Modeling the effect of sevoflurane on corrected QT prolongation: A pharmacodynamic analysis

Abstract

Background: Sevoflurane may prolong the corrected QT (QTc) interval in healthy humans when administered for induction and maintenance of anesthesia. Little information is available about the dose-response relationship of sevoflurane on the QTc interval. We performed a pharmacodynamic analysis of the relationship between end-tidal sevoflurane concentration (CET) and the QTc. Methods: Twenty-one patients aged 20-50 yr were enrolled in this study. Sevoflurane concentrations were progressively increased and then decreased over 15 min at the start of anesthesia; CET and automated QT interval were recorded continuously. Pharmacodynamic analysis using a sigmoid E max model was performed to assess the concentration-effect relationship. Results: Maximal CET was 4.30 ± 0.33%.Measured baseline and maximally prolonged QTc interval values were 351.7 ± 15.4 ms and 397.8±17.5 ms, respectively. During sevoflurane anesthesia, increased concentrations were correlated with prolonged QTc interval. Hysteresis between the CET and QTc interval were observed and accounted for in the model.Ce50 and ke0 were 2.5 ± 1.4 and 2.0 ± 1.0, respectively. The median prediction error, median absolute prediction error, and the coefficient of determination (R2) were 0.02%, 0.75%, and 0.95, respectively. The effect-site concentration (Ce50) and QTc interval data fit to a sigmoid Emax model. Conclusions: Among patients receiving sevoflurane for anesthesia, QTc interval changes correlate to anesthetic level. The Ce50 for significant QTc change is at clinically relevant levels of sevoflurane anesthesia. © 2010, the American Society of Anesthesiologists, Inc.