Longitudinal Profiling of Plasma Cytokines and Its Association With Postoperative Delirium in Elderly Patients Undergoing Major Lower Limb Surgery: A Prospective Observational Study
Longitudinal Profiling of Plasma Cytokines and Its Association With Postoperative Delirium in Elderly Patients Undergoing Major Lower Limb Surgery: A Prospective Observational Study
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接受下肢大手术的老年患者血浆细胞因子的纵向分析及其与术后谵妄的关系：一项前瞻性观察研究
DOI：
10.1213/ane.0000000000006250
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发表时间：
2022-10
期刊：
影响因子：
--
通讯作者：
Mervyn Maze
中科院分区：
文献类型：
--
作者：
Zhang Yu;Hu Jun;Zuo Weiguang;He Pei;Xue Qi;Feng Xiaomei;Zhang Ye;Mervyn Maze
背景：手术伴随全身炎症反应，可能预示易感个体的谵妄。关于血浆促炎细胞因子的变化轨迹及其与术后谵妄（POD）的潜在相关性知之甚少。本研究纵向评估了促炎和抗炎血浆细胞因子反应以及老年手术患者POD的发展，以研究与可能指示致病机制的细胞因子个体和/或簇的相关性。方法：一项前瞻性纵向研究试图招募60岁以上的患者，这些患者计划在全身麻醉下进行大型下肢手术。分别于术前和术后第1天至术后第4天采血，测定血浆白细胞介素1β（IL-1β）、IL-2、IL-4、IL-6、可溶性IL-6受体（sIL-6 R）、IL-10和肿瘤坏死因子-α（TNF-α）。使用混淆评估方法对参与者进行POD评估，每天两次，持续4天。通过基于组的轨迹建模分析确定血浆细胞因子的术后变化轨迹，该轨迹建模分析由时间依赖性考克斯回归模型识别的不同细胞因子提供信息。研究结果：评估了188例患者的合格性，其中129例接受了大手术，126例有完整的数据集可用于最终分析。126例患者中有31例（24.6%）诊断为POD。时间依赖性考克斯回归模型显示，高水平的IL-6和sIL-6 R水平与POD发生的风险相关。两簇模型（稳定的较低水平和波动的较高水平）被认为是统计学上最适合IL-6和sIL-6 R轨迹的模型。IL-6水平波动性升高的受试者中谵妄发生率较高（73.3% vs 18.0%，P = 0.001），sIL-6 R水平波动性升高的受试者中谵妄发生率也较高（81.3% vs 16.4%，P = 0.001）。结论：由于更高的IL-6和sIL-6 R水平与POD的更高风险显著相关，并且IL-6反式信号传导需要该组合，因此该途径的激活可能与POD相关。此外，确定高水平的IL-6和sIL-6 R的组合是否可以作为POD随后发展的早期生物标志物将是重要的。
BACKGROUND: Surgery is accompanied by a systemic inflammatory response that may presage delirium in susceptible individuals. Little is known about the trajectory of plasma proinflammatory cytokines and their potential associations with postoperative delirium (POD). The current study longitudinally assessed both pro and anti-inflammatory plasma cytokine response and development of POD in older surgical patients to investigate associations with individual and/or clusters of cytokines that may indicate pathogenic mechanisms. METHODS: A prospective longitudinal study sought to enroll patients >60 years old who were scheduled for major lower limb surgery under general anesthesia. Blood was obtained preoperatively and postoperatively from day 1 through postoperative day 4 for measurement of plasma interleukin-1β (IL-1β), IL-2, IL-4, IL-6, soluble IL-6 receptor (sIL-6R), IL-10, and tumor necrosis factor-α (TNF-α). Participants were assessed for POD twice daily for 4 days using the confusion assessment method. Trajectory of postoperative changes in plasma cytokines was determined by a group-based trajectory modeling analysis that was informed by distinct cytokines identified by time-dependent Cox regression model. RESULTS: One hundred eighty-eight patients were assessed for eligibility of whom 129 underwent major surgery and 126 had complete datasets for final analysis. POD was diagnosed in 31 of 126 patients (24.6%). Time-dependent Cox regression model identified that higher IL-6 and sIL-6R levels were associated with higher risk of developing POD. A two-cluster model (stable lower and fluctuating higher levels) was considered to be the most statistically appropriate model for IL-6 and sIL-6R trajectory. More participants with fluctuating higher IL-6 were delirious (73.3% vs 18.0%, P = .001) as were those with fluctuating higher sIL-6R (81.3% vs 16.4%, P = .001). CONCLUSIONS: As higher IL-6 and sIL-6R levels were significantly associated with higher risk of POD and the combination is required for IL-6 trans-signaling, it is possible that activation of this pathway may be associated with POD. Furthermore, it will be important to determine whether high levels of the combination of IL-6 and sIL-6R can be an early biomarker for the subsequent development of POD.
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