瑞芬太尼协同性影响丙泊酚的降压效应

Pharmacody namic interaction modeling of p rop ofol and remifentanil on blood p ressure

目的构建丙泊酚对有创血压影响的药效学模型，确定其对血压影响的量效关系，探索瑞芬太尼和其他因素对丙泊酚药效学模型的影响，并分析建立的模型对临床用药的提示。方法将40例无术前用药、美国麻醉医师协会（ASA）分级Ⅰ或Ⅱ级、择期在全身麻醉下行手术的患者随机分入丙泊酚组和瑞芬太尼组，采用交叉对照研究。以靶控输注方式分两个阶段递增和递减药物浓度（丙泊酚1～5μg／mL、瑞芬太尼1～7ng／mL），经洗脱期后，给予第2种药物。每隔1min记录血流动力学指标，以收缩压（SBP）百分比变化（ASBP）作为观察指标，ASBP=（SBP观察值-SBP基础值）／SBP基础值×100％，采用非线性混合效应模型对研究数据进行分析。结果丙泊酚对血压影响的药效学可采用药物作用引起的最大ASBP变化（Emax）模型较好地拟合，瑞芬太尼是药效学模型所有参数的显著影响因素，此外，年龄显著影响Emax（P〈0．05）。最终的药效学模型参数分别为无药物作用时ASBP（E0，基础效应）=-2．71＋0．348×瑞芬太尼浓度（CR），Emax=-35．5—0．952×CR-0．511×（年龄-50）；浓度与-△SBP关系的斜率（γ）=1．89＋0．161×CR；ASBP变化达50％时的药物效应室浓度（C50）=1．11—0．0517×CR。结论瑞芬太尼以剂量依赖性方式协同丙泊酚降压。年龄对丙泊酚一瑞芬太尼相互作用时的降压幅度具有显著影响，年龄越大，降血压效应越明显。瑞芬太尼增加了丙泊酚降低血压的敏感性。

Objective Based on pharmacodynamic indicator measured by invasive systolic pressure, to model propofol pharmacodynamics and to determine concentration-effect relationship and all possible covariates including remifentanil, so as to analyze clinical significance of pharmacodynamic model. Methods Forty patients without premedication, American Society of Anesthesiologists （ASA） Ⅰ or Ⅱ, undergoing selective operations under general anesthesia were randomly divided into propofol group and remifentanil group in the cross-control study. Then the patients received either propofol or remifentanil alone in a stepwise incremental and decremental concentration via a target controlled infusion. Thereafter, the respective second drug was infused to a fixed target concentration in clinical range （1- 5 pg/mL propofol and 1- 7 ng/mL remifentanil） after elution. Invasive systolic blood pressure （SBP） was recorded every minute, and individual percentage change of SBP was used as pharmacodynamic indicator. Finally, the nonlinear mixed effect model was used to analyze pharmacodymic parameters. Results The concentration-SBP relationship of propofol was described better by a Sigmoid Emax, model. In the concentration range examined, remifentanil altered the propofol pharmacodynamics significantly. In addition, age significantly increased Er,,= （P〈0.05）. The final pharmacodynamic model parameters were E0 = -2.71＋ 0.348 XCR, Emax= -35.5 - 0.952×CR- 0.511× （age-50）, Gamma （γ） = 1.89 ＋ 0. 161×CR, 050 = 1. 11 - 0. 051 7 ×CR, respectively. Conclusion Remifetanil can decrease SBP in coordination with propofol by dose dependent way. The greater age, the larger decreasing amplitude of SBP. Remifentanil can increase the sensitivity of propofol in decreasing SBP.