Response surface modeling of alfentanil-sevoflurane interaction on cardiorespiratory control and bispectral index

Background: Respiratory depression is a serious side effect of anesthetics and opioids, The authors examined the influence of the combined administration of sevoflurane and alfentanil on ventilatory control, heart rate (IIR), and Bispectral Index (BIS) in healthy volunteers. Methods: Step decreases in end-tidal partial pressure of oxygen from normoxia into hypoxia (similar to 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (similar to 48 mmHg) were performed in nine male volunteers at various concentrations of alfentanil and sevoflurane, ranging from 0 to 50 ng/ml for alfentanil and from 0 to 0.4 end-tidal concentration (ET%) for sevoflurane, and with various combinations of alfentanil and sevoflurane. The alfentanil-sevoflurane interactions on normoxic resting (hypercapnic) ventilation ((V) over dot(i)), HR, hypoxic (V) over dot(i), and HR responses and BIS were assessed by construction of response surfaces that related alfentanil and sevoflurane to effect using a population analysis. Results: Concentration-effect relations were linear for alfentanil and sevoflurane. Synergistic interactions were observed for resting (V) over dot(i) and resting HR. Depression of (V) over dot(i) by 25% occurred at 38 +/- 11 ng/ml alfentanil (population mean i: SE) and at 0.7 +/- 0.4 ET% sevoflurane. One possibility for 25% reduction when alfentanil and sevoflurane are combined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interactions were observed for hypoxic (V) over dot(i) and HR responses and BIS. Depression of the hypoxic (V) over dot(i) response by 25% occurred at 16 +/- 1 ng/ml alfentanil and 0.14 +/- 0.05 ET% sevoflurane. The effect of sevoflurane on the BIS (25% reduction of BIS occurred at 0.45 +/- 0.08 ET%) was independent of the alfentanil concentration. Conclusions: Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination of alfentanil and sevoflurane causes more depression of (V) over dot(i) and HR than does the summed effect of each drug administered separately. The effects of combining alfentanil and sevoflurane on hypoxic (V) over dot(i) and HR responses and BIS could be predicted from the separate dose-response curves, Over the dose range tested, the hypoxic response is more sensitive to the effects of anesthetics and opioids relative to resting ventilation.