Abstract
IntroductionThe aim of this study was to describe the population pharmacokinetics of vancomycin in critically ill patients treated with and without extracorporeal membrane oxygenation (ECMO).MethodsWe retrospectively reviewed data from critically ill patients treated with ECMO and matched controls who received a continuous infusion of vancomycin (35 mg/kg loading dose over 4 hours followed by a daily infusion adapted to creatinine clearance, CrCl)). The pharmacokinetics of vancomycin were described using non-linear mixed effects modeling.ResultsWe compared 11 patients treated with ECMO with 11 well-matched controls. Drug dosing was similar between groups. The median interquartile range (IQR) vancomycin concentrations in ECMO and non-ECMO patients were 51 (28 to 71) versus 45 (37 to 71) mg/L at 4 hours; 23 (16 to 38) versus 29 (21 to 35) mg/L at 12 hours; 20 (12 to 36) versus 23 (17–28) mg/L at 24 hours (ANOVA, P =0.53). Median (ranges) volume of distribution (Vd) was 99.3 (49.1 to 212.3) and 92.3 (22.4 to 149.4) L in ECMO and non-ECMO patients, respectively, and clearance 2.4 (1.7 to 4.9) versus 2.3 (1.8 to 3.6) L/h (not significant). Insufficient drug concentrations (that is drug levels <20 mg/dL) were more common in the ECMO group. The pharmacokinetic model (non-linear mixed effects modeling) was prospectively validated in five additional ECMO-treated patients over a 6-month period. Linear regression analysis comparing the observed concentrations and those predicted using the model showed good correlation (r2 of 0.67; P <0.001).ConclusionsVancomycin concentrations were similar between ECMO and non-ECMO patients in the early phase of therapy. ECMO treatment was not associated with significant changes in Vd and drug clearance compared with the control patients.
Highlights
The aim of this study was to describe the population pharmacokinetics of vancomycin in critically ill patients treated with and without extracorporeal membrane oxygenation (ECMO)
As vancomycin is expected to be poorly soluble in organic materials, drug concentrations and CL would be only minimally affected by ECMO, while the use of priming fluids and the cardiovascular alterations, which are often associated with the use of ECMO, would contribute to increase its volume of distribution (Vd) [9]
In contrast to studies on aminoglycosides, vancomycin Vd was similar in neonates treated with ECMO compared to controls (0.45 ± 0.18 versus 0.39 ± 0.12 L/kg), whereas half-life was significantly shorter during ECMO (8.3 ± 2.2 versus 6.5 versus 2.0 h, P = 0.02) [27]
Summary
The aim of this study was to describe the population pharmacokinetics of vancomycin in critically ill patients treated with and without extracorporeal membrane oxygenation (ECMO). Shekar et al highlighted that the major PK changes commonly associated with ECMO are an increased volume of distribution (Vd) and decreased drug clearance (CL) [7], the extent of such changes remains poorly characterized, especially in adult patients. Emerging in vitro/ex vivo data on dose requirements for adult patients on ECMO suggest that standard drug regimens may be inadequate [8], because of significant drug sequestration on the ECMO tubing and/ or membrane leading to lower plasma concentrations [9]. When renal replacement therapy (RRT) is initiated in those patients, the risk of insufficient drug levels when standard regimens are used is around 20% and warrants close monitoring of vancomycin concentrations [14]
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