title: 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 Emax 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 (R) 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.
authors.affiliation: Department of Anesthesiology and Pain Medicine, Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Han
authors.forename: Kyungsoo
authors.initials: K
authors.lastname: Park
authors.forename: Seong Bok
authors.initials: SB
authors.lastname: Jang
authors.forename: Steven E
authors.initials: SE
authors.lastname: Kern
mesh_terms: D000328:Adult; D018685:Anesthetics, Inhalation / Q000009:adverse effects* / Q000493:pharmacokinetics; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008738:Methyl Ethers / Q000009:adverse effects* / Q000493:pharmacokinetics; D008875:Middle Aged; D015233:Models, Statistical; D011229:Preanesthetic Medication; D000077149:Sevoflurane; D055815:Young Adult
chemical_list: D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D000077149:Sevoflurane