Suerte Angely Claire C, Liddle Lane J, Abrahart Ashley, Khiabani Elmira, Colbourne Frederick
Department of Psychology, Faculty of Science, University of Alberta, Edmonton, Canada.
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Canada.
Ther Hypothermia Temp Manag. 2024 Dec;14(4):229-242. doi: 10.1089/ther.2024.0012. Epub 2024 Jul 1.
Therapeutic hypothermia (TH) lessens ischemic brain injury. Cytoprotective agents can augment protection, although it is unclear which combinations are most effective. The objective of this study is to identify which cytoprotective drug works best with delayed TH. Following PRISMA guidelines, a systematic review (PubMed, Web of Science, MEDLINE, Scopus) identified controlled experiments that used an focal ischemic stroke model and evaluated the efficacy of TH (delay of ≥1 hour) coupled with cytoprotective agents. This combination was our main intervention compared with single treatments with TH, drug, or no treatment. Endpoints were brain injury and neurological impairment. The CAMARADES checklist for study quality and the SYRCLE's risk of bias tool gauged study quality. Twenty-five studies were included. Most used young, healthy male rats, with only one using spontaneously hypertensive rats. Two studies used mice models, and six used adult animals. Study quality was moderate (median score = 6), and risk of bias was high. Pharmacological agents provided an additive effect on TH for all outcomes measured. Magnesium coupled with TH had the greatest impact compared with other agent-TH combinations on all outcomes. Longer TH durations improved both behavioral and histological outcomes and had greater cytoprotective efficacy than shorter durations. Anti-inflammatories were the most effective in reducing infarction (standardized mean difference [SMD]: -1.64, confidence interval [CI]: [-2.13, -1.15]), sulfonylureas reduced edema the most (SMD: -2.32, CI: [-3.09, -1.54]), and antiapoptotic agents improved behavioral outcomes the most (normalized mean difference: 52.38, CI: [45.29, 59.46]). Statistically significant heterogeneity was observed ( = 82 - 98%, all < 0.001), indicating that studies wildly differ in their effect size estimates. Our results support the superiority of adding cytoprotective therapies with TH (vs. individual or no therapy). Additional exploratory and confirmatory studies are required to identify and thoroughly assess combination therapies owing to limited work and inconsistent translational quality.
治疗性低温（TH）可减轻缺血性脑损伤。细胞保护剂可增强保护作用，尽管尚不清楚哪种组合最为有效。本研究的目的是确定哪种细胞保护药物与延迟性TH联合使用效果最佳。按照PRISMA指南，进行了一项系统综述（检索了PubMed、Web of Science、MEDLINE、Scopus），确定了使用局灶性缺血性中风模型并评估TH（延迟≥1小时）联合细胞保护剂疗效的对照实验。与单独使用TH、药物或不进行治疗的单一疗法相比，这种联合疗法是我们的主要干预措施。终点指标为脑损伤和神经功能缺损。采用CAMARADES研究质量清单和SYRCLE偏倚风险工具评估研究质量。共纳入25项研究。大多数研究使用年轻、健康的雄性大鼠，只有一项研究使用自发性高血压大鼠。两项研究使用小鼠模型，六项研究使用成年动物。研究质量中等（中位数评分=6），偏倚风险较高。对于所有测量的结局，药理剂对TH具有相加作用。与其他药剂-TH组合相比，镁联合TH对所有结局的影响最大。较长的TH持续时间改善了行为和组织学结局，并且比短持续时间具有更大的细胞保护功效。抗炎药在减少梗死方面最有效（标准化均数差[SMD]：-1.64，置信区间[CI]：[-2.13，-1.15]），磺脲类药物在减轻水肿方面最有效（SMD：-2.32，CI：[-3.09，-1.54]），抗凋亡剂在改善行为结局方面最有效（标准化均数差：52.38，CI：[45.29，59.46]）。观察到具有统计学意义的异质性（I²=82%-98%，所有P<0.001），表明各研究在效应量估计方面差异很大。我们的结果支持TH联合细胞保护疗法（相对于单独治疗或不治疗）的优越性。由于相关研究有限且转化质量不一致，需要进行更多的探索性和验证性研究来确定并全面评估联合疗法。
