Improvement In Neurological Outcome Research Articles

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<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<0.05) effect to improve sensorimotor functions (mNSS, 3±1, FF, 6±1%, p<0.05, n=7) compared to the monotherapies. Confocal microscopic analysis showed that stimulation significantly (p<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<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.

Abstract 191: Alcohol Consumption Before Injury Did Not Improve Neurological Outcomes In Patients With Severe Traumatic Brain Injury: A Nationwide, Retrospective Cohort Study

Introduction: Traumatic brain injury (TBI) is a major global public health concern. Notably, alcohol may confer neuroprotective effects by inhibiting of N-methyl-D-aspartate receptors; however, the impact of alcohol exposure before injury on neurological outcomes in patients with TBI has not been well studied. Hypothesis: We evaluated whether alcohol consumption before injury was associated with favorable neurological outcomes in patients with severe TBI using a large, national trauma registry. Methods: This study was a retrospective analysis of data collected into the Japan Trauma Data Bank from 2017 to 2021. Patients over 20 years old with severe TBI, defined as head Abbreviated Injury Scale score of 4 or 5, were included. We excluded patients with unknown alcohol status or outcomes. Subjects were divided into two groups (alcohol group vs. non-alcohol group) based on whether or not they were exposed to alcohol before injury. The primary outcome was favorable neurological outcomes (Glasgow Outcome Scale score of 4 or 5) at hospital discharge. A multivariate logistic regression analysis was conducted to adjust potential cofounders including age, sex, injury severity, emergency treatment, and emergency transfusion. Results: A total of 1,482 patients were included, with a median age of 73 years old; 381 of the patients were women. Median Injury Severity Score was 24. Of the 1,482 patients, 284 were in the alcohol group and 1,208 were in the non-alcohol group. Favorable neurological outcomes were observed in 159 (56%) and 563 (47%) of patients, with median hospital length of stay of 21 days and 18 days in the alcohol group and non-alcohol group, respectively. Multivariate logistic regression analysis showed alcohol consumption before injury was not associated with favorable neurological outcomes (adjusted OR: 0.96, 95% CI: 0.72 - 1.29). Conclusions: Alcohol consumption before injury had no positive impact on neurological outcomes in patients with severe TBI.

Inhaled Carbon Dioxide Improves Neurological Outcomes by Downregulating Hippocampal Autophagy and Apoptosis in an Asphyxia-Induced Cardiac Arrest and Resuscitation Rat Model.

Background Protracted cerebral hypoperfusion following cardiac arrest (CA) may cause poor neurological recovery. We hypothesized that inhaled carbon dioxide (CO2) could augment cerebral blood flow (CBF) and improve post-CA neurological outcomes. Methods and Results After 6-minute asphyxia-induced CA and resuscitation, Wistar rats were randomly allocated to 4 groups (n=25/group) and administered with different inhaled CO2 concentrations, including control (0% CO2), 4% CO2, 8% CO2, and 12% CO2. Invasive monitoring was maintained for 120 minutes, and neurological outcomes were evaluated with neurological function score at 24 hours post-CA. After the 120-minute experiment, CBF was 242.3% (median; interquartile range, 221.1%-267.4%) of baseline in the 12% CO2 group while CBF fell to 45.8% (interquartile range, 41.2%-58.1%) of baseline in the control group (P<0.001). CBF increased along with increasing inhaled CO2 concentrations with significant linear trends (P<0.001). At 24 hours post-CA, compared with the control group (neurological function score, 9 [interquartile range, 8-9]), neurological recovery was significantly better in the 12% CO2 group (neurological function score, 10 [interquartile range, 9.8-10]) (P<0.001) while no survival difference was observed. Brain tissue malondialdehyde (P=0.02) and serum neuron-specific enolase (P=0.002) and S100β levels (P=0.002) were significantly lower in the 12% CO2 group. TUNEL (terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine triphosphate nick-end labeling)-positive cell densities in hippocampal CA1 (P<0.001) and CA3 (P<0.001) regions were also significantly reduced in the 12% CO2 group. Western blotting showed that beclin-1 (P=0.02), p62 (P=0.02), and LAMP2 (lysosome-associated membrane protein 2) (P=0.01) expression levels, and the LC3B-II:LC3B-I ratio (P=0.02) were significantly lower in the 12% CO2 group. Conclusions Administering inhaled CO2 augmented post-CA CBF, mitigated oxidative brain injuries, ameliorated neuronal injury, and downregulated apoptosis and autophagy, thereby improving neurological outcomes.

Early Treatment with Metformin Improves Neurological Outcomes in Lafora Disease.

Lafora disease is a fatal form of progressive myoclonic epilepsy caused by mutations in the EPM2A or NHLRC1/EPM2B genes that usually appears during adolescence. The Epm2a-/- and Epm2b-/- knock-out mouse models of the disease develop behavioral and neurological alterations similar to those observed in patients. The aim of this work is to analyze whether early treatment with metformin (from conception to adulthood) ameliorates the formation of Lafora bodies and improves the behavioral and neurological outcomes observed with late treatment (during 2months at 10months of age). We also evaluated the benefits of metformin in patients with Lafora disease. To assess neurological improvements due to metformin administration in the two mouse models, we evaluated the effects on pentylenetetrazol sensitivity, posturing, motor coordination and activity, and memory. We also analyzed the effects on Lafora bodies, neurodegeneration, and astrogliosis. Furthermore, we conducted a follow-up study of an initial cohort of 18 patients with Lafora disease, 8 treated with metformin and 10 untreated. Our results indicate that early metformin was more effective than late metformin in Lafora disease mouse models improving neurological alterations of both models such as neuronal hyperexcitability, motor and memory alterations, neurodegeneration, and astrogliosis and decreasing the formation of Lafora bodies. Moreover, patients receiving metformin had a slower progression of the disease. Overall, early treatment improves the outcome seen with late metformin treatment in the two knock-out mouse models of Lafora disease. Metformin-treated patients exhibited an ameliorated course of the disease with slower deterioration of their daily living activities.

Associations of cephalad drainage in neonatal veno-venous ECMO – A mixed-effects, propensity score adjusted retrospective analysis of 20 years of ELSO data

BackgroundNeurologic complications can occur during neonatal Veno-Venous (VV) ECMO. The addition of a cephalad drainage cannula (i.e., VVDL+V) to dual lumen cannulation (i.e., VVDL) has been advocated to reduce such complications, but previous studies have presented mixed results. MethodsData from the ECMO Registry of the Extracorporeal Life Support Organization was used to extract all neonates (≤28 days old) who underwent VV ECMO for respiratory support between 2000 and 2019. Primary outcomes were mortality, conversion to Veno-Arterial (VA) ECMO, pump flows, and complications. A mixed-effects, propensity score adjusted analysis was performed. Results4,275 neonates underwent VV ECMO, 581 (13.6%) via VVDL+V cannulation, and 3,694 (86.4%) via VVDL. On unadjusted analyses, VVDL+V patients had higher rates of mortality (25.5% vs 19.0%, p<0.001), conversion to VA ECMO (14.5% vs 4.1%, p<0.001), and higher pump flows at 4 h from ECMO initiation (112.7 vs 105.5 mL/Kg/min, p<0.001), but lower at 24 h (100.3 vs 104.0 mL/Kg/min, p = 0.004), and a higher proportion of them experienced hemorrhagic (29.3% vs 18.3%, p<0.001), cardiovascular (60.8% vs 45.8%, p<0.001), and mechanical (42.5% vs 32.6%, p<0.001) complications compared to VVDL patients. After adjusting for propensity scores and the multi-level nature of ELSO data, there were no differences in neurologic outcomes, pump flows, or mortality. Rather, VVDL+V cannulation was associated with higher rates of conversion to VA ECMO (adjusted odds ratio [AOR] 43.3, 95% CI 24.3 – 77.4, p<0.001), and increased mechanical (AOR 2.2, 95% CI 1.6 – 3.0, p<0.001) and hemorrhagic (AOR 2.0, 95% CI 1.4 – 3.0, p<0.001) complications. ConclusionsIn this analysis, VVDL+V cannulation was not associated with any improvement in neurologic outcomes, pump flows, or mortality, but was rather associated with higher rates of conversion to Veno-Arterial ECMO, mechanical, and hemorrhagic complications.

Implementation of an Evidence-Based Prenotification Process for Patients With Stroke to Improve Neurological Outcomes.

BACKGROUND: Endovascular mechanical thrombectomy can improve clinical outcomes in eligible patients with acute ischemic stroke (AIS), but its efficacy is time dependent. This quality improvement project aimed to examine whether a revised evidence-based neurological deficit algorithm initiated in the emergency department could reduce door-to-groin puncture time to less than 90 minutes and improve neurological outcomes in AIS patients who received mechanical thrombectomy. METHODS: Retrospective chart reviews occurred between September 2020 and April 2021, which included 25 patients. Clinical and time data were collected from AIS patients who were 18 years and older, presented for care with AIS symptoms, and deemed candidates for thrombectomy for a period of 6 months. A revised neurological deficit algorithm was initiated, and education was presented to appropriate staff. Postintervention chart reviews occurred from August 2021 to January 2022, which included 25 patients. RESULTS: Door-to-groin puncture time did not improve to less than 90 minutes; however, there was a slight improvement in time from 106 minutes in the preintervention to 98 minutes in the postintervention ( P = .534). Although the outcome measures were not clinically significant, there was a statistically significant decrease in response time to acute stroke call down ( P < .01). Door-to-computed tomography also improved, which was 14.42 minutes for the preintervention group and 5.25 minutes for the postintervention group ( P < .001). Finally, the mean National Institutes of Health Stroke Scale on discharge for the preintervention group was 11.92, and that of the postintervention group was 6.05 on discharge ( P < .01). CONCLUSIONS: Implementation of the revised neurological deficit algorithm did not decrease the door-to-groin puncture time to less than 90 minutes. After implementation of the revised neurologic deficit algorithm, there were single variable improvements in several benchmarks, and this is a starting point for future quality improvement projects.

A Systematic Review with Meta-Analysis Investigating the Impact of Targeted Perfusion Parameters during Extracorporeal Cardiopulmonary Resuscitation in Out-of-Hospital and Inhospital Cardiac Arrest.

Evidence regarding perfusion conditions during extracorporeal cardiopulmonary resuscitation (ECPR) is rare. Therefore, we investigated the impact of perfusion parameters on neurologic outcome and survival in patients with in- or out-of-hospital cardiac arrest (IHCA; OHCA) treated with ECPR. We performed a systematic review with meta-analysis. The focus was set on perfusion parameters and their impact on survival and a goal neurological outcome using the cerebral performance category score of 1-2. We conducted random- and mixed-effects meta-analyses and computed pooled estimates and 95% confidence intervals (CI). We included a total of n = 1,282 ECPR (100%) patients from 20 ECPR studies. The target values of flow and mean arterial pressure (MAP) were frequently available. We transferred flow and MAP target values to high, medium, and low categories. The meta-analysis could not demonstrate a single effect of flow or MAP on outcome variables. In a second mixed-effects model, the combined occurrence of targeted flow and MAP as medium and high showed a significant effect on survival (OHCA: 52%, 95% CI: 29%, 74%; IHCA: 60%, 95% CI: 35%, 85%) and on neurological outcomes (OHCA: 53%, 95% CI: 27%, 78%; IHCA: 62%, 95% CI: 38%, 86%). Random-effects analysis showed also that IHCA led to a significant 11% (p = 0.006; 95% CI: 3%, 18%) improvement in survival and 12% (p = .005; 95% CI: 4%, 21%) improvement in neurological outcomes compared to OHCA. A combination of medium flow and high MAP showed advantages in survival and for neurological outcomes. We also identified improved outcomes for IHCA.

A Systematic Review with Meta-Analysis Investigating the Impact of Targeted Perfusion Parameters during Extracorporeal Cardiopulmonary Resuscitation in Out-of-Hospital and Inhospital Cardiac Arrest

Evidence regarding perfusion conditions during extracorporeal cardiopulmonary resuscitation (ECPR) is rare. Therefore, we investigated the impact of perfusion parameters on neurologic outcome and survival in patients with in- or out-of-hospital cardiac arrest (IHCA; OHCA) treated with ECPR. We performed a systematic review with meta-analysis. The focus was set on perfusion parameters and their impact on survival and a goal neurological outcome using the cerebral performance category score of 1–2. We conducted random- and mixed-effects meta-analyses and computed pooled estimates and 95% confidence intervals (CI). We included a total of n = 1,282 ECPR (100%) patients from 20 ECPR studies. The target values of flow and mean arterial pressure (MAP) were frequently available. We transferred flow and MAP target values to high, medium, and low categories. The meta-analysis could not demonstrate a single effect of flow or MAP on outcome variables. In a second mixed-effects model, the combined occurrence of targeted flow and MAP as medium and high showed a significant effect on survival (OHCA: 52%, 95% CI: 29%, 74%; IHCA: 60%, 95% CI: 35%, 85%) and on neurological outcomes (OHCA: 53%, 95% CI: 27%, 78%; IHCA: 62%, 95% CI: 38%, 86%). Random-effects analysis showed also that IHCA led to a significant 11% (p = 0.006; 95% CI: 3%, 18%) improvement in survival and 12% (p = .005; 95% CI: 4%, 21%) improvement in neurological outcomes compared to OHCA. A combination of medium flow and high MAP showed advantages in survival and for neurological outcomes. We also identified improved outcomes for IHCA.

167. Neurologic outcomes of adult spinal deformity patients with baseline preoperative lower extremity weakness: will they improve following surgery?

<h3>BACKGROUND CONTEXT</h3> Adult spinal deformity (ASD) patients undergoing surgery risk neurological decline following surgery. However, surgery may be the key in improving outcomes in patients starting with lower extremity motor deficits at baseline (BL). We aim to analyze the improvement in neurological outcomes of ASD patients undergoing spinal reconstruction with BL and 6-week postoperative lower extremity motor scores (LEMS). <h3>PURPOSE</h3> The aim of this study is to analyze the improvement in neurological outcomes of adult patients undergoing deformity surgery with baseline abnormal LEMS. <h3>STUDY DESIGN/SETTING</h3> Multicenter, prospective cohort. <h3>PATIENT SAMPLE</h3> A total of 205 patients were included in the study. <h3>OUTCOME MEASURES</h3> Patient and procedural factors that lead to the improvement in neurological outcomes of adult patients undergoing deformity surgery with baseline abnormalLEMS. <h3>METHODS</h3> ASD patients ages = 18 were prospectively studied from 2018-2021. All patients underwent an instrumented PSF with a few also having an ASF of the lumbar spine. Patients were dichotomized based on BL LEMS (NML = 50, ABML < 50). The ABNML group was then dichotomized based on whether LEMS improved overall from BL or experienced no change or declined by first postoperative follow-up (PO) and various factors were analyzed and compared using standard statistical tests. <h3>RESULTS</h3> Of the 205 patients evaluated, 134 (65.4%) were NML and 71 were ABNML (34.3%) at BL. Among the 71 patients with ABML LEMS at BL, 49% (N=35) improved to NML levels, 21% (N=15) improved from BL levels but not to NML, 20% (N=14) remained the same, and 10% (N=7) declined further at 6week PO. Compared to ABNML patients with no change or a decline in LEMS at first PO, patients who improved overall (70%; N=50) had significantly more decompressions performed (86% vs 57%; p=0.0092), and had more PCOs performed intraoperatively (90% vs 62%, p=0.0074). There were no statistical differences between the groups in age, BL LEMS, BMI, total instrumented vertebrae (TIV), EBL, and OR time. Overall, the number of patients with NML LEMS at 6 weeks PO increased by 7.5% (65.4% to 70.2%; p<.0001). <h3>CONCLUSIONS</h3> Seventy percent of patients with ABML LEMS at BL improved their motor strength by the first PO visit, while 30% stayed the same or declined. ABNML patients who improved from BL had significantly more decompressions performed and, surprisingly, more PCOs performed. Interestingly, patient factors between the two groups demonstrated no statistical differences further highlighting that improvement may be influenced by the differences in surgical techniques. <h3>FDA DEVICE/DRUG STATUS</h3> This abstract does not discuss or include any applicable devices or drugs.

Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats.

Ketone bodies including β-hydroxybutyrate (β-HB) have been proved the therapeutic potential in diverse neurological disorders. However, the role of β-HB in the regulation of neurological injury after cardiac arrest (CA) remains unclear. We investigated the effect of β-HB on brain mitochondrial dysfunction and neurological function after CA. A rat model of CA was established by asphyxia. The rats were randomly divided into three groups: sham group, control group, and β-HB group. Animals received 200 mg/kg β-HB or same volume vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Neurological function was evaluated by neurologic deficit score and Y-maze. Neuronal cell loss and apoptosis were detected through hematoxylin-eosin staining, Nissl staining, and TdT-mediated dUTP nick-end labeling assay. Oxidative stress levels were determined by immunohistochemical staining of 4-hydoxynonenal and 8-hydroxy-2′-deoxyguanosine. Furthermore, mitochondrial ultrastructure of brain cells was observed by transmission electron microscopy. In addition, the protein expression levels of Bak, caspase 3, gasdermin D, caspase 1, brain-derived neurotrophic factor, dynamin-related protein 1 (Drp1), and phospho-Drp1 (ser616) were measured. We found that neurological function and survival rate were significantly higher in the β-HB group compared with the control group. β-HB also reduced neurons death and neurological oxidative stress after CA. Moreover, β-HB reduced neurological injury from apoptosis and pyroptosis after CA. In addition, β-HB maintained the structural integrity of brain mitochondria, prevented mitochondrial fission, and increased brain energy metabolism after CA. In conclusion, β-HB beneficially affected the neurological function of rats after global cerebral ischemia, associated with decreased mitochondrial fission, and improved mitochondrial function. Our results suggest that β-HB might benefit patients suffering from neurological dysfunction after CA.

Protocol for a Multicenter, Prospective, Observational Pilot Study on the Implementation of Resource-Stratified Algorithms for the Treatment of Severe Traumatic Brain Injury Across Four Treatment Phases: Prehospital, Emergency Department, Neurosurgery, and Intensive Care Unit.

BACKGROUND:Severe traumatic brain injury (sTBI) is a public health issue with great disparity among low- and middle-income countries where the implementation of evidence-based guidelines is challenging because resources are often unavailable. A consensus process including experts in the prehospital, emergency department, neurosurgery, and intensive care unit took place in Colombia to develop a set of stratified protocols called BOOTStraP, targeting resource-poor environments, but it has not been systematically implemented and tested.OBJECTIVE:To identify the facilitators of, and barriers to, collecting data about patients with sTBI and to implement a stratified protocol across the treatment phases of prehospital, emergency department, neurosurgery, and intensive care unit in low-resource settings. We also aim to identify a possible association between adherence to these protocols and outcomes for these patients.METHODS:A prospective, observational, before and after, pilot study will be performed in three phases as follows: before implementation, implementation, and after implementation. The BOOTStraP protocols will be implemented in three Colombian centers.EXPECTED OUTCOMES:We expect to find numerous barriers during the implementation phase. We also expect moderate adherence to the protocols. However, we expect to find an increase in the survival rate to hospital discharge and an improvement in neurological outcomes at discharge.DISCUSSION:This pilot study will serve as a first step to identify variables that are critical to successful implementation, to be considered for the design of a future large-scale international study to measure the effectiveness of resource-based protocols and to improve outcomes from sTBI.

Awake Mapping With Transopercular Approach in Right Insular-Centered Low-Grade Gliomas Improves Neurological Outcomes and Return to Work.

Asleep vs awake surgery for right insula-centered low-grade glioma (LGG) is still debated. To compare neurological outcomes and return to work after resection for right insular/paralimbic LGG performed without vs with awake mapping. A personal surgical experience of right insula-centered LGG was analyzed, by comparing 2 consecutive periods. In the first period (group 1), patients underwent asleep surgery with motor mapping. In the second period (group 2), patients underwent intraoperative awake mapping of movement and cognitive functions. This consecutive series included 143 LGGs: 41 in group 1 (1999-2009) and 102 in group 2 (2009-2020). There were no significant difference concerning preoperative clinicoradiological characteristics and histopathology results between both groups. Intraoperative motor mapping was positive in all cases in group 1. In group 2, beyond motor mapping, somatosensory, visuospatial, language, and/or cognitive functions were identified during cortical-subcortical stimulation. Postoperatively, 3 patients experienced a long-lasting deterioration with 2 hemiparesis due to deep stroke (1.3%) and 1 severe depressive syndrome, all of them in group 1 vs none in group 2 (P = .022). The rate of RTW was 81.5% in group 1 vs 95.5% in group 2 (P = .016). The tumor volume and extent of resection did not significantly differ across both groups. This is the first study comparing asleep vs awake surgery for right insula-centered LGG. Despite similar extent of resection, functional outcomes were significantly better in awake patients by avoiding permanent neurological impairment and by increasing RTW. These results support the mapping of higher-order functions during awake procedure.

Healthy Serum-Derived Exosomes Improve Neurological Outcomes and Protect Blood-Brain Barrier by Inhibiting Endothelial Cell Apoptosis and Reversing Autophagy-Mediated Tight Junction Protein Reduction in Rat Stroke Model.

Blood–brain barrier (BBB) dysfunction causing edema and hemorrhagic transformation is one of the pathophysiological characteristics of stroke. Protection of BBB integrity has shown great potential in improving stroke outcome. Here, we assessed the efficacy of exosomes extracted from healthy rat serum in protection against ischemic stroke in vivo and in vitro. Exosomes were isolated by gradient centrifugation and ultracentrifugation and exosomes were characterized by transmission electron microscopy (TEM) and nanoparticle tracking video microscope. Exosomes were applied to middle cerebral artery occlusion (MCAO) rats or brain microvascular endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD) injury. Serum-derived exosomes were injected intravenously into adult male rats 2 h after transient MCAO. Infarct volume and gross cognitive function were assessed 24 h after reperfusion. Poststroke rats treated with serum-derived exosomes exhibited significantly reduced infarct volumes and enhanced neurological function. Apoptosis was assessed via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining and the expression of B-cell lymphoma-2 (Bcl-2), Bax, and cleaved caspase-3 24 h after injury. Our data showed that serum exosomes treatment strikingly decreased TUNEL+ cells in the striatum, enhanced the ratio of Bcl-2 to Bax, and inhibited cleaved caspase-3 production in MCAO rats and OGD/reoxygenation insulted bEnd.3 cells. Under the consistent treatment, the expression of microtubule-associated protein 1 light chain 3B-II (LC3B-II), LC3B-I, and Sequestosome-1 (SQSTM1)/p62 was detected by Western blotting. Autolysosomes were observed via TEM. We found that serum exosomes reversed the ratio of LC3B-II to LC3B-I, prevented SQSTM1/p62 degradation, autolysosome formation, and autophagic flux. Together, these results indicated that exosomes isolated from healthy serum provided neuroprotection against experimental stroke partially via inhibition of endothelial cell apoptosis and autophagy-mediated BBB breakdown. Intravenous serum-derived exosome treatment may, therefore, provide a novel clinical therapeutic strategy for ischemic stroke.

Ultra-early Spinal Decompression Surgery Can Improve Neurological Outcome of Complete Cervical Spinal Cord Injury; a Systematic Review and Meta-analysis.

Introduction:Early decompression within the first 24 hours after spinal cord injury (SCI) is proposed in current guidelines. However, the possible benefits of earlier decompression are unclear. Thus, the present meta-analysis aims to investigate the existing evidence regarding the efficacy of ultra-early decompression surgery (within 12 hours after SCI) in improving patients’ neurological status.Methods:A search was performed in Medline, Embase, Scopus and Web of Science electronic databases, until the end of August 2021. Cohort studies and clinical trials were included in the present study. Exclusion criteria were absence of an early or late surgery group, failure to report neurological status based on the American spinal injury association impairment scale (AIS) grade, failure to perform the surgery within the first 12 hours after SCI, and duplicate reports and review articles. Two independent reviewers performed data collection, and risk of bias and certainty of evidence assessments. The outcome was reported as odds ratio (OR) and 95% confidence interval (CI).Results:Data from 16 articles, which studied 868 patients, were included. Compared to early or late decompression surgery, ultra-early decompression surgery significantly improves patients’ neurological status (OR = 2.25; 95% CI: 1.41 to 3.58). However, ultra-early surgery in thoracolumbar injuries is not significantly more effective than early to late surgery. Moreover, ultra-early surgery in patients with a baseline AIS A increases the chance of neurologic resolvent up to 3.86 folds (OR=3.86; 95% CI: 1.50 to 9.91). Contrastingly, ultra-early surgery does not result in significant improvement compared to early to late surgery in patients with AIS B (OR = 1.32; 95% CI: 0.51 to 3.45), AIS C (OR = 1.83; 95% CI: 0.72 to 4.64), and AIS D (OR = 0.99; 95% CI: 0.31 to 3.17).Conclusion:Current guidelines emphasize that spinal decompression should be performed within 24 hours after SCI, regardless of injury severity and location. However, results of the present study demonstrated that certain considerations may be taken into account when performing decompression surgery: 1) in patients with AIS A injury, decompression surgery should be performed as soon as possible, since its efficacy in neurological improvement is 3.86 folds higher in the first 12 hours after injury. 2) ultra-early decompression surgery in patients with cervical injury is more effective than in patients with thoracic or lumbar injuries. 3) postponing decompression surgery to 24 hours in SCI patients with AIS B to D does not significantly affect the neurological outcome.

Контрольована нормотермія в пацієнтів у критичному стані з травматичним ушкодженням головного мозку

Актуальність. Гіпертермія викликає церебральне пошкодження в результаті реалізації трьох механізмів: клітинних, місцевих і системних ефектів. Метою даного дослідження були вивчення ефективності контро­льованої нормотермії в комплексі інтенсивної терапії пацієнтів із черепно-мозковою травмою, ускладненою розвитком гіпертермії центрального генезу, рефрактерної до фармакологічної терапії, оцінка її впливу на швидкість неврологічного відновлення і рівень летальності. Матеріали та методи. Обстежено 60 пацієнтів (середній вік — 41,05 ± 12,90 року) із діагнозом «тяжка черепно-мозкова травма». Пацієнти були розподілені на 4 групи: I (n = 15) — пацієнти з температурою тіла 38,3–39,5 °С, у яких проводилась контрольована нормотермія гіпотермом Blanketrol II (CSZ, США) для досягнення цільового значення температури тіла 37 °С; II група (n = 15) — пацієнти з температурою тіла ≥ 39,5 °С, яким здійснювали індукцію охолодження інфузією розчину Рінгера лактат (4 °С) у дозі 20–23 мл/кг із подальшим підтриманням контрольованої нормотермії гіпотермом Blanketrol II для досягнення цільового значення температури тіла 37 °С; III група (n = 15) — пацієнти з гіпертермією (38,3–39,5 °С), у яких проводилась стандартна інтенсивна терапія; IV група (n = 15) — пацієнти з гіпертермією ≥ 39,5 °С, яким здійснювали стандартну інтенсивну терапію. У всіх пацієнтів оцінювалися динаміка неврологічного статусу за шкалою коми Глазго, тривалість проведення механічної вентиляції легенів. Результати перенесеної черепно-мозкової травми визначалися за шкалою СРС (Сerebral Performance Categories) на 28-му добу дослідження. Результати. У I і III групах пацієнтів не було виявлено вірогідних відмінностей за рівнем вихідної гіпертермії — 38,98 ± 0,28 та 38,94 ± 0,27 °С відповідно. Відзначалася тенденція до глибшого неврологічного дефіциту початково в I групі порівняно з III групою пацієнтів — 6,26 ± 0,77 і 6,60 ± 0,71 бала за шкалою коми Глазго відповідно. Навпаки, у II групі пацієнтів початково було виявлено вірогідно більш глибокий неврологічний дефіцит (5,33 ± 0,47 бала, p &lt; 0,05) порівняно з пацієнтами IV групи (5,66 ± 0,47 бала). При аналізі тривалості механічної вентиляції легень не було виявлено вірогідних відмінностей між I (10,86 ± 9,49 доби) і III (10,26 ± 4,13 доби) групами. Була визначена тенденція більш тривалого проведення респіраторної підтримки в IV групі (25,53 ± 8,09 доби) порівняно з пацієнтами II групи (18,86 ± 8,39 доби). Рівень летальності становив у I групі 20 %, у III — 13,3 %, у II — 33,3 %, у IV — 46,7 %, однак ці відмінності також були невірогідними. При аналізі неврологічного статусу на 28-му добу з використанням шкали СРС була відзначена тенденція до поліпшення результатів у хворих I групи (2,20 ± 1,27 бала) порівняно з пацієнтами III групи (2,86 ± 1,08 бала). Було виявлено вірогідне поліпшення неврологічних результатів у хворих II групи (2,6 ± 1,4 бала, p &lt; 0,05) порівняно з пацієнтами IV групи (3,66 ± 1,49 бала). Не були визначені клінічно значущі побічні ефекти запропонованих варіантів контрольованої нормотермії. Виснов­ки. Запропонований спосіб здійснення контрольованої нормотермії створює більш сприятливі умови для більш повного відновлення порушених неврологічних функцій після тяжкої черепно-мозкової травми.

Retraction of: Abstract 03: High-Dose Intranasal Insulin During CPR Improves Neurological Outcomes in a Rat Model of Cardiac Arrest

Retraction of: Abstract 03: High-Dose Intranasal Insulin During CPR Improves Neurological Outcomes in a Rat Model of Cardiac Arrest

B.2 Neurologic outcome trajectory following neonatal arterial ischemic stroke (NAIS): A longitudinal observational study

Background: Studies evaluating long-term neurologic outcomes following NAIS are scanty. We aimed to study the emergence pattern of neurologic deficits following NAIS. Methods: Neonates diagnosed with AIS were prospectively enrolled and outcomes were evaluated using the validated Pediatric Stroke Outcome Measure-Severity Classification Scheme. Neurologic outcomes were classified as normal/mild, moderate or severe. Trend analysis was conducted using Cochran-Armitage test. Results: A total of 126 neonates (59% males) were followed for a median of 5.2 years (IQR:3.4-6.4 years). The proportion of children classified as normal/mild declined from 94% to 76% &gt;5 years post-stroke (p&lt;0.01). Moderate and severe outcomes increased from 5% to 15% and 1% to 8% (p=0.01), respectively. Sensorimotor, language and cognitive deficits emerged in 16%, 14%, and 17% of enrolled neonates, respectively. Of those who had normal/mild outcomes at baseline, 83 remained stable throughout the study. Improvement in neurologic outcomes was seen in 8 children. Thirty-five neonates had emerging deficits at one point during follow-up. Congenital heart disease predicted the emergence of deficits (odds ratio=3.3, 95% confidence interval:1.01-10.5). Conclusions: Emerging deficits following NAIS are not uncommon and can equally manifest in sensorimotor, language or cognitive domains. Thus, long-term follow-up and close monitoring of outcomes following NAIS is crucial.

Neurological outcome at 30-day as an estimator of 1-year functional status after out-of-hospital cardiac arrest with post-encephalopathy

Abstract Background Implantation of implantable cardioverter-defibrillators (ICD) for secondary prevention is fully recommended for those with an estimated survival over 1-year with a good functional status. However, we often face the difficulty to estimate the functional status and hesitate to implant ICD for patients with post-resuscitation encephalopathy. Methods There were 2391 out-of-hospital cardiac arrest (OHCA) patients transferred to 2 hospitals. We included 405 cardiovascular arrest patients, who got return of spontaneous circulation (ROSC) from January 2015 to December 2018. Among the patients, 343 patients could be considered to be implanted ICD for secondary prevention according to the initial waveform or the causes of OHCA. At 1-month later, 184 patients (54%) survived. To assess the association of functional status at 30-day and 1-year, we investigated patients' characteristics, pre-hospital information and clinical findings, and evaluated the neurological outcome according to the cerebral performance category (CPC) scale. Results At 1-month later, 145 patients (79%) survived with CPC≤2, and 39 patients (21%) survived with CPC&amp;gt;2. Bystander CPR (P=0.009), pre-hospital ROSC (P&amp;lt;0.001), low lactate level on admission (P=0.001), high geriatric nutritional risk index score (P&amp;lt;0.001) and without ECMO (P=0.002) were significantly associated with good neurological outcome at 30-day. The 1-year Kaplan-Meier event rate revealed significantly different survival rate (CPC&amp;gt;2 at 30-day:38.5%, vs CPC≤2 at 30-day:97.2%; P&amp;lt;0.001). In multivariate analysis, CPC scale at 30-day (OR 0.022; 95% CI 0.003–0.140; p&amp;lt;0.001) was the independent predictor of favorable neurological outcome at 1-year. Among the patients with CPC&amp;gt;2 at 30-day, only 3 patients (7.7%) of CPC=3 achieved the improvement of neurological outcome at 1-year (CPC≤2), while no patient of CPC=4 did. And one patient (2.5%) with CPC=3 was implanted ICD during the follow-up period. Twenty-five patients (64%) died of non-cardiovascular death with frailty of post-resuscitation encephalopathy after they were transferred to other hospital with the acceptation and intention of the do-not-attempt-resuscitation. Conclusions Neurological prognosis at 30-day after OHCA might be an estimator of 1-year functional status to guide us to implant ICD for secondary prevention. Funding Acknowledgement Type of funding sources: None.