Temporal limits of therapeutic hypothermia onset in clinical trials for acute ischemic stroke: How early is early enough?

Stroke is one of the leading causes of mortality and morbidity worldwide, and yet, current treatment is limited to thrombolysis through either t-PA or mechanical thrombectomy. While therapeutic hypothermia has been adopted in clinical contexts such as neuroprotection after cardiac resuscitation and neonatal hypoxic-ischemic encephalitis, it is yet to be used in the context of ischemic stroke. The lack of ameliorative effect in ischemic stroke patients may be tied to the delayed cooling induction onset. In the trials where the cooling was initiated with significant delay (mostly systemic cooling methods), minimal benefit was observed; on the other hand, when cooling was initiated very early (mostly selective cooling methods), there was significant efficacy. Another timing factor that may play a role in amelioration may be the onset of cooling relative to thrombolysis therapy. Current understanding of the pathophysiology of acute ischemic injury and ischemia-reperfusion injury suggests that hypothermia before thrombolysis may be the most beneficial compared to cooling initiation during or after reperfusion. As many of the systemic cooling methods tend to require longer induction periods and extensive, separate procedures from thrombolysis therapy, they are generally delayed to hours after recanalization. On the other hand, selective cooling was generally performed simultaneously to thrombolysis therapy. As we conduct and design therapeutic hypothermia trials for stroke patients, the key to their efficacy may lie in quick and early cooling induction, both respective to the symptom onset and thrombolysis therapy.