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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 Therapeutic hypothermia is commonly used in comatose survivors’ post-cardiopulmonary resuscitation (CPR). It is unknown whether outcome predictors perform accurately after hypothermia treatment. Methods Post-CPR comatose survivors were prospectively enrolled. Six outcome predictors [pupillary and corneal reflexes, motor response to pain, and somatosensory-evoked potentials (SSEP) >72 h; status myoclonus, and serum neuron-specific enolase (NSE) levels <72 h] were systematically recorded. Poor outcome was defined as death or vegetative state at 3 months. Patients were considered “sedated” if they received any sedative drugs ≤12 h prior the 72 h neurological assessment. Results Of 85 prospectively enrolled patients, 53 (62%) underwent hypothermia. Furthermore, 53 of the 85 patients (62%) had a poor outcome. Baseline characteristics did not differ between the hypothermia and normothermia groups. Sedative drugs at 72 h were used in 62 (73%) patients overall, and more frequently in hypothermia than in normothermia patients: 83 versus 60% (P = 0.02). Status myoclonus <72 h, absent cortical responses by SSEPs >72 h, and absent pupillary reflexes >72 h predicted poor outcome with a 100% specificity both in hypothermia and normothermia patients. In contrast, absent corneal reflexes >72 h, motor response extensor or absent >72 h, and peak NSE >33 ng/ml <72 h predicted poor outcome with 100% specificity only in non-sedated patients, irrespective of prior treatment with hypothermia. Conclusions Sedative medications are commonly used in proximity of the 72-h neurological examination in comatose CPR survivors and are an important prognostication confounder. Patients treated with hypothermia are more likely to receive sedation than those who are not treated with hypothermia.

Objective-Outcome prediction is challenging in comatose post-cardiac arrest survivors. We assessed the feasibility and prognostic utility of brain diffusion-weighted MRI (DWI) during the first week.Corresponding Author Christine AC Wijman, MD, PhD, Stanford Stroke Center, 701 Welch Road, B325, Palo Alto, CA 94304, Fax: (650) Tel: (650) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMethods-Consecutive comatose post-cardiac arrest patients were prospectively enrolled. MRI data of patients who met predefined specific prognostic criteria were used to determine distinguishing ADC thresholds. Group 1: death at 6 months and absent motor response or absent pupillary reflexes or bilateral absent cortical responses at 72 hours, or vegetative at 1 month. Group 2A: Glasgow outcome scale (GOS) score of 4 or 5 at 6 months. Group 2B: GOS of 3 at 6 months. The percentage of voxels below different apparent diffusion coefficient (ADC) thresholds was calculated at 50 × 10 −6 mm 2 /sec intervals.Results-Overall, 86% of patients underwent MR imaging. Fifty-one patients with 62 brain MRIs were included in the analyses. Forty patients met the specific prognostic criteria. The percentage of brain volume with an ADC value below 650-700 × 10 −6 mm 2 /sec best differentiated between group 1 and groups 2A and 2B combined (p<0.001), while the 400-450 × 10 −6 mm 2 /sec threshold best differentiated between groups 2A and 2B (p=0.003). The ideal time window for prognostication using DWI was between 49 to 108 hours after the arrest. When comparing MRI in this time window with the 72 hour neurological examination MRI improved the sensitivity for predicting poor outcome by 38% while maintaining 100% specificity (p=0.021).Interpretation-Quantitative DWI in comatose post-cardiac arrest survivors holds great promise as a prognostic adjunct.Approximately 350,000 cardiac arrests occur annually in the United States1. Up to half of these patients are successfully resuscitated. In the past, only 10% to 30% of comatose postcardiac arrest patients had good functional recovery. These numbers will likely improve with the increasing use of therapeutic hypothermia2 , 3.Post-cardiac arrest brain injury is a common cause of morbidity and mortality. Many comatose post-cardiac arrest patients die or survive with severe disability after a prolonged intensive care unit stay associated with a tremendous cost burden4 , 5. Conversely, the potential for premature withdrawal of life support from patients who may have a chance of functional recovery represents an additional ethical dilemma. Thus, early accurate identification of patients who have no likelihood of meaningful recovery is a very important health care issue.Although several prognostic variables have been studied in comatose post-cardiac arrest patients, the currently accepted variables (neurological examination, neurophysiologic tests, and serum markers) have substantive limitations. First, they identify only a subset of poor outcome patients with high specificity. Se...

Background and Purpose-Knowledge on the natural history and clinical impact of perihematomal edema (PHE) associated with intracerebral hemorrhage is limited. We aimed to define the time course, predictors, and clinical significance of PHE measured by serial magnetic resonance imaging. Methods-Patients with primary supratentorial intracerebral hemorrhage Ն5 cm 3 underwent serial MRIs at prespecified intervals during the first month. Hematoma (H v ) and PHE (E v ) volumes were measured on fluid-attenuated inversion recovery images. Relative PHE was defined as E v /H v . Neurologic assessments were performed at admission and with each MRI. Barthel Index, modified Rankin scale, and extended Glasgow Outcome scale scores were assigned at 3 months. Results-Twenty-seven patients with 88 MRIs were prospectively included. Median H v and E v on the first MRI were 39 and 46 cm 3 , respectively. Median peak absolute E v was 88 cm 3 . Larger hematomas produced a larger absolute E v (r 2 ϭ0.6) and a smaller relative PHE (r 2 ϭ0.7). Edema volume growth was fastest in the first 2 days but continued until 12Ϯ3 days. In multivariate analysis, a higher admission hematocrit was associated with a greater delay in peak PHE (Pϭ0.06). Higher admission partial thromboplastin time was associated with higher peak rPHE (Pϭ0.02). Edema volume growth was correlated with a decline in neurologic status at 48 hours (81 vs 43

Background: Symptomatic intracerebral hemorrhage (SICH) following thrombolytic therapy for acute ischemic stroke is associated with a high rate of morbidity and mortality. Knowledge of the risk factors associated with SICH following thrombolyitc therapy may provide insight into the pathophysiological mechanisms underlying the development of SICH, lead to the development of treatments that reduce the risk of SICH and have implications for the design of future stroke trials. Methods: Relevant studies were identified through a search in Pubmed. Included studies used multivariate analyses to identify independent risk factors for SICH following thrombolytic therapy. For each variable that was found to have a significant association with SICH, a secondary literature search was conducted to identify additional reports on the specific relationship between that variable and SICH. Summary of Review: Twelve studies met inclusion criteria for the systematic review. Extent of hypoattenuated brain parenchyma on pretreatment CT and elevated serum glucose or history of diabetes were independent risk factors for thrombolysis-associated SICH in six of the twelve studies. Symptom severity was an independent risk factor in three of the studies and advanced age, increased time to treatment, high systolic blood pressure, low platelets, history of congestive heart failure and low plasminogen activator inhibitor levels were found to be independent risk factors for SICH in a single study. Although these data should not alter the current guidelines for the use of rt-PA in acute stroke, they may help develop future strategies aimed at reducing the rate of thrombolysis-associated SICH.

Background and Purpose-Diffusion-weighted magnetic resonance imaging of the brain is a promising technique to help predict functional outcome in comatose survivors of cardiac arrest. We aimed to evaluate prospectively the temporal-spatial profile of brain apparent diffusion coefficient changes in comatose survivors during the first 8 days after cardiac arrest. Methods-Apparent diffusion coefficient values were measured by 2 independent and blinded investigators in predefined brain regions in 18 good-and 15 poor-outcome patients with 38 brain magnetic resonance imaging scans and were compared with those of 14 normal controls. The same brain regions were also assessed qualitatively by 2 other independent and blinded investigators. Results-In poor-outcome patients, cortical structures, in particular the occipital and temporal lobes, and the putamen exhibited the most profound apparent diffusion coefficient reductions, which were noted as early as 1.5 days and reached a nadir between 3 and 5 days after the arrest. Conversely, when compared with normal controls, good-outcome patients exhibited increased diffusivity, in particular in the hippocampus, temporal and occipital lobes, and corona radiata. By qualitative magnetic resonance imaging readings, 1 or more cortical gray matter structures were judged to be moderately to severely abnormal in all poor-outcome patients except for the 3 patients imaged within 24 hours after the arrest. Conclusions-Brain diffusion-weighted imaging changes in comatose, postcardiac arrest survivors in the first week after the arrest are region and time dependent and differ between good-and poor-outcome patients. With increasing use of magnetic resonance imaging in this context, it is important to be aware of these relations. (Stroke. 2010;41:1665-1672.)

on behalf of the DEFUSE Investigators Background-Studies evaluating predictors of tPA-associated symptomatic intracerebral hemorrhage (SICH) have typically focused on clinical and CT-based variables. MRI-based variables have generally not been included in predictive models, and little is known about the influence of reperfusion on SICH risk. Methods-Seventy-four patients were prospectively enrolled in an open-label study of intravenous tPA administered between 3 and 6 hours after symptom onset. An MRI was obtained before and 3 to 6 hours after tPA administration. The association between several clinical and MRI-based variables and tPA-associated SICH was determined using multivariate logistic regression analysis. SICH was defined as a Ն2 point change in National Institutes of Health Stroke Scale Score (NIHSSS) associated with any degree of hemorrhage on CT or MRI. Reperfusion was defined as a decrease in PWI lesion volume of at least 30% between baseline and the early follow-up MRI. Results-SICH occurred in 7 of 74 (9.5%) patients. In univariate analysis, NIHSSS, DWI lesion volume, PWI lesion volume, and reperfusion status were associated with an increased risk of SICH (PϽ0.05). In multivariate analysis, DWI lesion volume was the single independent baseline predictor of SICH (odds ratio 1.42; 95% CI 1.13 to 1.78 per 10 mL increase in DWI lesion volume). When early reperfusion status was included in the predictive model, the interaction between DWI lesion volume and reperfusion status was the only independent predictor of SICH (odds ratio 1.77; 95% CI 1.25 to 2.50 per 10 mL increase in DWI lesion volume). Conclusion-Patients with large baseline DWI lesion volumes who achieve early reperfusion appear to be at greatest risk of SICH after tPA therapy.