Targeted temperature management for acute ischemic stroke

Introduction
Targeted temperature management (sometimes called therapeutic temperature management or therapeutic hypothermia) has shown benefit in hypoxic-ischemic brain injury after cardiac arrest, and has been proposed as a potential treatment for ischemic stroke.

Proposed mechanisms of benefit
Hong has summarized these mechanisms as follows:

Animal studies
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Clinical trials in patients receiving no reperfusion therapy or intravenous thrombolytics
There is no evidence that targeted temperature management is of benefit in acute ischemic stroke patients receiving no reperfusion therapy or receiving intravenous tPA (although trials were all small so data is very limited).

Cooling for Acute Ischemic Brain Damage (COOL-AID, 2004)
This study randomized 40 patients with acute ischemic stroke within 12 hours of onset to either TTM to goal 33°C with endovascular cooling (Reprieve Endovascular Temperature Management System) for 24 hours or standard medical management. Baseline NIHSS was ~15 and ~70% of patients received tPA. There were no differences in clinical outcomes, but a nonsignificant trend toward less DWI volume growth in the hypothermia group. The study showed feasibility but was underpowered to determine outcomes.

Intravascular Cooling in the Treatment of Stroke Longer tPA window (ICTuS-L, 2010)
This study randomized 58 patients with acute ischemic stroke within 6 hours of onset to either TTM to goal 33°C with endovascular cooling (Innercool Celsius Control System) for 24 hours or standard medical management. Baseline NIHSS was ~14 and ~80% of patients received IV tPA. There were no differences in functional outcomes assessed by mRS at 3 months. There were statistically more cases of pneumonia in the TTM group (50% vs 10%, p=0.001).

Intravascular Cooling in the Treatment of Stroke 2 (ICTuS 2, 2016)
This trial initially planned to enroll 1600 patients but was halted after only 120 patients due to (probably slow recruitment and) trials showing benefit of thrombectomy. They randomized 120 patients with acute ischemic stroke within 3 hours of onset to either TTM to goal 33°C with endovascular cooling (Innercool Celsius Control System) for 24 hours or standard medical management. Baseline NIHSS was ~14 and all patients received IV tPA. There were no differences in functional outcomes assessed by mRS at 3 months. Pneumonia had numerically more cases in the TTM group (19% vs 10.5%) and mortality was numerically higher in the TTM group (15.9%) than standard care group (8.8%), (OR 1.95 with 95% CI 0.56-7.79).

EuroHYP-1 (2018)
This trial was proposed in 2014, planning to enroll 1500 patients with acute ischemic stroke within 6 hours of onset to either TTM to goal 34-35°C with cold saline and/or surface cooling vs. standard medical management. The study results remain unpublished in a journal, but the results were announced in 2018. The publication of thrombectomy trials in 2015 slowed recruitment significantly so that the study was terminated early. A total of 98 patients were enrolled and there were no difference in functional outcome or serious adverse events.

Endovascular treatment and TTM
Combined intra-arterial cold saline infusion has some potential for neuroprotection combined with endovascular thrombectomy, but requires further study. It has been suggested that the combination of endovascular treatment, with its high reperfusion rates, combined with TTM, may be of benefit. In 2004 Ding et al. studied intraarterial infusion of cold saline in a rat model of ischemia and showed decreased infarct volumes and improved functional outcomes. In 2016, Chen et al. showed feasibility in a pilot study of 26 patients and claimed safety, but there was a 15.4% incidence of vasospasm an a 38.5% incidence of pneumonia. Intrajugular infusion for hypothermia has shown similar neuroprotective results as intra-arterial cooling.

In 2018, Wu et al. published a nonrandomized trial in which the practitioner would make a decision for cooling or not, and use endovascular infusion of cold saline (4°C) into the artery of planned thrombectomy, infusion at 10 mL/min via a microcatheter distal to the clot prior to recanalization and then 30 mL/min via access catheter after recanalization for 10 minutes. Baseline NIHSS was 17 in the cooling group and 16 in the control group, and time to treatment was similar for both groups. There were no differences in safety outcomes. For efficacy, there was numerically smaller infarct volume at follow-up imaging in the TTM group (~64 mL) compared with the control group (78 mL), which reached statistical significance after adjustment for baseline variables (p=0.068 unadjusted, p=0.038 adjusted). There was a numerical trend towards more independence in the TTM group (51%) vs controls (41%).