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Background: To evaluate the feasibility and safety of a fast initiation of cooling to a target temperature of 35°C by means of transnasal cooling in patients with anterior circulation large vessel occlusion (LVO) undergoing endovascular thrombectomy (EVT)., Methods: Patients with an LVO onset of <24 hour who had an indication for EVT were included in the study. Transnasal cooling (RhinoChill) was initiated immediately after the patient was intubated for EVT and continued until an oesophageal target temperature of 35°C was reached. Hypothermia was maintained with surface cooling for 6-hour postrecanalisation, followed by active rewarming (+0.2°C/hour). The primary outcome was defined as the time required to reach 35°C, while secondary outcomes comprised clinical, radiological and safety parameters., Results: Twenty-two patients (median age, 77 years) were included in the study (14 received additional thrombolysis, 4 additional stenting of the proximal internal carotid artery). The median time intervals were 309 min for last-seen-normal-to-groin, 58 min for door-to-cooling-initiation, 65 min for door-to-groin and 123 min for door-to-recanalisation. The target temperature of 35°C was reached within 30 min (range 13-78 min), corresponding to a cooling rate of 2.6 °C/hour. On recanalisation, 86% of the patients had a body temperature of ≤35°C. The median National Institutes of Health Stroke Scale at admission was 15 and improved to 2 by day 7, and 68% of patients had a good outcome (modified Rankin Scale 0-2) at 3 months. Postprocedure complications included asymptomatic bradycardia (32%), pneumonia (18%) and asymptomatic haemorrhagic transformation (18%)., Conclusion: The combined application of hypothermia and thrombectomy was found to be feasible in sedated and ventilated patents. Adverse events were comparable to those previously described for EVT in the absence of hypothermia. The effect of this procedure will next be evaluated in the randomised COmbination of Targeted temperature management and Thrombectomy after acute Ischemic Stroke-2 trial., Competing Interests: Competing interests: MF is an employee of the company BrainCool., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Over the last century, significant milestones have been achieved in managing critical illness and diagnosing and treating neurological diseases. Building upon these milestones, the field of neurocritical care emerged in the 1980 and 1990 s at the convergence of critical care medicine and acute neurological treatment. This comprehensive review presents a historical account of key developments in neurocritical care in both the United States and Europe, with a special emphasis on German contributions. The scope of the review encompasses: the foundations of neurocritical care, including post-operative units in the 1920s and 30s, respiratory support during the poliomyelitis epidemics in the 40 and 50 s, cardiac and hemodynamic care in the 60 and 70 s, and stroke units in the 80 and 90 s; key innovations including cerebral angiography, computed tomography, and intracranial pressure and multi-modal monitoring; and advances in stroke, traumatic brain injury, cardiac arrest, neuromuscular disorders, meningitis and encephalitis. These advances have revolutionized the management of neurological emergencies, emphasizing interdisciplinary teamwork, evidence-based protocols, and personalized approaches to care., (© 2023. The Author(s).)

Background and Purpose: Acute stroke frequently causes cardiovascular-autonomic dysfunction (CAD). Studies of CAD recovery are inconclusive, whereas poststroke arrhythmias may wane within 72 h. We evaluated whether poststroke CAD recovers within 72 h upon stroke onset in association with neurological improvement or increased use of cardiovascular medication., Methods: In 50 ischemic stroke patients (68 ± 13 years old) who-prior to hospital-admission-had no known diseases nor took medication affecting autonomic modulation, we assessed National Institutes of Health Stroke Scale (NIHSS) scores, RR intervals (RRIs), systolic and diastolic blood pressure (BP), respiration rate, parameters reflecting total autonomic modulation (RRI SD, RRI total powers), sympathetic modulation (RRI low-frequency powers, systolic BP low-frequency powers), and parasympathetic modulation (square root of mean squared differences of successive RRIs [RMSSD], RRI high-frequency powers), and baroreflex sensitivity within 24 h (Assessment 1) and 72 h after stroke onset (Assessment 2) and compared data to those of 31 healthy controls (64 ± 10 years). We correlated delta NIHSS values (Assessment 1 - Assessment 2) with delta values of autonomic parameters (Spearman rank correlation tests; significance: p < 0.05)., Results: At Assessment 1, patients were not yet on vasoactive medication and had higher systolic BP, respiration rate, and heart rate, that is, lower RRIs, but lower RRI SD, RRI coefficient of variance, RRI low-frequency powers, RRI high-frequency powers, RRI total powers, RMSSDs, and baroreflex sensitivity. At Assessment 2, patients were on antihypertensives, had higher RRI SD, RRI coefficient of variance, RRI low-frequency powers, RRI high-frequency powers, RRI total powers, RMSSDs, and baroreflex sensitivity but lower systolic blood pressure and NIHSS values than at Assessment 1; values no longer differed between patients and controls except for lower RRIs and higher respiration rate in patients. Delta NIHSS scores correlated inversely with delta values of RRI SD, RRI coefficient of variance, RMSSDs, RRI low-frequency powers, RRI high-frequency powers, RRI total powers, and baroreflex sensitivity., Conclusions: In our patients, CAD recovery was almost complete within 72 h after stroke onset and correlated with neurological improvement. Most likely, early initiation of cardiovascular medication and probably attenuating stress supported rapid CAD recovery., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

This review article summarizes the major clinical studies in neurological emergency and intensive care medicine from the end of 2020 to 2021 on the topics: recanalizing treatment in ischemic stroke, usefulness and effect of brain tissue oxygen monitoring in subarachnoid hemorrhage, efficacy of induced hypothermia in patients with cardiac arrest (CA), value of early cranial imaging after CA, relevance of rapid management and effects of different anticonvulsants in status epilepticus and incidence of critical illness polyneuropathy myopathy in intensive care unit patients with COVID-19 infections., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Background: Stroke may compromise cardiovascular-autonomic modulation (CAM). The longitudinal post-stroke CAM alterations remain unclear as previous studies excluded patients with cardiovascular medication. This study evaluated whether CAM dysfunction improves after several months in patients under typical clinical conditions, i.e., without excluding patients with cardiovascular medication., Methods: In 82 ischemic stroke patients [33 women, 64.9 ± 8.9 years, NIHSS-scores 2 (interquartile range 1-5)], we evaluated the applications of cardiovascular medication before stroke, during autonomic tests performed within 1 week, 3 and 6 months after stroke onset. We determined resting RR intervals (RRI), systolic, diastolic blood pressures (BPsys), respiration, parameters reflecting total CAM [RRI-standard deviation (RRI-SD), RRI-total powers], sympathetic [RRI-low-frequency powers (RRI-LF), BPsys-LF powers] and parasympathetic CAM [RMSSD, RRI-high-frequency powers (RRI-HF powers)], and baroreflex sensitivity. ANOVA or Friedman tests with post hoc analyses compared patient data with data of 30 healthy controls, significance was assumed for P < 0.05., Results: More patients had antihypertensive medication after than before stroke. First-week CAM testing showed lower RRIs, RMSSD, RRI-SDs, RRI-total powers, RRI-HF powers, and baroreflex sensitivity, but higher BPsys-LF powers in patients than controls. After 3 and 6 months, patients had significantly higher RRIs, RRI-SDs, RRI-total powers, RMSSDs, RRI-HF powers, and baroreflex sensitivity, but lower BPsys-LF powers than in the 1st week; RMSSDs and RRI-HF powers no longer differed between patients and controls. However, 6-month values of RRIs, RRI-SDs, and baroreflex sensitivity were again lower in patients than controls., Conclusions: Even mild strokes compromised cardiovagal modulation and baroreflex sensitivity. After 3 months, CAM had almost completely recovered. Recovery might be related to the mild stroke severity. Presumably, CAM recovery was also promoted by the increased application of cardiovascular medication. Yet, slight CAM dysfunction after 6 months suggests continuing autonomic vulnerability., (© 2022. The Author(s).)

Background and Purpose: Ischemic stroke may induce cardiovascular autonomic dysfunction, but most previous studies have included patients with anterior circulation ischemic stroke or brainstem stroke. It remains unclear whether posterior circulation ischemic stroke (PCIS) without brainstem involvement also compromises cardiovascular autonomic modulation (CAM). Therefore, we aimed to assess CAM in PCIS patients with and without brainstem involvement., Methods: In four subgroups of 61 PCIS patients (14 occipital lobe, 16 thalamic, 12 cerebellar, and 19 brainstem strokes) and 30 healthy controls, we recorded RR intervals (RRIs), systolic (SBP) and diastolic blood pressure (DBP), and respiration at supine rest during the first week after stroke onset. We calculated parameters reflecting total CAM (RRI-standard deviation [RRI-SD], RRI-total powers), predominantly sympathetic CAM (RRI-low-frequency [LF] powers and SBP-LF powers] and parasympathetic CAM (root mean square of successive RRI differences [RMSSD], RRI-high-frequency [HF] powers), sympathetic-parasympathetic balance (RRI-LF/HF ratios), and baroreflex sensitivity (BRS). Values were compared among the four PCIS groups and controls using one-way ANOVA Kruskal-Wallis tests, with post-hoc analyses. Significance was assumed for p &lt; 0.05., Results: In each PCIS subgroup, values for RRI, RRI-SD, RMSSD, RRI-HF powers, and BRS were significantly lower, while SBP-LF powers were higher than in the controls. Only in patients with occipital lobe stroke were RRI-LF/HF ratios significantly higher than in controls. Otherwise, autonomic variables did not differ among the four PCIS subgroups., Conclusions: During the first week after stroke onset, our PCIS patients with occipital lobe, thalamic, cerebellar, or brainstem strokes all had reduced cardiovagal modulation, compromised baroreflex, and increased peripheral sympathetic modulation. The RRI-LF/HF ratios suggest that sympathetic predominance is slightly more prominent after occipital lobe stroke. PCIS may trigger cardiovascular autonomic dysfunction even without brainstem involvement., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

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 after minimally invasive ICH evacuation. More research is needed to further refine the use and combination of these promising treatment paradigms for this patient population., Competing Interests: Author NB has received research funding from Becton Dickenson, Maryland Industrial Partnerships, Department of Defense. Author TB owns equity in a start-up investigating mechanisms of local cooling for ICH. Authors TB and CK are listed inventors in IP relating to cooling after ICH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BE declared a shared affiliation with the author PL to the handling editor at the time of review., (Copyright © 2022 Baker, Kellner, Colbourne, Rincon, Kollmar, Badjatia, Dangayach, Mocco, Selim, Lyden, Polderman and Mayer.)

Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Fever in the acute phase of stroke leads to an unfavorable clinical outcome and increased mortality. However, no specific form of effective fever treatment has been established, so far. We analyzed the effectiveness of our in-house standard operating procedure (SOP) of fever treatment. Methods: This SOP was analyzed for a period of 33 weeks. Patients with cerebral ischemia (ischemic stroke, transient ischemic attack) or cerebral hemorrhage (intracerebral, subarachnoid) and body temperature elevation of ≥ 37.5°C within the first 6 days after admission were eligible for inclusion in the analysis. The results of SOP group, who's data have been collected prospectively were then compared with a historical control group that had been treated conventionally 1 year earlier in the same period. The data of control group have been collected in retrospect. The primary endpoint was the total duration of the fever for the first 6 days after admission to the stroke unit. Results: A total of 130 patients (mean age of 78 ± 12) received 370 antipyretic interventions. Sequential application of paracetamol ( n = 245), metamizole ( n = 53) and calf compress ( n = 15) led to significant reduction in body temperature. In patients who did not respond to these applications, normothermia could be achieved after infusion of the cooled saline solution. Normothermia could be achieved within 120 min in more than 90% of the cases treated by the SOP. The SOP reduced the fever duration in the 6 days significantly, from 12.2 ± 2.7 h [95% confidence interval (CI) for mean] in the control group to 3.9 ± 1.0 h (95% CI) in the SOP group ( p < 0.001). The SOP was rated to be reasonable and effective. Conclusion: Our in-house SOP is cost-efficient and effective for fever treatment in stroke patients, that can be implemented by local health care professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Hedtmann, Schwab and Kollmar.)

Introduction: Noninvasive temperature modulation by localized neck cooling might be desirable in the prehospital phase of acute hypoxic brain injuries. While combined head and neck cooling induces significant discomfort, peripheral vasoconstriction, and blood pressure increase, localized neck cooling more selectively targets blood vessels that supply the brain, spares thermal receptors of the face and skull, and might therefore cause less discomfort cardiovascular side effects compared to head- and neck cooling. The purpose of this study is to assess the effects of noninvasive selective neck cooling on cardiovascular parameters and cerebral blood flow velocity (CBFV)., Methods: Eleven healthy persons (6 women, mean age 42 ± 11 years) underwent 90 min of localized dorsal and frontal neck cooling (EMCOOLS Brain.Pad™) without sedation. Before and after cooling onset, and after every 10 min of cooling, we determined rectal, tympanic, and neck skin temperatures. Before and after cooling onset, after 60- and 90-min cooling, we monitored RR intervals (RRI), systolic, diastolic blood pressures (BPsys, BPdia), laser Doppler skin blood flow (SBF) at the index finger pulp, and CBFV at the proximal middle cerebral artery (MCA). We compared values before and during cooling by analysis of variance for repeated measurements with post hoc analysis (significance: p < 0.05)., Results: Neck skin temperature dropped significantly by 9.2 ± 4.5 °C (minimum after 40 min), while tympanic temperature decreased by only 0.8 ± 0.4 °C (minimum after 50 min), and rectal temperature by only 0.2 ± 0.3 °C (minimum after 60 min of cooling). Index finger SBF decreased (by 83.4 ± 126.0 PU), BPsys and BPdia increased (by 11.2 ± 13.1 mmHg and 8.0 ± 10.1 mmHg), and heart rate slowed significantly while MCA-CBFV remained unchanged during cooling., Conclusions: While localized neck cooling prominently lowered neck skin temperature, it had little effect on tympanic temperature but significantly increased BP which may have detrimental effects in patients with acute brain injuries.

Targeted temperature management, or therapeutic hypothermia, is a potent neuroprotective approach after ischemic brain injury. Hypothermia should be induced as soon as possible after the onset of acute stroke to assure better outcomes. Accordingly, drugs with a fast-acting hypothermic effect sustainable through the period of emergency transportation to hospital would have clinical advantages. Activation of the transient receptor potential vanilloid-1 (TRPV1) can induce hypothermia. Our immunohistochemical investigations confirmed that TRPV1 was distributed to perivascular and periventricular regions of the rat brain, where TRPV1 can be easily detected by TRPV1 agonists. An endogenous TRPV1 selective agonist, N -oleoyldopamine (OLDA), and a synthetic antagonist, AMG 9810, were injected intraperitoneally into healthy adult male Wister rats, and brain and core temperatures and gross motor activities were monitored. Comparison with baseline temperatures showed that TRPV1 injection immediately induced mild hypothermia ( p  < 0.05 in brain and p  < 0.01 in body), and AMG 9810 induced immediate mild hyperthermia (not significant). However, the OLDA-induced hypothermia did not decrease lesion volume after middle carotid artery occlusion in rats. Relative to vehicle, OLDA yielded poorer outcomes and AMG 9810 yielded better outcomes in neurological scores and lesion size. Our study showed that, as an agonist of TRPV1, OLDA has suitable hypothermia-inducing properties, but did not decrease lesion volume. Therefore, the search for novel TRPV1 agonists and/or antagonists providing hypothermia and neuroprotection should continue. Further investigations should also target OLDA-induced transient hypothermia combined with long-term hypothermia maintenance with surface cooling, which mimics the anticipated clinical use of this class of drug.

In intensive care medicine neuroprotection is understood mostly as various measures to avoid secondary brain damage after initial trauma, as in stroke, intracranial hemorrhage and resuscitation. Every brain trauma differs in the damage pattern and dynamics depending on the primary form of injury. Therefore, there are targeted treatment approaches depending on the pathophysiology of the medical condition. In addition, neuroprotective methods are desirable that are effective in the majority of patients with acute brain injury. In actual fact, in all forms of acute brain injury certain pathophysiological courses are encountered, which can lead to secondary brain damage depending on the intensity, e.g. reperfusion injury, damage to the blood-brain barrier and excitotoxicity. There is evidence to suggest that the creation of physiologically normal conditions leads to a favorable situation for the damaged brain. This article firstly describes the relevance of neuroprotective measures in neurocritical care medicine. Subsequently, general pathophysiological mechanisms in brain trauma are described. Following this, the pathophysiology and treatment options in brain pressure crises (reduction of intracranial pressure), anemia (transfusion management), hyperglycemia and hypoglycemia (adjustment of the blood sugar level) are dealt with. Finally, the use and benefits of therapeutic hypothermia are discussed. This has a special position as the only clinically effective individual measure for neuroprotection. The focus here is on the application following circulatory and cardiac arrest and resuscitation.

Antibodies against adenylate kinase 5 (AK5) have been described in patients with non-paraneoplastic limbic encephalitis, mainly in men around 70 years of age. Routine testing with specific cell-based assays is not yet available. Three patients with episodic anterograde memory problems and depression had extensive limbic lesions and developed severe atrophy, mainly of the medial temporal lobes. The antibodies were identified in serum and CSF based on the typical staining pattern of AK5 antibodies on a tissue-based assay (here, unfixed mouse brain). Subsequently, they were confirmed by a research laboratory through a cell-based assay., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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., (© European Stroke Organisation 2019.)

Targeted temperature management (TTM) might improve outcome of patients with severe subarachnoid hemorrhage (SAH) in which vasospasm, delayed cerebral ischemia (DCI), and increased intracranial pressure (ICP) are frequent and severe complications. A series of patients ( n  = 3) with severe aneurysmatic SAH were treated by TTM if they developed ICP crisis and/or severe vasospasm diagnosed by angiography. Once these complications were detected, body core temperature (BCT) was rapidly decreased to 35°C or 33°C, if necessary. BCT induced and maintained by surface cooling remained at the desired level for at least 72 hours. Rewarming was performed by 1°C, only if the target parameters ICP and velocities in the serial Doppler sonography indicating macrovascular vasospasm improved to regular levels. In case of increase of ICP or middle cerebral arteries velocities BCT was decreased again to the last effective level. The patients developed vasospasm between days 6 and 12 after SAH. All aneurysms were treated by coiling. BCT was reduced between days 6 and 12 after SAH. Total duration of BCT <36.5°C was between 5.5 and 8 days. It remained <35°C for 4-6 days, and at 33°C for 3 days on average. ICP could be sufficiently controlled in all patients, because no ICP crisis was observed during TTM and after rewarming. Two patients developed minor DCI. Side effects of prolonged ventilation of 7-18 days included pneumonia for two patients that could be treated sufficiently. Other complications were one case of ventriculitis and two temporary deliriums. Outcome of the patients was good because no focal neurological symptoms could be detected after rehabilitation. TTM represents a promising treatment approach for severe SAH in which standard treatment is often limited and experimental. It deserves further clinical investigation in a larger cohort.

Importance: Moderate hypothermia in addition to early decompressive hemicraniectomy has been suggested to further reduce mortality and improve functional outcome in patients with malignant middle cerebral artery (MCA) stroke., Objective: To investigate whether moderate hypothermia vs standard treatment after early hemicraniectomy reduces mortality at day 14 in patients with malignant MCA stroke., Design, Setting, and Participants: This randomized clinical trial recruited patients from August 2011 through September 2015 at 6 German university hospitals with dedicated neurointensive care units. Of the patients treated with hemicraniectomy and assessed for eligibility, patients were randomly assigned to either standard care or moderate hypothermia. Data analysis was completed from December 2016 to June 2018., Interventions: Moderate hypothermia (temperature, 33.0 ± 1.0°C) was maintained for at least 72 hours immediately after hemicraniectomy., Main Outcomes and Measures: The primary outcome was mortality rate at day 14 compared with the Fisher exact test and expressed as odds ratio (ORs) with 95% CIs. Rates of patients with serious adverse events were estimated for the period of the first 14 days after hemicraniectomy and 12 months of follow-up. Secondary outcome measures included functional outcome at 12 months., Results: Of the 50 study participants, 24 were assigned to standard care and 26 to moderate hypothermia. Twenty-eight were male (56%); the mean (SD) patient age was 51.3 (6.6) years. Recruitment was suspended for safety concerns: 12 of 26 patients (46%) in the hypothermia group and 7 of 24 patients (29%) receiving standard care had at least 1 serious adverse event within 14 days (OR, 2.05 [95% CI, 0.56-8.00]; P = .26); after 12 months, rates of serious adverse events were 80% (n = 20 of 25) in the hypothermia group and 43% (n = 10 of 23) in the standard care group (hazard ratio, 2.54 [95% CI, 1.29-5.00]; P = .005). The mortality rate at day 14 was 19% (5 of 26 patients) in the hypothermia group and 13% (3 of 24 patients) in the group receiving standard care (OR, 1.65 [95% CI, 0.28-12.01]; P = .70). There was no significant difference regarding functional outcome after 12 months of follow-up., Interpretation: In patients with malignant MCA stroke, moderate hypothermia early after hemicraniectomy did not improve mortality and functional outcome compared with standard care, but may cause serious harm in this specific setting., Trial Registration: http://www.drks.de, identifier DRKS00000623.

Stroke is a leading cause of death, disability and is a symptom burden worldwide. It impacts patients and their families in various ways, including physical, emotional, social, and spiritual aspects. As stroke is potentially lethal and causes severe symptom burden, a palliative care (PC) approach is indicated in accordance with the definition of PC published by the WHO in 2002. Stroke patients can benefit from a structured approach to palliative care needs (PCN) and the amelioration of symptom burden. Stroke outcome is uncertain and outlook may change rapidly. Regarding these challenges, core competencies of PC include the critical appraisal of various treatment options, and openly and respectfully discussing therapeutic goals with patients, families, and caregivers. Nevertheless, PC in stroke has to date mainly been restricted to short care periods for dying patients after life-limiting complications. There is currently no integrated concept for PC in stroke care addressing the appropriate moment to initiate PC for stroke patients, and the question of how to screen for symptoms remains unanswered. Therefore, PC for stroke patients is often perceived as a stopgap in cases of unfavorable prognosis and very short survival times. In contrast, PC can provide much more for stroke patients and support a holistic approach, improve quality of life and ensure treatment according to the patient's wishes and values. In this short review we identify key aspects of PC in stroke care and current barriers to implementation. Additionally, we provide insights into our approach to PC in stroke care.

Targeted temperature management (TTM), or therapeutic hypothermia, is one of the most potent neuroprotective approaches after ischemic and traumatic brain injuries. TTM has been applied clinically with various methods, but effective achievement and maintenance of the target temperature remain challenging. Furthermore, timing of cooling and target body and brain temperature to optimize effectiveness for neuroprotection and to minimize side effects are yet to be standardized. Focal brain cooling is a potential strategy to minimize adverse effects of systemic TTM. In this study, we report on a focal brain cooling device for animals and its effectiveness of focal cooling in several animal models of ischemic cerebral stroke. A focal brain cooling device was constructed using a Peltier's element, a thermoelectric heat pump. The device was validated for its cooling ability, and optimal settings to induce an effective intracranial temperature were determined using male Sprague-Dawley rats. Transient and permanent middle cerebral artery occlusions were experimentally induced, and focal brain cooling was applied using the device varying the timing and duration of cooling. The stroke-induced infarct and edema volumes were evaluated from Nissl-stained cryosections. The focal brain cooling device was able to decrease and subsequently maintained cerebral hypothermia in free-moving rats without altering the core temperature. The device with validated intracranial temperatures produced neuroprotective effects in the acute phase of ischemic neural death, reperfusion injury, progressing damage to the penumbra, and edema formation. In conclusion, our validated focal cooling device enabled rapid and accurate cerebral TTM in rats. Using this device, we were able to test the neuroprotective effect of focal TTM in several pathological stages of cerebral ischemia, which warrants further studies to develop clinically feasible TTM procedures for patients with cerebral stroke.

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: 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., (© 2015 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.)

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., (© 2014 World Stroke Organization.)

Background: Cerebral ischemia is associated with infectious complications due to immunosuppression and decreased T lymphocyte activity. G-CSF, which has neuroprotective properties, is known to modulate inflammatory processes after induced stroke. The aim of our study was to investigate the impact of G-CSF in experimental stroke and to compare two different modes of treatment, focusing on circulating T lymphocytes., Methods: Cerebral ischemia was induced in Wistar rats by occlusion of the middle cerebral artery, followed by reperfusion after 1h. G-CSF was applied either as a single dose 30 min after occlusion, or daily for seven days. Silver staining was used to determine infarct size. T lymphocytes in the peripheral blood were measured before and 7 days after induced cerebral ischemia by flow cytometry. In addition, migration of CD3-expressing T lymphocytes into the brain was investigated by immunohistochemistry., Results: Both single dose and daily treatment with G-CSF significantly reduced infarct size. A significant improvement of neurological outcome was only observed after single application of G-CSF. While a decrease in peripheral T lymphocytes was detected seven days after induced stroke, no reduction was observed in the G-CSF-treated groups. Apart from that, G-CSF significantly reduced the number of brain migrated T lymphocytes in both treatment settings as compared to vehicle., Conclusion: A single dose of G-CSF exerted neuroprotective effects in ischemic stroke, which were less pronounced after daily G-CSF application. Both treatment strategies inhibited stroke-induced reduction of T lymphocytes in peripheral blood, which may have contributed to the reduction of infarct size., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background: Receiving information that one has a dissected cervical artery, which can cause a stroke at any time, is obviously traumatic, but details about the psychiatric and psychosocial sequelae are not known. We investigated the prevalence of and risk factors for posttraumatic stress disorder (PTSD) in patients with spontaneous cervical artery dissection (CD) and the impact of PTSD on their psychosocial functioning., Methods: Patients admitted because of CD between 2006 and 2010 were retrospectively examined using a diagnostic PTSD measure (Posttraumatic Diagnostic Scale). Patients between 2011 and 2012 were examined prospectively. To identify potential predictors for PTSD, we examined all patients' stress coping strategies (brief COPE inventory), anxiety and depression (Hospital Anxiety and Depression Scale), impairment by preventive medication, time since diagnosis and their neurologic (modified Rankin Scale) and cognitive status. To identify the psychosocial impact of PTSD, we examined quality of life (Short-Form 36)., Results: Data of 47 retrospectively contacted patients and 15 prospectively examined patients were included. Twenty-eight patients (45.2%) met the diagnostic criteria for PTSD. A significantly reduced health-related quality of life (HRQoL) was found in 27 patients (43.5%) for mental health and in 8 patients (12.9%) for physical health. Results of logistic regression analysis revealed that the use of maladaptive coping strategies was predictive of the disorder (P < .0001). Age, sex, mRS score, impairment caused by medication, and time since diagnosis were not predictive for PTSD. The presence of PTSD itself was the only significant predictor for reduced mental HRQol (P = .0004). Age, sex, mRS score, impairment caused by medication, and total Hospital Anxiety and Depression Scale score were not predictive for reduced mental HRQoL., Conclusions: PTSD seems to occur frequently in patients with CD and is associated with reduced mental HRQoL. Because the presence of a maladaptive coping style is correlated with PTSD, teaching patients better coping skills might be helpful., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: Observational studies suggest that infections are a common complication of therapeutic hypothermia. We performed a systematic review and meta-analysis of randomized trials to examine the risk of infections in patients treated with hypothermia., Data Sources: PubMed, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched for eligible studies up to October 1, 2012., Study Selection: We included randomized controlled clinical trials of therapeutic hypothermia induced in adults for any indication, which reported the prevalence of infection in each treatment group., Data Extraction: For each study, we collected information about the baseline characteristics of patients, cooling strategy, and infections., Data Synthesis: Twenty-three studies were identified, which included 2,820 patients, of whom 1,398 (49.6%) were randomized to hypothermia. Data from another 31 randomized trials, involving 4,004 patients, could not be included because the occurrence of infection was not reported with sufficient detail or not at all. The risk of bias in the included studies was high because information on the method of randomization and definitions of infections lacked in most cases, and assessment of infections was not blinded. In patients treated with hypothermia, the prevalence of all infections was not increased (rate ratio, 1.21 [95% CI, 0.95-1.54]), but there was an increased risk of pneumonia and sepsis (risk ratios, 1.44 [95% CI, 1.10-1.90]; 1.80 [95% CI, 1.04-3.10], respectively)., Conclusion: The available evidence, subject to its limitations, strongly suggests an association between therapeutic hypothermia and the risk of pneumonia and sepsis, whereas no increase in the overall risk of infection was observed. All future randomized trials of hypothermia should report on this important complication.

Background and Purpose: Granulocyte colony-stimulating factor (G-CSF; AX200; Filgrastim) is a stroke drug candidate with excellent preclinical evidence for efficacy. A previous phase IIa dose-escalation study suggested potential efficacy in humans. The present large phase IIb trial was powered to detect clinical efficacy in acute ischemic stroke patients., Methods: G-CSF (135 µg/kg body weight intravenous over 72 hours) was tested against placebo in 328 patients in a multinational, multicenter, randomized, and placebo-controlled trial (NCT00927836; www.clinicaltrial.gov). Main inclusion criteria were ≤9-hour time window after stroke onset, infarct localization in the middle cerebral artery territory, baseline National Institutes of Health Stroke Scale score range of 6 to 22, and baseline diffusion-weighted imaging lesion size ≥15 mL. Primary and secondary end points were the modified Rankin scale score and the National Institutes of Health Stroke Scale score at day 90, respectively. Data were analyzed using a prespecified model that adjusted for age, National Institutes of Health Stroke Scale score at baseline, and initial infarct volume (diffusion-weighted imaging)., Results: G-CSF treatment failed to meet the primary and secondary end points of the trial. For additional end points such as mortality, Barthel index, or infarct size at day 30, G-CSF did not show efficacy either. There was, however, a trend for reduced infarct growth in the G-CSF group. G-CSF showed the expected peripheral pharmacokinetic and pharmacodynamic profiles, with a strong increase in leukocytes and monocytes. In parallel, the cytokine profile showed a significant decrease of interleukin-1., Conclusions: G-CSF, a novel and promising drug candidate with a comprehensive preclinical and clinical package, did not provide any significant benefit with respect to either clinical outcome or imaging biomarkers., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: NCT00927836.

Rationale: Although decompressive hemicraniectomy clearly reduces mortality in severe space-occupying middle cerebral artery infarction (so-called malignant middle cerebral artery infarction), every fifth patient still dies in the acute phase and every third patient is left with moderate to severe disability. Therapeutic hypothermia is a neuroprotective and antiedematous treatment option that has shown promising effects in severe stroke. A combination of both treatment strategies may have the potential to further reduce mortality and morbidity in malignant middle cerebral artery infarction, but needs evaluation of its efficacy within the setting of a randomized clinical trial., Aims: The DEcompressive surgery Plus hypoTHermia for Space-Occupying Stroke (DEPTH-SOS) trial aims to investigate safety and feasibility of moderate therapeutic hypothermia (33°C ± 1) over at least 72 h in addition to early decompressive hemicraniectomy (≤48 hours after symptom onset) in patients with malignant middle cerebral artery infarction., Design: The DEcompressive surgery Plus hypoTHermia for Space-Occupying Stroke is a prospective, multicenter, open, two-arm (1:1) comparative, randomized, controlled trial., Study Outcomes: The primary end-point is mortality at day 14. The secondary end-points include functional outcome at day 14 and at 12 months follow-up, and complications related to hypothermia., Discussion: The results of this trial will provide data on safety and feasibility of moderate hypothermia in addition to decompressive hemicraniectomy in malignant middle cerebral artery infarction. Furthermore, efficacy data on early mortality and long-term functional outcome will be obtained, forming the basis of subsequent trials., (© 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.

Cerebral ischemia provokes an inflammatory cascade, which is assumed to secondarily worsen ischemic tissue damage. Linking adaptive and innate immunity dendritic cells (DCs) are key regulators of the immune system. The hematopoietic factor G-CSF is able to modulate DC-mediated immune processes. Although G-CSF is under investigation for the treatment of stroke, only limited information exists about its effects on stroke-induced inflammation. Therefore, we investigated the impact of G-CSF on cerebral DC migration and maturation as well as on the mediated immune response in an experimental stroke model in rats by means of transient middle cerebral artery occlusion (tMCAO). Immunohistochemistry and quantitative PCR were performed of the ischemic brain and flow cytometrical analysis of peripheral blood. G-CSF led to a reduction of the infarct size and an improved neurological outcome. Immunohistochemistry confirmed a reduced migration of DCs and mature antigen-presenting cells after G-CSF treatment. Compared to the untreated tMCAO group, G-CSF led to an inhibited DC activation and maturation. This was shown by a significantly decreased cerebral transcription of TLR2 and the DC maturation markers, CD83 and CD86, as well as by an inhibition of stroke-induced increase in immunocompetent DCs (OX62⁺OX6⁺) in peripheral blood. Cerebral expression of the proinflammatory cytokine TNF-α was reduced, indicating an attenuation of cerebral inflammation. Our data suggest an induction of DC migration and maturation under ischemic conditions and identify DCs as a potential target to modulate postischemic cerebral inflammation. Suppression of both enhanced DC migration and maturation might contribute to the neuroprotective action of G-CSF in experimental stroke., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background and Purpose: Localized head and neck cooling might be suited to induce therapeutic hypothermia in acute brain injury such as stroke. Safety issues of head and neck cooling are undetermined and may include cardiovascular autonomic side effects that were identified in this study., Methods: Ten healthy men (age 35±13 years) underwent 120 minutes of combined head and neck cooling (Sovika, HVM Medical). Before and after onset of cooling, after 60 and 120 minutes, we determined rectal, tympanic, and forehead skin temperatures, RR intervals, systolic and diastolic blood pressures (BP), laser-Doppler skin blood flow at the index finger and cheek, and spectral powers of mainly sympathetic low-frequency (0.04-0.15 Hz) and parasympathetic high-frequency (0.15-0.5 Hz) RR interval oscillations and sympathetic low-frequency oscillations of BP. We compared values before and during cooling using analysis of variance with post hoc analysis; (significance, P<0.05)., Results: Forehead skin temperature dropped by 5.5±2.2°C with cooling onset and by 12.4±3.2°C after 20 minutes. Tympanic temperature decreased by 4.7±0.7°C within 40 minutes, and rectal temperature by only 0.3±0.3°C after 120 minutes. Systolic and diastolic BP increased immediately on cooling onset and rose by 15.3±20.8 mm Hg and 16.5±13.4 mm Hg (P=0.004) after 120 minutes, whereas skin blood flow fell significantly during cooling. RR intervals and parasympathetic RR interval high-frequency powers increased with cooling onset and were significantly higher after 60 and 120 minutes than they were before cooling., Conclusions: Head and neck cooling prominently reduced tympanic temperature and thus might also induce intracerebral hypothermia; however, it did not significantly lower body core temperature. Profound skin temperature decrease induced sympathetically mediated peripheral vasoconstriction and prominent BP increases that are not offset by simultaneous parasympathetic heart rate slowing. Prominent peripheral vasoconstriction and BP increase must be considered as possibly harmful during head and neck cooling.

Background and Purpose: Anticoagulation is a highly effective secondary prevention in patients with cardioembolic stroke and atrial fibrillation/flutter (AF). However, the condition remains underdiagnosed, because paroxysmal AF may be missed by diagnostic tests in the acute phase. In this study, the sensitivity of AF detection was assessed for serial electrocardiographic recordings and continuous stroke unit telemetric monitoring with or without a structured algorithm to analyze telemetric data (SEA-AF)., Methods: Three hundred forty-six consecutive patients with acute ischemic stroke were prospectively included and subjected to standard telemetric monitoring. In addition, telemetric data were separately analyzed following SEA-AF, consisting of a structured evaluation of episodes with high risk for AF and a chronological beat-to-beat screening of the full registration. Serial electrocardiograms were conducted in 24-hour intervals., Results: Median effective telemetry monitoring time was 75.5 hours (interquartile range 64-86 hours). Overall, AF was diagnosed in 119 of 346 patients (34.4%). The structured reading algorithm was the most sensitive method to detected AF. Conventional telemetry and serial electrocardiographic assessments were less effective. However, only 35% of patients with previously documented paroxysmal AF and negative baseline electrocardiogram demonstrated AF episodes during monitoring., Conclusions: Continuous stroke unit telemetry using SEA-AF shows a significantly higher detection rate for AF compared with daily electrocardiographic assessments and standard telemetry without structured reading. The low overall probability to detect paroxysmal AF with either method during the first days after stroke demonstrates the urgent need for complementary diagnostic strategies such as long-term monitoring and frequent follow-up assessments. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT01177748.

Background: Hypothermia is neuroprotective in experimental stroke and may extend the so far limited therapeutic time window for thrombolysis. Therefore, hypothermia of 34°C and its effects on delayed thrombolysis including reperfusion-associated injury were investigated in a model of thromboembolic stroke (TE)., Methods: Male Wistar rats (n = 48) were subjected to TE. The following treatment groups were investigated: control group - normothermia (37°C); thrombolysis group - rt-PA 90 min after TE; hypothermia by 34°C applied 1.5 to 5 hours after TE; combination therapy- hypothermia and rt-PA. After 24 hours infarct size, brain edema and neuroscore were assessed. Protein markers for inflammation and adhesion, gelatinase activity, and blood brain barrier (BBB) disruption were determined. MRI-measurements investigated infarct evolution and blood flow parameters., Results: The infarct volume and brain swelling were smaller in the hypothermia group compared to the other groups (p < 0.05 to p < 0.01). Thrombolysis resulted in larger infarct and brain swelling than all others. Hypothermia in combination with thrombolysis reduced these parameters compared to thrombolysis (p < 0.05). Moreover, the neuroscore improved in the hypothermia group compared to control and thrombolysis. Animals of the combination therapy performed better than after thrombolysis alone (p < 0.05). Lower serum concentration of sICAM-1, and TIMP-1 were shown for hypothermia and combination therapy. Gelatinase activity was decreased by hypothermia in both groups., Conclusions: Therapeutic hypothermia reduced side-effects of rt-PA associated treatment and reperfusion in our model of TE.

OPINION STATEMENT: The use of tissue plasminogen activator (tPA) is the major treatment method for acute ischemic stroke, but it reaches only a very limited number of stroke patients. Although neuroprotectants may be useful in stroke patients in principle, promising animal data have not yet been successfully transferred to stroke patients. However, many arguments favor the successful translation of therapeutic hypothermia (TH) to stroke patients: it is a multimodal method, there is a strong correlation between fever and outcome in stroke patients, and TH has been shown to be beneficial in other kinds of acute brain injury (resuscitation, perinatal asphyxia). In addition, it is useful in controlling intracranial pressure caused by brain edema. So far, available data from clinical studies are not sufficient to recommend TH for the routine treatment of acute ischemic stroke. The quality of trials and the number of stroke patients treated by TH are far too low to prove efficacy or futility, but multicenter randomized controlled clinical trials are on their way. Studies in awake stroke patients will use TH very early in the clinical setting, which implies certain problems. The use of TH in awake individuals requires methods to suppress cold-induced vegetative responses such as shivering and sympathic activation, clinically relevant side effects that need to be monitored and treated carefully. In mass-occupying ischemic stroke, randomized trials will evaluate the neuroprotective effects of controlling edema and intracranial pressure. Because the optimal depth, duration, and methods of cooling are not clear, only large randomized controlled trials will set the baseline from which TH as a neuroprotective therapy can be optimized and brought successfully to stroke patients.

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: Intracerebral haemorrhage is the most feared complication in patients who are on treatment with vitamin K antagonists. Vitamin K antagonist related intracerebral haemorrhage occurs in about 10% of patients. Intracerebral haemorrhage has the worst prognosis of all subtypes of stroke including spontaneous intracerebral haemorrhage, and a mortality rate of up to about 65%. The higher rate of haematoma expansion due to rebleeding is thought to be responsible for the higher mortality. Current international treatment recommendations include fresh frozen plasma and prothrombin complex concentrate. It is known that these substances lower the international normalised ratio, and thus it is assumed that normalisation of coagulopathy may lead to haemostasis and reduction of rebleeding. However, the issue of whether to use fresh frozen plasma or prothrombin complex concentrate for urgent reversal of vitamin K antagonists is unresolved: safety and efficacy of these treatments have never been studied in a randomised controlled trial. Our questions are: how effective are the two substances in normalisation of the international normalized ratio? How feasible is it to apply either of these treatments in an acute situation? What is the safety profile of each of these substances? Is there a difference in haematoma growth and clinical outcome?, Method: We designed a prospective, randomised, controlled multicentre trial to compare biological efficacy and safety of fresh frozen plasma and prothrombin complex concentrate in vitamin K antagonist related intracerebral haemorrhage. The study is observer-blinded for laboratory, neuroradiological, and clinical outcomes. Patients will be included if a computed tomography scan shows an intraparenchymal or subdural haematoma within 12 h after onset of symptoms, if the patient is on treatment with vitamin K antagonists, and the international normalized ratio is ≥2. Primary endpoint is the normalisation of the international normalized ratio (≤1·2) within three-hours after the start of antagonising therapy. Main exclusion criteria are secondary intracerebral haemorrhage, other known coagulopathies, and known acute ischaemic events., Discussion: We discuss the rationale of our trial on the basis of the current recommendations and specific aspects of trial design as, time window, choice of endpoints, dosing of fresh frozen plasma and prothrombin complex concentrate, monitoring and analysis of safety parameters, and rescue treatment., Conclusion: This will be the first prospective trial comparing fresh frozen plasma and prothrombin complex concentrate in the indication of vitamin K antagonist related intracerebral hemorrhage. Recruitment of subjects started in August 2009. Until now, 19 patients have been included., (International Journal of Stroke © 2011 World Stroke Organization. No claim to original US government works.)

Background: Fever after acute cerebral injury is associated with unfavorable functional outcome and increased mortality, but there is controversy about the optimal antipyretic treatment. This study investigated an institutional standard operating procedure (SOP) for fever treatment in stroke patients including a sequence of pharmacologic and physical interventions., Methods: A 4-step antipyretic SOP was established for patients with acute cerebral ischemia or hemorrhage and a body temperature ≥37.5°C within the first 6 days after admission. Data on the course of body temperature, duration of fever and achievement of normothermia were recorded. Results were compared to a historic control group that underwent conventional treatment., Results: A total of 77 patients (mean age 70.4 ± 14.2 years) received 331 antipyretic interventions. Sequential administration of paracetamol (n = 219), metamizole (n = 71) and calf packing (n = 24) resulted in a significant drop in body temperature after 60 min in each instance. In 5 of 9 cases which were refractory to previous attempts, normothermia followed the infusion of ice-cooled saline. In more than 90% of cases treated per protocol, normothermia was achieved within 120 min. Compared to conventional treatment, fever burden was significantly lower within the first 4 days after admission (p < 0.001)., Conclusion: This SOP may help to optimize antipyretic treatment for stroke patients., (Copyright © 2011 S. Karger AG, Basel.)

Clinical data clearly show that elevated body temperature contributes to an unfavorable outcome after ischemic and hemorrhagic stroke. Two promising therapeutic strategies arise from this observation: (1) treatment of fever aiming to sustain normothermia and (2) induced hypothermia, targeting core body temperatures below 36.5°C. A limited number of studies investigated antipyretic strategies after acute stroke and their results were rather disappointing in terms of clinical efficacy. For that reason, it remains unproven, whether sufficient fever treatment improves functional outcome. On the other hand, strong experimental evidence supports neuroprotective effects of induced hypothermia after stroke. Yet, clinical data on this topic remain preliminary and rely on a limited number of patients, mostly enrolled in nonrandomized trials. Therefore, induced hypothermia may be considered safe and feasible after ischemic stroke, but little can be said regarding efficacy. This review summarizes the data, both on fever treatment and induced hypothermia following stroke, starting with a synopsis of the most important experimental investigations, leading to the latest clinical trials. Given the promising data and the lack of successful acute neuroprotective therapies available thus far, suggestions are given for future investigation on both topics., (Copyright © 2011 S. Karger AG, Basel.)

Background: Prehospital cooling of acute stroke patients would be ideal when associated with minor or no side effects. Therefore, we evaluated a cooling cap for the surface of head and cervical regions in awake volunteers., Methods: 10 healthy volunteers were treated by external cooling for 190 min using a gel-based cooling device. Vital signs, rectal temperature, tympanic temperature, the extent of shivering and individual perception of frostiness and discomfort were measured., Results: All participants (median age 35 years) successfully completed the treatment and experienced only mild to moderate discomfort. No serious adverse events and no shivering were noticed. There was a significant drop in the tympanic temperature to 34.68°C (difference from baseline: 1.7°C, 95% CI: 0.61-2.7°C, p = 0.001), in the rectal temperature to 36.65°C (difference from baseline: 0.65°C, 95% CI: 0.06-1.2°C, p = 0.019) and in the heart rate (difference from baseline: 15 beats/min, 95% CI: 0.63-30 beats/min, p = 0.035)., Conclusion: Treatment with the cooling device was well tolerated by all participants. The technique had measurable effects on core body temperature (rectal) and tympanic temperature (may reflect temperature at the external ear and skin rather than intracranial). It can be considered as a simple therapeutic approach to patients with suspected stroke in the prehospital setting., (Copyright © 2011 S. Karger AG, Basel.)

Large intracerebral hemorrhage (ICH) is associated with poor outcome. In a recent pilot study, therapeutic hypothermia (TH) prevented perihematomal edema growth and led to a high survival rate. Patients of this pilot study were now investigated 12 months after ICH. Twelve patients were treated with mild TH of 35°C for 10 days. All patients survived day 90 after ICH and were investigated with the modified Rankin Scale (mRS) at day 90 and after 12 months. At day 90, only two patients showed a mRS of 3, whereas all other had a mRS of 4 and 5. After 12 months, 2 patients had died, whereas 6 patients (50%) were able to walk without assistance (mRS 3). TH may be a promising treatment option for patients with large ICH, since pilot data indicate a high survival rate and a high chance for an acceptable functional long-term outcome.

Background and Purpose: Because of the narrow therapeutic range for thrombolysis in stroke, accurate weight-based dosing is essential for efficacy and safety. Stroke patients are frequently incapable to communicate their correct body weight (BW). Thus, dosing is often based on BW estimation, which may lead to dosing errors. The aim of our study was to evaluate availability of BW information, accuracy of estimations, and final dosing of Alteplase (tissue plasminogen activator [tPA]) in a routine clinical setting., Methods: A total of 109 consecutive intravenous thrombolysis patients were prospectively included in the study. Recruitment concluded with 100 complete data sets. Before therapy, BW was estimated independently by 2 physicians, 2 emergency nurses, and a neuroradiological technical assistant. Patients were weighed, and anthropometric measurements for BW approximation were taken. Dosing errors were assessed. Clinical outcome was evaluated at 90 days., Results: Of 109 patients, 55 (50.5%) were unable to provide information on their BW. Of those, 11 (20%) were accompanied by relatives able to give BW information. For all patients, estimation errors rates ranged from 20.8% (patient's own estimation) up to 38.2% (treating physician) and 42.2% (emergency nurse). Finally, 29 patients received an Alteplase dosage diverging >10% from the optimal dose. Twelve were under- and 17 overdosed. Underdosage was an independent predictor for worse outcome in multivariate analysis., Conclusions: Our study shows that reliable BW data are missing for a majority of intravenous thrombolysis patients. Measuring BW before administering Alteplase remains challenging. Given dosing errors in one-third of patients and the observed impact on outcome, standardized weighing before thrombolysis should be considered. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01006434.

Background and Purpose: Granulocyte colony-stimulating factor (G-CSF) is a promising stroke drug candidate. The present phase IIa study assessed safety and tolerability over a broad dose range of G-CSF doses in acute ischemic stroke patients and explored outcome data., Methods: Four intravenous dose regimens (total cumulative doses of 30-180 μg/kg over the course of 3 days) of G-CSF were tested in 44 patients in a national, multicenter, randomized, placebo-controlled dose escalation study (NCT00132470; www.clinicaltrial.gov). Main inclusion criteria were a 12-hour time window after stroke onset, infarct localization to the middle cerebral artery territory, a baseline National Institutes of Health Stroke Scale range of 4 to 22, and presence of diffusion-weighted imaging/perfusion-weighted imaging mismatch., Results: Concerning the primary safety end points, we observed no increase of thromboembolic events in the active treatment groups, and no increase in related serious adverse events. G-CSF led to expected increases in neutrophils and monocytes that resolved rapidly after end of treatment. We observed a clinically insignificant drug-related decrease of platelets. As expected from the low number of patients, we did not observe significant differences in clinical outcome in treatment vs. placebo. In exploratory analyses, we observed an interesting dose-dependent beneficial effect of treatment in patients with DWI lesions > 14-17 cm³., Conclusions: We conclude that G-CSF was well-tolerated even at high dosages in patients with acute ischemic stroke, and that a substantial increase in leukocytes appears not problematic in stroke patients. In addition, exploratory analyses suggest treatment effects in patients with larger baseline diffusion-weighted imaging lesions. The obtained data provide the basis for a second trial aimed to demonstrate safety and efficacy of G-CSF on clinical end points.

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.