patients receiving gentamicin during ECMO therapy.
- Data collected encompassed patient demographics, laboratory values, gentamicin concentrations, and ECMO parameters.
- Population pharmacokinetic analysis utilized NONMEM software, followed by simulations for dose optimization.
Main Results:
- A 2-compartment pharmacokinetic model was identified, with fat-free mass, serum creatinine, and ultrafiltration rate as significant covariates.
- Simulations suggested an empiric gentamicin dose of 4-5 mg/kg/dose every 24 hours for neonates and infants.
- Traditional dosing methods resulted in elevated gentamicin trough concentrations in older pediatric patients.
Conclusions:
- Fat-free mass is a critical determinant for gentamicin dosing in pediatric ECMO patients.
- Serum creatinine serves as a valuable marker for adjusting gentamicin dosage in this population.
- Implementing these findings can lead to more precise and effective gentamicin therapy during ECMO.
Background:
Gentamicin pharmacokinetics may be altered in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO). Description of gentamicin pharmacokinetics and relevant variables can improve dosing.
Methods:
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.
Results:
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.
Conclusions:
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.
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