Anoxia in the mammalian brain leads to hyper-excitability and cell death; however, this cascade of events does not occur in the anoxia-tolerant brain of the western painted turtle, Chrysemys picta belli. The painted turtle has become an important anoxia-tolerant model to study brain, heart, and liver function in the absence of oxygen, but being anoxia-tolerant likely means that decapitation alone is not a suitable method of euthanasia. Many anesthetics have long-term effects on ion channels and are not appropriate for same day experimentation. Using whole-cell electrophysiological techniques, we examine the effects of the anesthetic, Alfaxalone, on pyramidal cell action potential amplitude, threshold, rise and decay time, width, frequency, whole cell conductance, and evoked GABAA receptors currents to determine if any of these characteristics are altered with the use of Alfaxalone for animal sedation. We find that Alfaxalone has no long-term impact on action potential parameters or whole-cell conductance. When acutely applied to naïve tissue, Alfaxalone did lengthen GABAA receptor current decay rates by 1.5-fold. Following whole-animal sedation with Alfaxalone, evoked whole cell GABAA receptor current decay rates displayed an increasing trend with 1 and 2 hours after brain sheet preparation, but showed no significant change after a 3-hour washout period. Therefore, we conclude that Alfaxalone is a suitable anesthetic for same day use in electrophysiological studies in western painted turtle brain tissue.

UNASSIGNED: Questions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl).
UNASSIGNED: To compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.
UNASSIGNED: This unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023.
UNASSIGNED: Naloxone administered as 1 dose (4 mg/0.1 mL) at 0, 2.5, 5, and 7.5 minutes (test), 2 doses at 0 and 2.5 minutes (test), and 1 dose at 0 and 2.5 minutes (reference).
UNASSIGNED: The primary outcome was the first prespecified time with higher naloxone plasma concentration. The secondary outcome was estimated brain hypoxia time following simulated fentanyl overdoses using a physiologic pharmacokinetic-pharmacodynamic model. Naloxone concentrations were compared using paired tests at 3 prespecified times across the 3 groups, and simulation results were summarized using descriptive statistics.
UNASSIGNED: This study included 21 participants, and 18 (86%) completed the trial. The median participant age was 34 years (IQR, 27-50 years), and slightly more than half of participants were men (11 [52%]). Compared with 1 naloxone dose at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes (7.95 vs 4.42 ng/mL; geometric mean ratio, 1.95 [1-sided 97.8% CI, 1.28-∞]), whereas 2 doses at 0 and 2.5 minutes significantly increased the plasma concentration at 4.5 minutes (2.24 vs 1.23 ng/mL; geometric mean ratio, 1.98 [1-sided 97.8% CI, 1.03-∞]). No drug-related serious adverse events were reported. The median brain hypoxia time after a simulated fentanyl 2.97-mg intravenous bolus was 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0 and 2.5 minutes, 4.5 minutes (IQR, 2.1-∞ minutes) with 1 naloxone dose at 0, 2.5, 5, and 7.5 minutes, and 3.7 minutes (IQR, 1.5-∞ minutes) with 2 naloxone doses at 0 and 2.5 minutes.
UNASSIGNED: In this clinical trial with healthy participants, compared with 1 intranasal naloxone dose administered at 0 and 2.5 minutes, 1 dose at 0, 2.5, 5, and 7.5 minutes significantly increased naloxone plasma concentration at 10 minutes, whereas 2 doses at 0 and 2.5 minutes significantly increased naloxone plasma concentration at 4.5 minutes. Additional research is needed to determine optimal naloxone dosing in the community setting.
UNASSIGNED: ClinicalTrials.gov Identifier: NCT04764630.

Cortical spreading depolarization (SD) imposes a massive increase in energy demand and therefore evolves as a target for treatment following acute brain injuries. Anesthetics are empirically used to reduce energy metabolism in critical brain conditions, yet their effect on metabolism during SD remains largely unknown. We investigated oxidative metabolism during SD in brain slices from Wistar rats. Extracellular potassium ([K+]o), local field potential and partial tissue oxygen pressure (ptiO2) were measured simultaneously. The cerebral metabolic rate of oxygen (CMRO2) was calculated using a reaction-diffusion model. By that, we tested the effect of clinically relevant concentrations of isoflurane on CMRO2 during SD and modeled tissue oxygenation for different capillary pO2 values. During SD, CMRO2 increased 2.7-fold, resulting in transient hypoxia in the slice core. Isoflurane decreased CMRO2, reduced peak [K+]o, and prolonged [K+]o clearance, which indicates reduced synaptic transmission and sodium-potassium ATPase inhibition. Modeling tissue oxygenation during SD illustrates the need for increased capillary pO2 levels to prevent hypoxia. In the absence thereof, isoflurane could improve tissue oxygenation by lowering CMRO2. Therefore, isoflurane is a promising candidate for pre-clinical studies on neuronal survival in conditions involving SD.

OBJECTIVE: Cerebral anoxia is the absence or near absence of oxygen in the brain\'s arterial blood supply. One cause of cerebral anoxia is acute cardiorespiratory failure, which, if left untreated, can lead to brain tissue necrosis, causing an anoxic brain injury (AnBI). AnBI causes a range of motor and cognitive deficits, though long-term (> 2.0 years) neuropsychological sequelae of AnBI are not well understood.
METHODS: A 66-year-old female presented for a neuropsychological evaluation 5.4 years status post myocardial infarction complicated by cardiac arrest requiring cardiopulmonary resuscitation (CPR) for one hour. The patient was comatose for two weeks and initially exhibited a 20-year- retrograde amnesia (RA). She reportedly reached a cognitive plateau approximately 2.5 years after the original insult. 4.9 years after the original insult, a new emergence of severe functional impairment was observed. Relevant medical history was significant for hypertension, hypocholesterolemia, and coronary artery disease. Neuroimaging revealed mild cortical atrophy and mild microvascular ischemia.
RESULTS: Her neurocognitive profile demonstrated impairments in all assessed cognitive domains. Her MMSE score declined 11 points in 2 months. Behavioral observations and assessment findings demonstrated features of Balint\'s Syndrome (e.g., optic apraxia, optic ataxia, simultanagnosia).
CONCLUSIONS: The patient\'s AnBI was severe, given multiple markers: CPR duration, coma length, and RA. Moreover, her decline in functional ability demonstrates that a resurgence of functional impairment 5.4 years status post a severe AnBI is possible, highlighting the importance of neuropsychological monitoring over time.

Late auditory evoked potentials, and notably mismatch negativity (MMN) and P3 responses, can be used as part of the multimodal prognostic evaluation in post-anoxic disorders of consciousness (DOC). MMN response preferentially stems from the temporal cortex and the arcuate fasciculus. Situations with discrepant evaluations, for example MMN absent but P3 present, are frequent and difficult to interpret. We hypothesize that discrepant MMN-/P3+ results could reflect a higher prevalence of lesions in MMN generating regions. This study presents correlations between neurophysiological and neuroradiological results.
This retrospective study was conducted on 38 post-anoxic DOC patients. Brain lesions were analyzed on 3T MRI both anatomically and through computation of the local arcuate fasciculus fractional anisotropy values on Diffusion Tensor Imaging sequences. Neurophysiological data and outcome were also analyzed.
Our cohort included 8 MMN-/P3+, 7 MMN+/P3+, 21 MMN-/P3- and 2 MMN-/P3+ patients, assessed at a median delay of 20.5 days since cardiac arrest. Our results show that MMN-/P3+ patients tended to have fewer temporal and basal ganglia lesions than MMN-/P3- patients, and more than MMN+/P3+ patients (p-values for trend: p = 0.02 for temporal and p = 0.02 for basal ganglia lesions). There was a statistical difference across groups for mean fractional anisotropy values in the arcuate fasciculus (p = 0.008). The percentage of patients regaining consciousness at three months in MMN-/P3+ patients was higher than in MMN-/P3- patients and lower than in MMN+/P3+ patients.
This study suggests that discrepancies in late auditory evoked potentials may be linked to focal post-anoxic brain lesions, visible on brain MRI.

To investigate the frequency of induced EEG burst suppression pattern during continuous IV anesthesia (IVAD) and associated outcomes in adult patients treated for refractory status epilepticus (RSE).
Patients with RSE treated with anesthetics at a Swiss academic care center from 2011 to 2019 were included. Clinical data and semiquantitative EEG analyses were assessed. Burst suppression was categorized as incomplete burst suppression (with ≥20% and <50% suppression proportion) or complete burst suppression (with ≥50% suppression proportion). The frequency of induced burst suppression and association of burst suppression with outcomes (persistent seizure termination, in-hospital survival, and return to premorbid neurologic function) were the endpoints.
We identified 147 patients with RSE treated with IVAD. Among 102 patients without cerebral anoxia, incomplete burst suppression was achieved in 14 (14%) with a median of 23 hours (interquartile range [IQR] 1-29) and complete burst suppression was achieved in 21 (21%) with a median of 51 hours (IQR 16-104). Age, Charlson comorbidity index, RSE with motor symptoms, the Status Epilepticus Severity Score and arterial hypotension requiring vasopressors were identified as potential confounders in univariable comparisons between patients with and without any burst suppression. Multivariable analyses revealed no associations between any burst suppression and the predefined endpoints. However, among 45 patients with cerebral anoxia, induced burst suppression was associated with persistent seizure termination (72% without vs 29% with burst suppression, p = 0.004) and survival (50% vs 14% p = 0.005).
In adult patients with RSE treated with IVAD, burst suppression with ≥50% suppression proportion was achieved in every fifth patient and not associated with persistent seizure termination, in-hospital survival, or return to premorbid neurologic function.

BACKGROUND: Prior studies have investigated the association between duration of resuscitation and short-term outcomes following in-hospital cardiac arrest (IHCA). However, it remains unknown whether there is an association between duration of resuscitation and long-term survival and functional outcomes.
METHODS: We linked data from the Danish in-hospital cardiac arrest registry with nationwide registries and identified 8,727 patients between 2013 and 2019. Patients were stratified into four groups (A-D) according to quartiles of duration of resuscitation. Standardized average probability of outcomes was estimated using logistic regression.
RESULTS: Of 8,727 patients, 53.1% (n = 4,604) achieved return of spontaneous circulation. Median age was 74 (1st-3rd quartile [Q1-Q3] 65-81 years) and 63.1% were men. Among all IHCA patients the standardized 30-day survival was 62.0% (95% CI 59.8-64.2%) for group A (<5 minutes), 32.7% (30.8-34.6%) for group B (5-11 minutes), 14.4% (12.9-15.9%) for group C (12-20 minutes) and 8.1% (7.0-9.1%) for group D (21 minutes or more). Similarly, 1-year survival was also highest for group A (50.4%; 48.2-52.6%) gradually decreasing to 6.6% (5.6-7.6%) in group D. Among 30-day survivors, survival without anoxic brain damage or nursing home admission within one-year post-arrest was highest for group A (80.4%; 78.2-82.6%), decreasing to 73.3% (70.0-76.6%) in group B, 67.2% (61.7-72.6%) in group C and 73.3% (66.9-79.7%) in group D.
CONCLUSIONS: Shorter duration of resuscitation attempt during an IHCA is associated with higher 30-day and 1-year survival. Furthermore, we found that the majority of 30-day survivors were still alive 1-year post-arrest without anoxic brain damage or nursing home admission despite prolonged resuscitation.

Mortality and brain injury are common adverse outcomes in infants born <28 weeks. Conventional pulse oximetry may not detect subclinical changes prior to deterioration and fails to detect changes within the brain. Increasing evidence supports the use of cerebral near-infrared spectroscopy (NIRS) in the early care of preterm infants, yet the impact of specific interventions on cerebral oxygenation and the relationship between cerebral hypoxia and brain injury on MRI remain to be determined.
100 infants <28 completed weeks of gestation will be recruited for a prospective, multicenter intervention trial. After informed consent, infants will undergo cerebral NIRS monitoring starting within 6 h of birth and continuing through 72 h. Infants with persistent cerebral desaturation will receive interventions following a standard treatment algorithm selected by the provider based on the patient\'s clinical condition. Providers will record the timing and choice of intervention(s) and term equivalent brain MRI will be performed for survivors. There are three objectives of this study: 1) to identify the relationship between cerebral hypoxia burden and brain injury on term-equivalent MRI. 2) to identify most common interventions after cerebral hypoxia, and 3) to quantify frequency of occult cerebral hypoxia events.
There is increasing evidence for the role of early cerebral NIRS monitoring in the neuroprotective care of preterm infants. This phase-II trial will provide essential data to improve the intervention approach, model the effect size of interventions on a wider extent of brain injury, and quantify the discrepancy between measurements of systemic and cerebral hypoxia.

BACKGROUND: Ischemic brain injury is a major hurdle that limits the survival of resuscitated out-of-hospital cardiac arrest (OHCA).
METHODS: The aim of this study is to assess the feasibility and potential for reduction of ischemic brain injury in adult OHCA patients treated with high- or low-dose Neu2000K, a selective blocker of N-methyl-D-aspartate (NMDA) type 2B receptor and also a free radical scavenger, or given placebo. This study is a phase II, multicenter, randomized, double-blinded, prospective, intention-to-treat, placebo-controlled, three-armed, safety and efficacy clinical trial. This trial is a sponsor-initiated trial supported by GNT Pharma. Successfully resuscitated OHCA patients aged 19 to 80 years would be included. The primary outcome is blood neuron-specific enolase (NSE) level on the 3rd day. The secondary outcomes are safety, efficacy defined by study drug administration within 4 h in > 90% of participants, daily NSE up to 5th day, blood S100beta, brain MRI apparent diffusion coefficient imaging, cerebral performance category (CPC), and Modified Rankin Scale (mRS) at 5th, 14th, and 90th days. Assuming NSE of 42 ± 80 and 80 ± 80 μg/L in the treatment (high- and low-dose Neu2000K) and control arms with 80% power, a type 1 error rate of 5%, and a 28% of withdrawal prior to the endpoint, the required sample size is 150 patients.
CONCLUSIONS: The AWAKE trial explores a new multi-target neuroprotectant for the treatment of resuscitated OHCA patients.
BACKGROUND: ClinicalTrials.gov NCT03651557 . Registered on August 29, 2018.

BACKGROUND: Rapid disease progression in neuroemergencies is associated with blood-brain barrier (BBB) disruption. We investigated a less invasive strategy for assessing BBB status by evaluating S100 calcium-binding protein B (S100B) and neuron-specific enolase (NSE) at early stages of the hypoxic-ischemic brain injury (HIBI) cascade.
METHODS: This retrospective study used prospectively collected data from patients with out-of-hospital cardiac arrest (August 2019-July 2021). Albumin specimens obtained from serum and cerebrospinal fluid via arterial catheter and lumbar puncture were used to measure the albumin quotient (Qa), which is widely accepted as the gold standard method for detecting BBB disruption. Serum S100B and NSE levels were measured simultaneously following the return of spontaneous circulation. We conducted linear regression to evaluate the relationship between S100B and Qa and the predictive performance of S100B for abnormal Qa. The primary study outcome was abnormal Qa (>0.007).
RESULTS: Forty-one patients were enrolled; 30 showed an abnormal Qa suggestive of BBB disruption. S100B levels were significantly higher than in those with a normal Qa (0.244 μg/L [interquartile range [IQR], 0.146-0.823 vs 0.754 μg/L [IQR, 0.317-2.228], P = .03). We report a positive correlation between serum S100B and Qa (R2 = 0.110; P = .04). The area under the receiver operating characteristics curve (AUROC) evaluating the predictive performance of S100B with respect to abnormal Qa was 0.718 (95% confidence interval, 0.556-0.847). The cutoff value for S100B (with respect to BBB disruption) in the total cohort was 0.283 μg/L (sensitivity, 80.0%; specificity, 72.7%). Subgroup analyses in patients with serum neuron-specific enolase (NSE) levels of <40.8 ng/mL (excluding those with established neuronal cell injury) showed an improved correlation coefficient (R2 = 0.382; P < .01) and predictive performance (AUROC, 0.836 [95% confidence interval, 0.629-0.954]) compared with the total cohort.
CONCLUSIONS: Serum S100B obtained at an early stage of the HIBI cascade is associated with abnormal Qa, suggesting BBB disruption. The predictive performance of S100B and the correlation between serum S100B and Qa can be improved using a complementary strategy (i.e., evaluations of S100B and NSE levels) that combines considerations of cell damage in astrocytes and neurons.