Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
Br J Anaesth. 2021 May;126(5):996-1008. doi: 10.1016/j.bja.2020.12.040. Epub 2021 Feb 26.
Novel preventive therapies are needed for postoperative delirium, which especially affects older patients. A mouse model is presented that captures inflammation-associated cortical slow wave activity (SWA) observed in patients, allowing exploration of the mechanistic role of prostaglandin-adenosine signalling.
EEG and cortical cytokine measurements (interleukin 6, monocyte chemoattractant protein-1) were obtained from adult and aged mice. Behaviour, SWA, and functional connectivity were assayed before and after systemic administration of lipopolysaccharide (LPS)+piroxicam (cyclooxygenase inhibitor) or LPS+caffeine (adenosine receptor antagonist). To avoid the confounder of inflammation-driven changes in movement which alter SWA and connectivity, electrophysiological recordings were classified as occurring during quiescence or movement, and propensity score matching was used to match distributions of movement magnitude between baseline and post-LPS administration.
LPS produces increases in cortical cytokines and behavioural quiescence. In movement-matched data, LPS produces increases in SWA (likelihood-ratio test: χ(4)=21.51, P<0.001), but not connectivity (χ(4)=6.39, P=0.17). Increases in SWA associate with interleukin 6 (P<0.001) and monocyte chemoattractant protein-1 (P=0.001) and are suppressed by piroxicam (P<0.001) and caffeine (P=0.046). Aged animals compared with adult animals show similar LPS-induced SWA during movement, but exaggerated cytokine response and increased SWA during quiescence.
Cytokine-SWA correlations during wakefulness are consistent with observations in patients with delirium. Absence of connectivity effects after accounting for movement changes suggests decreased connectivity in patients is a biomarker of hypoactivity. Exaggerated effects in quiescent aged animals are consistent with increased hypoactive delirium in older patients. Prostaglandin-adenosine signalling may link inflammation to neural changes and hence delirium.
需要新的预防术后谵妄的疗法，因为术后谵妄特别影响老年患者。本文提出了一种小鼠模型，该模型捕捉到了在患者中观察到的与炎症相关的皮质慢波活动（SWA），从而可以探索前列腺素-腺苷信号转导的机制作用。
从成年和老年小鼠中获得脑电图和皮质细胞因子测量值（白细胞介素 6、单核细胞趋化蛋白-1）。在系统给予脂多糖（LPS）+吡罗昔康（环氧化酶抑制剂）或 LPS+咖啡因（腺苷受体拮抗剂）前后，测定行为、SWA 和功能连接。为了避免炎症驱动的运动变化改变 SWA 和连接的混杂因素，将电生理记录分类为在静止或运动期间发生，并使用倾向评分匹配来匹配基线和 LPS 给药后运动幅度的分布。
LPS 导致皮质细胞因子增加和行为静止。在运动匹配数据中，LPS 会增加 SWA（似然比检验：χ(4)=21.51，P<0.001），但不会增加连接（χ(4)=6.39，P=0.17）。SWA 的增加与白细胞介素 6（P<0.001）和单核细胞趋化蛋白-1（P=0.001）相关，并被吡罗昔康（P<0.001）和咖啡因（P=0.046）抑制。与成年动物相比，老年动物在运动时表现出类似的 LPS 诱导的 SWA，但在静止时细胞因子反应增强和 SWA 增加。
清醒时细胞因子-SWA 相关性与谵妄患者的观察结果一致。在考虑运动变化后，连接效应缺失表明患者的连接减少是活动减少的生物标志物。在静止的老年动物中，作用增强与老年患者中更严重的活动减少性谵妄一致。前列腺素-腺苷信号可能将炎症与神经变化联系起来，从而导致谵妄。
