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.)

ContributionsMagdy Selim --organized the trial hypotheses, designed the trial, provided guidance about the data analysis and interpretation and presentation of the data, and drafted most of the sections of the manuscript. Lydia Foster --involved in the statistical analysis and data interpretation, and Contributed to the development and revisions to the manuscript. Claudia Moy --involved in the oversight of the trial conduct and progress Guohua Xi --organized the trial hypotheses, and provided critical revisions to the manuscript. MH, MJ, VS, and WC contributed to recruitment and randomization of trial participants, and provided critical revisions to the manuscript. LM and SG were involved in the design of the trial and provided critical revisions to the manuscript. Casey Norton --provided volumetric measurements of imaging data. Yuko Palesch --involved in the design of the study, statistical analysis and data interpretation, and provided critical revisions to the manuscript. Sharon yeatts --involved in the design of the study, statistical analysis and data interpretation, and contributed to the development and revisions to the manuscript. The idef investigators (see appendix) --contributed to the identification and, when eligible, randomization of trial participants. DECLARATION OF INTERESTSThis was an investigator-initiated study, funded by the NINDS (U01 NS074425). Deferoxamine Mesylate is a generic drug, and there was no commercial or industrial support for the trial. None of the authors has any competing interests related to the submitted work. MS reports grants from the NIH/NINDS (i-DEF) and the American Heart Association (outside the submitted work), and personal fees for serving on the advisory board of CSL Behring (outside the submitted work) during the conduct of the trial. SDY reports grant support from the NINDS, personal fees from Genentech and other fees from CR Bard Inc. (outside the submitted work) during the conduct of the study. SG, LDF, YP, and GX report grants from the NIH/NINDS. MDH reports personal fees from Merck, nonfinancial support from Hoffmann-La Roche Canada Ltd, grants from Covidien (Medtronic), grants from Boehringer-Ingleheim, grants from Stryker Inc., grants from Medtronic LLC, grants from NoNO Inc., (outside the submitted work); In addition, MDH has a patent Systems and Methods for Assisting in Decision-Making and Triaging for Acute Stroke Patients pending to US Patent office Number: 62/086,077 and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software, is a director of the Canadian Federation of Neurological Sciences, a not-for-profit group and has received grant support from Alberta Innovates Health Solutions, CIHR, Heart & Stroke Foundation of Canada, and NINDS. LM, VS, WC, MJ, CM, and CN have nothing to disclose.

Background and Purpose Treatment with the iron chelator, deferoxamine mesylate (DFO), improves neurological recovery in animal models of Intracerebral hemorrhage (ICH). We aimed to evaluate the feasibility, safety, and tolerability of varying dose-tiers of DFO in patients with spontaneous ICH, and to determine the Maximum Tolerated Dose (MTD) to be adopted in future efficacy studies. Methods A multicenter, phase-I, dose-finding study using the Continual Reassessment Method. DFO was administered by an intravenous infusion for 3 consecutive days, starting within 18 hours of ICH onset. Subjects underwent repeated clinical assessments through 90 days, and CT neuroimaging pre- and post-drug administration. Results Twenty subjects were enrolled into 5 dose tiers, starting with 7 mg/kg/day and ending with 62 mg/kg/day as the MTD. Median age was 68 years (range: 50–90); 60% were men; and median GCS and NIHSS scores on admission were 15 (5–15) and 9 (0–39), respectively. ICH location was lobar in 40%, deep in 50%, and brainstem in 10%; intraventricular hemorrhage was present in 15%. DFO was discontinued due to adverse events in 2 subjects (10%). Six subjects (30%) experienced 12 serious adverse events (SAEs), none were drug-related. DFO infusions were associated with mild blood pressure lowering effects. Fifty percent of patients had mRS ≤2 and 39% had mRS 4–6 on day-90; 15% died. Conclusions Consecutive daily infusions of DFO after ICH are feasible, well-tolerated, and not associated with excessive SAEs or mortality. Our findings lay the groundwork for future studies to evaluate the efficacy of DFO in ICH.

Introduction Current guidelines for management of critically ill stroke patients suggest that treatment in a neurocritical care unit (NCCU) and/or by a neurointensivist (NI) may be beneficial, but the contribution of each to outcome is unknown. The relative impact of a NCCU vs. NI on short- and long-term outcomes in patients with acute ischemic stroke (AIS), intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (SAH) was assessed. Methods 2,096 stroke patients admitted to a NCCU or non-neuro ICU at a tertiary stroke center were analyzed before the appointment of a NI, during the NI’s tenure, and after the NI departed and was not replaced. Data included admission ICU type, availability of a NI, age, NIHSS, ICH score and 3 and 12 month outcome. Results For AIS, compared to the time interval with a NI, departure of the NI predicted a worse rate of return to pre-stroke function at 3 months. For ICH, NCCU treatment predicted shorter ICU and hospital LOS but had no effect on short or long term outcomes. No effect of a NI was seen. For SAH, availability of an NI (but not an NCCU) predicted improved outcomes but longer ICU LOS. Disposition and in-hospital mortality improved when a NI was present, but continued improvement did not occur after the NI’s departure. Conclusion Presence of an NI was associated with improved clinical outcomes. This effect was more evident in patients with SAH. Patients with ICH tend to have poor outcomes regardless of the presence of a NCCU or a NI.

The efficacy of glucocorticoids is well established in ameliorating edema associated with brain tumors and in improving outcome in subsets of patients with bacterial meningitis. Despite frequently encouraging experimental results, clinical trials of glucocorticoids in ischemic stroke, intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and traumatic brain injury have not shown a definite therapeutic effect. The evidence supporting glucocorticoid therapy for spinal cord injury is controversial; however methylprednisolone continues to be widely employed in this setting.

Background: Recent studies have shown that intra-arterial recanalization therapy (IAT) for acute ischemic stroke (AIS) is associated with worse clinical outcomes when performed under general anesthesia (GA) compared to local anesthesia, with or without conscious sedation. The reasons for this association have not been systematically studied. Methods: We retrospectively reviewed 190 patients who underwent IAT for anterior circulation AIS from January 2008 to December 2012 at our institution. Baseline demographics, vessels involved, acute stroke treatment including intravenous tissue type plasminogen activator (tPA) use, use of GA vs. monitored anesthesia care (MAC), location of thrombus, recanalization grade, radiologic post-procedural intracerebral hemorrhage, and 30-day outcomes were collected. Relevant clinical time points were recorded. Detailed intra-procedural hemodynamics including maximum/minimum heart rate, systolic blood pressure (BP), diastolic BP, mean BP, use of pressors and episodes of hypotension were collected. Our study's outcomes were as follows: in-hospital mortality, 30-day good outcome (mRS ≤2), successful recanalization and radiologic post-procedural intracerebral hemorrhage. Results: Ninety-one patients received GA and 99 patients received MAC. There was no significant difference in the NIHSS score between the two groups but the GA group had a higher number of ICA occlusions (31.9 vs. 18.2%, p = 0.043). The time from the start of anesthesia to incision (23.0 ± 12.5 min vs. 18.7 ± 11.3 min, p = 0.020) and the time from the start of anesthesia to recanalization (110 ± 57.2 vs. 92.3 ± 43.0, p = 0.045) was longer in the GA group. The time from incision to recanalization was not significantly different between the two groups. mRS 0-2 was achieved in 22.8% of patients in the MAC group compared to 14.9% in GA (p = 0.293). Higher mortality was seen in the GA group (25.8 vs. 13.3%, p = 0.040). Successful recanalization (TICI 2b-3) was similar between the GA and MAC (57.8 vs. 48.5%, p = 0.182) groups, but GA had a higher number of parenchymal hematomas (26.3 vs. 10.1%, p = 0.003). There was no difference in the intra-procedural hemodynamic variables between the GA and MAC groups. Anesthesia type was an independent predictor for mortality (along with age and initial NIHSS), and the only independent predictor for parenchymal hematomas, with MAC being protective for both. Conclusion: Our study has confirmed previous findings of GA being associated with poorer outcomes and higher mortality in patients undergoing IAT for AIS. Detailed analysis of intra-procedural hemodynamics did not reveal any significant difference between the two groups. Parenchymal hematoma was the major driver of the difference in outcomes.

Objectives To explore the relationship between levels of non-protein bound iron in cerebrospinal fluid and the development of early brain injury in patients with aneurysmal SAH. Design Prospective observational cohort pilot study. Setting Neurointensive care unit of an academic, tertiary medical center Patients Patients admitted with aneurysmal subarachnoid hemorrhage Hunt and Hess grades 2 to 4 requiring ventriculostomy insertion as part of their clinical management. Interventions None. Measurements and main results Samples of cerebrospinal fluid (CSF) were obtained on days 1, 3, and 5. A fluorometric assay that relies on an oxidation sensitive probe was used to measure unbound iron, and levels of iron-handling proteins were measured by means of enzyme-linked immunosorbent assays. We prospectively collected and recorded demographic, clinical, and radiological data. A total of 12 patients were included in this analysis. Median Hunt and Hess score on admission was 3.5 (IQR: 1) and median modified Fisher scale score was 4 (IQR: 1). Seven of 12 patients (58%) developed delayed cerebral ischemia (DCI). Day 5 non-transferrin bound iron (NTBI) (7.88±1 vs. 3.58± 0.8, p= 0.02) and mean NTBI (7.39± 0.4 vs. 3.34±0.4 p= 0.03) were significantly higher in patients who developed DCI. Mean and day 3 levels of redox-active iron correlated with development of angiographic vasospasm in logistic regression analysis (p= 0.02); while mean redox-active iron and lower levels of ceruloplasmin on days 3, 5 and peak were correlated with development of deep cerebral infarcts. Conclusions our preliminary data indicate a causal relationship between unbound iron and brain injury following SAH and suggest a possible protective role for ceruloplasmin in this setting, particularly in the prevention of cerebral ischemia. Further studies are needed to validate these findings and to probe their clinical significance.

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