Piperacillin Population Pharmacokinetics in Children Supported With Extracorporeal Membrane Oxygenation

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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 m2) 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 m2 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 m2).

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