Bouillon Thomas, Bruhn Joergen, Radu-Radulescu Lucian, Andresen Corina, Cohane Carol, Shafer Steven L
Department of Anesthesia, Inselspital Berne.
Anesthesiology. 2004 Feb;100(2):240-50. doi: 10.1097/00000542-200402000-00010.
Despite the ubiquitous use of propofol for anesthesia and conscious sedation and numerous publications about its effect, a pharmacodynamic model for propofol-induced ventilatory depression in the non-steady state has not been described. To investigate propofol-induced ventilatory depression in the clinically important range (at and below the metabolic hyperbola while carbon dioxide is accumulating because of drug-induced ventilatory depression), the authors applied indirect effect modeling to Paco2 data at a fraction of inspired carbon dioxide of 0 during and after administration of propofol.
Ten volunteers underwent determination of their carbon dioxide responsiveness by a rebreathing design. The parameters of a power function were fitted to the end-expiratory carbon dioxide and minute ventilation data. The volunteers then received propofol in a stepwise ascending pattern with use of a target-controlled infusion pump until significant ventilatory depression occurred (end-tidal pressure of carbon dioxide > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 microg/ml. Propofol pharmacokinetics and the Paco2 were determined from frequent arterial blood samples. An indirect response model with Bayesian estimates of the pharmacokinetics and carbon dioxide responsiveness in the absence of drug was used to describe the Paco2 time course. Because propofol reduces oxygen requirements and carbon dioxide production, a correction factor for propofol-induced decreasing of carbon dioxide production was included.
The following pharmacodynamic parameters were found to describe the time course of hypercapnia after administration of propofol (population mean and interindividual variability expressed as coefficients of variation): F (gain of the carbon dioxide response), 4.37 +/- 36.7%; ke0, CO2, 0.95 min-1 +/- 59.8%; baseline Paco2, 40.9 mmHg +/- 12.8%; baseline minute ventilation, 6.45 l/min +/- 36.3%; kel, CO2, 0.11 min-1 +/- 34.2%; C50,propofol, 1.33 microg/ml +/- 49.6%; gamma, 1.68 +/- 21.3%.
Propofol at common clinical concentrations is a potent ventilatory depressant. An indirect response model accurately described the magnitude and time course of propofol-induced ventilatory depression. The indirect response model can be used to optimize propofol administration to reduce the risk of significant ventilatory depression.
尽管丙泊酚在麻醉和清醒镇静中被广泛使用，且有大量关于其作用的文献发表，但尚未有非稳态下丙泊酚诱导通气抑制的药效学模型被描述。为了研究临床上重要范围内（在代谢双曲线及以下，由于药物诱导的通气抑制导致二氧化碳蓄积）丙泊酚诱导的通气抑制，作者在丙泊酚给药期间及之后，将间接效应模型应用于吸入二氧化碳分数为0时的动脉血二氧化碳分压（Paco2）数据。
10名志愿者通过重复呼吸设计测定其二氧化碳反应性。将幂函数的参数拟合到呼气末二氧化碳和分钟通气数据。然后，志愿者使用靶控输注泵以逐步递增的方式接受丙泊酚，直至出现明显的通气抑制（呼气末二氧化碳分压>65 mmHg和/或即将出现呼吸暂停）。此后，将浓度降至1 μg/ml。通过频繁采集动脉血样测定丙泊酚药代动力学和Paco2。使用在无药物情况下对药代动力学和二氧化碳反应性进行贝叶斯估计的间接反应模型来描述Paco2的时间进程。由于丙泊酚降低氧气需求和二氧化碳生成，纳入了丙泊酚诱导二氧化碳生成减少量的校正因子。
发现以下药效学参数可描述丙泊酚给药后高碳酸血症的时间进程（总体均值和个体间变异性以变异系数表示）：F（二氧化碳反应增益），4.37%±36.7%；ke0,CO2，0.95 min-1±59.8%；基线Paco2，40.9 mmHg±12.8%；基线分钟通气量，6.45 l/min±36.3%；kel,CO2，0.11 min-1±34.2%；C50,丙泊酚，1.33 μg/ml±49.6%；γ，1.68±21.3%。
临床常见浓度的丙泊酚是一种强效通气抑制剂。间接反应模型准确描述了丙泊酚诱导通气抑制的程度和时间进程。该间接反应模型可用于优化丙泊酚给药，以降低明显通气抑制的风险。
