Response surface analysis of sevoflurane-remifentanil interactions on consciousness during anesthesia

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 OANS. Sevoflurane alone could produce OANS 〈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 OANS 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.