Doufas Anthony G, Morioka Nobutada, Mahgoub Adel N, Bjorksten Andrew R, Shafer Steven L, Sessler Daniel I
Department of Anesthesia, Stanford University School of Medicine, Palo Alto, California, USA.
Anesth Analg. 2009 Sep;109(3):778-86. doi: 10.1213/ane.0b013e3181b0fd0f.
In previous studies, we showed that failure to respond to automated responsiveness monitor (ARM) precedes potentially serious sedation-related adversities associated with loss of responsiveness, and that the ARM was not susceptible to false-positive responses. It remains unknown, however, whether loss and return of response to the ARM occur at similar sedation levels. We hypothesized that loss and return of response to the ARM occur at similar sedation levels in individual subjects, independent of the propofol effect titration scheme.
Twenty-one healthy volunteers aged 20-45 yr underwent propofol sedation using an effect-site target-controlled infusion system and two different dosing protocol schemes. In all, we increased propofol effect-site concentration (Ce) until loss of response to the ARM occurred. Subsequently, the propofol Ce was decreased either by a fixed percentage (20%, 30%, 40%, 50%, 60%, and 70%; fixed percentage protocol, n = 10) or by a linear deramping (0.1, 0.2, and 0.3 microg x mL(-1) x min(-1); deramping protocol, n = 11) until the ARM response returned. Consequently, the propofol Ce was maintained at the new target for a 6-min interval (Ce plateau) during which arterial samples for propofol determination were obtained, and a clinical assessment of sedation (Observer's Assessment of Alertness/Sedation [OAA/S] score) performed. Each participant in the two protocols experienced each percentage or deramping rate of Ce decrease in random order. The assumption of steady state was tested by plotting the limits of agreement between the starting and ending plasma concentration (Cp) at each Ce plateau. The probability of response to the ARM as a function of propofol Ce, Bispectral Index (BIS) of the electroencephalogram, and OAA/S score was estimated, whereas the effect of the protocol type on these estimates was evaluated using the nested model approach (NONMEM). The combined effect of propofol Ce and BIS on the probability for ARM response was also evaluated using a fractional probability model (P(BIS/Ce)).
The measured propofol Cp at the beginning and the end of the Ce plateau was almost identical. The Ce50 of propofol for responding to the ARM was 1.73 (95% confidence interval: 1.55-2.10) microg/mL, whereas the corresponding BIS50 was 75 (71.3-77). The OAA/S50 probability for ARM response was 12.5/20 (12-13.4). A fractional probability (P(BIS/Ce)) model for the combined effect of BIS and Ce fitted the data best, with an estimated contribution for BIS of 63%. Loss and return of ARM response occurred at similar sedation levels in individual subjects.
Reproducible ARM dynamics in individual subjects compares favorably with clinical and electroencephalogram sedation end points and suggests that the ARM could be used as an independent instrumental guide of drug effect during propofol-only sedation.
在先前的研究中，我们表明对自动反应性监测仪（ARM）无反应先于与反应性丧失相关的潜在严重镇静相关不良事件出现，并且ARM不易出现假阳性反应。然而，对ARM反应的丧失和恢复是否在相似的镇静水平下发生仍不清楚。我们假设在个体受试者中，对ARM反应的丧失和恢复发生在相似的镇静水平，与丙泊酚效应滴定方案无关。
21名年龄在20 - 45岁的健康志愿者使用效应室靶控输注系统和两种不同的给药方案接受丙泊酚镇静。总体而言，我们增加丙泊酚效应室浓度（Ce）直至对ARM无反应出现。随后，丙泊酚Ce以固定百分比（20%、30%、40%、50%、60%和70%；固定百分比方案，n = 10）或线性递减（0.1、0.2和0.3μg·mL⁻¹·min⁻¹；递减方案，n = 11）降低，直至ARM反应恢复。随后，丙泊酚Ce在新靶点维持6分钟间隔（Ce平台期），在此期间采集用于丙泊酚测定的动脉样本，并进行镇静的临床评估（观察者警觉/镇静评估[OAA/S]评分）。两个方案中的每位参与者以随机顺序经历每个Ce降低的百分比或递减率。通过绘制每个Ce平台期起始和结束血浆浓度（Cp）之间的一致性界限来检验稳态假设。估计对ARM反应的概率作为丙泊酚Ce、脑电图双谱指数（BIS）和OAA/S评分的函数，而使用嵌套模型方法（NONMEM）评估方案类型对这些估计值的影响。还使用分数概率模型（P(BIS/Ce)）评估丙泊酚Ce和BIS对ARM反应概率的联合效应。
Ce平台期开始和结束时测得的丙泊酚Cp几乎相同。对ARM有反应的丙泊酚Ce50为1.73（95%置信区间：1.55 - 2.10）μg/mL，而相应的BIS50为75（71.3 - 77）。对ARM反应的OAA/S50概率为12.5/20（12 - 13.4）。BIS和Ce联合效应的分数概率（P(BIS/Ce)）模型对数据拟合最佳，BIS的估计贡献为63%。在个体受试者中，ARM反应的丧失和恢复发生在相似的镇静水平。
个体受试者中可重复的ARM动态与临床和脑电图镇静终点相比具有优势，表明在仅使用丙泊酚镇静期间，ARM可作为药物效应的独立仪器指导。
