Piperacillin Population Pharmacokinetics in Children Supported With Extracorporeal Membrane Oxygenation.

Abstract

Objective: To characterize piperacillin population pharmacokinetics (PK) in critically ill children with and without extracorporeal membrane oxygenation (ECMO) support and to optimize piperacillin dosing regimens to attain the PK target of 100% free time above minimum inhibitory concentration (fT > minimum inhibitory concentration).

Design: Post hoc secondary analysis of a two-center, population PK modeling and simulation study (registered at clinicaltrials.gov , NCT02539407).

Settings: PICUs at tertiary care centers, September 2015-November 2021.

Patients: Thirty-three children supported with ECMO and 50 non-ECMO control patients treated with piperacillin (± tazobactam).

Interventions: Administration of piperacillin at 300 mg/kg/d by continuous infusion or 75 mg/kg every 6 hours by intermittent infusion.

Measurements and main results: A one-compartment linear-elimination model described best the piperacillin data. Clearance was driven by body weight and estimated glomerular filtration rate (eGFR). In a typical 11-kg patient, ECMO circuit volume-to-weight ratio increased the volume of distribution by 34%. Monte Carlo simulations across eGFR strata (30-60, 60-90, 90-150, 150-200, 200-300 mL/min/1.73 m 2 ) showed that a continuous infusion of 300 mg/kg/d allowed greater than or equal to 90% of target attainment in all groups. Patients with an eGFR greater than 200 mL/min/1.73 m 2 required 400 mg/kg/d to have 90% of target attainment.

Conclusions: Continuous infusion of 300 mg/kg/d piperacillin reliably achieves PK target across all renal-function ranges in children undergoing support with ECMO. Dose escalation to 400 mg/kg/d is required for augmented renal clearance (eGFR > 200 mL/min/1.73 m 2 ).