title: Response surface analysis of sevoflurane-remifentanil interactions on consciousness during anesthesia.
abstract: BACKGROUND
  Recently, the combination of sevoflurane and remifentanil has been widely used in general anesthesia. In this study, we investigated the sevoflurane-remifentanil pharmacodynamic interactions at clinical concentrations using the observer's assessment of alertness/sedation (OAA/S) and the bispectral index (BIS) by response surface analysis.
  
  
  METHODS
  Totally 65 American Society of Anesthesiologists (ASA) I patients age 20 to 50 years old were included in this study. Patients were randomly assigned to be anesthetized with different target end-tidal sevoflurane concentrations that ranged from 0.2% to 3.4% in increments of 0.2%. The end-tidal sevoflurane concentration was maintained constant throughout the study. Remifentanil was infused with a target controlled infusion (TCI) system at increasing step-wise concentrations from 1 ng/ml to 10 ng/ml. The values of OAA/S and BIS at different sevoflurane-remifentanil concentration combinations were measured. The pharmacodynamic interactions between sevoflurane and remifentanil were analyzed by a response surface method. The three-dimensional response surfaces were constructed with Minitab Software. Model parameters were estimated with NONMEM program.
  
  
  RESULTS
  Sevoflurane and remifentanil acted synergistically on OAA/S. Sevoflurane alone could produce OAA/S ≤ 1 at a minimal alveolar concentration (MAC) of 0.93%. When used in combination with remifentanil at 1, 3, 6, and 10 ng/ml, the corresponding sevoflurane MACs were reduced to 0.79%, 0.58%, 0.48%, and 0.38%, with reductions of 17.2%, 37.6%, 48.4%, and 62.0% from baseline, respectively. In patients administered remifentanil alone, the OAA/S score was ≥ 3 even when the remifentanil concentration reached 10 ng/ml. BIS was closely associated with the sevoflurane concentration and the remifentanil concentration did not noticeably influence the relationship between the sevoflurane concentration and BIS. A sevoflurane concentration of (1.04 ± 0.19)% to (1.81 ± 0.21)% could maintain a BIS between 60 and 40.
  
  
  CONCLUSIONS
  The response surface method can analyze the pharmacodynamic interactions between remifentanil and sevoflurane qualitatively and quantitatively. Within the range of our study (remifentanil ≤ 10 ng/ml, sevoflurane ≤ 3.4%), the two drugs produced synergistic effects on OAA/S but had no interactive effect on BIS. A guideline of BIS between 40 and 60 may cause excessive anesthesia when opioids are used to maintain anesthesia.
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, China.
authors.forename: Hui-Ling
authors.initials: HL
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Yang
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Guo
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Zhang
authors.forename: Shan-Shan
authors.initials: SS
authors.lastname: Bi
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
mesh_terms: D000328:Adult; D000758:Anesthesia / Q000379:methods*; D003243:Consciousness / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008738:Methyl Ethers / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008875:Middle Aged; D010880:Piperidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077208:Remifentanil; D000077149:Sevoflurane; D055815:Young Adult
chemical_list: D008738:Methyl Ethers; D010880:Piperidines; D000077149:Sevoflurane; D000077208:Remifentanil