丙泊酚和瑞芬太尼在抑制强直电刺激中的药效学相互作用

Pharmacodynamic interaction between propofol and remifentanil on the tolerance response to electrical tetanus stimuli

目的:应用响应曲面分析法观察在静脉麻醉诱导期间,丙泊酚和瑞芬太尼在抑制强直电刺激(electrical tetanus stimuli,ETS)引起的体动和循环反应中的药效学相互作用。方法:选择ASAⅠ～Ⅱ级、年龄18～65岁的择期手术患者70例。丙泊酚和瑞芬太尼通过靶控输注系统输注给药,在研究过程中维持丙泊酚的靶浓度不变,阶梯式增加瑞芬太尼的靶浓度,当药物的血浆浓度与效应室浓度达到平衡后,评估患者对ETS引起的体动反应和循环反应。应用响应曲面模型分析丙泊酚与瑞芬太尼在抑制ETS中的药效学相互作用;应用NONMEM软件分析拟合药效反应的模型参数;应用Minitab软件绘制三维响应曲面图。结果:响应曲面分析法可以定性和定量地分析丙泊酚和瑞芬太尼的药效学相互作用规律。丙泊酚(≤9mg/L)和瑞芬太尼(≤10μg/L)相互作用的三维响应曲面表明,二者在抑制ETS引起的体动反应和循环反应时具有明显的协同作用。瑞芬太尼1μg/L可使丙泊酚抑制ETS体动和循环反应的C50值降低40.1%和45.0%;瑞芬太尼2μg/L时,丙泊酚抑制ETS体动和循环反应的C50值分别降低71.5%和72.8%;将瑞芬太尼血浆浓度增加至3μg/L时,丙泊酚抑制ETS体动和循环反应的C50值降低82.1%和83.7%;当瑞芬太尼≥3μg/L时,丙泊酚在抑制ETS体动和循环反应的C50值下降幅度变缓,表现出封顶效应。结论:响应曲面分析法可以定性和定量地分析丙泊酚和瑞芬太尼的药效学相互作用规律;丙泊酚(≤9mg/L)与瑞芬太尼(≤10μg/L)在抑制ETS引起的体动反应和循环反应上具有明显的协同作用;瑞芬太尼在降低丙泊酚抑制ETS体动反应和循环反应的C50值上表现出封顶效应。

Objective：To describe the pharmacodynamic interaction between propofol and remifentanil in suppressing somatic and hemodynamic responses to electrical tetanus stimuli （ETS） during induction of intravenous anesthesia with response surface method.Methods：Seventy patients of ASA Ⅰor Ⅱ,aged 18-65 years,scheduled for elective surgery were anesthetized by propofol and remifentanil.Propofol was administered with a target-controlled infusion （TCI） device at a target concentration that remained constant throughout the study,and remifentanil was administered with a TCI device at increasing staircase target concentrations.The somatic and hemodynamic responses to electrical tetanus stimuli were assessed multiple times after allowing for plasma effect site equilibration.The pharmacodynamic interaction between propofol and remifentanil was analyzed by response surface method.The three-dimensional response surfaces were constructed with Minitab Software.Model parameters were estimated with NONMEM.Results：Response surface method characterized the pharmacodynamic interactions between propofol （0-9 mg/L） and remifentanil （0-10 μg/L） qualitatively and quantitatively.The three-dimensional response surfaces showed considerable synergy between propofol and remifentani for blunting somatic and hemodynamic responses to ETS.When the target concentration of remifentani was 1 μg/L,2 μg/L and 3 μg/L,the C50 of propofol for blunting somatic responses to ETS decreased by 40.1%,71.5% and 82.1% respectively;and the C50 of propofol for blunting hemodynamic responses to ETS decreased by 45.0%,72.8% and 83.7% respectively.However,further increases in remifentanil only modestly reduced the C50 of propofol associated with loss of response to ETS.Ceiling effect was seen.Conclusion：Response surface method can analyze the pharmacodynamic interactions quanlitatively and quantitatively.The response surface models revealed the significant synergy between propofol （≤9 mg/L） and remifentanil （≤10 μg/L） for blunting somatic and hemodynamic responses to electrical tetanus stimuli.The ceiling effects of remifentanil were demonstrated in the reduction of propofol C50 regarding tolerance of responses to ETS.