Department of Anaesthesiology and Critical Care, Perelman School of Medicine, Philadelphia, PA, USA; Department of Bioengineering, School of Engineering and Applied Science, Philadelphia, PA, USA.
Department of Anaesthesiology and Critical Care, Perelman School of Medicine, Philadelphia, PA, USA.
Br J Anaesth. 2020 Sep;125(3):308-320. doi: 10.1016/j.bja.2020.05.031. Epub 2020 Jul 11.
Recent studies point to a fundamental distinction between population-based and individual-based anaesthetic pharmacology. At the population level, anaesthetic potency is defined as the relationship between drug concentration and the likelihood of response to a stimulus. At the individual level, even when the anaesthetic concentration is held constant, fluctuations between the responsive and unresponsive states are observed. Notably, these spontaneous fluctuations exhibit resistance to state transitions R. Therefore, the response probability in each individual depends not just upon the drug concentration, but also upon responses to previous stimuli. Here, we hypothesise that R is distinct from drug potency and is differentially modulated by different anaesthetics.
Adult (14-24 weeks old) C57BL/6J male mice (n=60) were subjected to repeated righting reflex (RR) assays at equipotent steady-state concentrations of isoflurane (0.6 vol%), sevoflurane (1.0 vol%), and halothane (0.4 vol%).
Fluctuations in RR were observed for all tested anaesthetics. Analysis of these fluctuations revealed that R was differentially modulated by different anaesthetics (F[2, 56.01]=49.59; P<0.0001). Fluctuations in RR were modelled using a stochastic dynamical system. This analysis confirmed that the amount of noise that drives behavioural state transitions depends on the anaesthetic agent (F[2, 42.86]=16.72; P<0.0001).
Whilst equipotent doses of distinct anaesthetics produce comparable population response probabilities, they engage dramatically different dynamics in each individual animal. This manifests as a differential aggregate propensity to exhibit state transitions. Thus, resistance to state transitions is a fundamentally distinct, novel measure of individualised anaesthetic pharmacology.
最近的研究表明，人群基础和个体基础麻醉药理学之间存在根本区别。在人群水平上，麻醉效力定义为药物浓度与对刺激产生反应的可能性之间的关系。在个体水平上，即使麻醉浓度保持不变，也会观察到反应和无反应状态之间的波动。值得注意的是，这些自发波动表现出对状态转变 R 的抵抗力。因此，每个个体的反应概率不仅取决于药物浓度，还取决于对先前刺激的反应。在这里，我们假设 R 与药物效力不同，并且受到不同麻醉剂的差异调节。
成年（14-24 周龄）C57BL/6J 雄性小鼠（n=60）在等效的异氟烷（0.6 体积%）、七氟烷（1.0 体积%）和氟烷（0.4 体积%）稳定状态浓度下接受重复翻正反射（RR）测定。
所有测试的麻醉剂都观察到 RR 的波动。对这些波动的分析表明，R 受到不同麻醉剂的差异调节（F[2, 56.01]=49.59；P<0.0001）。使用随机动力学系统对 RR 的波动进行建模。该分析证实，驱动行为状态转变的噪声量取决于麻醉剂（F[2, 42.86]=16.72；P<0.0001）。
虽然不同的麻醉剂具有等效的剂量会产生类似的群体反应概率，但它们在每个个体动物中表现出截然不同的动力学。这表现为表现出状态转变的个体差异聚合倾向。因此，对状态转变的抵抗力是个体麻醉药理学的一个根本不同的新的度量标准。
