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Sufentanil (mean total dose 2 μ/kg) was compared with fentanyl (mean total dose 15 μ/kg) as a supplement to 60% N2O anesthesia in 30 adult patients undergoing general surgical procedures. Comparisons were made with respect to stability of hemodynamic variables (heart rate and systolic and diastolic blood pressure), changes in stress hormones (cortisol, antidiuretic hormone, epinephrine, norepinephrine, and dopamine), recovery of alertness and orientation, time to extubation, postoperative analgesia, and measures of respiratory depression (resting end-tidal carbon dioxide tension [PETCO2], CO2 response curve for minute ventilation [δVE/δPETCO2]). Hemodynamic variables remained stable and similar in both groups throughout the study. Plasma hormone levels remained similar to baseline in both groups until 1 h postoperatively when epinephrine levels were significantly elevated in both groups (P < 0.05). Recovery times, including time to extubation, were similar in both groups. Patients given sufentanil had less pain 30 min post-operatively than those given fentanyl, although at 60 min postoperatively pain levels were similar in both groups. Small but significant elevations in resting PETCO2 were seen in both groups postoperatively (P < 0.05), but postoperative δVE/δPETCO2 responses were significantly depressed only in patients receiving fentanyl (P < 0.05). The results of this study demonstrate that sufentanil–N2O anesthesia is as effective as fentanyl–N2O in attenuating the hemodynamic and hormonal responses to the stress of general surgery. Because continuous intraoperative PETCO2 monitoring was not employed in this study, intraoperative hypocapnea cannot be strictly excluded as a possible influence on the postoperative measures of ventilatory drive. However, the results of this study suggest that sufentanil–N2O results in less profound respiratory depression and greater analgesia in the immediate postoperative period after general surgery.