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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: Hematopoietic growth factors have been suggested to induce neuroprotective and regenerative effects in various animal models of cerebral injury. However, the pathways involved remain widely unexplored., Aims: This study aimed to investigate effects of local and systemic administration of granulocyte colony-stimulating factor on brain damage, functional recovery, and cerebral neurogenesis in an intracerebral haemorrhage whole blood injection model in rats., Methods: Eight-week-old male Wistar rats (n = 100) underwent induction of striatal intracerebral haemorrhage by autologous whole blood injection or sham procedure and were randomly assigned to either (a) systemic treatment with granulocyte colony-stimulating factor (60 μg/kg) for five-days; (b) single intracerebral injection of granulocyte colony-stimulating factor (60 μg/kg) into the cavity; or (c) application of vehicle for five-days. Bromodeoxyuridine-labelling and immunohistochemistry were used to analyze proliferation and survival of newly born cells in the sub-ventricular zone and the hippocampal dentate gyrus. Moreover, functional deficits and lesion volume were assessed until day 42 after intracerebral haemorrhage., Results: Differences in lesion size or hemispheric atrophy between granulocyte colony-stimulating factor-treated and control groups did not reach statistical significance. Neither systemic, nor local granulocyte colony-stimulating factor administration induced neurogenesis within the dentate gyrus or the sub-ventricular zone. The survival of newborn cells in these regions was prevented by intracerebral granulocyte colony-stimulating factor application. A subtle benefit in functional recovery at day 14 after intracerebral haemorrhage induction was observed after granulocyte colony-stimulating factor treatment., Conclusion: There was a lack of neuroprotective or neuroregenerative effects of granulocyte colony-stimulating factor in the present rodent model of intracerebral haemorrhage. Conflicting results from functional outcome assessment require further research., (© 2013 The Authors. International Journal of Stroke © 2013 World Stroke Organization.)

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.

Background: Intracerebral hemorrhage accounts for up to 15% of all strokes and is frequently associated with poor functional outcome and high mortality. So far, there is no clear evidence for a specific therapy, apart from general stroke unit or neurointensive care and management of secondary complications. Promising experimental and pilot clinical data support the use of therapeutic hypothermia after intracerebral hemorrhage., Aims: The study aims to determine if therapeutic hypothermia improves survival rates and reduces cerebral lesion volume after large intracerebral hemorrhage compared with conventional treatment., Material and Methods: The Cooling in IntraCerebral Hemorrhage trial is a prospective, multicenter, interventional, randomized, parallel, two-arm (1 : 1) phase II trial with blinded end-point adjudication. Enrolment: 50 patients (age: 18 to 65 years) with large (25 to 64 ml on cranial computertomography), primary intracerebral hemorrhage of the basal ganglia or thalamus within 6 to 18 h after symptom onset are randomly allocated to therapeutic hypothermia for eight-days or conventional temperature management. In the therapeutic hypothermia group, a target temperature of 35.0°C is achieved by endovascular catheters and followed by slow controlled rewarming. Data analysis is based on the intent-to-treat population. The primary outcome measure of the study is the development in total lesion volume on cranial computertomography (intracerebral hemorrhage plus perihemorrhagic edema on day 8 ± 0.5 and day 1 ± 0.5 after intracerebral hemorrhage) and the mortality after 30 days. Secondary end-points are the in-hospital mortality, mortality, and functional outcome (modified Rankin Scale and Barthel-Index) after 90 and 180 days. Safety measures include any adverse events associated with therapeutic hypothermia., Discussion: In the face of a lack of evidence-based therapies for patients with large intracerebral hemorrhage, new promising approaches are desperately needed, but need evaluation in randomized controlled trials., Conclusion: The results of Cooling in IntraCerebral Hemorrhage trial are believed to directly influence future therapy of large intracerebral hemorrhage.

Background and Purpose: The prognosis of spontaneous intracerebral hemorrhage (sICH) is poor because of the mass effect arising from the hematoma and the associated peri-hemorrhagic edema, leading to increased intracranial pressure. Because the efficacy of surgical and anti-edematous treatment strategies is limited, we investigated the effects of mild induced hypothermia in patients with large sICH., Methods: Twelve patients with supratentorial sICH >25 mL were treated by hypothermia of 35 degrees C for 10 days. Evolution of hematoma volume and perifocal edema was measured by cranial CT. Functional outcome was assessed after 90 days. These patients were compared to patients (n=25; inclusion criteria: sICH volume >25 mL, no acute restriction of medical therapy on admission) from the local hemorrhage data bank (n=312). Side effects of hypothermia were analyzed., Results: All patients from both groups needed mechanical ventilation and were treated in a neurocritical care unit. All hypothermic patients (mean age, 60+/-10 years) survived until day 90, whereas 7 patients died in the control group (mean age, 67+/-7 years). Absolute hematoma size on admission was 58+/-29 mL (hypothermia) compared to 57+/-31 mL (control). In the hypothermia group, edema volume remained stable during 14 days (day 1, 53+/-43 mL; day 14, 57+/-45 mL), whereas edema significantly increased in the control group from 40+/-28 mL (day 1) to 88+/-47 mL (day 14). ICH continuously dissolved in both groups. Pneumonia rate was 100% in the hypothermia group and 76% in controls (P=0.08). No significant side effects of hypothermia were observed., Conclusions: Hypothermia prevented the increase of peri-hemorrhagic edema in patients with large sICH.

Background: Venous thromboembolism (VTE) is a common complication after stroke. Application of low molecular weight heparins (LMWH) has been proven to be beneficial for the prevention of VTE in ischemic stroke patients. However, there is no consensus whether and how to administer LMWH for prevention of thrombotic complications after acute spontaneous intracerebral hemorrhage (sICH), the main concern being possible hematoma growth. The objective of this study was to assess the safety of early subcutaneous LMWH in patients with sICH with respect to hemorrhage enlargement., Methods: A total of 97 patients with sICH were analyzed. LMWH (either enoxaparin-natrium or dalteparin-natrium) were initiated within 36 h after admission in all patients without clinical evidence of hemorrhage enlargement or an absence of evidence of hematoma growth on CT. Hematoma growth (significant when >33%, moderate when >20%) was assessed on follow-up CT between days 5 and 11., Results: None of the patients showed a significant hemorrhage growth. Between days 2 and 10, 2 patients experienced a moderate hematoma enlargement of 22.4 and 20.9%. None of the included patients developed a fatal lung embolism., Conclusions: Early application of subcutaneous LMWH for prevention of venous thromboembolism seems to be safe, and probably does not increase the risk of hematoma growth in patients with sICH., (Copyright (c) 2008 S. Karger AG, Basel.)

Objectives: Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracranial hemorrhage (ICH). The search for surrogate parameters that allow treatment stratification for spontaneous ICH continues. We aimed to examine perihemorrhagic ischemic changes with an animal experimental MRI study., Methods: A high field MRI compatible setup for male Wistar rats was established using a double injection model. ICH was stereotactically placed into the right basal ganglia of 29 Wistar rats. Coronal T2-WI, T2*-WI and DWI were generated with a 2.35 T animal MRI scanner 15 min, 60 min and 210 min after ICH. Clot signal characteristics, clot volumes and normalized ADC values were analyzed in four hematoma regions (core, periphery, outer rim, healthy ipsilateral tissue) in all sequences., Results: T2*-WI and DWI reliably demonstrated ICH in 100% with only small deviation from the applied volume (-20% to +26%) whereas T2-WI failed to conspicuously show ICH. There were no perihemorrhagic ADC decreases consistent with ischemic cytotoxic edema but a mild vasogenic edema surrounding the ICH could be observed., Conclusion: T2*-WI and DWI are accurate for the diagnosis of hyperacute ICH. According to serial and crossectional ADC analysis, there is no hint towards the existence of a perihemorrhagic ischemic area that might be saved by early intervention. Future studies should focus on perfusion and metabolic/neurotoxic studies of this particular area and neurotoxic properties of the surrounding edema.

Background and Purpose: Cerebral ischemia has been proposed as a contributing mechanism to secondary neuronal injury after intracerebral hemorrhage (ICH). The search for surrogate parameters that allow treatment stratification for spontaneous ICH continues. We sought to assess the presence and prognostic effect of perihemorrhagic ischemic changes and hypoperfusion in a prospective stroke MRI study., Methods: We performed stroke MRI in 32 patients with hyperacute ICH (mean, 16.9+/-17.2 mL) within 6 hours after symptom onset (mean, 3.1+/-1.3 hours). Clinical data at baseline (National Institutes of Health Stroke Scale) and on day 90 (Barthel Index, modified Rankin Scale) were assessed. Perihemorrhagic perfusion- and diffusion-weighted imaging changes were assessed in a 1-cm-wide area around the clot., Results: Despite a mild perihemorrhagic mean transit time prolongation of 0.7+/-1.1 second, there were no significant perihemorrhagic apparent diffusion coefficient or mean transit time changes indicating irreversible ischemia or hypoperfusion. ICH size, time to imaging, or clinical severity at baseline or outcome were not reflected by changes of relative apparent diffusion coefficient or perfusion-weighted imaging. ICH size correlated with baseline clinical severity (r=0.51, P=0.005). There was a significant association (P=0.0494) and a significant negative correlation (r=-0.468, P=0.0103) of perihemorrhagic perfusion change with time from symptom onset not associated with ICH size., Conclusions: Perihemorrhagic hypoperfusion probably is a consequence of reduced metabolic demand (diaschisis) rather than a sign of ischemia. We found no evidence for a perihemorrhagic and potentially salvageable ischemic penumbra in hyperacute ICH. Further studies should address metabolic, toxic, apoptotic, and microvascular aspects.

Background and purpose: Therapeutic hypothermia (TH), or targeted temperature management (TTM), is a classic treatment option for reducing inflammation and potentially other destructive processes across a wide range of pathologies, and has been successfully used in numerous disease states. The ability for TH to improve neurological outcomes seems promising for inflammatory injuries but has yet to demonstrate clinical benefit in the intracerebral hemorrhage (ICH) patient population. Minimally invasive ICH evacuation also presents a promising option for ICH treatment with strong preclinical data but has yet to demonstrate functional improvement in large randomized trials. The biochemical mechanisms of action of ICH evacuation and TH appear to be synergistic, and thus combining hematoma evacuation with cooling therapy could provide synergistic benefits. The purpose of this working group was to develop consensus recommendations on optimal clinical trial design and outcomes for the use of therapeutic hypothermia in ICH in conjunction with minimally invasive ICH evacuation. Methods: An international panel of experts on the intersection of critical-care TH and ICH was convened to analyze available evidence and form a consensus on critical elements of a focal cooling protocol and clinical trial design. Three focused sessions and three full-group meetings were held virtually from December 2020 to February 2021. Each meeting focused on a specific subtopic, allowing for guided, open discussion. Results: These recommendations detail key elements of a clinical cooling protocol and an outline for the roll-out of clinical trials to test and validate the use of TH in conjunction with hematoma evacuation as well as late-stage protocols to improve the cooling approach. The combined use of systemic normothermia and localized moderate (33.5 °C) hypothermia was identified as the most promising treatment strategy. Conclusions: These recommendations provide a general outline for the use of TH afterminimally invasive ICH evacuation. More research is needed to further refine the use and combination of these promising treatment paradigms for this patient population. [ABSTRACT FROM AUTHOR]