Modeling the Effect of Sevoflurane on Corrected QT Prolongation A Pharmacodynamic Analysis

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 (C-ET) 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; C-ET 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 C-ET 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 C-ET and QTc interval were observed and accounted for in the model. C-e50 and k(e0) were 2.5 +/- 1.4 and 2.0 +/- 1.0, respectively. The median prediction error, median absolute prediction error, and the co-efficient of determination (R-2) were 0.02%, 0.75%, and 0.95, respectively. The effect-site concentration (C-e50) and QTc interval data fit to a sigmoid E-max model. Conclusions: Among patients receiving sevoflurane for anesthesia, QTc interval changes correlate to anesthetic level. The C-e50 for significant QTc change is at clinically relevant levels of sevoflurane anesthesia.