Antimicrobial Disposition During Pediatric Continuous Renal Replacement Therapy Using an Ex Vivo Model

Abstract

Objectives: Little is known on the impact of continuous renal replacement therapy on antimicrobial dose requirements in children. In this study, we evaluated the pharmacokinetics of commonly administered antimicrobials in an ex vivo continuous renal replacement therapy model. Design: An ex vivo continuous renal replacement therapy circuit was used to evaluate drug-circuit interactions and determine the disposition of five commonly used antimicrobials (meropenem, piperacillin, liposomal amphotericin B, caspofungin, and voriconazole). Setting: University research laboratory. Patients: None. Interventions: Antimicrobials were administered into a reservoir containing whole human blood. The reservoir was connected to a pediatric continuous renal replacement therapy circuit programmed for a 10 kg child. Continuous renal replacement therapy was performed in the hemodiafiltration mode and in three phases correlating with three different continuous renal replacement therapy clearance rates: 1) no clearance (0 mL/kg/hr, to measure adsorption), 2) low clearance (20 mL/kg/hr), and 3) high clearance (40 mL/kg/hr). Blood samples were drawn directly from the reservoir at baseline and at 5, 20, 60, and 180 minutes during each phase. Five independent continuous renal replacement therapy runs were performed to assess inter-run variability. Antimicrobial concentrations were measured using validated liquid chromatography-mass spectrometry assays. A closed-loop, flow-through pharmacokinetic model was developed to analyze concentration-time profiles for each drug. Measurements and Main Results: Circuit adsorption of antimicrobials ranged between 13% and 27%. Meropenem, piperacillin, and voriconazole were cleared by the continuous renal replacement therapy circuit and clearance increased with increasing continuous renal replacement therapy clearance rates (7.66 mL/min, 4.97 mL/min, and 2.67 mL/min, respectively, for high continuous renal replacement therapy clearance). Amphotericin B and caspofungin had minimal circuit clearance and did not change with increasing continuous renal replacement therapy clearance rates. Conclusions: Careful consideration of drug-circuit interactions during continuous renal replacement therapy is essential for appropriate drug dosing in critically ill children. Antimicrobials have unique adsorption and clearance profiles during continuous renal replacement therapy, and this knowledge is important to optimize antimicrobial therapy.