Table 2: Self-controlled clinical trials (quasi experiment) of feasibility and efficacy of hypothermic intervention for stroke.

Reference Study design Intervention Patients Hypothermia induction Impact on stroke severity Mortality [29] a Nonrandomized, open label, self-controlled, single-center (quasi-experiment) Mild hypothermia induced by external cooling within 4 to 24 hours of symptoms onset. Target temperature (33°C) 25 patients with severe ischemic stroke, median SSS 24, mean GCS 9 Target temperature reached in 3.5 to 6.2 h. Does not clear report the % of patients reaching target temperature, apparently all of them. Mean initial ICP mmHg and reduced to mmHg during hypothermia Surviving patients displayed SSS 29 after 4 weeks and 38 three months after stroke 11/25 patients died [28]b Nonrandomized, open label, self-controlled, single-center (quasi-experiment) Mild hypothermia induced by external cooling within 6 hours of symptoms onset. Target temperature (33°C) 20 patients with severe ischemic stroke, median SSS 27, mean GCS 9 All patients reached target temperature in about 5-6 h. Mean SSS was , mean mRS 3 and mean BI 65 four weeks after stroke ICP decreased with initiation of hypothermia 8/20 patients died [27] Nonrandomized, open label, self-controlled, single-center (quasi-experiment) Mild hypothermia induced by external cooling as soon as possible (no mention of time delay after symptoms onset). Target temperature (33-34°C) 6 patients with severe ischemic stroke Mean duration of hypothermia 63.5 h Does not clear report the % of patients reaching target temperature, apparently all of them. Decreased CMRO2, transiently reduced CBF and controlled ICP 2/6 patients died of intractable intracranial hypertension [25] Nonrandomized, open label, self-controlled, single-center (quasi-experiment) Mild hypothermia induced by endovascular device within 3 h of symptoms onset Target temperature (33-34°C) 10 patients with acute ischemic stroke NIHSS 4–12 Temperature dropped from °C by a maximum of °C () at 52±16 min after hypothermia induction. Does not clear report the % of patients reaching target temperature, apparently all of them. NIHSS at discharge (1) improved compared to admission (5.5) () NR [26] Nonrandomized, open label, self-controlled, single-center (quasi-experiment) Mild hypothermia induced by external () or intravascular () cooling methods within 6 h of symptoms onset. Target temperature (33–34.5°C) 18 acute stroke patients NIHSS 13 patients reached target temperature (mean latency 9h43, mean duration 19h48). 2 patients were not cooled due to catheter or machine failure. NIHSS 15 to 9 in 24 h NIHSS 6 at discharge 2/18 patients died

(a) Published in Stroke. (b) Published in Acta Neurochirurgica Supplementum. BI: Barthel index; CBF: cerebral blood flow; CMRO2: cerebral metabolic rate of oxygen; GCS: Glasgow Come Scale; ICP: intracranial pressure; mRS: modified Rankin scale; NIHSS: NIH Stroke Scale; NR: not reported; SSS: Scandinavian Stroke Scale.