Smith C, McEwan A I, Jhaveri R, Wilkinson M, Goodman D, Smith L R, Canada A T, Glass P S
Department of Anesthesia, Duke University Medical Center, Durham, North Carolina 27707.
Anesthesiology. 1994 Oct;81(4):820-8; discussion 26A.
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.
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 micrograms/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 micrograms/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 (Cp50s and Cp95s, respectively) and to skin incision (Cp50i and Cp95i, respectively), were calculated by logistic regression.
There were 56 evaluable patients for calculating the propofol Cp50s and 53 patients for calculating the propofol Cp50i. For propofol alone the Cp50s was 3.3 micrograms/ml and the Cp95s 5.4 microgram/ml. Increasing fentanyl concentrations reduced the Cp50s (P = 0.03), and increasing age decreased the Cp50s (P = 0.04). For propofol alone the Cp50i was 15.2 (95% confidence interval 7.6-22.8) micrograms/ml and the Cp95i 27.4 micrograms/ml. Increasing fentanyl concentrations markedly reduced the Cp50i (P < 0.01), with a 50% reduction in Cp50i produced by 0.63 ng/ml fentanyl. The propofol Cp50i was decreased by 63% with 1 ng/ml fentanyl and 89% by 3 ng/ml fentanyl. At higher fentanyl concentrations the decrease in Cp50i was proportionally less, demonstrating a ceiling effect.
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 Cp50i for propofol is seen with fentanyl concentrations greater than 3 ng/ml.
我们之前已经证明，在1个标准大气压下，为防止50%暴露于最大有害刺激的患者或动物出现运动反应所需的异氟烷最低肺泡浓度会因芬太尼浓度的增加而显著降低。丙泊酚全静脉麻醉正日益普及，但全静脉麻醉所需的丙泊酚浓度或丙泊酚与芬太尼之间的相互作用尚未明确。
通过计算机辅助持续输注给予丙泊酚和芬太尼，以提供伪稳态浓度，并使血浆-血液浓度与其生物相浓度达到平衡。为诱导麻醉，将患者随机分配为仅接受丙泊酚或接受丙泊酚加0.2、0.8、1.5、3.0和4.5 ng/ml芬太尼。在每组中，患者被随机分配以将丙泊酚浓度目标设定为1.5 - 10微克/毫升。在7分钟和10分钟时采集动脉血样本，随后测量丙泊酚和芬太尼浓度。在10分钟时，通过患者对简单口头指令的反应能力评估意识丧失情况。此后输入新的丙泊酚目标浓度以确保意识丧失，并给予琥珀酰胆碱以促进气管插管。患者被重新随机分配到新的丙泊酚目标浓度（1 - 19微克/毫升），直至皮肤切开。在皮肤切开前和皮肤切开后1分钟，再次采集动脉血样本，随后测量芬太尼和丙泊酚浓度。在皮肤切开时及之后1分钟观察患者是否有目的的运动。仅纳入刺激前后药物浓度相差在35%以内的样本。通过逻辑回归计算50%或95%的患者对口头指令无反应（分别为Cp50s和Cp95s）以及对皮肤切开无反应（分别为Cp50i和Cp95i）时的丙泊酚血药浓度。
有56例可评估患者用于计算丙泊酚Cp50s，53例患者用于计算丙泊酚Cp50i。仅使用丙泊酚时，Cp50s为3.3微克/毫升，Cp95s为5.4微克/毫升。芬太尼浓度增加会降低Cp50s（P = 0.03），年龄增加会降低Cp50s（P = 0.04）。仅使用丙泊酚时，Cp50i为15.2（95%置信区间7.6 - 22.8）微克/毫升，Cp95i为27.4微克/毫升。芬太尼浓度增加会显著降低Cp50i（P < 0.01），0.63 ng/ml芬太尼可使Cp50i降低50%。1 ng/ml芬太尼可使丙泊酚Cp50i降低63%，3 ng/ml芬太尼可使其降低89%。在较高芬太尼浓度时，Cp50i的降低比例较小，显示出封顶效应。
我们明确了意识丧失所需的丙泊酚浓度，并表明其会因芬太尼浓度增加和年龄增加而降低。单独用于皮肤切开的丙泊酚浓度较高，但会因芬太尼而显著降低。当芬太尼浓度大于3 ng/ml时，丙泊酚的Cp50i会出现封顶效应。
