The interaction of fentanyl on the Cp50 of propofol for loss of consciousness and skin incision

Abstract

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 μg/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 μg/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 concentration incision and for 1 min the patient was observed for 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 (C(P50)s and C(P95)s, respectively) and to skin incision (C(P50)i and C(P95)i, respectively), were calculated by logistic regression. Results: There were 56 evaluable patients for calculating propofol C(P50)s and 53 patients for calculating the propofol C(P50)i. For propofol alone the C(P50)s was 3.3 μg/ml and the C(P95)s 5.4 μg/ml. Increasing fentanyl concentrations reduced the C(P50)s (P = 0.03), and increasing age decreased the C(P50)s (P = 0.04). For propofol alone the C(P50)i was 15.2 (95% confidence interval 7.6-22.8) μg/ml and the C(P95)i 27.4 μg/ml. Increasing fentanyl concentrations markedly reduced the C(P50)i (P < 0.01), with a 50% reduction in C(P50)i produced by 0.63 ng/ml fentanyl. The propofol C(P50)i was decreased by 63% with 1 ng/ml fentanyl and 89% by 3 ng/ml fentanyl. At higher fentanyl concentrations the decrease in C(P50)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 C(P50)i for propofol is seen with fentanyl concentration greater than 3 ng/ml.