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.

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.

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.

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.

Hyponatremia is an independent predictor of in-hospital mortality in spontaneous intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Hyponatremia is the most frequent electrolyte disturbance in critical care. Across various disciplines, hyponatremia is associated with increased mortality and longer hospital stay, yet in intracerebral hemorrhage (ICH) no data are available. This the first study that investigated the prevalence and clinical associations of hyponatremia in patients with ICH. METHODS: This observational study included all consecutive spontaneous ICH patients (n=464) admitted during a 5-year period to the Department of Neurology. Patient characteristics, in-hospital measures, mortality, and functional outcome (90 days and 1 year) were analyzed to determine the effects of hyponatremia (Na<135 mEq/L). Multivariable regression analyses were calculated for factors associated with hyponatremia and predictors of in-hospital mortality. RESULTS: The prevalence of hyponatremia on hospital admission was 15.6% (n=66). Normonatremia was achieved and maintained in almost all hyponatremia patients<48 hours. In-hospital mortality was roughly doubled in hyponatremia compared with nonhyponatremia patients (40.9%; n=27 versus 21.1%; n=75), translating into a 2.5-fold increased odds ratio (P<0.001). Multivariable analyses identified hyponatremia as an independent predictor of in-hospital mortality (odds ratio, 2.2; 95% confidence interval, 1.05-4.62; P=0.037). Within 90 days after ICH, hyponatremia patients surviving hospital stay were also at greater risk of death (odds ratio, 4.8; 95% confidence interval, 2.1-10.6; P<0.001); thereafter, mortality rates were similar. CONCLUSIONS: Hyponatremia was identified as an independent predictor of in-hospital mortality with a fairly high prevalence in spontaneous ICH patients. The presence of hyponatremia at hospital admission is related to an increased short-term mortality in patients surviving acute care, possibly reflecting a preexisting condition that is linked to worse outcome due to greater comorbidity. Correction of hyponatremia does not seem to compensate its influence on mortality, which strongly warrants future research.

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.

Intraventricular fibrinolysis does not increase perihemorrhagic edema after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Additional intraventricular hemorrhage leads to higher mortality and worse functional outcome after intracerebral hemorrhage (ICH). Intraventricular fibrinolysis (IVF) with recombinant tissue plasminogen activator (rtPA) is an emerging treatment strategy for such patients. However, experimental studies suggest that rtPA may exert proedematous effects and lead to increased perihemorrhagic edema (PHE) after ICH. We aimed to compare the course of PHE after ICH between patients who received IVF with rtPA and controls matched for ICH volume. METHODS: Patients were identified retrospectively from our institutional ICH database. Sixty-four patients with ICH and intraventricular hemorrhage who were treated with IVF were compared with 64 controls, who did not receive IVF, matched for ICH volume. The course of PHE was assessed on computed tomography scans (day 1, days 2 and 3, days 4-6, 7-9, and 10-12) using a threshold-based semiautomatic volumetric algorithm. Relative PHE was calculated as a ratio of PHE volume and initial ICH volume. RESULTS: The matching algorithm resulted in similar mean ICH volumes in both groups (20.01 ± 17.5 mL, IVF vs 20.08 ± 17.1 mL, control). Intraventricular hemorrhage volume was larger in the IVF group (26.8 ± 19.2 mL vs 9.2 ± 13.4 mL). The mean total rtPA dose used for IVF was 8 ± 6 mg. PHE increased over time in both groups until day 12. At all investigated time points, there was no significant difference in relative PHE between the IVF group and controls (F=0.39; P=0.844). CONCLUSIONS: IVF with rtPA did not lead to a relevant increase in PHE after ICH. rtPA doses used in the current study seem to be safe regarding PHE.

Clearing bloody cerebrospinal fluid: clot lysis, neuroendoscopy and lumbar drainage.

PURPOSE OF REVIEW: Bloody cerebrospinal fluid (CSF) is a major cause of morbidity and mortality in intraventricular hemorrhage (IVH) and subarachnoid hemorrhage (SAH). Different treatment strategies aiming at faster clearance of bloody CSF have emerged. The present review focuses on recent developments in the investigation of those treatments. RECENT FINDINGS: Intraventricular fibrinolysis (IVF) for accelerated IVH-resolution has been clinically tested since the early 1990s. The lately summarized evidence from smaller studies indicates that IVF may result in a benefit in mortality and outcome. Recent investigations have elucidated different aspects of IVF, mainly related to safety. Neuroendoscopy has also emerged as a minimally invasive technique allowing fast removal of IVH. The capability of lumbar drainage to reduce vasospasm after SAH has been tested in a large trial. SUMMARY: IVF is relatively well tolerated and accelerates clot clearance after IVH. The effect of IVF on clinical outcome and mortality is currently being investigated in a large-scale phase III clinical trial. Neuroendoscopy is feasible for the treatment of IVH, however, larger trials are lacking. Lumbar drainage reduces the incidence of vasospasm after SAH. An ongoing phase III trial has been designed to test its influence on outcome. Lumbar drainage may also reduce shunt-dependency after IVH.

Mild prolonged hypothermia for large intracerebral hemorrhage.

BACKGROUND: Perihemorrhagic edema (PHE) develops after intracerebral hemorrhage (ICH). It can worsen the clinical situation by its additional mass effect. Therapeutic hypothermia (TH) might be an effective method to control PHE, but has not been sufficiently studied in ICH patients. METHODS: We report data on n = 25 consecutive patients with large supratentorial ICH (volume > 25 ml) who were treated by mild TH of 35 °C for 8-10 days. Body temperature was controlled by endovascular cooling catheters. We followed the clinical course during hospital stay and measured volumes of ICH and PHE in regularly performed serial cranial computed tomography. Outcome was assessed after 3 and 12 months. These data were compared to a historical group of n = 25 patients with large ICH. RESULTS: While PHE continuously increased in the historical control group up to day 10, PHE volumes in the hypothermia group remained stable. There was a significant difference from day 3 after symptom onset. Shivering (36 %) and pneumonia (96 %) were the most frequent complications during TH. Mortality rate was 8.3 % in TH versus 16.7 % in the control group after 3 months and 28 versus 44 % after 1 year. CONCLUSIONS: These data support the promising results of our first case series on TH in large ICH. TH prevents the development of PHE and its complications. Side effects of TH appeared often, but could be treated sufficiently. Therefore, TH might represent a new therapy for PHE after large ICH, but has to be further tested in randomized trials.

Neuroendocrine changes in patients with spontaneous supratentorial intracerebral hemorrhage.

BACKGROUND: Neuroendocrine changes have been reported after ischemic stroke, subarachnoid hemorrhage, and brain trauma. As there are no corresponding data in patients with intracerebral hemorrhage (ICH) we analyzed various neuroendocrine parameters to investigate possible alterations in hormone profiles of patients with ICH. METHODS: Twenty patients with ICH were prospectively enrolled in the study. Patients were a priori parted into two groups: Ten non-ventilated patients treated on the stroke-unit (hemorrhage volumes <20 ml, "small ICH"), and 10 ventilated patients treated on the neurocritical care unit (hematoma volumes >20 ml with possible additional ventricular involvement ("large ICH"). Neuroendocrine parameters were compared between both groups referring to reference values. The following parameters were obtained over a period of 9 days in 20 patients with spontaneous supratentorial ICH: thyrotropin, free thiiodothyronine and thyroxine, human growth hormone, insulin-like growth factor 1, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, adrenocorticotropic hormone, and cortisol. RESULTS: Small ICH patients were in a median 71 (54-88) years old and had a mean ICH volume of 9.5 ± 6.5 ml, whereas large ICH patients were 65 (47-80) years old and showed a mean volume of 56 ± 30.2 ml. None of the patients revealed pathological alterations for thyrotropin, free thiiodothyronine, thyroxine, human growth hormone, insulin-like growth factor 1, and testosterone. There was only a mild decrease of adrenocorticotropic hormone and cortisol on day 3 in large ICH patients. Small ICH patients showed pathologically elevated levels of luteinizing and follicle-stimulating hormone throughout the observation period. Large ICH patients showed a marked increase of prolactin that developed during the course. CONCLUSIONS: Overall, neuroendocrine changes in ICH patients are not as profound as reported for ischemic stroke or subarachnoid hemorrhage. The clinical significance of increased LH and FSH levels in small ICH is unclear, whereas elevation of prolactin in large ICH was anticipated. Future randomized controlled trials should also focus on neuroendocrine parameters to clarify the impact of possible hormonal alterations on functional outcome.

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.

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.

Posterior reversible encephalopathy syndrome.

Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered mental status, visual disturbances, and seizures. Radiological features typically include edema of the posterior cerebral regions, especially of the parietooccipital lobes. Atypical imaging features, such as involvement of anterior cerebral regions, deep white matter, and the brain stem are also frequently seen. Vasoconstriction is common in vascular imaging. Different conditions have been associated with PRES, but toxemia of pregnancy, solid organ or bone marrow transplantation, immunosuppressive treatment, cancer chemotherapy, autoimmune diseases, and hypertension are most commonly described. The pathophysiology of PRES is unclear and different hypotheses are being discussed. Posterior reversible encephalopathy syndrome is best managed by monitoring and treatment in the setting of a neurointensive care unit. The prognosis is usually benign with complete reversal of clinical symptoms within several days, when adequate treatment is immediately initiated. Treatment of severe hypertension, seizures, and withdrawal of causative agents represent the hallmarks of specific therapy in PRES. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Therefore, awareness of PRES is of crucial importance for the intensivist.

Natural course of perihemorrhagic edema after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: There is only limited knowledge on the time course of perihemorrhagic edema (PHE) after intracerebral hemorrhage (ICH). We aimed to investigate the chronological PHE course and its relation to in-hospital mortality in a large retrospective ICH cohort. METHODS: Patients with supratentorial ICH treated at our institution between 2006 and 2009, who had received at least 3 CT scans in the course of conservative treatment, were included in the present analysis. PHE at Days 1, 2, 3, 4 to 6, 7 to 11, 12 to 16, 17 to 21, and >22 was assessed using a threshold based semiautomatic volumetric algorithm. A chart review was performed to achieve data on duration of stay, ventilation, treatment with external ventricular drains, and in-hospital mortality. RESULTS: Two hundred nineteen patients aged 69.9±10.5 years with deep (n=103) or lobar (n=116) ICH were included in the study. Mean ICH volume was 35.7±31.5 mL. Mean absolute PHE volume significantly increased from initially 32.6±29.9 mL to 63.7±46.7 mL at Days 7 to 11. No significant changes were observed at later time points. ICH volume was strongly correlated with absolute PHE volume (ρ=0.8, P<0.001) and inversely correlated with relative PHE (ρ=-0.4 to -0.5, P<0.001). Increase in absolute PHE between Days 1 and 3 was significantly predictive for in-hospital mortality (P=0.014, ExpB=1.04). CONCLUSIONS: PHE develops early after ICH and doubles within the first 7 to 11 days after the initial bleeding event. This additional mass effect may contribute to secondary clinical deterioration and mortality, especially in larger ICH. Because of its inverse correlation with ICH volume, relative PHE may not be suitable for analyses considering the clinical impact of PHE.

Effects of continuous hypertonic saline infusion on perihemorrhagic edema evolution.

BACKGROUND AND PURPOSE: Mass effect of hematoma and the associated perihematomal edema are commonly responsible for neurological deterioration after intracerebral hemorrhage. Efficacy of surgical and medical therapy is limited. We studied the effect of early continuous hypertonic saline infusion on development of perihematomal edema after severe spontaneous supratentorial hemorrhage. METHODS: Patients with spontaneous lobar and basal ganglia/thalamic bleeding >30 mL (n=26) were treated with early (<72 hours) continuous hypertonic saline infusion (3%) to achieve sodium of 145 to 155 mmol/L and osmolality of 310 to 320 mOsmol/kg. Evolution of absolute edema volume and relative edema volume (ratio absolute edema volume/initial hematoma volume) was assessed on repeated cranial CT and compared to historical patients (n=64) identified on database with hematoma >30 mL. RESULTS: In the treatment group, absolute edema volume was significant smaller between day 8 and day 14 (P(absolute edema volume)= 0.04) and relative edema volume was significant smaller between day 2 and day 14 (P(relative edema volume)=0.02). Intracranial pressure crisis (>20 mm Hg for >20 minutes or new anisocoria) occurred less frequently in the treatment group (12 versus 56; P=0.048). In-hospital mortality was 3 (11.5%) in the hypertonic saline group and 16 (25%) in the control group (P=0.078). Side effects theoretically associated with hypertonic saline including cardiac arrhythmia and acute heart and renal failure occurred in both groups to a similar extent. CONCLUSIONS: Early and continuous infusion of hypertonic saline in patients with severe spontaneous intracerebral hemorrhage was feasible and safe. The beneficial effect of this treatment regimen on edema evolution and outcome has to be demonstrated in a controlled trial.

Dose effect of intraventricular fibrinolysis in ventricular hemorrhage.

BACKGROUND AND PURPOSE: The aim of the current study was to investigate the dose-dependent efficacy of intraventricular fibrinolysis (IVF) in patients with severe intraventricular hemorrhage (IVH). METHODS: Patients with intracerebral hemorrhage, severe IVH, and obstructive hydrocephalus with the need for external ventricular drainage were treated with IVF through external ventricular drainage. The time course of IVH resolution and the safety profile were compared between patients treated with high-dose IVF (4 mg alteplase every 12 hours, maximum 20 mg; n=32) and low-dose IVF (1 mg alteplase every 8 hours, maximum 12 mg; n=22). CT scans on Days 1 to 4, 7 ± 1 and 10 ± 1 after admission, were analyzed volumetrically. Outcome was assessed after 3 months. RESULTS: The overall effect of IVF dosage was not significantly different between the 2 groups (F=1.3, P=0.25). The course of IVH volume in the third and fourth ventricles was similar with high- and low-dose IVF. High-dose IVF resulted in lower total IVH volumes on Days 7 (4.4 ± 4.2 mL versus 8.8 ± 8.1 mL; P=0.01) and 10 (1.4 ± 2.8 mL versus 4.9 ± 65.8 mL; P=0.005). Total clot half-life was 78 ± 43 hours in the low-dose and 56 ± 25 hours in the high-dose group (P=0.02). One asymptomatic ventricular bleeding, 2 cases of ventriculitis, and 1 death due to pulmonary embolism occurred in the high-dose group. There was no difference in outcome at 3 months. CONCLUSIONS: Low-dose IVF (3 mg alteplase/day) has a similar effect on IVH clearance from the third and fourth ventricles and a similar safety profile when compared with high-dose IVF (8 mg alteplase/day).

Early continuous hypertonic saline infusion in patients with severe cerebrovascular disease.

OBJECTIVE: To study the safety and the effects of early continuous hypertonic saline infusion in patients with cerebral edema and underlying cerebrovascular disease. DESIGN: Retrospective analysis. SETTING: University medical center. PATIENTS: Neurologic intensive care unit population with mixed cerebrovascular diseases. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between May 2008 and December 2009, 100 patients with severe intracerebral hemorrhage, cerebral ischemia, or aneurysmal subarachnoid hemorrhage and signs of intracranial hypertension received within ≤72 hrs after symptom onset a continuous infusion of hypertonic saline (3%, target sodium 145-155 mmol/L, target osmolality 310-320 mOsm/kg) over 13 (4-23) days. We analyzed the frequency of episodes with elevated intracranial pressure (new anisocoria or intracranial pressure >20 mm Hg for ≥20 mins), inhospital mortality, and the occurrence of adverse effects theoretically associated with hypertonic saline. The findings were compared with those of a historical control group (n = 115, 2007-2008) with equal underlying disease. In the treatment group, fewer episodes of critically elevated intracranial pressure (92 vs. 167, p = .027) in fewer patients (50 of 100 = 50.0% vs. 69 of 115 = 60.0% patients, p = .091) were observed, and inhospital mortality was significantly decreased (17.0% vs. 29.6%, p = .037). Adverse events, including cardiac arrhythmia, heart, liver or renal dysfunction, or pulmonary edema, occurred in both groups to a similar extent. CONCLUSIONS: Early and continuous infusion of hypertonic saline in patients with severe cerebrovascular disease and impending intracranial hypertension is safe and might reduce the frequency of intracranial pressure crises and mortality rate. A randomized controlled trial is warranted to confirm our findings and to evaluate the effects of hypertonic saline on functional outcomes.