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Introduction: The popular traditional Chinese medicine (TCM) compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) through effects on brain edema, hematoma absorption, and the immune system. This study is to assess whether FYTF-919 is safe and effective as compared to matching placebo treatment in patients with acute ICH., Methods: The ongoing Chinese Herbal medicine in patients with Acute INtracerebral hemorrhage (CHAIN) is a multicenter, prospective, randomized, double-blind placebo-controlled trial of FYTF-919 in patients with acute ICH at 20-30 hospital sites in China. Eligible ICH patients presenting within 48 h after symptom onset are randomly allocated to receive either FYTF-919 (100 mL per day × 28 d, oral) or matching placebo. A sample size of 1,504 patients is estimated to provide 90% power (α 0.05) to detect a ≥20% improvement in average utility-weight scores on the modified Rankin scale (UW-mRS) assessed at 90 days, with 6% non-adherence and 10% lost to follow-up. The primary efficacy outcome is UW-mRS at 90 days. Secondary outcomes include binary measures of the mRS, neurological impairment on the National Institute of Health Stroke Scale, and health-related quality of life on the EuroQol EQ-5D-5L scale at different time points over 6 months of follow-up. The key safety measure is serious adverse events., Conclusion: CHAIN is on schedule to provide reliable evidence over the benefits of a popular herbal TCM for the treatment of acute ICH., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) is an international, multicenter, stepped-wedge (4 phases/3 steps) cluster randomized trial involving 110 hospitals in mainly low- and middle-income countries during 2017-2022. The aim is to determine the effectiveness of a goal-directed care bundle of intensive blood pressure (BP) lowering, glycemic control, antipyrexia, and anticoagulation reversal treatment versus usual standard of care, in patients with acute intracerebral hemorrhage (ICH). After a "usual care" period, hospitals were randomly allocated to implementing care-bundle protocols for control targets (systolic BP <140 mm Hg; glucose 6.1-7.8/7.8-10.0 mmol/L according to diabetes mellitus status; temperature ≤37.5°C; normalization of anticoagulation). A sample size of 8,360 patients (mean 19 per phase per site) provides 90% power (α = 0.05) for a 5.6% absolute improvement in the primary outcome of scores on the modified Rankin scale at 6 months, analyzed by ordinal logistic regression. A detailed statistical analysis plan (SAP) was developed to prespecify the method of analysis for all outcomes and key variables collected in the trial. The primary analysis will use ordinal logistic regression adjusted for the stepped-wedge design. The SAP also includes planned sensitivity analyses, including covariate adjustments, missing data imputations, and subgroup analysis. This SAP allows transparent, verifiable, and prespecified analyses in consideration of the challenges in conducting the study during the COVID pandemic. It also avoids analysis bias arising from prior knowledge of the findings in determining the benefits and harms of a care bundle in acute ICH., (The Author(s). Published by S. Karger AG, Basel.)

Background: The third INTEnsive care bundle with blood pressure Reduction in Acute Cerebral Haemorrhage Trial is an ongoing international, multicentre, stepped wedge, cluster-randomized trial to determine the effectiveness of a goal-directed care bundle (early intensive blood pressure [BP] lowering, glycaemic control, treatment of pyrexia, and reversal of anticoagulation), as compared to standard of care, on patient-centred outcomes after acute intracerebral haemorrhage (ICH). An embedded process evaluation aims to identify factors related to the uptake and implementation of the intervention. Herein, we present the process evaluation results for hospital sites in China., Methods/design: A mixed methods approach, including surveys, focused group discussions and interviews with clinicians, routine monitoring, and recruitment logs were used to collect data across purposively sampled hospitals. Medical Research Council guidance and normalization process theory were used as theoretical frameworks for design, data analysis, and synthesis., Results: Twenty quantitative surveys were completed with clinicians, and 26 interviews and 2 focus group discussions were conducted during 2019-2020. The care bundle was generally delivered as planned and acceptable by doctors and nurses, but difficulties were reported in achieving the protocol-defined target levels of BP and glycaemic control. Resistance to implementing the care bundle occurred for patients perceived to be at high risk of adverse effects. Common organizational contextual factors that impeded implementation included delayed processes and limited medication supply, while established background care procedures, expertise, and capacity influenced its integration into routine practice. Areas to facilitate implementation included optimizing workflow within available resources, having a dedicated team, and recognizing the potential benefits of the intervention., Conclusions: Varied established care protocols across sites, different levels of background expertise, and lack of staff capacity impeded the integration of goal-directed care bundle into routine practice for ICH patients in China. Ready identification, and efforts to address, these barriers could facilitate uptake of future guideline-recommended interventions for the management of patients with ICH., (© 2021 S. Karger AG, Basel.)

Objective: To study the effect of intensive blood pressure reduction in patients with moderate to severe intracerebral hemorrhage (ICH) within the subjects recruited in Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial., Design: Randomized, multicenter, 2 group, open-label clinical trial., Setting: A total of 110 sites in the USA, Japan, China, Taiwan, South Korea, and Germany., Patients: A total of 1,000 patients underwent randomization from May 2011 till September 2015., Interventions: We analyzed the effect of intensive (goal 110-139 mm Hg) over standard (goal 140-179 mm Hg) systolic blood pressure (SBP) reduction using intravenous nicardipine within 4.5 h of symptom onset in moderate to severe grade subjects with ICH in a non-prespecified analysis. Moderate to severe grade was defined by Glasgow Coma Scale score <13 or baseline National Institutes of Health Stroke Scale score ≥10 or baseline intraparenchymal hemorrhage volume ≥30 mL or presence of intraventricular hemorrhage. The primary outcome was death or disability (score 4-6 on the modified Rankin scale) at 3 months after randomization ascertained by a blinded investigator., Measurements and Main Results: Of a total of 682 subjects who met the definition of moderate to severe grade (mean age 61.9 ± 13.1 years, 62.5% men) with a mean baseline SBP of 174.7 ± 24.8 mm Hg, the frequency of hematoma expansion was significantly lower among subjects randomized to intensive SBP reduction than among subjects randomized to standard SBP reduction (20.4 vs. 27.9%, relative risk [RR]: 0.7; 95% confidence interval [CI]: 0.55-0.96). The primary endpoint of death or disability was observed in 52.5% (170/324) of subjects receiving intensive SBP reduction and 48.9% (163/333) of subjects receiving standard SBP reduction (RR: 1.1; 95% CI: 0.9-1.2)., Conclusions: Intensive SBP lowering reduced the frequency of hematoma expansion but did not reduce the rate of death or disability in patients with moderate to severe grade ICH., (© 2020 S. Karger AG, Basel.)

Background: Spontaneous intracerebral hemorrhage (ICH) is a frequent cerebrovascular disorder and still associated with high mortality and poor clinical outcomes. The purpose of this review was to update a 15-year-old former meta-analysis on randomized clinical trials (RCTs) addressing the question of whether ICH patients treated with dexamethasone have better outcomes than controls., Methods: The electronic databases PubMed, SCOPUS, and Cochrane as well as web platforms on current clinical trials were searched for the years 1970-2020 without constriction on language. Data were extracted and outcomes were pooled for conventional and cumulative meta-analysis using a commercial software program (www.Meta-Analysis.com)., Results: Finally, 7 RCTs were identified and analyzed including 248 participants in the dexamethasone groups and 242 in the control groups. Five studies showed a high risk of bias. The overall relative risk (RR) for death was 1.32 (95% confidence interval [CI] 0.99-1.76; p = 0.06) and did not differ significantly between the 2 groups. After exclusion of studies with high risk of bias, the RR for death was 1.37 (95% CI 0.54-3.42; p = 0.51). The RR for poor outcome did not differ significantly between the 2 groups analyzed for all included studies (RR = 0.69; 95% CI 0.47-1; p = 0.05) and after exclusion of studies with high risk of bias (RR = 0.7; 95% CI 0.45-1.08; p = 0.11). The RR for complications did not differ significantly including all studies (RR = 1.29; 95% CI 0.77-2.17; p = 0.34) and after exclusion of studies with high risk of bias (RR = 1.27; 95% CI 0.18-8.89; p = 0.81). The cumulative statistics delivered no other results; however, it pointed out fewer complications over time in the dexamethasone group., Conclusion: Clear evidence of a beneficial or negative effect of dexamethasone is still lacking. Modern RCTs or observational studies with propensity design are necessary to evaluate the efficacy and safety of treatment with dexamethasone in patients with ICH., (© 2020 S. Karger AG, Basel.)

Background: Prevention of hematoma enlargement in oral anticoagulation-associated intracerebral hemorrhage (OAC-ICH) focuses on blood pressure (BP) reduction and OAC reversal. We investigated whether treatment efficiency and clinical outcomes differ between OAC-ICH patients admitted outside versus during regular working hours., Methods: Based on pooled data of multicenter cohort studies, we grouped OAC-ICH patients (vitamin K antagonist [VKA], non-vitamin K oral anticoagulant [NOAC]) according to on- vs. off-hour admission. Primary outcome was the functional outcome using the modified Rankin scale (mRS) dichotomized into favorable (mRS 0-3) and unfavorable (mRS 4-6) and mortality at 3 months. Secondary outcome measures included the occurrence of hematoma enlargement, the proportions of patients with systolic BP <140 mm Hg and with anticoagulation treatment achieving international normalized ratio (INR) levels <1.3 at 4 h. Propensity score matching (PSM) was performed to account for imbalances in baseline characteristics., Results: The study population consisted of 76/126 NOAC-ICH patients and 1,005/1,470 VKA patients presenting during off-hours. Functional outcome and mortality rates were not significantly different among PSM patients with VKA-ICH and NOAC-ICH during on- vs. off-hours (mRS 4-6 VKA-ICH: on-hour: 239/357 [66.9%] vs. 253/363 [69.7%] off-hour; p = 0.43; NOAC-ICH: on-hour 26/42 [61.9%] vs. off-hour: 37/57 [64.9%]; p = 0.76; mRS 6 VKA-ICH: on-hour: 127/357 [35.6%] vs. off-hour: 148/363 [40.8%]; p = 0.15; -NOAC-ICH: on-hour 17/42 [40.5%] vs. off-hour: 16/57 [28.1%]; p = 0.20). There were no differences detectable regarding the secondary outcome measures (i.e., hematoma enlargement, the proportion of patients who achieved systolic BP levels <140 mm Hg at 4 h as well as anticoagulation treatment achieving INR levels <1.3 at 4 h) in OAC patients., Conclusion: Our study implies that BP reduction and anticoagulation reversal management are well established and associated with similar rates of hematoma enlargement and clinical outcomes in on- vs. off-hour admitted OAC-ICH patients., (© 2020 S. Karger AG, Basel.)

Background: Neurological deterioration (ND) has a major influence on the prognosis of intracerebral hemorrhage (ICH); however, factors associated with ND occurring after 24 h of ICH onset are unknown., Methods: We performed exploratory analyses of data from the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 trial, which compared intensive and standard blood pressure lowering treatment in ICH. NDs were captured on the adverse event case report form. Logistic regression analysis was performed to examine the independent predictors of late ND., Results: Among 1,000 participants with acute ICH, 82 patients (8.2%) developed early ND (≤24 h), and 64 (6.4%) had late ND. Baseline hematoma volume (adjusted OR [aOR] per 1-cm3 increase 1.04, 95% CI 1.02-1.06, p < 0.0001), hematoma volume increase in 24 h (aOR 2.24, 95% CI 1.23-4.07, p = 0.008), and the presence of intraventricular hemorrhage (IVH; aOR 2.38, 95% CI 1.32-4.29, p = 0.004) were independent predictors of late ND (vs. no late ND). Late ND was a significant risk factor for poor 90-day outcome (OR 3.46, 95% CI 1.82-6.56). No statistically significant difference in the incidence of late ND was noted between the 2 treatment groups., Conclusions: Initial hematoma volume, early hematoma volume expansion, and IVH are independent predictors of late ND after ICH. Intensive reduction in the systolic blood pressure level does not prevent the development of late ND., (© 2020 S. Karger AG, Basel.)

Objective: Intracerebral hemorrhage (ICH) is associated with high morbidity and mortality. Prognosis estimation would be helpful for the treatment decision making in ICH patients. The ICH-score was published in 2001 to estimate the 30-day mortality in conservatively treated patients with ICH. We evaluated the reproducibility of the ICH-score in ICH patients undergoing fibrinolytic therapy., Methods: We performed a retrospective analysis of patients with supratentorial ICH managed by fibrinolytic therapy and evaluated the 30-day mortality. The ICH-score was then applied to match the mortality in our patients with the mortality predicted by the ICH-score. The ICH-score is based on parameters available at admission: age, hematoma volume, intraventricular expansion, and clinical status according to the Glasgow Coma Scale., Results: A total of 233 patients were analyzed. The 30-day mortality rate was 30% (70/233). An age of ≥80 years was associated with a significantly higher mortality rate (OR 2.26, chi-square test p = 0.01). A hematoma volume of ≥30 mL led significantly more often to 30-day mortality (OR 3.72, chi-square test p = 0.01). The mortality was significantly higher in the patients with intraventricular hemorrhage (2.97, chi-square test p = 0.003). The ICH-score showed a significant correlation with mortality (chi-square test, p < 0.0001). The following mortality rates were estimated using the ICH-score in our cohort: 1 = 0% (0/13), 2 = 0% (0/51), 3 = 1.3% (1/82), 4 = 43% (13/31), 5 = 100% (56/56)., Conclusion: The ICH-score not only allows a reliable estimation of the 30-day mortality in patients with ICH treated conservatively but also treated by clot lysis. Compared to conservative treatment, the fibrinolytic therapy reduced the 30-day mortality in the patients with ICH-scores 1-4. Patients with ICH-score 5 do not have a benefit of fibrinolytic therapy and should no longer be considered to be candidates for fibrinolytic therapy., (© 2019 S. Karger AG, Basel.)

Background: Data on cognitive impairment after acute intracerebral hemorrhage (ICH) are limited. This study is aimed at determining the frequency and predictors of cognitive impairment among participants of the pilot phase, Intensive Blood Pressure (BP) Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1)., Methods: INTERACT1 was an open randomized trial of early intensive (target systolic BP <140 mm Hg) compared with contemporaneous guideline-recommended BP lowering in 404 patients with elevated systolic BP (150-220 mm Hg) within 6 h of ICH onset. Cognitive impairment was defined by scores ≤24 on the Mini-Mental State Examination (MMSE) assessed by interview on follow-up at 90 days., Results: A total of 231 (64.5%) of 358 90-day survivors had MMSE scores for analyses, and 75 (32.5%) had cognitive impairment. In multivariable analysis, older age (OR 2.48, 95% CI 1.73-3.56 per 10-year increase; p < 0.001), female sex (OR 2.06, 95% CI 1.00-4.23; p = 0.049), prior ICH (OR 2.87, 95% CI 1.08-7.65; p = 0.035), high baseline National Institute of Health Stroke Scale score (OR 1.06, 95% CI 1.00-1.13; p = 0.044), and high mean systolic BP over the first 24 h post-randomization (OR 1.34, 95% CI 1.07-1.68/10 mm Hg increase; p = 0.011) were independently associated with cognitive impairment., Conclusions: One third of patients have significant cognitive impairment early after ICH, which is more frequent in the elderly, females, those with prior ICH, and more severe initial neurological deficit and with persistently high early systolic BP., (© 2017 S. Karger AG, Basel.)

Background: The first specific antidote for non-vitamin K antagonist oral anticoagulants (NOAC) has recently been approved. NOAC antidotes will allow specific treatment for 2 hitherto problematic patient groups: patients with oral anticoagulant therapy (OAT)-associated intracerebral hemorrhage (ICH) and maybe also thrombolysis candidates presenting on oral anticoagulation (OAT). We aimed to estimate the frequency of these events and hence the quantitative demand of antidote doses on a stroke unit., Methods: We extracted data of patients with acute ischemic stroke and ICH (<24 h after symptom onset) in the years 2012-2015 from a state-wide prospective stroke inpatient registry. We selected 8 stroke units and determined the mode of OAT upon admission in 2012-2013. In 2015, the mode of OAT became a mandatory item of the inpatient registry. From the number of anticoagulated patients and the NOAC share, we estimated the current and future demand for NOAC antidote doses on stroke units., Results: Eighteen percent of ICH patients within 6 h of symptom onset or an unknown symptom onset were on OAT. Given a NOAC share at admission of 40%, about 7% of all ICH patients may qualify for NOAC reversal therapy. Thirteen percent of ischemic stroke patients admitted within 4 h presented on anticoagulation. Given the availability of an appropriate antidote, a NOAC share of 50% could lead to a 6.1% increase in thrombolysis rate., Conclusions: Stroke units serving populations with a comparable demographic structure should prepare to treat up to 1% of all acute ischemic stroke patients and 7% of all acute ICH patients with NOAC antidotes. These numbers may increase with the mounting prevalence of atrial fibrillation and an increasing use of NOAC., (© 2016 S. Karger AG, Basel.)

Background: Prothrombin complex concentrates (PCCs) are frequently used to reverse the effect of vitamin K antagonists (VKAs) in patients with non-traumatic intracerebral hemorrhage (ICH). However, information on the rate of thromboembolic events (TEs) and allergic events after PCC therapy in VKA-ICH patients is limited., Methods: Consecutive VKA-ICH patients treated with PCC at our institution between December 2004 and June 2014 were included into this retrospective observational study. We recorded international normalized ratio (INR) values before and after PCC treatment, baseline clinical characteristics including the premorbid modified Rankin Scale (pmRS) score, TE and allergic event that occurred during the hospital stay. All events were classified by 3 reviewers as being 'related', 'probably related', 'possibly related', 'unlikely related' or 'not related' to treatment with PCC. To identify factors associated with TEs, log-rank analyses were applied., Results: Two hundred and five patients were included. Median INR was 2.8 (interquartile range (IQR) 2.2-3.8) before and 1.3 (IQR 1.2-1.4) after PCC treatment and a median of 1,500 IU PCC (IQR 1,000-2,500) was administered. Nineteen TEs were observed (9.3%); none were classified 'related' but 9 were classified as 'possibly' or 'probably related' to PCC infusion (4.4%). One allergic reaction (0.5%), 'unlikely related' to PCC, was observed. In the whole cohort, PCC doses >2,000-3,000 IU, ICH volumes >40 ml, National Institute of Health Stroke Scale values >10 and a pmRS >2 were associated with the development of TEs (p = 0.031, p = 0.034, p = 0.050 and p = 0.036, respectively)., Conclusions: Overall, INR reversal with PCC appears safe. Though no clear relationship between higher PCC dosing and TEs was observed, PCC doses between >2,000 and 3,000 IU and higher morbidity at ICH onset were associated with TEs. Hence, individual titration of PCC to avoid exposure to unnecessarily high doses using point-of-care devices should be prospectively explored., (© 2016 S. Karger AG, Basel.)

Background: Different aspects of acute stroke management and strategies for stroke prevention derive from two viewpoints: specific traditional and historical backgrounds and evidence-based medicine from modern randomized controlled trials (RCTs), meta-analysis and authorized clinical practice guidelines (GLs). Regarding intracerebral hemorrhage (ICH), Cerebrovascular Diseases published the 2006 European stroke initiative recommendations for the management of ICH. In 2009, the revised Japanese GLs for the management of stroke, including that of ICH, appeared in Japanese. Whereas GLs for the prevention and treatment of ischemic stroke were presented in detail, recommendations with regard to ICH are relatively rare both in Japan and Europe., Methods: Since 2011, the authors have met repeatedly and have compared the latest versions of published European and Japanese GLs for ischemic and hemorrhagic strokes. Many aspects have only been addressed in one but left out in the other GLs, which consequently founded the basis for the comparison. Classification of evidence levels and recommendation grades defined by the individual committees differed between both original GLs., Results: Aspects of major importance were similar and hence did not need extensive interpretation, mostly due to a lack of evidence from appropriate RCTs worldwide. The target level to which systolic blood pressure should be lowered is quite high; <170 mm Hg for patients with known hypertension in Europe and <180 mm Hg in Japan. The results of ongoing clinical trials are awaited for the optimal target level and optimal medications. Concerning ICH associated with oral anticoagulant therapy, both guidelines give similar recommendations, namely that anticoagulation should be discontinued and the international normalized ratio of prothrombin time should be normalized with prothrombin complex concentrate or fresh-frozen plasma and additional vitamin K. Patients with ICH were treated surgically, often based on individual decisions - more frequently in Japan, depending on the association with hypertension. Patients with large or intraventricular bleedings were only treated if a life-saving performance was considered, irrespective of the neurological outcome. Infra- and supratentorial differences were similarly addressed in both GLs., Conclusion: This brief survey - when compared with the lengthy original recommendations - provides a stimulating basis for an extended interest among Japanese and European stroke clinicians to learn from their individual experiences and to strengthen efforts for joint cooperation in treating and preventing stroke all around the globe., (Copyright © 2013 S. Karger AG, Basel.)

Background: Intracerebral hemorrhage (ICH) causes 10-15% of primary strokes, with mortality related to hematoma volume. Blood pressure (BP) reduction may attenuate hematoma expansion. ACCELERATE (the Evaluation of Patients with Acute Hypertension and Intracerebral Hemorrhage with Intravenous Clevidipine Treatment) is a pilot study representing the first evaluation of safety and efficacy of intravenous clevidipine for the rapid treatment of hypertension in ICH patients., Methods: ICH patients with a systolic BP (SBP) >160 mm Hg who present within 6 h (n = 27) or 12 h (n = 10) of symptoms were prospectively enrolled, treated with open-label clevidipine until SBP ≤160 mm Hg was achieved and then titrated to keep target SBP between 140-160 mm Hg., Results: A total of 35 patients with baseline median Glasgow Coma Scale score of 12, median NIH Stroke Scale score of 14, mean SBP of 186 mm Hg and a mean time from onset of symptoms of 5.5 h received clevidipine. Median time to achieve SBP target range was 5.5 min. All patients achieved target SBP within 30 min; 96.9% achieved target SBP with clevidipine monotherapy. CT scans showed minimal hematoma volume change for the overall population (median change 0.01 ml, -2.9%). Mild/moderate hypotension was reported in 3 patients and resolved with dose reduction or drug discontinuation., Conclusion: Clevidipine monotherapy was effective and safe for rapid BP reduction in this cohort of critically ill ICH patients. Overall, patients showed minimal hematoma expansion with BP reduction, suggesting that rapid BP control with clevidipine may have a beneficial impact on hematoma expansion and warrants further investigation., (Copyright © 2013 S. Karger AG, Basel.)

Background: The American Heart Association and the American Stroke Association recommend intravenous (IV) thrombolysis up to 4.5 h from acute ischemic stroke symptom onset based on its proven benefit in improving patient outcomes. We analyzed data from the Minnesota Stroke Registry to assess the rates of IV thrombolytic utilization and the process of care in this expanded window., Methods: We identified patients who had received IV recombinant tissue plasminogen activator (rt-PA) at any of the 19 participating hospitals from January 1, 2008 till December 31, 2010. Treatment groups were those actually treated by IV rt-PA in 0-3 h and those treated by IV rt-PA in 3-4.5 h. Duration from symptom onset to arrival in the emergency department (ED) was dichotomized to cohorts of 0-2 and 2-3.5 h. We determined the overall utilization of IV rt-PA in the expanded window and calculated door-to-needle times for the two treatment windows. We also ascertained the rates of symptomatic intracerebral hemorrhage between the two treatment groups., Results: Out of the total 519 patients who received IV rt-PA for acute ischemic stroke, 433 (83%) were treated within 0-3 h and 86 (17%) within 3-4.5 h. Of all the patients who received IV rt-PA within 3-4.5 h, 45% arrived at the ED within 2 h of symptom onset. Median door-to-needle time for the 0- to 3-hour window was 74.5 min [interquartile range (IQR) 57-90] and 54 min (IQR 43.5-70.5) for the 3- to 4.5-hour window. Based on arrival time to the ED, door-to-needle time of ≤60 min was achieved by only 31% (142/458) of patients who arrived within 0-2 h of their symptom onset compared to 61% (37/61) of those who arrived at the ED within 2-3.5 h of their symptom onset. Fifty-nine (14%) patients in the 0- to 3-hour group and 17 (20%) patients in the 3- to 4.5-hour group received a combination of IV rt-PA and endovascular treatments. Among patients with documented admission National Institutes of Health Stroke Scale scores, the values (median with IQR) were different between the 0- to 3- and the 3- to 4.5-hour group, i.e. 10 (IQR 5-18) and 7 (IQR 4-14), respectively., Conclusion: Patients who received IV rt-PA within the 3- to 4.5-hour window comprised 17% of all IV rt-PA cases treated in the Minnesota Stroke Registry hospitals after the new guidelines recommended a time window expansion. Almost half of these patients would have qualified for treatment within the 0- to 3-hour window as they presented within 0-2 h of symptom onset. Patients arriving 2-3.5 h after symptom onset received thrombolysis on average 20 min faster than patients arriving within 2 h of symptom onset., (Copyright © 2012 S. Karger AG, Basel.)

Intracerebral hemorrhage (ICH) is associated with higher mortality and morbidity than any other form of stroke. However, there currently are no treatments proven to improve outcomes after ICH, and therefore, new effective therapies are urgently needed. Growing insight into ICH pathophysiology has led to the development of neuroprotective strategies that aim to improve the outcome through reduction of secondary pathologic processes. Many neuroprotectants target molecules or pathways involved in hematoma degradation, inflammation or apoptosis, and have demonstrated potential clinical benefits in experimental settings. We extensively reviewed the current understanding of ICH pathophysiology as well as promising experimental neuroprotective agents with particular focus on their mechanisms of action. Continued advances in ICH knowledge, increased understanding of neuroprotective mechanisms, and improvement in the ability to modulate molecular and pathologic events with multitargeting agents will lead to successful clinical trials and bench-to-bedside translation of neuroprotective strategies., (Copyright © 2010 S. Karger AG, Basel.)

Background: The present study was carried out to determine the effect of prothrombin complex concentrate (PCC) on hematoma enlargement (HE) and the early clinical outcome of intracerebral hemorrhage (ICH) patients on long-term warfarin treatment., Methods: The medical records and computed tomography (CT) images of 50 consecutive ICH patients on long-term warfarin treatment (35 men, 15 women; 69 ± 12 years old) were reviewed. International normalized ratio (INR) values, frequency of HE and clinical outcome were compared between patients treated with and without PCC., Results: INR values on admission were above 2.0 in 37 patients, of whom 19 were given PCC (PCC group) and 18 were not given PCC (control group). In these 37 patients, the frequency of HE (p = 0.017), the number of patients with a poor clinical outcome (modified Rankin Scale score ≥3 at 30 days or at discharge; p = 0.045) and in-hospital mortality (p = 0.042) were significantly higher in the control than in the PCC group. On multivariate logistic regression analysis with adjustment, PCC administration was independently associated (odds ratio 0.03, 95% confidence interval 0.00-0.63; p = 0.023) with a reduction in poor clinical outcome in ICH patients whose INR values were >2.0 on admission., Conclusions: Immediate INR reversal with PCC may prevent HE and subsequent poor outcome., (Copyright © 2010 S. Karger AG, Basel.)

Background: Inhibition of the c-Jun N-terminal kinase (JNK) pathway by the TAT-coupled peptide XG-102 (formerly D- JNKI1) induces strong neuroprotection in ischemic stroke in rodents. We investigated the effect of JNK inhibition in intracerebral hemorrhage (ICH)., Methods: Three hours after induction of ICH by intrastriatal collagenase injection in mice, the animals received an intravenous injection of 100 microg/kg of XG-102. The neurological outcome was assessed daily and the mice were sacrificed at 6 h, 1, 2 or 5 days after ICH., Results: XG-102 administration significantly improved the neurological outcome at 1 day (p < 0.01). The lesion volume was significantly decreased after 2 days (29 +/- 11 vs. 39 +/- 5 mm(3) in vehicle-treated animals, p < 0.05). There was also a decreased hemispheric swelling (14 +/- 13 vs. 26 +/- 9% in vehicle-treated animals, p < 0.05) correlating with increased aquaporin 4 expression., Conclusions: XG-102 attenuates cerebral edema in ICH and functional impairment at early time points. The beneficial effects observed with XG-102 in ICH, as well as in ischemic stroke, open the possibility to rapidly treat stroke patients before imaging, thereby saving precious time., (Copyright 2010 S. Karger AG, Basel.)

Background and Purpose: Depression is a frequent and important complication of stroke. Few data exist on the prevalence of depression/depressed mood after intracerebral hemorrhage (ICH) and the relationship between depression/depressed mood and the quality of life (QoL) more generally experienced by survivors of ICH., Methods: Factor Seven for Acute Hemorrhagic Stroke (FAST) was a randomized, multicenter, double-blind, placebo-controlled trial conducted between May 2005 and February 2007 at 122 sites in 22 countries. All patients were evaluated at day 90 after ICH onset for depressed mood and QoL with the Hamilton Depression Rating Scale (HDRS) and the EuroQoL, respectively. Multivariate stepwise logistic regression was used to develop a predictive model for depressed mood at day 90. Relationships between HDRS and EuroQoL scores at day 90 were evaluated with Spearman correlation coefficients., Results: 657 patients were alive at 3 months after ICH onset; 596 (91%) completed the HDRS. Twenty percent reported an HDRS score >10, indicating at least a minor degree of depressed mood; 6% endorsed symptoms of severely depressed mood. Significant predictors of depressed mood included comorbidities (p = 0.0022), moderate to severe neurological impairment according to the National Institutes of Health Stroke Scale (NIHSS) at day 15 (p = 0.0097), physical disability as measured by the Barthel Index (BI) at day 15 (p = 0.0486), and female gender (p = 0.04), but not hemorrhage severity or a history of depression. Irrespective of the presence of post-ICH disability and impairment, the severity of depressed mood at day 90 was significantly correlated with poor QoL., Conclusion: Depressed mood affects approximately 20% of ICH survivors and adversely affects QoL. Physicians should be vigilant to ensure that chronically ill and severely impaired survivors of ICH are adequately monitored and treated for depression after ICH., (Copyright 2009 S. Karger AG, Basel.)

Background: Our purpose was to determine whether the onset-to-arrival time affects the outcome of stroke patients., Methods: We carried out a prospective multicenter study involving 1,817 patients with ischemic stroke and 1,226 with intracerebral hemorrhage who presented to hospitals within 24 h of symptom onset. The primary outcome was independent activity of daily living corresponding to a modified Rankin Scale (mRS) score or=8 h, p < 0.001). The median mRS scores at discharge in these groups were 3, 2 and 2, respectively (p < 0.001). After adjustment for underlying features and the initial NIHSS score, the independent activity of daily living at discharge was 1.73 times more common in patients in the earliest group than in the latest group (95% CI = 1.24-2.42, p = 0.001). A similar tendency was shown in the subanalysis for large-artery atherosclerosis and cardioembolic stroke. In intracerebral hemorrhage patients, both the initial NIHSS score and the mRS score at discharge decreased as the onset-to-arrival time increased. After multivariate adjustment, the independent activity of daily living was 2.33 times (p < 0.001) and 1.69 times (p = 0.006) less common in patients in the earliest (<1.2 h) and second tertile groups (1.2-3.5 h), respectively, than in the latest tertile group (>or=3.5 h)., Conclusions: Early hospital arrival improved the clinical outcome in ischemic stroke patients but not in patients with intracerebral hemorrhage., ((c) 2009 S. Karger AG, Basel.)

Background: Elevated intracranial pressure (ICP) is an important marker of neurological deterioration. The occurrence and significance of elevated ICP and low cerebral perfusion pressure (CPP) in aggressively treated spontaneous intraventricular hemorrhage (IVH) are not defined., Methods: We performed a secondary longitudinal exploratory data analysis of a randomized multicenter trial of urokinase (UK) versus placebo (Pcb) as a treatment for IVH. Eleven IVH patients who required an external ventricular drain (EVD) were randomized to receive either intraventricular UK or Pcb every 12 h until clinical response permitted EVD removal. ICP and CPP were recorded every 4 or 6 h, as well as before and 1 h after EVD closure for administration of study agent. ICP, CPP and the proportion of ICP readings above 20, 30, 40 and 50 mm Hg were analyzed., Results: Six UK and 5 Pcb patients aged 39-74 years (mean +/- standard deviation; 53 +/- 11 years) were enrolled. Initial ICP ranged from 0 to 38 mm Hg (10.9 +/- 11.0), initial CPP from 65 to 133 mm Hg (100.5 +/- 17.7). We recorded 472 ICP readings over the entire monitoring period. Of these 65 (14%) were >20 mm Hg, 23 (5%) >30 mm Hg, 9 (2%) >40 mm Hg and 3 (<1%) >50 mm Hg. Only 2 of 141 intraventricular injections of study agent with EVD closure were not tolerated and required reopening of the EVD., Conclusions: In the intensive care unit, initial ICP measured with an EVD was uncommonly elevated (1/11 patients) in this group of severe IVH patients despite acute obstructive hydrocephalus. Frequent monitoring reveals ICP elevation >20 mm Hg in 14% of observations during use of EVD. ICP elevation, though it can occur, is not routinely associated with EVD closure for thrombolytic treatment with UK., (Copyright 2009 S. Karger AG, Basel.)

Background: Much effort has been made to study first-ever stroke patients. However, recurrent stroke has not been investigated as extensively. It is unclear which risk factors dominate, and whether adequate secondary prevention has been provided to patients who suffer from recurrent stroke. Also, the different types of recurrent stroke need further evaluation., Methods: The study included patients with recurrent stroke admitted to twenty-three Swedish stroke centers. The type of previous and recurrent stroke was determined, as well as evaluation (when applicable) of recurrent ischemic stroke according to the TOAST classification. Presence of vascular risk factors was registered and compared to the type of stroke. Also assessed was ongoing secondary prevention treatment at recurrent stroke onset., Results: A total of 889 patients with recurrent stroke (mean age 77) were included in the study. Of these, 805 (91%) had ischemic stroke, 78 (9%) had intracerebral hemorrhage and 6 (<1%) stroke of unknown origin. The most frequent vascular risk factors were hypertension (75%) and hyperlipidemia (56%). Among the 889 patients, 29% had atrial fibrillation. Of the patients in the ischemic group with cardiac embolism, only 21% were on anticoagulation treatment. The majority of the patients (75%) had their most recent previous stroke >12 months before admission., Conclusions: Few patients had a recurrent stroke shortly after the previous stroke in this study. This indicates that it is meaningful to prevent a second event with an adequate long-term treatment strategy for secondary prevention after first-ever stroke. There also seems to be a clear potential for improving secondary prevention after stroke.

Background: We recently demonstrated that recombinant activated factor VII (rFVIIa) given to patients presenting within 3 h of acute spontaneous intracerebral hemorrhage (ICH) reduces mortality (18% vs. 29%) and poor outcome (modified Rankin Scale, mRS, 4-6, 53 vs. 69%). This analysis was performed to determine the impact of rFVIIa on health-related quality of life (HRQoL) in those patients., Methods: In a prospective, randomized controlled trial, 399 patients (mean age, 66 years) received placebo, 40, 80 or 160 microg/kg of rFVIIa within 4 h of acute ICH. At 90 days, HRQoL was assessed with the EuroQoL (EQ-5D), a 5-dimensional measure of health which also includes the Visual Analogue Scale. Additionally, each level of the 90-day mRS was adjusted, using 4 different previously published utility values, to obtain a clearer picture of perceived HRQoL., Results: Among the 5 dimensions of EQ-5D, only mobility rating was significantly better for rFVIIa-treated patients (serious problems, 34 vs. 54%; p = 0.01). Yet, the utility value (scaled 1.0 = perfect health and 0.0 = dead) associated with the composite EQ-5D demonstrated significantly better HRQoL (0.48 vs. 0.36; p = 0.01). This was also true for the EQ-5D Visual Analogue Scale score (44 vs. 36; p = 0.04). Finally, all 4 algorithms for applying utility scores to the mRS indicated that rFVIIa was associated with significantly better perceived HRQoL (all p < 0.006)., Conclusions: Treatment with rFVIIa within 4 h of acute spontaneous ICH improves HRQoL.

Background: Antiplatelet treatment remains the first choice for primary and secondary prevention of vascular diseases; even so, expected benefits may be offset by risk of bleeding, particularly cerebral hemorrhage. The aim of this study was to assess the influence of antiplatelet treatment on clinical outcome at hospital discharge., Materials and Methods: Consecutive patients with first-ever stroke due to a primary intraparenchymal hemorrhage were prospectively identified over a 4-year period (2000-2003). Data on hemorrhage location, vascular risk factors, and antiplatelet and anticoagulant treatment were collected. At discharge, outcome was measured using the modified Rankin Scale (disabling stroke > or =3). Patients treated with anticoagulant therapy were excluded from the study., Results: Of 457 consecutive patients with cerebral hemorrhage, 94 (20.5%) had been taking antiplatelet agents. The treated patients (mean age for antiplatelet group 78.9 +/- 9.0 years) were older than the nontreated patients (73.8 +/- 9.4, p = 0.02). In-hospital mortality was 23.4 and 23.1% (p = n.s.) for patients who had been taking antiplatelet agents or no treatment. Poor outcome at discharge was found in 52.1 and 59.7% (p = n.s.), respectively. Univariate analysis showed that age and coma at admission were predictors of disability at discharge, but antiplatelet treatment was not. Additionally, age and coma were shown to be determinants of disability at discharge after multivariate analysis: OR 1.03 per year (95% CI: 1.018-1.049), p < 0.001 and OR 1.68 (95% CI: 1.138-2.503), p = 0.009, respectively., Conclusions: Hemorrhagic stroke continues to be responsible for a high percentage of disability and death. Furthermore, it was seen here that functional outcome was independent of previous antiplatelet treatment.

Background: Intracerebral hemorrhage (ICH) is a devastating form of stroke for which the lack of treatment options, high mortality rate, and the tendency to severely disable result in high social and economic burden., Methods: We analyzed data in the Registry of the Canadian Stroke Network (RCSN). We sought to: (1) provide a descriptive analysis of ICH; (2) determine the proportion of ICH patients that might have been eligible for treatment with recombinant activated factor VII (rFVIIa) using criteria from a recent phase II trial; (3) compare 6-month outcomes of ICH patients with those of ischemic stroke patients, matched for gender, age, and stroke severity., Results: In the RCSN, 11% of all strokes were nontraumatic ICH. The median Canadian Neurological Scale score was 7. A minority (33%) of patients arrived to the emergency department in less than 3 h from onset. In this cohort, in-hospital mortality was 15%. At 6 months, a further 9% of patients had died and 58% had a slight to no disability (Stroke Impact Scale-16 score > or = 75). Approximately 20% of ICH patients would have been eligible for rFVIIa treatment. Compared to ischemic stroke, ICH showed a trend towards increased mortality at discharge (OR: 1.96, CI: 0.99-3.87). At 6-month follow-up, ICH showed increased mortality (OR: 2.27, CI: 1.29-3.97), yet functional outcomes were not significantly different., Conclusion: ICH patients had a higher case-fatality rate when compared to acute ischemic stroke, but survivors had similar functional outcomes. In Canada, about one fifth of ICH patients might potentially benefit from rFVIIa if it is approved, with the major exclusion factor being time., (Copyright 2006 S. Karger AG, Basel.)

Background: In experimental models citicoline has shown beneficial effects in intracerebral haemorrhage. Citicoline is a neuroprotectant drug with some beneficial effects in human ischaemic stroke and with an excellent safety profile. We decided to carry out a pilot study to test its safety and efficacy in human intracerebral haemorrhaging., Methods: In this double-blind, placebo-controlled pilot study, patients had to be previously independent, aged between 40 and 85 years, and had to be admitted within 6 h after onset of symptoms of an acute primary supratentorial hemispheric cerebral haemorrhage diagnosed by neuroimaging (CT or MRI). Baseline severity was defined as patients with a score larger than 8 points on the Glasgow Coma Scale and larger than 7 on the National Institutes of Health Stroke Scale. Patients received either a placebo or 1 g/12 h citicoline for 2 weeks (orally or intravenously). The primary aim was to evaluate safety with respect to the number of adverse events that occurred. The efficacy endpoint was the percentage of patients with a modified Rankin Score (mRS) at 3 months., Results: 19 patients in each group were included in the study. The incidence of serious adverse events was not different among groups (4 patients in each group). One patient in the placebo group was categorised as independent (mRS

This study investigated the effects of argatroban, a thrombin inhibitor, on brain edema and inflammation in a rat intracerebral hemorrhage (ICH) model. ICH was induced by injecting collagenase IV into the right caudate nucleus. Argatroban was administered intraperitoneally. Argatroban reduced brain edema from 44.6 to 14.3 microl at 72 h. Infiltration of polymorphonuclear leukocytes at 24 h and monocyte/macrophage at 24 and 72 h was significantly suppressed by argatroban. Argatroban did not increase the volume of hematoma. Systemic administration of argatroban reduced secondary brain damage including edema and inflammation in a rat ICH model., (Copyright 2005 S. Karger AG, Basel)

Patients with intracranial haemorrhage may sometimes require antithrombotic drugs or be inadvertently given antithrombotic therapy. We systematically reviewed all published trials comparing any antithrombotic agent with control among patients with any form of intracranial haemorrhage. We extracted data on deaths, recurrent intracranial haemorrhage and functional outcome. There were 9 randomised trials of 5 different antithrombotic agents versus control in patients with subarachnoid haemorrhage (6 trials, n = 1,224) or with acute intracerebral haemorrhage (3 trials, n = 819). The overall odds ratio (OR) for death among patients with any intracranial haemorrhage given an antiplatelet agent (8 trials, 1,997 patients) was 0.85 (95% confidence interval, CI, 0.63-1.15), and for recurrent intracranial haemorrhage it was 1.00 (95% CI 0.73-1.37). The corresponding ORs for patients with intraparenchymal cerebral haemorrhage were 0.96 (0.62-1.5) and 1.02 (0.5-1.8), respectively, but 65% of these patients received only a few doses of antithrombotic treatment. The overall OR for death in patients with any intraparenchymal cerebral haemorrhage given heparin compared with control (3 trials, 819 patients, subcutaneous heparin) was 0.96 (95% CI 0.38-2.40), and for recurrent intracranial haemorrhage it was 2.00 (95% CI 0.86-4.70). There were no reliable data on the effects of antithrombotic agents on functional outcome. These scant data do not support reliable conclusions about the safety or otherwise of antithrombotic agents in patients with acute intracranial haemorrhage. Antithrombotic agents should be avoided where possible in patients with acute intracerebral haemorrhage., (Copyright 2002 S. Karger AG, Basel)

Unlabelled: Standard magnetic resonance imaging (MRI) techniques failed to image adequately acute hemorrhagic transformation (HT). Therefore, computed tomography (CT) is still needed to exclude intracerebral hemorrhage. New MRI techniques such as diffusion- and perfusion-weighted imaging (DWI and PWI) may improve the early detection of HT. The utility of this approach requires a direct comparison of the sensitivity of CT with these MRI techniques., Methods: Nine patients experienced an acute carotid artery territory ischemic stroke diagnosed on a first CT performed 3.8 +/- 2 h after the onset of stroke. They underwent a second CT 12 +/- 4 h after the onset of stroke, followed 35 +/- 10 min later by an MRI protocol including: (1) an axial isotropic DWI SE echo-planar imaging (EPI) sequence; (2) time of flight MR angiography (TOF MRA); (3) PWI with an axial T(2)*-weighted gradient echo EPI sequence using 20 ml gadolinium contrast agent (Gd-DTPA); HT was characterized on DWI SE EPI as a heterogeneous area of signal loss within the ischemic area; (4) at day 7, CT was also performed in all patients who had an early suspicion of bleeding according to MRI., Results: An HT was detected exclusively with CT in 1 out of 9 patients, while an MRI pattern of HT was found in 6 out of 9 patients. In 5 of these 6 patients, the CT scan did not show an obvious pattern of HT. Day 7 CT confirmed HT in all patients who had early suspicion of bleeding according to DWI criteria., Conclusion: This study suggests that new MRI techniques may allow an early detection of HT, thus improving the management of stroke., (Copyright 2001 S. Karger AG, Basel)

Objective: Supratentorial lobar hemorrhage can be devastating. Outcome prediction at presentation is important in triage and management decisions as well as appropriate resource utilization. We performed a decision tree analysis combining clinical and CT scan features to predict poor and hopeless outcome at initial presentation in patients with lobar hemorrhage., Methods: We analyzed 81 patients with spontaneous lobar hemorrhage presenting within 48 hours of initial neurologic symptoms. In the first analysis, poor outcome was defined as Glasgow outcome score (GOS) of 1 (death), 2 (vegetative state) or 3 (dependence) at discharge. A second analysis was based on worst possible outcome (GOS 1-2). Binary recursive partitioning was fitted in a model, and odds ratios with 95% confidence intervals (CI) were calculated., Results: Lobes involved were temporal (36%), parietal (33%), frontal (25%) and occipital (6%). Seventy-three percent of patients presented less than 17 h after initial ictus. The probability of poor outcome was 97% (CI 85-100%) in patients with hemorrhage greater than 40 cm(3). In the subset of patients with a volume less than 40 cm(3), time interval from ictus to presentation (< 17 h) together with a Glasgow coma score (GCS) less than or equal to 13 predicted poor outcome. Eighty-five percent (CI 42-99%) of those presenting early with GCS less than or equal to 13 had a poor outcome. In the second analysis, all patients with GCS less than or equal to 12 and septum pellucidum shift > 6 mm had GOS of 1 or 2 (CI 72-100%)., Conclusion: Poor outcome in patients with lobar hemorrhage is associated with a hemorrhage size of more than 40 cm(3), GCS less than or equal to 13, but also dependent on time interval between ictus and presentation. This is consistent with prior studies demonstrating deterioration from enlargement may occur when patients present early on. Stupor and septum pellucidum shift greater than 6 mm on CT scan at presentation predict a hopeless outcome in conservatively treated patients. Ninety-one percent of patients were treated medically, thus these outcomes are largely a reflection of the natural history of spontaneous lobar hemorrhage. These signs may influence triage and management decisions., (Copyright 2001 S. Karger AG, Basel)

There is insufficient information on the prognosis and safety of anticoagulation in acute cerebral vein and dural sinus thrombosis (CVDST). To describe the clinical aspects and medical management of CVDST in Portuguese hospitals, to evaluate the safety of anticoagulation in this setting, and to identify subgroups of CVDST patients with different prognoses, we registered symptomatic CVDST patients admitted to Portuguese hospitals since 1980. Cases were collected from file review up to 6/95 and from consecutively admitted patients from 6/95 to 6/98. One hundred and forty-two patients were included from 20 centers (51 retrospectively and 91 prospectively). One hundred and twelve patients (79%) were anticoagulated. There were only 6 new intracranial hemorrhages (4 in anticoagulated patients) and 2 systemic hemorrhages. Nine (6%) patients died. At discharge, 96 (68%), had recovered completely and only 6 (4%) were dependent (Rankin > or = 3). Significant multivariate predictors of death/dependency were central nervous system infection as a predisposing cause (odds ratio, OR = 15.4; 95% confidence interval CI = 111-1.1), encephalopathy on admission (OR = 5.2; 95% CI = 18.7-1.5) and hemorrhage on admission CT/MR (OR = 3.6; 95% CI = 12.9-1). Significant predictors of complete recovery were no encephalopathy on admission (OR = 5; 95% CI = 12.5-2.1), age < 45 years (OR = 3.8; 95% CI = 9.2-1.6) and anticoagulation (OR = 3.8; 95% CI = 9.6-1.5). It is possible to identify CVDST patients with potential bad or good prognosis in the acute phase. Anticoagulation was safe and a predictor of complete recovery in acute CVDST., (Copyright 2001 S. Karger AG, Basel)

The only randomized data on heparin treatment in acute cerebral sinus venous thrombosis (CSVT) are derived from a small number of patients. The rate of intracranial hemorrhages as a complication of high-dose heparin treatment is still unknown. This retrospective study evaluates the clinical features, neuroimaging monitoring and outcome of 42 patients with proven CSVT. Diagnosis was established by DSA, CT, MR tomography and MR angiography. All patients received heparin intravenously guided by doubling the aPTT value for 3 weeks, followed by oral anticoagulation. Partial or complete recanalization was found in 36 cases. 40 patients improved clinically, in 26 of them complete recovery was observed. One patient deteriorated and developed an apallic syndrome, one further patient died of septic multiorgan failure. Only in one patient was hemorrhagic transformation of infarcted brain tissue observed but without clinical deterioration.