Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation

Abstract

Aims: Extracorporeal membrane oxygenation (ECMO) is a life support system used during severe respiratory or cardiorespiratory failure. The objective of this study was to characterize the population pharmacokinetics of vancomycin during ECMO.

Methods: A population model was developed using WinNonMix (Version 2.0.1) from a total of 366 plasma observations in 45 patients, including term neonates, older children and adults. The study utilized both rich prospective and sparse retrospective data. Prospective samples were drawn at baseline and then 30, 60,90, 120, 180, 240, 300, 360 and 420 min postinfusion. Steady state concentrations were obtained retrospectively from an assay database, cross-referencing with the patients' medical records.

Results: Data were examined using a two-compartment model with an additive and proportional residual error. Model fit improved substantially when clearance, CL (l kg(-1) h(-1)) was modelled as a nonlinear function of serum creatinine (Cr) micromol l(-1). There was a linear relationship between CL and age up to 1000 days: CL (Age < 1000 days) = [2.4 + 0.0018 x Age (days)]/Cr; CL (Age > 1000 days) = 4.3/Cr. Age also influenced central volume (V1) when included in the model as a dichotomous variable: V1 (Age < 4000 days) = 0.45 l kg(-1); V1 (Age > 4000 days) = 0.36 l kg(-1). Intercompartmental clearance and tissue volume were estimated to be 0.09 l kg(-1) h(-1) and 0.25 l kg(-1), respectively. Model validation in a separate group of 20 patients revealed a bias of -7.7% and a precision of 26.7%.

Conclusions: The clearance of vancomycin was decreased and its volume of distribution increased in patients receiving ECMO, suggesting altered drug disposition during this treatment.

Figure 1

Plots of Bayesian posterior estimates of CL with covariates

Figure 2

Scatterplot of observed versus predicted plasma vancomycin concentrations (mg/L) indicated a closer distribution around the line of unity for the final model (B) versus the basic model (A)

Figure 3

Assessment of predictive performance of final population model in a separate set of 20 patients (110 observations): Plot of residual (observed minus predicted) versus predicted plasma vancomycin concentration

Figure 4

Simulated mean plasma profiles and 95% Confidence Intervals of Interindividual Variability in an age range ECMO population with serum creatinine of 100 micromol/L. (a) Neonate (1 day), 10 mg/kg every 24 hours (b) Child (1 year), 15 mg/kg every 24 hours (c) Child (10 years), 15mg/kg every 18 hours (d) Adult, 10 mg/kg every 12 hours.