Background: We have previously demonstrated that the minimum alveolar concentration of isoflurane at 1 atm that is required to prevent movement in 50% of patients or animals exposed to a maximal noxious stimulus is markedly reduced by increasing fentanyl concentrations. Total intravenous anesthesia with propofol is increasing in popularity, yet the propofol concentrations required for total intravenous anesthesia or the interaction between propofol and fentanyl have not yet been defined. Methods: Propofol and fentanyl were administered via computer-assisted continuous infusion to provide pseudo-steady-state concentrations and allow equilibration between plasma-blood concentration and their biophase concentration. For the induction of anesthesia patients were randomly allocated to receive propofol only or propofol plus fentanyl 0.2, 0.8, 1.5, 3.0, and 4.5 ng/ml. In each group patients were randomized to target propofol concentrations of 1.5-10 mu g/ml. At 7 and 10 min arterial blood samples were taken for subsequent measurement of propofol and fentanyl concentrations. At 10 min loss of consciousness was assessed by the patients' ability to respond to a simple verbal command. Thereafter a new target concentration of propofol was entered to ensure loss of consciousness, and succinylcholine was administered to facilitate tracheal intubation. Patients were rerandomized to a new target concentration of propofol (1-19 mu g/ml) until skin incision. Before skin incision and 1 min after skin incision, arterial blood samples were again obtained for subsequent measurement of fentanyl and propofol concentrations. At skin incision and for 1 min the patient was observed for purposeful movement. Only samples in which the pre- and poststimulus drug concentrations were within 35% of each other were included. The propofol blood concentration at which 50% or 95% of patients did not respond to verbal command (Cp(50)s and Cp(95)s, respectively) and to skin incision (Cp(50)i and CP(95)i, respectively), were calculated by logistic regression. Results: There were 56 evaluable patients for calculating the propofol Cp(50)s and 53 patients for calculating the propofol Cp(50)i. For propofol alone the CP(50)s was 3.3 mu g/ml and the Cp(95)s 5.4 mu g/ml. Increasing fentanyl concentrations reduced the Cp(50)s (P = 0.03), and increasing age decreased the Cp(50)s (P = 0.04). For propofol alone the Cp(50)i was 15.2 (95% confidence interval 7.6-22.8) mu g/ml and the Cp(95)i 27.4 mu g/ml. Increasing fentanyl concentrations markedly reduced the Cp(50)i (P < 0.01), with a 50% reduction in Cp(50)i produced by 0.63 ng/ml fentanyl. The propofol Cp(50)i was decreased by 63% with 1 ng/ml fentanyl and 89% by 3 ng/ml fentanyl. At higher fentanyl concentrations the decrease in Cp(50)i was proportionally less, demonstrating a ceiling effect. Conclusions: We defined the propofol concentration required for loss of consciousness and showed that it is reduced by increasing fentanyl concentration and by increasing age. The propofol concentration (alone) adequate for skin incision is high but is markedly reduced by fentanyl. A ceiling effect in the Cp(50)i for propofol is seen with fentanyl concentrations greater than 3 ng/ml.
