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 administrat ion 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 normox ia into hypoxia (similar to 50 mmHg) at constant end-tidal partial pressure of carbon dioxide (similar to 48 mmHg) were performed in nine male volunte ers 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 sevoflura ne. The alfentanil-sevoflurane interactions on normoxic resting (hypercapni c) ventilation ((V) over dot(i)), HR, hypoxic (V) over dot(i), and HR respo nses and BIS were assessed by construction of response surfaces that relate d alfentanil and sevoflurane to effect using a population analysis. Results: Concentration-effect relations were linear for alfentanil and sevo flurane. 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% sevofluran e. One possibility for 25% reduction when alfentanil and sevoflurane are co mbined is 13.4 ng/ml alfentanil plus 0.12 ET% sevoflurane. Additive interac tions were observed for hypoxic (V) over dot(i) and HR responses and BIS. D epression 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 sevofl urane on the BIS (25% reduction of BIS occurred at 0.45 +/- 0.08 ET%) was i ndependent of the alfentanil concentration. Conclusions: Response surface modeling was used successfully to analyze the effect of interactions between two drugs on respiration. The combination o f alfentanil and sevoflurane causes more depression of (V) over dot(i) and HR than does the summed effect of each drug administered separately. The ef fects of combining alfentanil and sevoflurane on hypoxic (V) over dot(i) an d HR responses and BIS could be predicted from the separate dose-response c urves, Over the dose range tested, the hypoxic response is more sensitive t o the effects of anesthetics and opioids relative to resting ventilation.