Iatrogenic cerebral amyloid angiopathy: A multinational case series and individual patient data analysis of the literature.

BACKGROUND: The transmission of amyloid ß (Aß) in humans leading to iatrogenic cerebral amyloid angiopathy (iCAA) is a novel concept with analogies to prion diseases. However, the number of published cases is low, and larger international studies are missing. AIMS: We aimed to build a large multinational collaboration on iCAA to better understand the clinical spectrum of affected patients. METHODS: We collected clinical data on patients with iCAA from Austria, Croatia, Italy, Slovenia, and Spain. Patients were included if they met the proposed Queen Square diagnostic criteria (QSC) for iCAA. In addition, we pooled data on disease onset, latency, and cerebrospinal fluid (CSF) biomarkers from previously published iCAA cases based on a systematic literature review. RESULTS: Twenty-seven patients (22% women) were included in this study. Of these, 19 (70%) met the criteria for probable and 8 (30%) for possible iCAA. Prior neurosurgical procedures were performed in all patients (93% brain surgery, 7% spinal surgery) at median age of 8 (interquartile range (IQR) = 4-18, range = 0-26 years) years. The median symptom latency was 39 years (IQR = 34-41, range = 28-49). The median age at symptom onset was 49 years (IQR = 43-55, range = 32-70). Twenty-one patients (78%) presented with intracranial hemorrhage and 3 (11%) with seizures. CONCLUSIONS: Our large international case series of patients with iCAA confirms a wide age boundary for the diagnosis of iCAA. Dissemination of awareness of this rare condition will help to identify more affected patients.

Peak Edema Extension Distance: An Edema Measure Independent from Hematoma Volume Associated with Functional Outcome in Intracerebral Hemorrhage.

BACKGROUND: Our objective was to test the association between hematoma volume and long-term (> 72 h) edema extension distance (EED) evolution and the association between peak EED and early EED increase with functional outcome at 3 months in patients with intracerebral hemorrhage (ICH). METHODS: This retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. EED, an edema measure defined as the distance between the hematoma border and the outer edema border, was calculated by using absolute hematoma and edema volumes. We used multivariable logistic regression accounting for age, ICH volume, and location and receiver operating characteristic analysis for assessing measures associated with functional outcome and EED evolution. Functional outcome after 3 months was assessed by using the modified Rankin Scale (0-3 = favorable, 4-6 = unfavorable). To identify properties associated with peak EED multivariable linear and logistic regression analyses were conducted. RESULTS: A total of 292 patients were included. Median age was 70 years (interquartile range [IQR] 62-78), median ICH volume on admission 17.7 mL (IQR 7.9-40.2), median peak perihemorrhagic edema (PHE) volume was 37.5 mL (IQR 19.1-60.6), median peak EED was 0.67 cm (IQR 0.51-0.84) with an early EED increase up to 72 h (EED72-0) of 0.06 cm (- 0.02 to 0.15). Peak EED was found to be independent of ICH volume (R2 = 0.001, p = 0.6). In multivariable analyses, peak EED (odds ratio 0.224, 95% confidence interval [CI] [0.071-0.705]) and peak PHE volume (odds ratio 0.984 [95% CI 0.973-0.994]) were inversely associated with favorable functional outcome at 3 months. Receiver operating characteristic analysis identified a peak PHE volume of 26.8 mL (area under the curve 0.695 [95% CI 0.632-0.759]; p ≤ 0.001) and a peak EED of 0.58 cm (area under the curve 0.608 [95% CI 0.540-0.676]; p = 0.002) as best predictive values for outcome discrimination. CONCLUSIONS: Compared with absolute peak PHE volume, peak EED represents a promising edema measure in patients with ICH that is largely hematoma volume-independent and nevertheless associated with functional outcome.

Effectiveness of Lumbar Cerebrospinal Fluid Drain Among Patients With Aneurysmal Subarachnoid Hemorrhage: A Randomized Clinical Trial.

Importance: After aneurysmal subarachnoid hemorrhage, the use of lumbar drains has been suggested to decrease the incidence of delayed cerebral ischemia and improve long-term outcome. Objective: To determine the effectiveness of early lumbar cerebrospinal fluid drainage added to standard of care in patients after aneurysmal subarachnoid hemorrhage. Design, Setting, and Participants: The EARLYDRAIN trial was a pragmatic, multicenter, parallel-group, open-label randomized clinical trial with blinded end point evaluation conducted at 19 centers in Germany, Switzerland, and Canada. The first patient entered January 31, 2011, and the last on January 24, 2016, after 307 randomizations. Follow-up was completed July 2016. Query and retrieval of data on missing items in the case report forms was completed in September 2020. A total of 20 randomizations were invalid, the main reason being lack of informed consent. No participants meeting all inclusion and exclusion criteria were excluded from the intention-to-treat analysis. Exclusion of patients was only performed in per-protocol sensitivity analysis. A total of 287 adult patients with acute aneurysmal subarachnoid hemorrhage of all clinical grades were analyzable. Aneurysm treatment with clipping or coiling was performed within 48 hours. Intervention: A total of 144 patients were randomized to receive an additional lumbar drain after aneurysm treatment and 143 patients to standard of care only. Early lumbar drainage with 5 mL per hour was started within 72 hours of the subarachnoid hemorrhage. Main Outcomes and Measures: Primary outcome was the rate of unfavorable outcome, defined as modified Rankin Scale score of 3 to 6 (range, 0 to 6), obtained by masked assessors 6 months after hemorrhage. Results: Of 287 included patients, 197 (68.6%) were female, and the median (IQR) age was 55 (48-63) years. Lumbar drainage started at a median (IQR) of day 2 (1-2) after aneurysmal subarachnoid hemorrhage. At 6 months, 47 patients (32.6%) in the lumbar drain group and 64 patients (44.8%) in the standard of care group had an unfavorable neurological outcome (risk ratio, 0.73; 95% CI, 0.52 to 0.98; absolute risk difference, -0.12; 95% CI, -0.23 to -0.01; P = .04). Patients treated with a lumbar drain had fewer secondary infarctions at discharge (41 patients [28.5%] vs 57 patients [39.9%]; risk ratio, 0.71; 95% CI, 0.49 to 0.99; absolute risk difference, -0.11; 95% CI, -0.22 to 0; P = .04). Conclusion and Relevance: In this trial, prophylactic lumbar drainage after aneurysmal subarachnoid hemorrhage lessened the burden of secondary infarction and decreased the rate of unfavorable outcome at 6 months. These findings support the use of lumbar drains after aneurysmal subarachnoid hemorrhage. Trial Registration: ClinicalTrials.gov Identifier: NCT01258257.

Endovascular stroke therapy outside core working hours in a nationwide stroke system.

BACKGROUND: Endovascular therapy (EVT) has been established as a major component in the acute treatment of large vessel occlusion stroke. However, it is unclear whether outcome and other treatment-related factors differ if patients are treated within or outside core working hours. METHODS: We analyzed data from the prospective nationwide Austrian Stroke Unit Registry capturing all consecutive stroke patients treated with EVT between 2016 and 2020. Patients were trichotomized according to the time of groin puncture into treatment within regular working hours (08:00-13:59), afternoon/evening (14:00-21:59) and night-time (22:00-07:59). Additionally, we analyzed 12 EVT treatment windows with equal patient numbers. Main outcome variables included favorable outcome (modified Rankin Scale scores of 0-2) 3 months post-stroke as well as procedural time metrics, recanalization status and complications. RESULTS: We analyzed 2916 patients (median age 74 years, 50.7% female) who underwent EVT. Patients treated within core working hours more frequently had a favorable outcome (42.6% vs 36.1% treated in the afternoon/evening vs 35.8% treated at night-time; p=0.007). Similar results were found when analyzing 12 treatment windows. All these differences remained significant in multivariable analysis adjusting for outcome-relevant co-factors. Onset-to-recanalization time was considerably longer outside core working hours, which was mainly explained by longer door-to-groin time (p<0.001). There was no difference in the number of passes, recanalization status, groin-to-recanalization time and EVT-related complications. CONCLUSIONS: The findings of delayed intrahospital EVT workflows and worse functional outcomes outside core working hours in this nationwide registry are relevant for optimization of stroke care, and might be applicable to other countries with similar settings.

Association of Intraventricular Fibrinolysis With Clinical Outcomes in Intracerebral Hemorrhage: An Individual Participant Data Meta-Analysis.

BACKGROUND: In patients with intracerebral hemorrhage (ICH), the presence of intraventricular hemorrhage constitutes a promising therapeutic target. Intraventricular fibrinolysis (IVF) reduces mortality, yet impact on functional disability remains unclear. Thus, we aimed to determine the influence of IVF on functional outcomes. METHODS: This individual participant data meta-analysis pooled 1501 patients from 2 randomized trials and 7 observational studies enrolled during 2004 to 2015. We compared IVF versus standard of care (including placebo) in patients treated with external ventricular drainage due to acute hydrocephalus caused by ICH with intraventricular hemorrhage. The primary outcome was functional disability evaluated by the modified Rankin Scale (mRS; range: 0-6, lower scores indicating less disability) at 6 months, dichotomized into mRS score: 0 to 3 versus mRS: 4 to 6. Secondary outcomes included ordinal-shift analysis, all-cause mortality, and intracranial adverse events. Confounding and bias were adjusted by random effects and doubly robust models to calculate odds ratios and absolute treatment effects (ATE). RESULTS: Comparing treatment of 596 with IVF to 905 with standard of care resulted in an ATE to achieve the primary outcome of 9.3% (95% CI, 4.4-14.1). IVF treatment showed a significant shift towards improved outcome across the entire range of mRS estimates, common odds ratio, 1.75 (95% CI, 1.39-2.17), reduced mortality, odds ratio, 0.47 (95% CI, 0.35-0.64), without increased adverse events, absolute difference, 1.0% (95% CI, -2.7 to 4.8). Exploratory analyses provided that early IVF treatment (≤48 hours) after symptom onset was associated with an ATE, 15.2% (95% CI, 8.6-21.8) to achieve the primary outcome. CONCLUSIONS: As compared to standard of care, the administration of IVF in patients with acute hydrocephalus caused by intracerebral and intraventricular hemorrhage was significantly associated with improved functional outcome at 6 months. The treatment effect was linked to an early time window <48 hours, specifying a target population for future trials.

Bedside Catheter Hematoma Evacuation in Vitamin K Antagonist-Related Intracerebral Hemorrhage: A Safe and Feasible Approach.

Background and Purpose: Although outcome in intracerebral hemorrhage (ICH) patients is generally not improved by surgical intervention, the use of minimally invasive surgery (MIS) has shown promising results. However, vitamin K antagonist (VKA)-related ICH patients are underrepresented in surgical treatment trials. We therefore assessed the safety and efficacy of a bedside MIS approach including local application of urokinase in VKA-related ICH. Methods: Patients with a VKA-related ICH > 20 ml who received bedside hematoma evacuation treatment (n = 21) at the University Medical Center Freiburg were retrospectively included for analysis and compared to a historical control group (n = 35) selected from an institutional database (University Medical Center Erlangen) according to identical inclusion criteria. Propensity score matching was performed to obtain comparable cohorts. The evolution of hematoma and peri-hemorrhagic edema (PHE) volumes, midline shift, and the occurrence of adverse events were analyzed. Furthermore, we assessed the modified Rankin Scale and NIHSS scores recorded at discharge. Results: Propensity score matching resulted in 16 patients per group with well-balanced characteristics. Median ICH volume at admission was 45.7 (IQR: 24.2-56.7) ml in the control group and 48.4 (IQR: 28.7-59.6) ml in the treatment group (p = 0.327). ICH volume at day 7 was less pronounced in the treatment group [MIS: 23.2 ml (IQR: 15.8-32.3) vs. control: 43.2 ml (IQR: 27.5-52.4); p = 0.013], as was the increase in midline shift up to day 7 [MIS: -3.75 mM (IQR: -4.25 to -2) vs. control: 1 mM (IQR: 0-2); p < 0.001]. No group differences were observed in PHE volume on day 7 [MIS: 42.4 ml (IQR: 25.0-72.3) vs. control: 31.0 ml (IQR: 18.8-53.8); p = 0.274] or mRS at discharge [MIS: 5 (IQR: 4-5) and 5 (IQR: 4-5); p = 0.949]. No hematoma expansion was observed. The catheter had to be replaced in 1 patient (6%). Conclusions: Bedside catheter-based hematoma evacuation followed by local thrombolysis with urokinase appears to be feasible and safe in cases of large VKA-related ICH. Further studies that assess the functional outcome associated with this technique are warranted. Clinical Trial Registration: DRKS00007908 (German Clinical Trial Register; www.drks.de).

Temporal trends in intracerebral hemorrhage: Evidence from the Austrian Stroke Unit Registry.

BACKGROUND: To assess changes in frequency, severity, complications, therapy and outcome of intracerebral hemorrhage in patients treated in stroke units in Austria, we evaluated data from the Austrian Stroke Unit Registry between 2008 and 2016. METHODS AND FINDINGS: Data of 6707 cases of ICH covering a time span of 9 years and including information on age, risk factors, pre-stroke modified Rankin Score (mRS), baseline stroke severity (NIHSS), complications, therapy, functional outcome, and mortality were extracted from the Austrian Stroke Unit Registry. A multivariate regularized logistic regression model and linear models for temporal dependence were computed for analyzing statistical inference and time trends. Bonferroni correction was applied to correct for multiple testing. Between 2008 and 2016, the proportion of ICH admissions to stroke units in Austria declined, with a shift among patients towards older age (>70 years, p = 0.04) and lower admission NIHSS scores. While no significant time trends in risk factors, pre-stroke mRS and medical complications were observed, therapeutic interventions declined significantly (p<0.001). Three-month mortality increased over the years independently (p = 0.003). CONCLUSIONS: Despite declining incidence and clinical severity of ICH we observed a clear increase in three-month mortality. This effect seems to be independent of predictors including age, admission NIHSS, pre-morbid MRS, or medical complications. The observations from this large retrospective database cohort study underline an urgent call for action in the therapy of ICH.

Therapeutic hypothermia for acute ischaemic stroke. Results of a European multicentre, randomised, phase III clinical trial.

INTRODUCTION: We assessed whether modest systemic cooling started within 6 hours of symptom onset improves functional outcome at three months in awake patients with acute ischaemic stroke. PATIENTS AND METHODS: In this European randomised open-label clinical trial with blinded outcome assessment, adult patients with acute ischaemic stroke were randomised to cooling to a target body temperature of 34.0-35.0°C, started within 6 h after stroke onset and maintained for 12 or 24 h , versus standard treatment. The primary outcome was the score on the modified Rankin Scale at 91 days, as analysed with ordinal logistic regression. RESULTS: The trial was stopped after inclusion of 98 of the originally intended 1500 patients because of slow recruitment and cessation of funding. Forty-nine patients were randomised to hypothermia versus 49 to standard treatment. Four patients were lost to follow-up. Of patients randomised to hypothermia, 15 (31%) achieved the predefined cooling targets. The primary outcome did not differ between the groups (odds ratio for good outcome, 1.01; 95% confidence interval, 0.48-2.13; p = 0.97). The number of patients with one or more serious adverse events did not differ between groups (relative risk, 1.22; 95% confidence interval, 0.65-1.94; p = 0.52). DISCUSSION: In this trial, cooling to a target of 34.0-35.0°C and maintaining this for 12 or 24 h was not feasible in the majority of patients. The final sample was underpowered to detect clinically relevant differences in outcomes. CONCLUSION: Before new trials are launched, the feasibility of cooling needs to be improved.

Peak perihemorrhagic edema correlates with functional outcome in intracerebral hemorrhage.

OBJECTIVE: To evaluate the association of perihemorrhagic edema (PHE) evolution and peak edema extent with day 90 functional outcome in patients with intracerebral hemorrhage (ICH) and identify pathophysiologic factors influencing edema evolution. METHODS: This retrospective cohort study included patients with spontaneous supratentorial ICH between January 2006 and January 2014. ICH and PHE volumes were studied using a validated semiautomatic volumetric algorithm. Multivariable logistic regression and propensity score matching (PSM) accounting for age, ICH volume, and location were used for assessing measures associated with functional outcome and PHE evolution. Clinical outcome on day 90 was assessed using the modified Rankin Scale (0-3 = favorable, 4-6 = poor). RESULTS: A total of 292 patients were included. Median age was 70 years (interquartile range [IQR] 62-78), median ICH volume on admission 17.7 mL (IQR 7.9-40.2). Besides established factors for functional outcome, i.e., ICH volume and location, age, intraventricular hemorrhage, and NIH Stroke Scale score on admission, multivariable logistic regression revealed peak PHE volume (odds ratio [OR] 0.984 [95% confidence interval (CI) 0.973-0.994]) as an independent predictor of day 90 outcome. Peak PHE volume was independently associated with initial PHE increase up to day 3 (OR 1.060 [95% CI 1.018-1.103]) and neutrophil to lymphocyte ratio on day 6 (OR 1.236 [95% CI 1.034-1.477; PSM cohort, n = 124]). Initial PHE increase (PSM cohort, n = 224) was independently related to hematoma expansion (OR 3.647 [95% CI 1.533-8.679]) and fever burden on days 2-3 (OR 1.456 [95% CI 1.103-1.920]). CONCLUSION: Our findings suggest that peak PHE volume represents an independent predictor of functional outcome after ICH. Inflammatory processes and hematoma expansion seem to be involved in PHE evolution and may represent important treatment targets.

Fibrinolytic for treatment of intraventricular hemorrhage: A meta-analysis and systematic review.

Background Intraventricular hemorrhage is a significant cause of mortality and morbidity worldwide. Treating intraventricular hemorrhage with intraventricular fibrinolytic therapy via a catheter is becoming an increasingly utilized intervention. Aims This meta-analysis aimed to investigate the role of intraventricular fibrinolytic treatment in hypertensive intraventricular hemorrhage patients and evaluate the effect sizes for survival as well as level of function at differing time points. Summary of review PubMed, CNKI, VIP, and Wanfang were searched using the terms "IVH" and "IVH and ICH" for human studies with adult patients published between January 1950 and July 2016. Seventeen publications were selected. Data analysis showed lower rates of mortality in the treatment group at 30 days ( P < 0.001), 180 days ( P = 0.001), 365 days ( P = 0.40), and overall ( P < 0.001). Pooling modified Rankin Scale and Glasgow outcome scale data, the treatment group had more good functional outcomes at 30 days ( P = 0.38), 90 days ( P = 0.04), 180 days ( P = 0.31), 365 days ( P = 0.76), and overall ( P = 0.02). Good functional outcome was defined as modified Rankin Scale score of 0 to 3 or a Glasgow outcome scale score of 3 to 5. Conclusions Intraventricular fibrinolytic for treatment of hypertensive intraventricular hemorrhage reduces mortality and potentially leads to an increased number of good functional outcomes. Different functional outcome scales (modified Rankin Scale or Glasgow outcome scale) produce different effect sizes. Intraventricular fibrinolytic treatment may offer intraventricular hemorrhage patients a targeted therapy that produces meaningful mortality benefit and possible functional outcome benefits.

Efficacy and safety of combined intraventricular fibrinolysis with lumbar drainage for prevention of permanent shunt dependency after intracerebral hemorrhage with severe ventricular involvement: A randomized trial and individual patient data meta-analysis.

OBJECTIVE: Intraventricular hemorrhage (IVH) is a negative prognostic factor in intracerebral hemorrhage (ICH) and is associated with permanent shunt dependency in a substantial proportion of patients post-ICH. IVH treatment by intraventricular fibrinolysis (IVF) was recently linked to reduced mortality rates in the CLEAR III study and IVF represents a safe and effective strategy to hasten clot resolution that may reduce shunt rates. Additionally, promising results from observational studies reported reductions in shunt dependency for a combined treatment approach of IVF plus lumbar drains (LDs). The present randomized, controlled trial investigated efficacy and safety of a combined strategy-IVF plus LD versus IVF alone-on shunt dependency in patients with ICH and severe IVH. METHODS: This randomized, open-label, parallel-group study included patients aged 18 to 85 years, prehospital modified Rankin Scale ≤3, ICH volume < 60ml, Glasgow Coma Scale of <9, and severe IVH with tamponade of the third and fourth ventricles requiring placement of external ventricular drainage (EVD). Over a 3-year recruitment period, patients were allocated to either standard treatment (control group receiving IVF consisting of 1mg of recombinant human tissue plasminogen activator every 8 hours until clot clearance of third and fourth ventricles) or a combined treatment approach of IVF and-upon clot clearance of third and fourth ventricles-subsequent placement of an LD for drainage of cerebrospinal fluid (CSF; intervention group). The primary endpoint consisted of permanent shunt placement indicated after a total of three unsuccessful EVD clamping attempts or need for CSF drainage longer than 14 days in both groups. Secondary endpoints included IVF- and LD-related safety, such as bleeding or infections, and functional outcome at 90 and 180 days. Conducted endpoint analyses used individual patient data meta-analyses. The study was registered at clinicaltrials.gov (NCT01041950). RESULTS: The trial was stopped upon predefined interim analysis after 30 patients because of significant efficacy of tested intervention. The primary endpoint was analyzed without dropouts and was reached in 43% (7 of 16) of the control group versus 0% (0 of 14) of the intervention group (p = 0.007). Meta-analyses were based on overall 97 patients, 45 patients receiving IVF plus LD versus 42 with IVF only. Meta-analyses on shunt dependency showed an absolute risk reduction of 24% for the intervention (LD, 2.2% [1 of 45] vs no-LD, 26.2% [11 of 42]; odds ratio [OR] = 0.062; confidence interval [CI], 0.011-0.361; p = 0.002). Secondary endpoints did not show significant differences for CSF infections (OR = 0.869;CI, 0.445-1.695; p = 0.680) and functional outcome at 90 days (OR = 0.478; CI, 0.190-1.201; p = 0.116), yet bleeding complications were significantly reduced in favor of the intervention (OR = 0.401; CI, 0.302-0.532; p < 0.001). INTERPRETATION: The present trial and individual patient data meta-analyses provide evidence that, in patients with severe IVH, as compared to IVF alone, a combined approach of IVF plus LD treatment is feasible and safe and significantly reduces rates of permanent shunt dependency for aresorptive hydrocephalus post-ICH. ANN NEUROL 2017;81:93-103.

Impact of Hypothermia Initiation and Duration on Perihemorrhagic Edema Evolution After Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) causes high morbidity and mortality. Recently, perihemorrhagic edema (PHE) has been suggested as an important prognostic factor. Therapeutic hypothermia may be a promising therapeutic option to treat PHE. However, no data exist about the optimal timing and duration of therapeutic hypothermia in ICH. We examined the impact of therapeutic hypothermia timing and duration on PHE evolution. METHODS: In this retrospective, single-center, case-control study, we identified patients with ICH treated with mild endovascular hypothermia (target temperature 35°C) from our institutional database. Patients were grouped according to hypothermia initiation (early: days 1-2 and late: days 4-5 after admission) and hypothermia duration (short: 4-8 days and long: 9-15 days). Patients with ICH matched for ICH volume, age, ICH localization, and intraventricular hemorrhage were identified as controls. Relative PHE, temperature, and intracranial pressure course were analyzed. Clinical outcome on day 90 was assessed using the modified Rankin scale (0-3=favorable and 4-6=poor). RESULTS: Thirty-three patients with ICH treated with hypothermia and 37 control patients were included. Early hypothermia initiation led to relative PHE decrease between admission and day 3, whereas median relative PHE increased in control patients (-0.05 [interquartile range, -0.4 to 0.07] and 0.07 [interquartile range, -0.07 to 0.26], respectively; P=0.007) and patients with late hypothermia initiation (0.22 [interquartile range 0.12-0.27]; P=0.037). After day 3, relative PHE increased in all groups without difference. Outcome was not different between patients treated with hypothermia and controls. CONCLUSIONS: Early hypothermia initiation after ICH onset seems to have an important impact on PHE evolution, whereas our data suggest only limited impact later than day 3 after onset.

Impact of Perihemorrhagic Edema on Short-Term Outcome After Intracerebral Hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating disease with ICH volume being the main predictor of poor outcome. The prognostic role of perihemorrhagic edema (PHE) is still unclear; however, available data are mainly derived from analyses during the first days after symptom onset. As PHE growth may continue up to 14 days after ICH, we evaluated PHE over a longer period of time and investigated its impact on short-term clinical outcome. METHODS: In this monocentric retrospective cohort study, patients with spontaneous supratentorial ICH were identified from our institutional data base. Different time points of CT scans were merged to time clusters for better comparison (day 1, 2-3, 4-6, 7-9, 10-12). Absolute volumes of ICH and PHE were obtained using a validated semiautomatic volumetric algorithm. Clinical outcome at discharge was assessed using the modified Rankin Scale (0-3 = favorable, 4-6 = poor). RESULTS: 220 patients (83 with favorable, 137 with poor outcome) were included in the final analysis. Mean ICH volume on admission was 22.8 [standard deviation (SD) 24.6] cm(3). Mean absolute PHE volume on admission was 22.5 (SD 20.8) cm(3) and increased to a mean peak volume of 38.1 (SD 31.4) cm(3) during 6.7 (SD 4.1) days on average. Besides GCS on admission, functional status before ICH, peak hematoma volume, lobar localization and fever burden, and high peak PHE volume predicted poor outcome at discharge [OR 0.977 (95 % CI 0.957-0.998)] in the multivariable analysis. CONCLUSIONS: PHE may have a negative impact on short-term functional outcome after ICH and therefore represent a possible treatment target.

Is Hypothermia Helpful in Severe Subarachnoid Hemorrhage? An Exploratory Study on Macro Vascular Spasm, Delayed Cerebral Infarction and Functional Outcome after Prolonged Hypothermia.

BACKGROUND: Therapeutic hypothermia (TH) is an established treatment after cardiac arrest and growing evidence supports its use as neuroprotective treatment in stroke. Only few and heterogeneous studies exist on the effect of hypothermia in subarachnoid hemorrhage (SAH). A novel approach of early and prolonged TH and its influence on key complications in poor-grade SAH, vasospasm and delayed cerebral ischemia (DCI) was evaluated. METHODS: This observational matched controlled study included 36 poor-grade (Hunt and Hess Scale >3 and World Federation of Neurosurgical Societies Scale >3) SAH patients. Twelve patients received early TH (<48 h after ictus), mild (35°C), prolonged (7 ± 1 days) and were matched to 24 patients from the prospective SAH database. Vasospasm was diagnosed by angiography, macrovascular spasm serially evaluated by Doppler sonography and DCI was defined as new infarction on follow-up CT. Functional outcome was assessed at 6 months by modified Rankin Scale (mRS) and categorized as favorable (mRS score 0-2) versus unfavorable (mRS score 3-6) outcome. RESULTS: Angiographic vasospasm was present in 71.0% of patients. TH neither influenced occurrence nor duration, but the degree of macrovascular spasm as well as peak spastic velocities were significantly reduced (p < 0.05). Frequency of DCI was 87.5% in non-TH vs. 50% in TH-treated patients, translating into a relative risk reduction of 43% and preventive risk ratio of 0.33 (95% CI 0.14-0.77, p = 0.036). Favorable functional outcome was twice as frequent in TH-treated patients 66.7 vs. 33.3% of non-TH (p = 0.06). CONCLUSION: Early and prolonged TH was associated with a reduced degree of macrovascular spasm and significantly decreased occurrence of DCI, possibly ameliorating functional outcome. TH may represent a promising neuroprotective therapy possibly targeting multiple pathways of DCI development, notably macrovascular spasm, which strongly warrants further evaluation of its clinical impact.

European Stroke Organisation (ESO) guidelines for the management of temperature in patients with acute ischemic stroke.

BACKGROUND: Hyperthermia is a frequent complication in patients with acute ischemic stroke. On the other hand, therapeutically induced hypothermia has shown promising potential in animal models of focal cerebral ischemia. This Guideline Document presents the European Stroke Organisation guidelines for the management of temperature in patients with acute ischemic stroke. METHODS: A multidisciplinary group identified related questions and developed its recommendations based on evidence from randomized controlled trials elaborating the Grading of Recommendations Assessment, Development, and Evaluation approach. This Guideline Document was reviewed within the European Stroke Organisation and externally and was approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. RESULTS: We found low-quality evidence, and therefore, we cannot make any recommendation for treating hyperthermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and hyperthermia; moderate evidence to suggest against routine prevention of hyperthermia with antipyretics as a means to improve functional outcome and/or survival in patients with acute ischemic stroke and normothermia; very low-quality evidence to suggest against routine induction of hypothermia as a means to improve functional outcome and/or survival in patients with acute ischemic stroke. CONCLUSIONS: The currently available data about the management of temperature in patients with acute ischemic stroke are limited, and the strengths of the recommendations are therefore weak. We call for new randomized controlled trials as well as recruitment of eligible patients to ongoing randomized controlled trials to allow for better-informed recommendations in the future.

Evidence-based guidelines for the management of large hemispheric infarction : a statement for health care professionals from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine.

Large hemispheric infarction (LHI), also known as malignant middle cerebral infarction, is a devastating disease associated with significant disability and mortality. Clinicians and family members are often faced with a paucity of high quality clinical data as they attempt to determine the most appropriate course of treatment for patients with LHI, and current stroke guidelines do not provide a detailed approach regarding the day-to-day management of these complicated patients. To address this need, the Neurocritical Care Society organized an international multidisciplinary consensus conference on the critical care management of LHI. Experts from neurocritical care, neurosurgery, neurology, interventional neuroradiology, and neuroanesthesiology from Europe and North America were recruited based on their publications and expertise. The panel devised a series of clinical questions related to LHI, and assessed the quality of data related to these questions using the Grading of Recommendation Assessment, Development and Evaluation guideline system. They then developed recommendations (denoted as strong or weak) based on the quality of the evidence, as well as the balance of benefits and harms of the studied interventions, the values and preferences of patients, and resource considerations.

Propofol-related urine discoloration in a patient with fatal atypical intracerebral hemorrhage treated with hypothermia.

INTRODUCTION: Mild therapeutic hypothermia is an increasingly recognised treatment option to reduce perihemorrhagic edema in severe intracerebral hemorrhage. CASE DESCRIPTION: We report the case of a 77-year old woman with atypical intracerebral hemorrhage that was treated with mild hypothermia in addition to osmotic therapy. The patient's urine subsequently showed a green discoloration. Urine discoloration was completely reversible upon discontinuation of propofol. DISCUSSION AND EVALUATION: Propofol-related urine discoloration may have been provoked by hypothermia. Due to the benign nature of this side effect, propofol should be stopped and gastrointestinal function should be supported. CONCLUSION: More studies are needed to show a causal role of hypothermia and related decreased enzymatic function.

EuroHYP-1: European multicenter, randomized, phase III clinical trial of therapeutic hypothermia plus best medical treatment vs. best medical treatment alone for acute ischemic stroke.

RATIONALE: Cooling reduced infarct size and improved neurological outcomes in animal studies modeling ischemic stroke, and also improved outcome in randomized clinical trials in patients with hypoxic-ischemic brain injury after cardiac arrest. Cooling awake patients with ischemic stroke has been shown feasible in phase II clinical trials. PRIMARY AIM: To determine whether systemic cooling to a target body temperature between 34·0 and 35·0°C, started within six-hours of symptom onset and maintained for 24 h, improves functional outcome at three-months in patients with acute ischemic stroke. DESIGN: International, multicenter, phase III, randomized, open-label clinical trial with blinded outcome assessment in 1500 patients aged 18 years or older with acute ischemic stroke and a National Institutes of Health Stroke Scale score of 6 up to and including 18. In patients randomized to hypothermia, cooling to a target body temperature of 34-35°C will be started within six-hours after symptom onset with rapid intravenous infusion of refrigerated normal saline or a surface cooling technique and maintained for 24 h with a surface or endovascular technique. Patients randomized to hypothermia will receive pethidine and buspirone to prevent shivering and discomfort. PRIMARY OUTCOME: Score on the modified Rankin Scale at 91 days, as analyzed with ordinal logistic regression and expressed as a common odds ratio. DISCUSSION: With 750 patients per intervention group, this trial has 90% power to detect 7% absolute improvement at the 5% significance level. The full trial protocol is available at http://www.eurohyp1.eu. ClinicalTrials.gov Identifier: NCT01833312.