Table 3: Parallel-controlled clinical trials of feasibility and efficacy of hypothermic intervention for stroke.

ReferenceStudy designInterventionPatientsHypothermia inductionImpact on stroke severityMortality

[30]Randomized, double-blinded, parallel control, multicenterMild hypothermia induced by external cooling during craniotomy surgery
Target temperature (33.5°C)
62 patients with intracranial aneurysm (33 hypothermia versus 29 normothermic controls) (hemorrhagic excluded)29/33 patients were effectively cooled (88%) within 1.0°C of target temperature. Hypothermics reached 33.7°C versus normothermic controls 36.6°C ( )No difference in NIHSS at 24 and 72 h after surgery.2/33 patients died in the hypothermic group versus 0/29 in the control group

[20]Nonrandomized, open label, parallel control, single-centerMild hypothermia induced by external cooling within 5–8 h of symptoms onset. Target temperature ( °C)19 acute stroke patients NIHSS (10 hypothermia versus 9 normothermic controls)Target temperature ( °C) reached in  h and maintained for h.
All patients in the hypothermia group reached target temperature
mRS at 3 months: (hypothermia) versus (control) (NS)
Hospital stay: (hypothermia) versus (control) (NS)
3/10 hypothermic patients died versus 2/9 deaths in the control group

[35]Nonrandomized, open label, parallel control, single-centerMild hypothermia induced by external cooling or endovascular cooling within 24 h of symptoms onset Target temperature (33°C)36 acute ischemic stroke patients NIHSS (19 hypothermia versus 17 hemicraniectomy)Target temperature (33°C) reached in  h.
Does not clear report the % of patients reaching target temperature, apparently all of them
NIHSS 17 (hypothermia) versus 21 (hemicraniectomy) ( )9/19 hypothermic patients died versus 2/17 hemicraniectomy ( )

[19]Randomized, open label, parallel control, multicenterMild hypothermia induced by endovascular device less than 9 hours of stroke symptoms onset. Target temperature (33°C)40 patients NIHSS (18 hypothermia versus 22 normothermic controls)13/18 patients were effectively cooled (72%), reaching target temperature in min. Mean time from stroke onset to cooling was NIHSS, mRS, and mean lesion growth were similar between groups (NS)5/18 patients died in the hypothermia group; 4/22 patients died in the control group

[34]Randomized, open label, parallel control, single-centerMild hypothermia induced by internal ( ) or external cooling ( ) immediately after surgery.
Target temperature (35°C)
25 severe ischemic stroke patients (12 craniectomy + hypothermia versus 13 craniectomy). Patients in the craniectomy control group were kept normothermic ( °C)Target temperature reached within  h.
Does not clear report the % of patients reaching target temperature, apparently all of them
Trend towards clinical improvement for the combined treatment NIHSS ( versus , and BI ( versus , ).
No significant difference were observed in mRS ( versus , ) after 6 months
1/12 hypothermic patients died versus 2/13 patients in the craniectomy group

[32]Nonrandomized, open label, parallel control, multicenterMild hypothermia induced by endovascular cooling within 12 h of symptoms onset Target temperature (33°C)18 acute ischemic stroke patients (7 effectively cooled versus 11 normothermic controls)7/18 patients were effectively cooled (39%) and tolerated up to °C versus normothermia in the control group °C ( ).
Target temperature (33°C)
Difference in brain edema during 36–48 h ( ) that vanished after 30 days.
No significant difference in NIHSS at catheter removal, and after 7 days. No difference in NIHSS or mRS after 30 days
NR

[31]Nonrandomized, open label, parallel control, single-centerMild hypothermia induced by external cooling within 10 to 24 h
of symptoms onset Target temperature (33°C)
30 severe stroke patients, mean SSS 17–17.5 (10 hypothermics versus 20 normothermic controls)Does not clear report the % of patients reaching target temperature, apparently all of themIntracranial pressure did not differ between groups MMP9 (biomarker of blood brain barrier breakdown) marginally lower in hypothermics ( )NR

[33]Randomized, double-blinded, parallel control, multicenterMild hypothermia induced by endovascular device within 0–3 or 3–6 hours of symptoms onset. Target temperature (33°C)58 patients with acute stroke symptoms (NIHSS 7≥)
28 hypothermia versus 30 normothermic controls.
Also compared the latency time from symptoms onset and the combination with thrombolytic therapy
Target temperature was reached in 20/28 patients (71.4%) in about 67 min (median time).
Patients not reaching target temperature had a mean temperature of °C.
Difference in NIHSS at 24 h due to sedation with meperidine: in the hypothermic group versus in the controls ( ).
The NIHSS was equivalent in both groups at 30 days ( versus ) and 90 days ( versus ). No difference in mRS at 90 days. Thrombolytic therapy (tPA) did not influence clinical outcome or occurrence of adverse events
6/28 patients died in the hypothermic group versus 5/30 in the control group Pneumonia occurred more frequently in hypothermic patients (7/28) than controls (2/30) ( )

ICP: intracranial pressure; MMP9: matrix metalloproteinase 9; mRS: modified Rankin scale; NIHSS: NIH Stroke Scale NR: not reported; NS: not statistically significant; SSS: Scandinavian Stroke Scale.