Background and Purpose-Induced hypothermia is a promising neuroprotective therapy. We studied the feasibility and safety of hypothermia and thrombolysis after acute ischemic stroke. Methods-Intravenous Thrombolysis Plus Hypothermia for Acute Treatment of Ischemic Stroke (ICTuS-L) was a randomized, multicenter trial of hypothermia and intravenous tissue plasminogen activator in patients treated within 6 hours after ischemic stroke. Enrollment was stratified to the treatment time windows 0 to 3 and 3 to 6 hours. Patients presenting within 3 hours of symptom onset received standard dose intravenous alteplase and were randomized to undergo 24 hours of endovascular cooling to 33°C followed by 12 hours of controlled rewarming or normothermia treatment. Patients presenting between 3 and 6 hours were randomized twice: to receive tissue plasminogen activator or not and to receive hypothermia or not. Results-In total, 59 patients were enrolled. One patient was enrolled but not treated when pneumonia was discovered just before treatment. All 44 patients enrolled within 3 hours and 4 of 14 patients enrolled between 3 to 6 hours received tissue plasminogen activator. Overall, 28 patients randomized to receive hypothermia (HY) and 30 to normothermia (NT). Baseline demographics and risk factors were similar between groups. Mean age was 65.5Ϯ12.1 years and baseline National Institutes of Health Stroke Scale score was 14.0Ϯ5.0; 32 (55%) were male. Cooling was achieved in all patients except 2 in whom there were technical difficulties. The median time to target temperature after catheter placement was 67 minutes (Quartile 1 57.3 to Quartile 3 99.4). At 3 months, 18% of patients treated with hypothermia had a modified Rankin Scale score of 0 or 1 versus 24% in the normothermia groups (nonsignificant). Symptomatic intracranial hemorrhage occurred in 4 patients (68); all were treated with tissue plasminogen activator Ͻ3 hours (1 received hypothermia). Six patients in the hypothermia and 5 in the normothermia groups died within 90 days (nonsignificant). Pneumonia occurred in 14 patients in the hypothermia and in 3 of the normothermia groups (Pϭ0.001). The pneumonia rate did not significantly adversely affect 3 month modified Rankin Scale score (Pϭ0.32). Conclusion-This study demonstrates the feasibility and preliminary safety of combining endovascular hypothermia after stroke with intravenous thrombolysis. Pneumonia was more frequent after hypothermia, but further studies are needed to determine its effect on patient outcome and whether it can be prevented. A definitive efficacy trial is necessary to evaluate the efficacy of therapeutic hypothermia for acute stroke. (Stroke. 2010;41:2265-2270.)

Background and Purpose Therapeutic hypothermia (TH) is a potent neuroprotectant approved for cerebral protection after neonatal hypoxia-ischemia and cardiac arrest. TH for acute ischemic stroke is safe and feasible in pilot trials. We designed a study protocol to provide safer, faster TH in stroke patients. Methods Safety procedures and 4°C saline infusions for faster cooling were added to the Intravascular Cooling Treatment in Acute Stroke (ICTuS) trial protocol. A femoral venous intravascular cooling catheter following intravenous rt-PA in eligible patients provided 24 hours cooling followed by a 12 hour re-warm. Serial safety assessments and imaging were performed. The primary endpoint was 3-month modified Rankin score 0,1. Results Of the intended 1600 subjects, 120 were enrolled before the study was stopped. Randomly, 63 were to receive hypothermia (HY) plus anti-shivering treatment and 57 normothermia (NT). Compared to prior studies, cooling rates were improved with a cold saline bolus, without fluid overload. The intention-to-treat primary outcome of 90-day mRS 0,1 occurred in 33% HY and 38% NT subjects, OR (95% CL) of 0.81 (0.36, 1.85). Serious adverse events occurred equally. Mortality was 15.9% HY and 8.8% NT subjects, OR (95% CL) of 1.95 (0.56, 7.79). Pneumonia occurred in 19% HY vs. 10.5% in NT subjects, OR (95% CL) of 1.99 (0.63, 6.98). Conclusion Intravascular TH was confirmed to be safe and feasible in rt-PA treated acute ischemic stroke patients. Protocol changes designed to reduce pneumonia risk appeared to fail, although the sample is small. Clinical trial registration clinicaltrials.gov NCT 01123161.