Nieuwenhuijs Diederik J F, Olofsen Erik, Romberg Raymonda R, Sarton Elise, Ward Denham, Engbers Frank, Vuyk Jaap, Mooren Rene, Teppema Luc J, Dahan Albert
Department of Anesthesiology, Leiden University Medical Center, The Netherlands.
Anesthesiology. 2003 Feb;98(2):312-22. doi: 10.1097/00000542-200302000-00008.
Since propofol and remifentanil are frequently combined for monitored anesthesia care, we examined the influence of the separate and combined administration of these agents on cardiorespiratory control and bispectral index in humans.
The effect of steady-state concentrations of remifentanil and propofol was assessed in 22 healthy male volunteer subjects. For each subject, measurements were obtained from experiments using remifentanil alone, propofol alone, and remifentanil plus propofol (measured arterial blood concentration range: propofol studies, 0-2.6 microg/ml; remifentanil studies, 0-2.0 ng/ml). Respiratory experiments consisted of ventilatory responses to three to eight increases in end-tidal Pco2 (Petco2). Invasive blood pressure, heart rate, and bispectral index were monitored concurrently. The nature of interaction was assessed by response surface modeling using a population approach with NONMEM. Values are population estimate plus or minus standard error.
A total of 94 responses were obtained at various drug combinations. When given separately, remifentanil and propofol depressed cardiorespiratory variables in a dose-dependent fashion (resting V(i) : 12.6 +/- 3.3% and 27.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; V(i) at fixed Petco of 55 mmHg: 44.3 +/- 3.9% and 57.7 +/- 3.5% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively; blood pressure: 9.9 +/- 1.8% and 3.7 +/- 1.1% depression at 1 microg/ml propofol and 1 ng/ml remifentanil, respectively). When given in combination, their effect on respiration was synergistic (greatest synergy observed for resting V(i)). The effects of both drugs on heart rate and blood pressure were modest, with additive interactions when combined. Over the dose range studied, remifentanil had no effect on bispectral index even when combined with propofol (inert interaction).
These data show dose-dependent effects on respiration at relatively low concentrations of propofol and remifentanil. When combined, their effect on respiration is strikingly synergistic, resulting in severe respiratory depression.
由于丙泊酚和瑞芬太尼常联合用于麻醉监测，我们研究了单独及联合使用这些药物对人体心肺功能控制和脑电双频指数的影响。
在22名健康男性志愿者中评估了瑞芬太尼和丙泊酚稳态浓度的作用。对每名受试者，分别进行了单独使用瑞芬太尼、单独使用丙泊酚以及瑞芬太尼加丙泊酚的实验（测得的动脉血浓度范围：丙泊酚研究为0 - 2.6微克/毫升；瑞芬太尼研究为0 - 2.0纳克/毫升）。呼吸实验包括对呼气末二氧化碳分压（Petco2）三次至八次升高的通气反应。同时监测有创血压、心率和脑电双频指数。使用NONMEM群体方法通过反应面模型评估相互作用的性质。数值为群体估计值加减标准误差。
在不同药物组合下共获得94个反应。单独使用时，瑞芬太尼和丙泊酚均以剂量依赖方式降低心肺变量（静息分钟通气量：丙泊酚浓度为1微克/毫升和瑞芬太尼浓度为1纳克/毫升时分别降低12.6±3.3%和27.7±3.5%；在Petco为55 mmHg时的分钟通气量：丙泊酚浓度为1微克/毫升和瑞芬太尼浓度为1纳克/毫升时分别降低44.3±3.9%和57.7±3.5%；血压：丙泊酚浓度为1微克/毫升和瑞芬太尼浓度为1纳克/毫升时分别降低9.9±1.8%和3.7±1.1%）。联合使用时，它们对呼吸的作用具有协同性（静息分钟通气量观察到最大协同作用）。两种药物对心率和血压的作用较小，联合使用时具有相加相互作用。在所研究的剂量范围内，瑞芬太尼即使与丙泊酚联合使用对脑电双频指数也无影响（无相互作用）。
这些数据表明，相对低浓度的丙泊酚和瑞芬太尼对呼吸有剂量依赖性影响。联合使用时，它们对呼吸的作用具有显著协同性，导致严重呼吸抑制。
