A Population Pharmacokinetic Analysis to Study the Effect of Extracorporeal Membrane Oxygenation on Cefepime Disposition in Children

Abstract

Objective:

Limited data exist on the effects of extracorporeal membrane oxygenation (ECMO) on pharmacokinetics of cefepime in critically ill pediatric patients. The objective was to describe cefepime disposition in children treated with ECMO using population pharmacokinetic modeling.

Design:

Multi-center, prospective observational study

Setting:

The pediatric and cardiac intensive care units of six sites of the Collaborative Pediatric Critical Care Research Network.

Patients:

Seventeen critically ill children (30 days to < 2 years old) on ECMO who received cefepime as standard of care between Jan 4, 2014 and August 24, 2015 were enrolled.

Interventions:

None.

Measurements/Results:

A pharmacokinetic model was developed to evaluate cefepime disposition differences due to ECMO. A two-compartment model with linear elimination, weight effects on clearance (CL), inter-compartmental clearance (Q), central volume of distribution (V1), and peripheral volume of distribution (V2) adequately described the data. The typical value of clearance in this study was 7.1 mL/min (1.9 mL/min/kg ^0.75) for a patient weighing 5.8kg. This value decreased by approximately 40% with the addition of renal replacement therapy. The typical value for V1 was 1170 mL. In the setting of blood transfusions, V1 increased by over 2-fold, but was reduced with increasing age of the ECMO circuit oxygenator.

Conclusion:

Cefepime clearance was reduced in pediatric patients treated with ECMO compared to previously reported values in children not receiving ECMO. The model demonstrated that the age of the ECMO circuit oxygenator is inversely correlated to V1. For free cefepime, only 14 of the 19 doses (74%) demonstrated a fT_MIC of 16 mg/L, an appropriate target for the treatment of pseudomonal infections, for greater than 70% of the dosing interval. Pediatric patients on ECMO might benefit from the addition of therapeutic drug monitoring of cefepime to assure appropriate dosing.