Department of Anesthesiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
Br J Anaesth. 2017 Aug 1;119(2):200-210. doi: 10.1093/bja/aex085.
Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties.
In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model. Volunteers were randomized to a session without background noise and a session with pre-recorded looped operating room background noise. Exploratory pharmacokinetic-pharmacodynamic modelling and covariate analysis were conducted in NONMEM using bispectral index (BIS) monitoring of processed EEG.
We found that both stimulation at the time of Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scale scoring and the presence or absence of ambient noise had an effect on the sedative properties of dexmedetomidine. The stimuli associated with MOAA/S scoring increased the BIS of sedated volunteers because of a transient 170% increase in the effect-site concentration necessary to reach half of the maximal effect. In contrast, volunteers deprived of ambient noise were more resistant to dexmedetomidine and required, on average, 32% higher effect-site concentrations for the same effect as subjects who were exposed to background operating room noise.
The new pharmacokinetic-pharmacodynamic models might be used for effect-site rather than plasma concentration target-controlled infusion for dexmedetomidine in clinical practice, thereby allowing tighter control over the desired level of sedation.
NCT01879865.
右美托咪定是一种选择性 α2-肾上腺素受体激动剂，具有独特的特性，如保持呼吸驱动和产生可唤醒的镇静作用。我们描述了右美托咪定镇静作用的药代动力学-药效学模型的开发，考虑到刺激对其镇静作用的影响。
在 18 名健康志愿者的两期随机研究中，使用 Dyck 模型通过目标控制输注以阶梯式方式输送右美托咪定。志愿者随机分配到无背景噪声的会话和带有预录循环手术室背景噪声的会话。使用处理后的脑电图双谱指数（BIS）监测，在 NONMEM 中进行探索性药代动力学-药效学模型构建和协变量分析。
我们发现，在 Modified Observer's Assessment of Alertness/Sedation（MOAA/S）评分时的刺激以及环境噪声的存在与否都对右美托咪定的镇静作用有影响。与 MOAA/S 评分相关的刺激会增加镇静志愿者的 BIS，因为达到最大效应的一半所需的效应部位浓度会暂时增加 170%。相比之下，没有环境噪声的志愿者对右美托咪定的抵抗力更强，需要平均高出 32%的效应部位浓度才能达到与暴露于手术室背景噪声的受试者相同的效果。
新的药代动力学-药效学模型可用于临床实践中右美托咪定的效应部位而不是血浆浓度目标控制输注，从而可以更紧密地控制所需的镇静水平。
NCT01879865。
