Background

Intracerebral hemorrhage (ICH) remains the deadliest form of stroke worldwide, inducing neuronal death through a wide variety of pathways. Therapeutic hypothermia (TH) is a robust and well studied neuroprotectant widely used across a variety of specialties.

Aims

This review summarizes results from preclinical and clinical studies to highlight the overall effectiveness of TH to improve long-term ICH outcomes while also elucidating optimal protocol regimens to maximize therapeutic effect.

Summary of Review

A systematic review was conducted across three databases to identify trials investigating the use of TH to treat ICH. A random-effects meta-analysis was conducted on preclinical studies, looking at neurobehavioral outcomes, blood brain barrier breakdown (BBB), cerebral edema, hematoma volume, and tissue loss. Several mixed-methods meta-regression models were also performed to adjust for variance and variations in hypothermia induction procedures. 21 preclinical studies and 5 human studies were identified. The meta-analysis of preclinical studies demonstrated a significant benefit in behavioral scores (ES=-0.43, p=0.02), cerebral edema (ES=1.32, p=0.0001), and BBB (ES=2.73, p=<0.00001). TH was not found to significantly affect hematoma expansion (ES=-0.24, p=0.12) or tissue loss (ES=0.06, p=0.68). Clinical study outcome reporting was heterogeneous, however there was recurring evidence of TH-induced edema reduction.

Conclusions

The combined preclinical evidence demonstrates that TH reduced multiple cell death mechanisms initiated by ICH, yet there is no definitive evidence in clinical studies. The cooling strategies employed in both preclinical and clinical studies were highly diverse, and focused refinement of cooling protocols should be developed in future preclinical studies. The current data for TH in ICH remains questionable despite the highly promising indications in preclinical studies. Definitive randomized controlled studies are still required to answer this therapeutic question.

背景

脑出血（ICH）仍然是世界范围内最致命的中风形式，通过多种途径诱导神经元死亡。低温治疗 (TH) 是一种强大且经过充分研究的神经保护剂，广泛应用于各个专业领域。

目标

本综述总结了临床前和临床研究的结果，以强调 TH 改善长期 ICH 结果的整体有效性，同时阐明最佳治疗方案以最大限度地提高治疗效果。

审查摘要

对三个数据库进行了系统评价，以确定调查使用 TH 治疗 ICH 的试验。对临床前研究进行了随机效应荟萃分析，观察神经行为结果、血脑屏障破坏（BBB）、脑水肿、血肿量和组织损失。还建立了几种混合方法元回归模型来调整低温诱导程序的方差和变化。确定了 21 项临床前研究和 5 项人体研究。临床前研究的荟萃分析表明，在行为评分（ES = -0.43，p = 0.02）、脑水肿（ES = 1.32，p = 0.0001）和BBB（ES = 2.73，p = <0.00001）方面具有显着益处。未发现 TH 显着影响血肿扩张（ES=-0.24，p=0.12）或组织损失（ES=0.06，p=0.68）。

结论

综合临床前证据表明 TH 减少了 ICH 引发的多种细胞死亡机制，但临床研究中尚无明确证据。临床前和临床研究中采用的冷却策略高度多样化，并且应在未来的临床前研究中对冷却方案进行有针对性的改进。尽管临床前研究显示出非常有希望的迹象，但当前 ICH 中 TH 的数据仍然值得怀疑。仍然需要明确的随机对照研究来回答这个治疗问题。