Improvement In Neurological Outcome Research Articles

Neurological outcome of cardiac arrest patients in mountain areas: An analysis of the Northern French Alps Emergency Network

BackgroundMountainous areas pose a challenge for the out-of-hospital cardiac arrest (OHCA) chain of survival. Survival rates for OHCAs in mountainous areas may differ depending on the location. Increased survival has been observed compared to standard location when OHCA occurred on ski slopes. Limited data is available about OHCA in other mountainous areas. The objective was to compare the survival rates with a good neurological outcome of OHCAs occurring on ski slopes (On-S) and off the ski slopes (OffS) compared to other locations (OL). MethodsAnalysis of prospectively collected data from the cardiac arrest registry of the Northern French Alps Emergency Network (RENAU) from 2015 to 2021. The RENAU corresponding to an Emergency Medicine Network between all Emergency Medical Services and hospitals of 3 counties (Isère, Savoie, Haute-Savoie). The primary outcome was survival at 30 days with a Cerebral Performance Category scale (CPC) of 1 or 2 (1: Good Cerebral Performance, 2: Moderate Cerebral Disability). ResultsA total of 9589 OHCAs were included: 213 in the On-S group, 141 in the Off-S group, and 9235 in the OL group. Cardiac etiology was more common in On-S conditions (On-S: 68.9% vs OffS: 51.1% vs OL: 66.7%, p < 0.001), while Off-S cardiac arrests were more often due to traumatic circumstances (OffS: 39.7% vs On-S: 21.7% vs OL: 7.7%, p < 0.001). Automated external defibrillator (AED) use before rescuers' arrival was lower in the Off-S group than in the other two groups (On-S: 15.2% vs OL: 4.5% vs OffS: 3.7%; p < 0.002). The first AED shock was longer in the Off-S group (median time in minutes: OffS: 22.0 (9.5–35.5) vs On-S: 10.0 (3.0–19.5) vs OL: 16.0 (11.0–27.0), p = 0.03). In multivariate analysis, on-slope OHCA remained a positive factor for 30-day survival with a CPC score of 1 or 2 with a 1.96 adjusted odds ratio (95% confidence interval (CI), 1.02–3.75, p = 0.04), whereas off-slope OHCA had an 0.88 adjusted odds ratio (95% CI, 0.28–2.72, p = 0.82). ConclusionsOHCAs in ski-slopes conditions were associated with an improvement in neurological outcomes at 30 days, whereas off-slopes OHCAs were not. Ski-slopes rescue patrols are efficient in improving outcomes.

An updated systematic review of neuroprotective agents in the treatment of spinal cord injury.

This systematic review aims to summarize the findings from all clinical randomized trials assessing the efficacy of potential neuroprotective agents in influencing the outcomes of acute spinal cord injuries (SCI). Following the PRISMA guidelines, we conducted comprehensive searches in four electronic databases (PubMed, Scopus, Cochrane Library, and Web of Science) up to September 5th, 2023. Our analysis included a total of 30 studies. We examined the effects of 15 substances/drugs: methylprednisolone, tirilazad mesylate, erythropoietin, nimodipine, naloxone, Sygen, Rho protein antagonist, granulocyte colony-stimulating factor, autologous macrophages, autologous bone marrow cells, vitamin D, progesterone, riluzole, minocycline, and blood alcohol concentration. Notable improvements in neurological outcomes were observed with progesterone plus vitamin D and granulocyte colony-stimulating factor. In contrast, results for methylprednisolone, erythropoietin, Sygen, Rho Protein, and Riluzole were inconclusive, primarily due to insufficient sample size or outdated evidence. No significant differences were found in the remaining evaluated drugs. Progesterone plus vitamin D, granulocyte colony-stimulating factor, methylprednisolone, Sygen, Rho Protein, and Riluzole may enhance neurological outcomes in acute SCI cases. It is worth noting that different endpoints or additional subgroup analyses may potentially alter the conclusions of individual trials. Therefore, certain SCI grades may benefit more from these treatments than others, while the overall results may remain inconclusive.

GPR55 Inactivation Diminishes Splenic Responses and Improves Neurological Outcomes in the Mouse Ischemia/Reperfusion Stroke Model.

Although strokes are frequent and severe, treatment options are scarce. Plasminogen activators, the only FDA-approved agents for clot treatment (tissue plasminogen activators (tPAs)), are used in a limited patient group. Moreover, there are few approaches for handling the brain's inflammatory reactions to a stroke. The orphan G protein-coupled receptor 55 (GPR55)'s connection to inflammatory processes has been recently reported; however, its role in stroke remains to be discovered. Post-stroke neuroinflammation involves the central nervous system (CNS)'s resident microglia activation and the infiltration of leukocytes from circulation into the brain. Additionally, splenic responses have been shown to be detrimental to stroke recovery. While lymphocytes enter the brain in small numbers, they regularly emerge as a very influential leukocyte subset that causes secondary inflammatory cerebral damage. However, an understanding of how this limited lymphocyte presence profoundly impacts stroke outcomes remains largely unclear. In this study, a mouse model for transient middle cerebral artery occlusion (tMCAO) was used to mimic ischemia followed by a reperfusion (IS/R) stroke. GPR55 inactivation, with a potent GPR55-specific antagonist, ML-193, starting 6 h after tMCAO or the absence of the GPR55 in mice (GPR55 knock out (GPR55ko)) resulted in a reduced infarction volume, improved neurological outcomes, and decreased splenic responses. The inhibition of GPR55 with ML-193 diminished CD4+T-cell spleen egress and attenuated CD4+T-cell brain infiltration. Additionally, ML-193 treatment resulted in an augmented number of regulatory T cells (Tregs) in the brain post-tMCAO. Our report offers documentation and the functional evaluation of GPR55 in the brain-spleen axis and lays the foundation for refining therapeutics for patients after ischemic attacks.

Abstract WMP111: Intra-Arterial Administration of Cerebral Endothelial Cell Derived Small Extracellular Vesicles Reduces Neurovascular Damage and Improves Neurological Outcome After Acute Ischemia in the Aged Rat

Stroke is a leading cause of death and disability worldwide, mainly affecting the elderly. Endovascular thrombectomy (EVT) is a standard of care therapy for stroke patients with large-vessel occlusion, however, the majority of these patients do not achieve full functional improvement. The present study tested the hypothesis that intra-arterial (IA) administration of cerebral endothelial cell derived small extracellular vesicles (CEC-sEVs) following transient middle cerebral artery occlusion (tMCAO) improves stroke outcome in the aged rat. CEC-sEVs (1x10 11 particles/injection) isolated from healthy adult rats were employed. Male aged rats (18 months, n=10/group) subjected to 3h tMCAO were randomly divided into the experimental groups. To examine whether IA injection of CEC-sEVs improves stroke outcome, CEC-sEVs were administered via the internal carotid artery (ICA) immediately following reperfusion by withdrawal of the occlusion filament. To examine whether intravenous administration (IV) of CEC-sEVs during tMCAO and then followed by IA CEC-sEVs upon reperfusion further enhances stroke outcome, CEC-sEVs were given at 30 min of tMCAO via a tail vein and upon reperfusion via the ICA. The ischemic rats treated with IA saline were used as a control. Neurological outcome and infarct volume were assessed in a blinded manner. IA CEC-sEVs upon reperfusion significantly reduced infarct volume (24±5% vs 31±6% in saline, p&lt;0.05) which was associated with robust improvement of neurological function from weeks 2 to 4 after tMCAO compared to saline treated rats. Moreover, rats treated with CEC-sEVs IV at 30min followed by IA treatment upon reperfusion further reduced infarct volume (16±6%) compared to rats treated with IA saline or CEC-sEVs. These rats also exhibited robust and early improvement of neurological function starting at 1d after tMCAO. In conclusion, IA administration of CEC-sEVs upon reperfusion significantly reduces ischemic damage, while an additional early (30min post stroke) dose of IV CEC-sEVs further enhances and accelerates the therapeutic effect of IA CEC-sEVs in the aged rats after tMCAO. Our data suggest that CEC-sEVs could potentially may be a therapy to amplify the efficacy of EVT even for elderly patients with acute ischemic stroke.

Venous pathology targeted surgical management in Hirayama disease: A comprehensive case series of nine cases exploring this potential etiology.

Hirayama disease is a rare cause of cervical myelopathy predominantly affecting young individuals. The disease is classically characterized by muscle atrophy in the distal upper limbs. While various etiopathogenesis such as dural sac dysplasia, nerve root dysplasia, structural abnormalities of the spinal ligament, and venous dysplasia have been proposed, this study explores the potential role of venous pathology and surgical management on the basis of it. This is a prospective descriptive case series of nine cases. The diagnosis was made based on the Huashan diagnostic criteria which includes clinical manifestation, imaging, and electrophysiology. In cases where magnetic resonance imaging (MRI) failed to demonstrate engorged veins, a computed tomography (CT) venogram of the cervical spine was used as an imaging tool. All patients underwent cervical laminectomy and coagulation of the posterior epidural venous plexus with or without laminoplasty. All the patients were followed up regularly; clinical improvement and neck disability index were assessed. All nine patients were male and exhibited classical clinical features, electrophysiological abnormalities, and MRI findings except, in one patient where a CT venogram helped in establishing the diagnosis as the MRI was inconclusive. Postoperatively, all patients had neurological improvement and stabilization of the disease. All patients who underwent CT venogram and cervical spine X-ray in neutral and dynamic position demonstrated no recurrence of engorged venous plexus or significant instability except one patient developing kyphosis. One patient experiencing symptoms in the other limb underwent a second surgery. This comprehensive case series strongly supports venous pathology as a potential etiology of Hirayama disease. Surgical management with laminectomy and venous coagulation with or without expansile laminoplasty has delivered consistent improvement in neurological outcomes and long-term disease stabilization without the restriction of movements and lesser complications. However, further research is warranted to elucidate the mechanism underlying cervical venous dilatation.

Improved Neurological Outcome of Perampanel for Hypoxic-Ischemic Encephalopathy in Patients After Out-of-Hospital Cardiac Arrest Resuscitation.

Although the resuscitation rate for out-of-hospital cardiac arrest (OHCA) patients in Japan is increasing due to the widespread use of automated external defibrillators, the proportion of patients who can return to society remains low at approximately 7%. Many patients have poor neurological outcomes and cannot return to society because of post-resuscitation hypoxic-ischemic encephalopathy. While the resumption of cardiac rhythm is important for patients with OHCA, improving neurological outcomes and returning to society are also important. To investigate whether perampanel, an antiepileptic drug that provides neurological protection against stroke and head injury, could improve neurological outcomes in patients resuscitated after OHCA. The participants included 33 patients with OHCA admitted to our hospital from January 2021 to June 2022 and 33 patients admitted before that time. Perampanel was administered to the patients in the intervention group immediately after resuscitation. We defined aCerebral Performance Category (CPC) scoreof 1.2 as a good neurological outcome. There was no significant difference in neurological outcomes at intensive care unit discharge between the intervention and non-intervention groups (number of CPC 1.2: 16/33 vs. 9/33); however, neurological outcomes at hospital discharge were significantly better in the intervention group (number of CPC 1.2: 19/33 vs. 9/33 P = 0.01). The α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor inhibitory and neuronal protective effects of perampanel may have inhibited the progression of hypoxic-ischemic encephalopathy, which develops after the resumption of cardiac rhythm, and suppressed neuronal damage. Early administration of perampanel after resuscitation of patients with OHCA may improve neurological outcomes.

Code ICH: A Call to Action.

Intracerebral hemorrhage is the most serious type of stroke, leading to high rates of severe disability and mortality. Hematoma expansion is an independent predictor of poor functional outcome and is a compelling target for intervention. For decades, randomized trials aimed at decreasing hematoma expansion through single interventions have failed to meet their primary outcomes of statistically significant improvement in neurological outcomes. A wide range of evidence suggests that ultra-early bundled care, with multiple simultaneous interventions in the acute phase, offers the best hope of limiting hematoma expansion and improving functional recovery. Patients with intracerebral hemorrhage who fail to receive early aggressive care have worse outcomes, suggesting that an important treatment opportunity exists. This consensus statement puts forth a call to action to establish a protocol for Code ICH, similar to current strategies used for the management of acute ischemic stroke, through which early intervention, bundled care, and time-based metrics have substantially improved neurological outcomes. Based on current evidence, we advocate for the widespread adoption of an early bundle of care for patients with intracerebral hemorrhage focused on time-based metrics for blood pressure control and emergency reversal of anticoagulation, with the goal of optimizing the benefit of these already widely used interventions. We hope Code ICH will endure as a structural platform for continued innovation, standardization of best practices, and ongoing quality improvement for years to come.

Banaba Restricts Brain Damage: Neuroprotective Role in Cerebral Ischemiareperfusion Injury

Background:: Glucose regulation and energy homeostasis mitigate energy crises milieu in reperfusion injury. We investigated Banaba for its outcomes on cerebral ischemia reperfusion (IR) injury using artery occlusion in rats. The pleiotropic activity of Banaba on various debilitating mechanisms inducing reperfusion injury was evaluated. Aim:: This study aimedto evaluate the pharmacological activity of Banaba (Lagerstroemia speciosa) extract on reperfusion injury and investigate the effect of Banaba on vascular permeability, oxidative stress and cellular damage in ischemia reperfusion injury in rats. Methods:: Transient ischemia and reperfusion through occlusion of the middle cerebral artery (MCAO) lead to Cerebral IR injury in Wistar rats; it was treated with oral administration of Banaba extract (100mg/kg and 200mg/kg). The injury outcomes were evaluated after 22 hours of reperfusion by determining cellular injury, its impact on musculoskeletal coordination, multiple free radical scavenging measures (SOD, GSH, LPO) and vascular permeability of the blood-brain barrier. Result:: Banaba treatment led to a marked improvement in neurological outcomes by enhanced coordination and reduced cerebral infarct in comparison to vehicle control ischemic group. Free radical scavenging activity (SOD and GSH) was significantly better, and lipid peroxidation was reduced by Banaba treatment; it also reduced the vascular permeability of the blood-brain barrier. We observed that a lower dose of Banaba (100 mg/kg) was more effective than the higher (200 mg/kg) in ischemic rats. The anti-inflammatory and anti-oxidant activity could drive the neuroprotective outcomes of Banaba in cerebral IR injury. The critical factor of the beneficial effect of Banaba in cerebral injury is the optimization of dose in this experimental setup of reperfusion injury using rats. Conclusion:: The recovery of injury could be attributed to Banaba’s multi-factorial effect targeting free radicals, inflammation, and necrosis during ischemiareperfusion injury.

Comprehensive simulation training for E-CPR improves the 1-year mortality of patients with refractory cardiac arrest

Abstract Background Extracorporeal cardiopulmonary resuscitation (E-CPR) has been utilized as a rescue strategy for patients with refractory cardiac arrest (CA). The collapse to ECMO initiation time (CTET) has a strong correlation with survival, but decisions of initiating E-CPR are sometimes difficult to make and the opportunities for developing teamwork skills are limited. Therefore, to improve the outcome of E-CPR, we developed a comprehensive simulation-based E-CPR training program. Purpose In the present study we assessed whether the E-CPR training improved the mortality and the neurological outcome. Methods E-CPR simulation training program was carried out twice a year to the medical team using a mock vascular model since October 2017. We enrolled 177 consecutive patients who underwent E-CPR from January 2012 to January 2022. The patients were divided into two groups: the pre-simulation and the post-simulation. The outcome was CTET, 1-year mortality and favorable neurological outcomes defined as cerebral performance categories (CPC) of 1 or 2 at hospital discharge. Results There were 86 patients in the Pre-simulation group and 91 patients in the Post-simulation group. No differences were found in age, rates of witnessed CA and bystander-CPR, shockable rhythms, or acute coronary syndrome (ACS). The frequency of use of the intra-aortic balloon pump was significantly higher in the Pre-simulation group compared to the Post-simulation group (74% vs. 23%; p &amp;lt;0.001), while the Impella device was only used in the Post-simulation group (46%), due to its availability in our institution since October 2017. Compared to Pre-simulation group, the CTET was significantly shorter (44 minutes vs. 33 minutes; p = 0.001), and the Kaplan-Meier analysis for 1-year survival was significantly higher with the Post-simulation group (12% vs. 23%; p = 0.02 by log-rank test). The rate of favorable neurological outcome was not significantly different between the two groups. However, when patients were analyzed separately by in-hospital CA (IHCA) and out-of-hospital CA (OHCA), no significant difference was observed in IHCA, whereas OHCA demonstrated a significant reduction in both door to ECMO initiation time and CTET, leading to a significant improvement in neurological outcome (3% vs. 20%; p = 0.04). Multivariate cox proportional hazard analysis revealed that age (hazard ratio [HR], 1.22 [10 years increase]; 95% confidence interval [CI], 1.07-1.41, p = 0.004), initial shockable rhythm (HR, 0.61; 95%CI 0.41-0.91, p = 0.01), combined use of Impella (HR, 0.59; 95% CI, 0.37–0.98, p = 0.02), and CTET (HR, 1.02, 95%CI, 1.01-1.03, p &amp;lt;0.0001) were significantly associated with the 1-year mortality. Conclusions The E-CPR training significantly improved the collapse to ECMO time. The faster deployment of ECMO increased the 1-year survival rate in patients with refractory CA. Additionally, the use of Impella (ECPELLA) may have improved the survival rate.The effect of simulation trainingKaplan-Meier analysis

Abstract 111: Combination Therapy of Hydrogen Inhalation and Hypothermic Temperature Control Improves Neurological Outcomes After Out-of-Hospital Cardiac Arrest

Background: In a randomized trial, we demonstrated that hydrogen (H 2 ) inhalation improves outcomes after cardiac arrest (CA). All patients underwent target temperature management (TTM), but the selection of a target temperature between 32 and 36 °C varied per institutional protocol. Hypothesis: The combination of hypothermic TTM and H 2 improves neurological outcomes after CA. Aims: This study aimed to investigate the interaction of H 2 and hypothermic TTM on neurological outcomes after CA. Methods: This post-hoc analysis of a randomized controlled trial (HYBRID II Trial; jRCTs031180352) included comatose patients after cardiogenic out-of-hospital CA (OHCA). They received either 2% H 2 mixed oxygen (H 2 group) or oxygen alone (control group) for 18 hours under hypothermic TTM (&lt;35°C) or normothermic TTM (35-36°C). A target temperature was reached quickly, maintained for 24 hours, and rewarmed over 48 hours. A good neurological outcome was defined as a Cerebral Performance Category (CPC) of 1 or 2 at 90 days. The neurological outcomes were compared between the H 2 and control groups under hypothermic or normothermic TTM. Results: The analysis included 72 patients with outcome data (39 and 33 patients in the H 2 and control group, respectively). Hypothermic TTM was implemented in 25 (64%) and 24 (73%) patients in the H 2 and control group, respectively (P=0.46). Under hypothermic TTM, 17 (68%) and 9 (38%) patients achieved CPC 1 or 2 in the H 2 and control group, respectively (relative risk 1.81 [95%CI: 1.05-3.66]). In contrast, under normothermic TTM, CPC of 1 or 2 was achieved in 5 (36%) and 4 (44%) patients (P&gt;0.99) in the H 2 and control group, respectively. A multivariable logistic regression analysis indicated that the interaction between H 2 and hypothermic TTM was independently associated with CPC 1 or 2 at 90 days (adjusted odds ratio 3.71 [95%CI: 1.14-12.1]) after adjusting for confounding factors including age, sex, witness status, bystander CPR implementation, shockable rhythm, CA duration, and time from the return of spontaneous circulation to gas inhalation. Conclusions: H 2 in combination with hypothermic TTM improved neurologicaloutcomes after cardiogenic OHCA. However, the favorable effects of inhaled H 2 were not observed under normothermic TTM.

Does Initiation of Prophylactic Antiseizure Medication Improve Neurological Outcomes in Patients With Acute Intracerebral Hemorrhage?

Objective: The objective of this study was to critically assess current evidence regarding the role of prophylactic antiseizure medication in patients presenting with acute intracerebral hemorrhage (ICH). Methods: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom-line conclusions. Participants included resident neurologists, a medical librarian, and content experts in the fields of epilepsy, stroke neurology, neurohospitalist medicine, and neurocritical care. Results: A randomized clinical trial was selected for critical appraisal. The trial assessed whether prophylactic levetiracetam (LEV) use reduced the risk of acute seizures in patients with ICH, as defined by clinical or electrographic seizure, captured by continuous electroencephalogram 72 hours after enrollment. A total of 42 patients were included in the final analysis (19 in the LEV group and 23 in the placebo group). There was a significantly higher occurrence of seizures in the placebo versus LEV group (LEV 16% vs placebo 43%, P = 0.043). There were no differences in functional outcomes between the groups at 3, 6, or 12 months (P &gt; 0.1). Conclusions: The role of prophylactic treatment with antiseizure medication in ICH remains unclear.

Hypothermia is Associated with Improved Neurological Outcomes After Mechanical Thrombectomy

Acute ischemic stroke (AIS) is the second leading cause of death globally. Mechanical thrombectomy (MT) has improved patient prognosis but expedient treatment is still necessary to minimize anoxic injury. Lower intraoperative body temperature decreases cerebral oxygen demand, but the role of hypothermia in treatment of AIS with MT is unclear. We retrospectively reviewed patients undergoing MT for AIS from 2014 to 2020 at our institution. Patient demographics, comorbidities, intraoperative parameters, and outcomes were collected. Maximum body temperature was extracted from minute-by-minute anesthesia readings, and patients with maximal temperature below 36°C were considered hypothermic. Risk factors were assessed by χ2 and multivariate ordinal regression. Of 68 patients, 27 (40%) were hypothermic. There was no significant association of hypothermia with patient age, comorbidities, time since last known well, number of passes intraoperatively, favorable revascularization, tissue plasminogen activator use, and immediate postoperative complications. Hypothermic patients exhibited better neurologic outcome at 3-month follow-up (P= 0.02). On multivariate ordinal regression, lower maximum intraoperative body temperature was associated with improved 3-month outcomes (P < 0.001), when adjusting for other factors influencing neurological outcomes. Other significant protective factors included younger age (P= 0.03), better revascularization (P= 0.03), and conscious sedation (P= 0.02). Lower intraoperative body temperature during MT was independently associated with improved neurological outcome in this single center retrospective series. These results may help guide clinicians in employing therapeutic hypothermia during MT to improve long-term neurologic outcomes from AIS, although larger studies are needed.

Sex- and Age-Based Disparities in Public Access Defibrillation, Bystander Cardiopulmonary Resuscitation, and Neurological Outcome in Cardiac Arrest

ImportanceYounger females with out-of-hospital cardiac arrest (OHCA) in public locations have less likelihood to receive public access defibrillation and bystander cardiopulmonary resuscitation (CPR). However, the association between age- and sex-based disparities and neurological outcomes remains underexamined.ObjectiveTo investigate the association between sex and age and the rate of receiving bystander CPR, automated external defibrillator defibrillation, and neurological outcomes in patients with OHCA.Design, Setting, and ParticipantsThis cohort study used the All-Japan Utstein Registry, a prospective, population-based, nationwide database in Japan containing data on 1 930 273 patients with OHCA between January 1, 2005, and December 31, 2020. The cohort comprised patients with OHCA of cardiac origin that was witnessed by citizens and treated by emergency medical service personnel. The data were analyzed from September 3, 2022, to May 5, 2023.ExposureSex and age.Main Outcomes and MeasuresThe primary outcome was favorable neurological outcome at 30 days after an OHCA. Favorable neurological outcome was defined as a Cerebral Performance Category score of 1 (indicating good cerebral performance) or 2 (indicating moderate cerebral disability). The secondary outcomes were the rates of receiving public access defibrillation and bystander CPR.ResultsThe 354 409 included patients who experienced bystander-witnessed OHCA of cardiac origin had a median (IQR) age of 78 (67-86) years and 136 520 were females (38.5%). The rate of receiving public access defibrillation was higher in males than females (3.2% vs 1.5%; P &amp;amp;lt; .001). Stratified by age, age- and sex-based disparities in prehospital lifesaving interventions by bystanders and in neurological outcomes were observed. Although younger females had a lower rate of receiving public access defibrillation and bystander CPR than males, younger females had a higher favorable neurological outcome compared with males of the same age (odds ratio [OR], 1.19; 95% CI, 1.08-1.31). In younger females with OHCA that was witnessed by nonfamily bystanders, receiving public access defibrillation (OR, 3.51; 95% CI, 2.34-5.27) or bystander CPR (OR, 1.62; 95% CI, 1.20-2.22) was associated with a favorable neurological outcome.Conclusions and RelevanceResults of this study suggest a pattern of significant sex- and age-based differences in bystander CPR, public access defibrillation, and neurological outcomes in Japan. Improvement in neurological outcomes in patients with OHCA, especially younger females, was associated with increased use of public access defibrillation and bystander CPR.

Extremely Low-Frequency Electromagnetic Stimulation (ELF-EMS) Improves Neurological Outcome and Reduces Microglial Reactivity in a Rodent Model of Global Transient Stroke.

Extremely low-frequency electromagnetic stimulation (ELF-EMS) was demonstrated to be significantly beneficial in rodent models of permanent stroke. The mechanism involved enhanced cerebrovascular perfusion and endothelial cell nitric oxide production. However, the possible effect on the neuroinflammatory response and its efficacy in reperfusion stroke models remains unclear. To evaluate ELF-EMS effectiveness and possible immunomodulatory response, we studied neurological outcome, behavior, neuronal survival, and glial reactivity in a rodent model of global transient stroke treated with 13.5 mT/60 Hz. Next, we studied microglial cells migration and, in organotypic hippocampal brain slices, we assessed neuronal survival and microglia reactivity. ELF-EMS improved the neurological score and behavior in the ischemia-reperfusion model. It also improved neuronal survival and decreased glia reactivity in the hippocampus, with microglia showing the first signs of treatment effect. In vitro ELF-EMS decreased (Lipopolysaccharide) LPS and ATP-induced microglia migration in both scratch and transwell assay. Additionally, in hippocampal brain slices, reduced microglial reactivity, improved neuronal survival, and modulation of inflammation-related markers was observed. Our study is the first to show that an EMF treatment has a direct impact on microglial migration. Furthermore, ELF-EMS has beneficial effects in an ischemia/reperfusion model, which indicates that this treatment has clinical potential as a new treatment against ischemic stroke.

Meta-Analysis Comparing Hypothermia Versus Normothermia in Patients After a Cardiac Arrest

The current American Heart Association 2022 guidelines recommend actively preventing fever by targeting a temperature ≤37.5°C for comatose patients after cardiac arrest. Contemporary randomized controlled trials (RCTs) show conflicting results regarding the benefit of targeted hypothermia (TH). We performed this updated meta-analysis of RCTs to evaluate the role of hypothermia in patients after a cardiac arrest. We searched Cochrane, MEDLINE, and EMBASE from inception to December 2022. Trials with patients randomly allocated for targeted temperature monitoring and reported neurologic and mortality outcomes were included. Statistical analysis was performed using Cochrane Review Manager using the random-effects model and calculated the pooled risk ratios of outcomes using the Mantel-Haenszel method. A total of 12 RCTs and 4,262 patients were included in the review. Compared with normothermia, the TH group had significantly improved neurologic outcomes (risk ratio 0.90, 95% confidence interval 0.83 to 0.98). However, no significant difference in mortality was observed (risk ratio 0.97, 95% confidence interval 0.90 to 1.06) between the groups. This meta-analysis supports the role of TH in patients after a cardiac arrest, especially secondary to improvement in neurologic outcomes.

Intranasal Delivery of Gene-Edited Microglial Exosomes Improves Neurological Outcomes after Intracerebral Hemorrhage by Regulating Neuroinflammation

Neural inflammatory response is a crucial pathological change in intracerebral hemorrhage (ICH) which accelerates the formation of perihematomal edema and aggravates neural cell death. Although surgical and drug treatments for ICH have advanced rapidly in recent years, therapeutic strategies that target and control neuroinflammation are still limited. Exosomes are important carriers for information transfer among cells. They have also been regarded as a promising therapeutic tool in translational medicine, with low immunogenicity, high penetration through the blood-brain barrier, and ease of modification. In our previous research, we have found that exogenous administration of miRNA-124-overexpressed microglial exosomes (Exo-124) are effective in improving post-injury cognitive impairment. From this, we evaluated the potential therapeutic effects of miRNA-124-enriched microglial exosomes on the ICH mice in the present study. We found that the gene-edited exosomes could attenuate neuro-deficits and brain edema, improve blood-brain barrier integrity, and reduce neural cell death. Moreover, the protective effect of Exo-124 was abolished in mice depleted of Gr-1+ myeloid cells. It suggested that the exosomes exerted their functions by limiting the infiltration of leukocyte into the brain, thus controlling neuroinflammation following the onset of ICH. In conclusion, our findings provided a promising therapeutic strategy for improving neuroinflammation in ICH. It also opens a new avenue for intranasal delivery of exosome therapy using miRNA-edited microglial exosomes.

386 Stereotactic Implantation of Autologous Mesenchymal Stem Cells Improves Neurological Outcomes in a Rat Model of Chronic Middle Cerebral Artery Stroke

INTRODUCTION: Limited treatment options exist for patients with chronic infarcts. Multipotent adult mesenchymal stem cells (MSC) show promise as a treatment for chronic stroke. Allogeneic MSCs have been implanted successfully in chronic stroke1,2. However, no literature evaluates the use of autologous MSCs delivered via stereotactic implantation. Autologous MSCs provide safety and accessibility benefits. METHODS: Male Sprague-Dawley rats underwent transient right MCAO for 120 minutes. Brain MRI and sensorimotor behavior were used to evaluate stroke. Sixteen days post stroke, tibial bone marrow was aspirated and MSCs were grown in a closed bioreactor. At 28 days post stroke, 3 trajectories of MSCs were implanted in the peri-infarct zone using a stereotactic robot. The treatments consisted of group 1 (5 x 106 cell dose, N = 6), group 2 (1 x 106 cell dose, N = 6) and a control group (saline injection, N = 9). In a second cohort of animals, Q-dot labeled autologous MSCs were tracked in the brain for 7 or 30 days. RESULTS: Behavior as determined by the modified neurological severity score (0-16) significantly improved in both groups. Stroke volume did not decrease. Histological analysis confirmed increased astrocyte and microglia presence in the affected hemisphere. Quantum dot analysis of injections showed presence of MSCs along trajectory as well as targeting perilesional brain tissue at 7 and 30 days post-implantation. CONCLUSIONS: Stereotactic injection of autologous MSCs represent an effective treatment for chronic stroke. Cells were effective at the lowest dose studied, with no added benefit at higher cell dosages. Unlike allogeneic MSCs which disappear over days to weeks3, autologous MSCs persist long term in the brain, potentially providing continued benefit. This treatment warrants human trials to study its effectiveness.

Abstract WP217: Increase Of Exosome Uptake By Activated Neurons In The Peri-infarct Region Improves Neurological Outcomes After Stroke

Background: We hypothesized that an increase of exosome uptake by activated neurons in the peri-infarct region enhances functional outcome. We tested this hypothesis by administering exosomes derived from cerebral endothelial cells (CEC-exos) to ischemic rats in conjunction with whisker stimulation. Methods and Results: Male adult rats were subjected to a transient right middle cerebral artery occlusion (tMCAO). Neuronal activation in the barrel cortex of the peri-infarct region after left whisker stimulation was confirmed by c-fos positive neurons. CEC-exos at a dose of 1x10^11 particles/injection were administered (i.v.) to tMCAO rats 15 min after whisker stimulation at every other day for 2 consecutive weeks, starting 1 day after tMCAO. Ischemic rats treated with CEC-exos alone or whisker stimulation alone significantly (p&lt;0.05) improved sensorimotor functions (modified neurological severity scores, mNSS, 6±1 in CEC-exos or stimulation; foot-fault, FF, 11±1% in CEC-exos, 14±1% in stimulation) compared to ischemic rats treated with PBS (mNSS, 10±1; FF, 25±2%, n=7/group). However, combination of whisker stimulation with CEC-exos resulted in a super-additive (p&lt;0.05) effect to improve sensorimotor functions (mNSS, 3±1, FF, 6±1%, p&lt;0.05, n=7) compared to the monotherapies. Confocal microscopic analysis showed that stimulation significantly (p&lt;0.05) increased neuronal uptake of CEC-exos (21±3 vs 3±1 exosomes/cell in CEC-exos alone, n=200 neurons/group), which was associated with significant (p&lt;0.05) reduction of axonal inhibitory protein Sema6a in axons of activated neurons (relative levels 0.11±0.02 vs 0.31±0.07 in CEC-exos alone, n=3) . Increased neuronal uptake of CEC-exos was further confirmed at the ultra-structural level. Conclusion: Activated neurons in the peri-infarct areas preferentially increase uptake of CEC-exos, which contributes to significantly enhanced and robust improvement of neurological outcome during stroke recovery.

529: SOVATELTIDE (TYCAMZZI) IN PATIENTS WITH CEREBRAL ISCHEMIC STROKE: A RANDOMIZED MULTICENTER STUDY

Introduction: Sovateltide (Tycamzzi™) is a novel first-in-class ETB receptor agonist and a synthetic analog of endothelin-1, which promotes neuroprotection, neuroregeneration, and neurovascular remodeling following CNS damage. Methods: A phase III, prospective, multicentric, randomized study was conducted in acute cerebral ischemic stroke (ACIS) patients 18 through 78 years of age. Following radiologic confirmation of ischemic stroke, patients could be enrolled with NIHSS score greater than 5. Excluded were patients with intracranial hemorrhage and those receiving endovascular therapy. Sovateltide was administered in three doses, each dose of 0.3 μg/kg, as an intravenous bolus at an interval of 3 hours ± 1 hour on day 1, day 3, and day 6 (total dose/day: 0.9 µg/kg). The primary objectives were to determine the neurological outcome based on the modified Rankin Scale (mRS) score, National Institute of Health Stroke Scale (NIHSS) score, and Barthel Index (BI) scale score from day 1 through day 90. Results: A significantly (p=0.004) greater number of patients in the sovateltide group (76.1%) had an improvement of mRS of ≥2 points from the baseline compared to the control group (52.8%) at 90 days of treatment. The scores on the mRS at 90 days show an ordinal shift that highly favors sovateltide therapy (56% in control vs. 81% in sovateltide shift in mRS range 0-2). The median score (IQR) of the NIHSS scale at 90 days was 3 (0 to 6) in the control and 1 (0 to 3) in the sovateltide group (p=0.003). An improvement of NIHSS of ≥6 points vs. baseline at 90 days of treatment was significant (p=0.033) in sovateltide (80.6%) compared to the control (64.2%) group. The median score (IQR) of the BI scale at 90 days was 85 (60 to 100) in control and 95 (80 to 100) in the sovateltide group (p=0.01). The number needed to treat (NNT) patients (having mRS of 2 or less at 90 days) with sovateltide was 5 (95% CI 2.6 to 12.2). All-cause mortality was 2.56% in the control and 5.00% in the sovateltide group. Conclusions: Sovateltide demonstrated a statistically significant and clinically meaningful improvement in neurological outcomes in patients with ACIS compared to the standard of care. In addition, sovateltide produced a remarkable ordinal shift in the mRS across the range at day 90 post-randomization.

Abstract 12070: Post-Cardiac Arrest Sedation Modulates Electroencephalographic Slow-Wave Activity and Promotes Neurological Recovery in a Mouse Model of Cardiac Arrest

Introduction: The majority of patients resuscitated from cardiac arrest (CA) present in coma or with an altered level of consciousness. Although CA survivors are routinely sedated during targeted temperature management, the effects of sedation on CA outcomes remain to be determined. Hypothesis: Post-CA sedation would modulate cerebral physiology and improve neurological outcomes in mice. Methods: Adult C57BL/6J mice of both sexes were subjected to potassium chloride-induced CA and thereafter resuscitated with manual chest compression. Starting at return of spontaneous circulation (ROSC) or at 60 minutes after ROSC, mice received intravenous infusion of propofol at 40 mg · kg -1 · h -1 , dexmedetomidine at 1 μg · kg -1 · h -1 , or normal saline for 2 hours. Body temperature was lowered and maintained at 33°C during sedation. Cerebral blood flow was measured for 4 hours after ROSC. Telemetric electroencephalogram (EEG) was recorded in freely moving mice from 3 days before up to 7 days after CA. Results: Sedation with propofol or dexmedetomidine starting at ROSC attenuated brain injury and improved survival in hypothermia-treated post-CA mice (propofol [13/16] vs. no sedation [4/16], P = 0.008; dexmedetomidine [14/16] vs. no sedation [4/16], P = 0.002). Mice that were not sedated after ROSC exhibited cerebral hyperemia immediately after resuscitation and EEG power in all frequency bands remained less than 20% of the baseline in the first 4 hours after ROSC. Administration of propofol or dexmedetomidine starting at ROSC attenuated cerebral hyperemia and induced slow-wave (0.5-4 Hz) EEG activity that reached near baseline levels during and early after sedation. Increased EEG activity within 6 hours after ROSC was associated with improvement in neurological outcomes at 24 hours post-CA. In contrast, delayed sedation starting at 60 minutes after ROSC failed to improve outcomes, without attenuating cerebral hyperemia and inducing slow-wave EEG activity. Conclusions: Post-CA sedation with propofol or dexmedetomidine improved neurological outcomes and survival in mice resuscitated from CA and treated with hypothermia. The beneficial effects of sedation were accompanied by attenuation of the cerebral hyperemic response and induction of EEG slow-wave activity.