Therapeutic hypothermia for acute ischemic stroke: from preclinical studies to clinical trials

Therapeutic hypothermia (TH) is acknowledged as a promising neuroprotective strategy in clinical settings. However, its application in managing acute ischemic stroke (AIS) remains unclear due to variable clinical outcomes in bench and bedsides. A comprehensive review of original studies concerning hypothermia in ischemic stroke was conducted, sourcing data from PubMed, Web of Science, Embase, and Ovid Medicine databases covering the period from January 1, 1990 to October 31, 2023. Our search strategy yielded 1,218 articles from PubMed, 1,094 from Web of Science, 3,083 from Embase, and 2,841 from Ovid Medicine. After removing duplicates, review articles, meta-analyses, and in vitro studies focusing on hypoxic-ischemic encephalopathy or global cerebral ischemia, a total of 304 articles out of 5,669 papers were ultimately selected for in-depth analysis. Overall, we have found that there are significant differences in depth, duration, and delay between bench and bedside studies. We want to introduce the concepts of "actual brain temperature", "hypothermia initiation time", and "effective hypothermic duration" as crucial for the optimization of hypothermic therapy in AIS. We recommend critical parameters for the clinical translation of hypothermia, including a target temperature range of 34-35°C, a duration of 2-4 h, immediate initiation post-insult, and natural rewarming processes. We also advocate for selective brain cooling when reperfusion therapy is achieved. We find great differences in administrating TH for AIS between bench and bedsides. More efforts are still needed to enhance the likelihood of successful clinical translation and deepen the understanding of hypothermia's role in AIS treatment.