Comparative population pharmacokinetics of fentanyl using non-linear mixed effect modeling: Burns vs. non-burns

Objective: Fentanyl is a commonly used analgesic and sedative for the burned in the operating theater as well as the burn care units. The aim of this study was to characterize fentanyl population pharmacokinetics in burns and to identify clinically significant covariates. Method: Twenty adults, aged 37 +/- 3 years, with 49 +/- 4% (mean +/- S.E.) total body surface area burn, were enrolled at 17 +/- 3 days after the injury. Twenty non-burn adults served as controls. After an intravenous bolus of 200 mcg fentanyl, the plasma concentrations were sequentially determined up to 4.5 h. Concentration-time profiles were subjected to nonlinear mixed effect modeling. Cardiac indices were estimated with esophageal Doppler monitor. Results: Burned patients have higher cardiac index than the non-burned. Three-compartment model was the best fit. The volumes of distribution were considerably expanded in all three compartments (27.9 L vs. 63.4 L, 64.7 L vs. 92.9 L,153 L vs. 301 L, respectively) compared to the non-burned. BURN was the single most important covariate significantly improving the model. Conclusion: The primary effect of burn trauma on fentanyl pharmacokinetics is substantially expanded volumes of distribution, i.e., dilutional. Difference in simulation, however, was insufficient to explain the augmented resistance to fentanyl, implying the importance of titrating analgesics to the clinical effect. (C) 2008 Elsevier Ltd and ISBI. All rights reserved.