Akinetic mutism and gait disturbance in a patient with delayed post-hypoxic leukoencephalopathy.

We report on a patient with delayed post-hypoxic leukoencephalopathy (DPHL) who showed akinetic mutism and gait disturbance, neural injuries that were demonstrated on diffusion tensor tractography (DTT). A patient was exposed to carbon monoxide (CO) and rapidly recovered; however, two weeks after onset, he began to show cognitive impairment and gait disturbance. At six weeks after CO exposure, he showed akinetic mutism and gait inability. DTT at 6-weeks post-exposure showed discontinuations in neural connectivities of the caudate nucleus to the medial prefrontal and orbitofrontal cortex in both hemispheres. In addition, the corticoreticulospinal tract revealed severe thinning in both hemispheres.

Outcome prediction in comatose cardiac arrest patients with initial shockable and non-shockable rhythms.

BACKGROUND: Prognosis after out-of-hospital cardiac arrest (OHCA) is presumed poorer in patients with non-shockable than shockable rhythms, frequently leading to treatment withdrawal. Multimodal outcome prediction is recommended 72 h post-arrest in still comatose patients, not considering initial rhythms. We investigated accuracy of outcome predictors in all comatose OHCA survivors, with a particular focus on shockable vs. non-shockable rhythms. METHODS: In this observational NORCAST sub-study, patients still comatose 72 h post-arrest were stratified by shockable vs. non-shockable rhythms for outcome prediction analyzes. Good outcome was defined as cerebral performance category 1-2 within 6 months. False positive rate (FPR) was used for poor and sensitivity for good outcome prediction accuracy. RESULTS: Overall, 72/128 (56%) patients with shockable and 12/50 (24%) with non-shockable rhythms had good outcome (p < .001). For poor outcome prediction, absent pupillary light reflexes (PLR) and corneal reflexes (clinical predictors) 72 h after sedation withdrawal, PLR 96 h post-arrest, and somatosensory evoked potentials (SSEP), all had FPR <0.1% in both groups. Unreactive EEG and neuron-specific enolase (NSE) >60 µg/L 24-72 h post-arrest had better precision in shockable patients. For good outcome, the clinical predictors, SSEP and CT, had 86%-100% sensitivity in both groups. For NSE, sensitivity varied from 22% to 69% 24-72 h post-arrest. The outcome predictors indicated severe brain injury proportionally more often in patients with non-shockable than with shockable rhythms. For all patients, clinical predictors, CT, and SSEP, predicted poor and good outcome with high accuracy. CONCLUSION: Outcome prediction accuracy was comparable for shockable and non-shockable rhythms. PLR and corneal reflexes had best precision 72 h after sedation withdrawal and 96 h post-arrest.

Treatment strategies for patients with out-of-hospital cardiac arrest associated with traumatic brain injury: A case series.

INTRODUCTION: Collapse after out-of-hospital cardiac arrest (OHCA) can cause severe traumatic brain injury (TBI). We aimed to investigate the clinical characteristics and treatment strategies for patients with OHCA and TBI. METHODS: We analyzed a consecutive cohort of patients with intrinsic OHCA retrospectively treated between January 2011 and December 2021 at a single critical care center, and presented a case series of seven patients. Patients with collapse-related TBI were examined for the causes and situations of cardiac arrest, laboratory data, radiological images, targeted temperature management (TTM), coronary angiography (CAG), percutaneous coronary intervention (PCI), and extracorporeal cardiopulmonary resuscitation (ECPR). RESULTS: Of the 197 patients with intrinsic OHCA, 7 (3.6%) had TBI (age range: 49-70 years; 6 men). All seven patients presented with ventricular fibrillation in the initial electrocardiograms, with four refractory cases treated with ECPR. All patients underwent CAG under heparinization, and four underwent PCI with antiplatelet administration. Initial head computed tomography indicated an intracranial hemorrhage (ICH) in three patients. ICH appeared or was exacerbated in six patients after CAG with or without PCI, except in one who underwent delayed PCI. All patients displayed elevated plasma D-dimer levels, and four underwent neurosurgical procedures. Four patients survived (three with cerebral performance category [CPC] 2, one with CPC 3) and three died; two had hypoxic-ischemic brain injury and one had severe TBI. CONCLUSION: Delayed ICH occurred frequently. Individualized management is required based on the extent of brain and cardiac damage, including optimal TTM, PCI procedures, and antiplatelet medications. Early detection of ICH and emergency treatment are critical for multi-disciplinary collaboration.

Monitoring of Brain Tissue Oxygen Tension in Cardiac Arrest: a Translational Systematic Review from Experimental to Clinical Evidence.

BACKGROUND: Cardiac arrest (CA) is a sudden event that is often characterized by hypoxic-ischemic brain injury (HIBI), leading to significant mortality and long-term disability. Brain tissue oxygenation (PbtO2) is an invasive tool for monitoring brain oxygen tension, but it is not routinely used in patients with CA because of the invasiveness and the absence of high-quality data on its effect on outcome. We conducted a systematic review of experimental and clinical evidence to understand the role of PbtO2 in monitoring brain oxygenation in HIBI after CA and the effect of targeted PbtO2 therapy on outcomes. METHODS: The search was conducted using four search engines (PubMed, Scopus, Embase, and Cochrane), using the Boolean operator to combine mesh terms such as PbtO2, CA, and HIBI. RESULTS: Among 1,077 records, 22 studies were included (16 experimental studies and six clinical studies). In experimental studies, PbtO2 was mainly adopted to assess the impact of gas exchanges, drugs, or systemic maneuvers on brain oxygenation. In human studies, PbtO2 was rarely used to monitor the brain oxygen tension in patients with CA and HIBI. PbtO2 values had no clear association with patients' outcomes, but in the experimental studies, brain tissue hypoxia was associated with increased inflammation and neuronal damage. CONCLUSIONS: Further studies are needed to validate the effect and the threshold of PbtO2 associated with outcome in patients with CA, as well as to understand the physiological mechanisms influencing PbtO2 induced by gas exchanges, drug administration, and changes in body positioning after CA.

Transcriptomic Hallmarks of Hypoxic-Ischemic Brain Injury: Insights from an in Vitro Model.

BACKGROUND: Hypoxic-ischemic injury of neurons is a pathological process observed in several neurological conditions, including ischemic stroke and neonatal hypoxic-ischemic brain injury (HIBI). An optimal treatment strategy for these conditions remains elusive. The present study delved deeper into the molecular alterations occurring during the injury process in order to identify potential therapeutic targets. METHODS: Oxygen-glucose deprivation/reperfusion (OGD/R) serves as an established in vitro model for the simulation of HIBI. This study utilized RNA sequencing to analyze rat primary hippocampal neurons that were subjected to either 0.5 or 2 h of OGD, followed by 0, 9, or 18 h of reperfusion. Differential expression analysis was conducted to identify genes dysregulated during OGD/R. Time-series analysis was used to identify genes exhibiting similar expression patterns over time. Additionally, functional enrichment analysis was conducted to explore their biological functions, and protein-protein interaction (PPI) network analyses were performed to identify hub genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was used for validation of hub-gene expression. RESULTS: The study included a total of 24 samples. Analysis revealed distinct transcriptomic alterations after OGD/R processes, with significant dysregulation of genes such as Txnip, Btg2, Egr1 and Egr2. In the OGD process, 76 genes, in two identified clusters, showed a consistent increase in expression; functional analysis showed involvement of inflammatory responses and signaling pathways like tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and interleukin 17 (IL-17). PPI network analysis suggested that Ccl2, Jun, Cxcl1, Ptprc, and Atf3 were potential hub genes. In the reperfusion process, 274 genes, in three clusters, showed initial upregulation followed by downregulation; functional analysis suggested association with apoptotic processes and neuronal death regulation. PPI network analysis identified Esr1, Igf-1, Edn1, Hmox1, Serpine1, and Spp1 as key hub genes. qRT-PCR validated these trends. CONCLUSIONS: The present study provides a comprehensive transcriptomic profile of an in vitro OGD/R process. Key hub genes and pathways were identified, offering potential targets for neuroprotection after hypoxic ischemia.

TMEM175 downregulation participates in impairment of the autophagy related lysosomal dynamics following neonatal hypoxic-ischemic brain injury.

The mechanism underlying long-term cognitive impairment caused by neonatal hypoxic-ischemic brain injury (HIBI) remains unclear. Autophagy is a closely related mechanism and may play a role in this process. We aimed to investigate the role of lysosomal transmembrane protein 175 (TMEM175) in the autophagy-lysosome pathway in neonatal rats with HIBI. A neonatal rat model of HIBI was established, hypoxia was induced, followed by left common carotid artery ligation. Expression levels of TMEM175 and the corresponding proteins involved in autophagy flux and the endolysosomal system fusion process were measured. Rats were administered TMEM175 plasmid via intracerebroventricular injection to induce overexpression. Brain damage and cognitive function were then assessed. TMEM175 was downregulated in the hippocampal tissue, and the autophagy-lysosome pathway was impaired following HIBI in neonatal rats. Overexpression of TMEM175 significantly mitigated neuronal injury and improved long-term cognitive and memory function in neonatal rats with HIBI. We found that improvement in the autophagy-lysosome pathway and endolysosomal system homeostasis, which are TMEM175 related, occurred via regulation of lysosomal membrane dynamic fusion. TMEM175 plays a critical role in maintaining the autophagy-lysosome pathway and endolysosomal homeostasis, contributing to the amelioration of neuronal injury and impaired long-term cognitive function following neonatal HIBI.

Perfusion system for studying dynamic metabolomics in rat brain slices exposed to oxygen-glucose deprivation using proton and phosphorus nuclear magnetic resonance.

The aim of the current study was to establish a controlled and reproducible model to study metabolic changes during oxygen-glucose deprivation (OGD) in rat brain using a nuclear magnetic resonance (NMR)-compatible perfusion system. Rat brains were cut into 400-µm thick slices and perfused with artificial cerebrospinal fluid (aCSF) in a 10-mm NMR tube inside a 600-MHz NMR spectrometer. Four experimental conditions were tested: (1) continuous perfusion with aCSF with glucose and normoxia, and (2) 30-, (3) 60-, or (4) 120-min periods of OGD followed by reperfusion of aCSF containing glucose and normoxia. The energetic state of perfused brain slices was measured using phosphorus (31 P) NMR and metabolite changes were measured using proton (1 H) NMR. aCSF samples were collected every 30 min and analyzed using 1 H NMR. The sample temperature was maintained at 36.7 ± 0.1°C and was checked periodically throughout the experiments. Brain slice histology was compared before and after OGD in the perfusion system using hematoxylin-eosin-saffron staining. NMR data clearly distinguished three severity groups (mild, moderate, and severe) after 30, 60, and 120 min of OGD, respectively, compared with the control group. 31 P NMR spectra obtained from controls showed that phosphocreatine levels were stable for 5 h inside the perfusion system. Control 1 H NMR spectra showed that lactate, N-acetylaspartic acid, glutamate, γ-aminobutyric acid, and creatine metabolite levels were stable over time, with lactate levels having a tendency to gradually increase due to the recirculation of the aCSF in the perfusion system. A controlled and reproducible perfusion system was established to study the energetic and metabolic changes in rat brain slices during and after OGD of varying severity.

A novel cardiac arrest severity score for the early prediction of hypoxic-ischemic brain injury and in-hospital death.

INTRODUCTION: Out-of-hospital cardiac arrest (OHCA) outcomes are unsatisfactory despite postcardiac arrest care. Early prediction of prognoses might help stratify patients and provide tailored therapy. In this study, we derived and validated a novel scoring system to predict hypoxic-ischemic brain injury (HIBI) and in-hospital death (IHD). METHODS: We retrospectively analyzed Korean Hypothermia Network prospective registry data collected from in Korea between 2015 and 2018. Patients without neuroprognostication data were excluded, and the remaining patients were randomly divided into derivation and validation cohorts. HIBI was defined when at least one prognostication predicted a poor outcome. IHD meant all deaths regardless of cause. In the derivation cohort, stepwise multivariate logistic regression was conducted for the HIBI and IHD scores, and model performance was assessed. We then classified the patients into four categories and analyzed the associations between the categories and cerebral performance categories (CPCs) at hospital discharge. Finally, we validated our models in an internal validation cohort. RESULTS: Among 1373 patients, 240 were excluded, and 1133 were randomized into the derivation (n = 754) and validation cohorts (n = 379). In the derivation cohort, 7 and 8 predictors were selected for HIBI (0-8) and IHD scores (0-11), respectively, and the area under the curves (AUC) were 0.85 (95% CI 0.82-0.87) and 0.80 (95% CI 0.77-0.82), respectively. Applying optimum cutoff values of ≥6 points for HIBI and ≥7 points for IHD, the patients were classified as follows: HIBI (-)/IHD (-), Category 1 (n = 424); HIBI (-)/IHD (+), Category 2 (n = 100); HIBI (+)/IHD (-), Category 3 (n = 21); and HIBI (+)/IHD (+), Category 4 (n = 209). The CPCs at discharge were significantly different in each category (p < 0.001). In the validation cohort, the model showed moderate discrimination (AUC 0.83, 95% CI 0.79-0.87 for HIBI and AUC 0.77, 95% CI 0.72-0.81 for IHD) with good calibration. Each category of the validation cohort showed a significant difference in discharge outcomes (p < 0.001) and a similar trend to the derivation cohort. CONCLUSIONS: We presented a novel approach for assessing illness severity after OHCA. Although external prospective studies are warranted, risk stratification for HIBI and IHD could help provide OHCA patients with appropriate treatment.

Are NIRS-derived cerebral autoregulation and ABPopt values different between hemispheres in hypoxic-ischemic brain injury patients following cardiac arrest?

PURPOSE: Near-infrared spectroscopy (NIRS) has been suggested as a non-invasive monitoring technique to set cerebral autoregulation (CA) guided ABP targets (ABPopt) in comatose patients with hypoxic-ischemic brain injury (HIBI) following cardiac arrest. We aimed to determine whether NIRS-derived CA and ABPopt values differ between left and right-sided recordings in these patients. METHODS: Bifrontal regional oxygen saturation (rSO2) was measured using INVOS or Fore-Sight devices. The Cerebral Oximetry index (COx) was determined as a CA measure. ABPopt was calculated using a published algorithm with multi-window weighted approach. A paired Wilcoxon signed rank test and intraclass correlation coefficients (ICC) were used to compare (1) systematic differences and (2) degree of agreement between left and right-sided measurements. RESULTS: Eleven patients were monitored. In one patient there was malfunctioning of the right-sided optode and in one patient not any ABPopt value was calculated. Comparison of rSO2 and COx was possible in ten patients and ABPopt in nine patients. The average recording time was 26 (IQR, 22-42) hours. The ABPopt values were not significantly different between the bifrontal recordings (80 (95%-CI 76-84) and 82 (95%-CI 75-84) mmHg) for the left and right recordings, p = 1.0). The ICC for ABPopt was high (0.95, 0.78-0.98, p < 0.001). Similar results were obtained for rSO2 and COx. CONCLUSION: We found no differences between left and right-sided NIRS recordings or CA estimation in comatose and ventilated HIBI patients. This suggests that in these patients without signs of localized pathology unilateral recordings might be sufficient to estimate CA status or provide ABPopt targets.

Oxidative Stress Markers in Human Brain and Placenta May Reveal the Timing of Hypoxic-Ischemic Injury: Evidence from an Immunohistochemical Study.

During pregnancy, reactive oxygen species (ROS) serve as crucial signaling molecules for fetoplacental circulatory physiology. Oxidative stress is thought to sustain the pathogenesis and progression of hypoxic-ischemic encephalopathy (HIE). A retrospective study was performed on the brains and placentas of fetuses and newborns between 36-42 weeks of gestation (Group_1: Fetal intrauterine deaths, Group_2: Intrapartum deaths, Group_3: Post-partum deaths, Control group sudden neonatal death); all groups were further divided into two subgroups (Subgroup_B [brain] and Subgroup_P [placenta]), and the study was conducted through the immunohistochemical investigations of markers of oxidative stress (NOX2, 8-OHdG, NT, iNOS), IL-6, and only on the brain samples, AQP4. The results for the brain samples suggest that NOX2, 8-OHdG, NT, iNOS, and IL-6 were statistically significantly expressed above the controls. iNOS was more expressed in the fetal intrauterine death (Group_1) and less expressed in post-partum death (Group_3), while in intrapartum death (Group_2), the immunoreactivity was very low. IL-6 showed the highest expression in the brain cortex of the fetal intrauterine death (Group_1), while intrapartum death (Group_2) and post-partum death (Group_3) showed weak immunoreactivity. Post-partum death (Group_3) placentas showed the highest immunoreactivity to NOX2, which was almost double that of the fetal intrauterine death (Group_1) and intrapartum death (Group_2) placentas. Placental tissues of fetal intrauterine death (Group_1) and intrapartum death (Group_2) showed higher expression of iNOS than post-partum death (Group_3), while the IL-6 expression was higher in the fetal intrauterine death (Group_1) than the post-partum death (Group_3). The AQP4 was discarded as a possible marker because the immunohistochemical reaction in the three groups of cases and the control group was negative. The goal of this study, from the point of view of forensic pathology, is to provide scientific evidence in cases of medical liability in the Obstetric field to support the clinical data of the timing of HIE.

Temperature control after cardiac arrest.

Most of the patients who die after cardiac arrest do so because of hypoxic-ischemic brain injury (HIBI). Experimental evidence shows that temperature control targeted at hypothermia mitigates HIBI. In 2002, one randomized trial and one quasi-randomized trial showed that temperature control targeted at 32-34 °C improved neurological outcome and mortality in patients who are comatose after cardiac arrest. However, following the publication of these trials, other studies have questioned the neuroprotective effects of hypothermia. In 2021, the largest study conducted so far on temperature control (the TTM-2 trial) including 1900 adults comatose after resuscitation showed no effect of temperature control targeted at 33 °C compared with normothermia or fever control. A systematic review of 32 trials published between 2001 and 2021 concluded that temperature control with a target of 32-34 °C compared with fever prevention did not result in an improvement in survival (RR 1.08; 95% CI 0.89-1.30) or favorable functional outcome (RR 1.21; 95% CI 0.91-1.61) at 90-180 days after resuscitation. There was substantial heterogeneity across the trials, and the certainty of the evidence was low. Based on these results, the International Liaison Committee on Resuscitation currently recommends monitoring core temperature and actively preventing fever (37.7 °C) for at least 72 h in patients who are comatose after resuscitation from cardiac arrest. Future studies are needed to identify potential patient subgroups who may benefit from temperature control aimed at hypothermia. There are no trials comparing normothermia or fever control with no temperature control after cardiac arrest.

Pyk2 inhibition attenuates hypoxic-ischemic brain injury in neonatal mice.

Newborns suffering from hypoxia-ischemia (HI) brain injury still lack effective treatment. Proline-rich tyrosine kinase 2 (Pyk2) is a non-receptor tyrosine kinase, which is highly correlated with transient ischemic brain injury in adult. In this study, we investigated the role of Pyk2 in neonatal HI brain injury. HI was induced in postnatal day 7 mouse pups by unilateral common carotid artery ligation followed by hypoxic exposure. Pyk2 interference lentivirus (LV-Pyk2 shRNA) was constructed and injected into unilateral cerebral ventricle of neonatal mice before HI. Infarct volume, pathological changes, and neurological behaviors were assessed on postnatal day 8-14. We showed that the phosphorylation level of Pyk2 was significantly increased in neonatal brain after HI, whereas LV-Pyk2 shRNA injection significantly attenuated acute HI brain damage and improved neurobehavioral outcomes. In oxygen-glucose deprivation-treated cultured cortical neurons, Pyk2 inhibition significantly alleviated NMDA receptor-mediated excitotoxicity; similar results were also observed in neonatal HI brain injury. We demonstrated that Pyk2 inhibition contributes to the long-term cerebrovascular recovery assessed by laser speckle contrast imaging, but cognitive function was not obviously improved as evaluated in Morris water maze and novel object recognition tests. Thus, we constructed lentiviral LV-HIF-Pyk2 shRNA, through which HIF-1α promoter-mediated interference of Pyk2 would occur during the anoxic environment. Intracerebroventricular injection of LV-HIF-Pyk2 shRNA significantly improved long-term recovery of cognitive function in HI-treated neonatal mice. In conclusion, this study demonstrates that Pyk2 interference protects neonatal brain from hypoxic-ischemic injury. HIF-1α promoter-mediated hypoxia conditional control is a useful tool to distinguish between hypoxic period and normal period. Pyk2 is a promising drug target for potential treatment of neonatal HI brain injury.

Mid-term (30- to 90-day) neurological changes in out-of-hospital cardiac arrest patients: A nationwide retrospective study (the JAAM-OHCA registry).

OBJECTIVE: Few studies have focused on mid/long-term neurological changes in out-of- hospital cardiac arrest (OHCA) survivors. Some studies suggest that there is still a slow, small, progressive improvement in cognitive function and quality of life for this population, even in the mid/long term. However, clinical data focused on mid/long-term outcomes for OHCA patients are still lacking. This study aimed to assess mid-term neurological changes in OHCA patients. We summarized patients' improved or worsened neurological changes between 30 and 90 days. Then we identified the relationship between clinical variables and 30- to 90-day neurological improvement. METHODS: A retrospective review of data (Jun 2014 - Dec 2017) from a Japanese nationwide OHCA registry was conducted. Inclusion criteria were OHCA patients ≥18 years old. Exclusion criteria were death within 30 days and missing Cerebral Performance Category (CPC) score at 30 and 90 days. We described the distributions of 30-day and 90-day CPC scores as well as the number and portion of patients whose CPC scores improved and worsened between 30 and 90 days. Additionally, factors affecting improved neurological changes over the time period were examined using multivariable logistic regression. RESULTS: Of the registry's 34,745 patients, 1868 were analyzed. Favorable neurological outcomes (CPC scores of 1 and 2) were seen in 1020/1868 patients at 90 days. CPC scores at 90 days were: CPC 1: 866 (46%), CPC 2: 154 (8.2%), CPC 3: 224 (12%), and CPC 4: 392 (20%), respectively. A total of 232 patients (CPC 5: 12%) died between 30 and 90 days. In 133 patients (7%), 90-day CPC scores improved compared to their 30-day scores. In 260 patients (14%), 90-day CPC scores worsened compared with their 30-day scores. Application of target temperature management was an independent factor for 30- to 90-day neurological improvement (adjusted odds ratio: 1.69, 95% confidence interval: 1.07-2.68). CONCLUSIONS: In our nationwide registry, 7% of resuscitated patients had improved neurological changes in the 30- to 90-day period; most of the improvements were CPC scores improving from 2 to 1. Target temperature management was an independent factor associated with CPC improvement over the 30- to 90-day period.

Association of hypoxic ischemic brain injury on early CT after out of hospital cardiac arrest with neurologic outcome.

AIM: This study aimed to describe the prevalence of hypoxic-ischemic brain injury (HIBI) on head CT (HCT) obtained within two hours of return of spontaneous circulation (ROSC) care in the Emergency Department following out-of-hospital cardiac arrest (OHCA) and evaluate the association between early HIBI and neurologic outcome. METHODS: Retrospective single center observational study of post-OHCA patients between 2009 and 2017. Two cohorts were analyzed: those who underwent non-contrast HCT within two hours of ROSC and all others who survived to ICU admission. HIBI was defined as the presence of cerebral edema and/or abnormal gray-white matter differentiation in the HCT interpretation by a neuroradiologist. The primary outcomes were the prevalence of HIBI on early HCT and the magnitude of the association between HIBI and survival with good neurologic outcome using multivariable logistic regression. RESULTS: Following OHCA, 333 of 520 patients (64%) underwent HCT within two hours of ROSC and HIBI was present in 96 of 333 patients (29%). Of the early HCT cohort, those with HIBI had a significantly lower hospital survival (2%) and favorable neurologic outcome (1%). In those without HIBI on imaging, 88 of 237 patients (37%) had a favorable outcome. After adjustment for confounding variables, HIBI on early HCT was independently associated with a decreased likelihood of good neurologic outcome (aOR 0.015, 95% CI 0.002-0.12). CONCLUSION: HIBI was present on 29% of HCTs obtained within 2 h of ROSC in the patients selected for early imaging by emergency physicians and was strongly and inversely associated with survival with a good neurologic outcome.

Monitoring of cerebrovascular pressure reactivity in children may predict neurologic outcome after hypoxic-ischemic brain injury.

OBJECTIVES: Impaired cerebral blood flow is a first-line reason of ischemic-hypoxic brain injury in children. The principal goal of intensive care management is to detect and prevent further cerebral blood flow deficits. This can be achieved by actively managing cerebral perfusion pressure (CPP) using input from cerebrovascular autoregulation (CAR). The main objective of the current study was to investigate CAR after cardiac arrest in children. METHODS: Nineteen consecutive children younger than 18 years after cardiopulmonary resuscitation, in whom intracranial pressure (ICP) was continuously measured, were included. Blood pressure and ICP were continuously monitored via ICM + software and actively managed using the pressure reactivity index (PRx) to achieve and maintain an optimal CPP. Outcome was scored using the extended Glasgow outcome scale (eGOS) at discharge and 6 months. RESULTS: Eight children died in hospital. At 6 months, further 4 children had an unfavorable (eGOS1-4) and 7 a favorable (eGOS5-8) outcome. Over the entire monitoring period, we found an elevated ICP (24.5 vs 7.4 mmHg), a lower CPP (50.3 vs 66.2 mmHg) and a higher PRx (0.24 vs - 0.01), indicating impaired CAR, in patients with unfavorable outcome. The dose of impaired autoregulation was significantly higher in unfavorable outcome (54.6 vs 29.3%). Analyzing only the first 72 h after cardiac arrest, ICP ≥ 10 mmHg and PRx > 0.2 correlated to unfavorable outcome. CONCLUSIONS: Significant doses of impaired CAR within 72 h after resuscitation are associated with unfavorable outcome. The inability to restore autoregulation despite active attempts to do so as well as an elevated ICP may serve as a bad prognostic sign indicating a severe initial hypoxic-ischemic brain injury.

EEG Patterns and Outcomes After Hypoxic Brain Injury: A Systematic Review and Meta-analysis.

Electroencephalography (EEG) is used to prognosticate recovery in comatose patients with hypoxic ischemic brain injury (HIBI) secondary to cardiac arrest. We sought to determine the prognostic use of specific EEG patterns for predicting disability and death following HIBI secondary to cardiac arrest. This systematic review searched Medline, Embase, and Cochrane Central up to January 2020. We included original research involving prospective and retrospective cohort studies relating specific EEG patterns to disability and death in comatose adult patients suffering HIBI post cardiac arrest requiring admission to an intensive care setting. We evaluated study quality using the Quality of Diagnostic Accuracy Studies 2 tool. Descriptive statistics were used to summarize study, patient, and EEG characteristics. We pooled study-level estimates of sensitivity and specificity for EEG patterns defined a priori using a random effect bivariate and univariate meta-analysis when appropriate. Funnel plots were used to assess publication bias. Of 5191 abstracts, 333 were reviewed in full text, of which 57 were included in the systematic review and 32 in meta-analyses. No reported EEG pattern was found to be invariably associated with death or disability across all studies. Pooled specificities of status epilepticus, burst suppression, and electrocerebral silence were high (92-99%), but sensitivities were low (6-39%) when predicting a composite outcome of disability and death. Study quality varied depending on domain; patient flow and timing performed was well conducted in all, whereas EEG interpretation was retrospective in 17 of 39 studies. Accounting for variable study quality, EEG demonstrates high specificity with a low risk of false negative outcome attribution for disability and death when status epilepticus, burst suppression, or electrocerebral silence is detected. Increased use of standardized cross-study protocols and definitions of EEG patterns are required to better evaluate the prognostic use of EEG for comatose patients with HIBI following cardiac arrest.

Role of Nuclear-Receptor-Related 1 in the Synergistic Neuroprotective Effect of Umbilical Cord Blood and Erythropoietin Combination Therapy in Hypoxic Ischemic Encephalopathy.

Neonatal hypoxic-ischemic encephalopathy (HIE) results in neurological impairments; cell-based therapy has been suggested as a therapeutic avenue. Previous research has demonstrated the synergistically potentiated therapeutic efficacy of human umbilical cord blood (UCB) by combining recombinant human erythropoietin (EPO) treatment for recovery from HIE. However, its molecular mechanism is not entirely understood. In the present study, we analyzed the mechanisms underlying the effect of combination treatment with EPO and UCB by transcriptomic analysis, followed by gene enrichment analysis. Mouse HIE model of the neonate was prepared and randomly divided into five groups: sham, HIE, and UCB, EPO, and UCB+EPO treatments after HIE. A total of 376 genes were differentially expressed when |log2FC| ≥ 1-fold change expression values were considered to be differentially expressed between UCB+EPO and HIE. Further assessment through qRT-PCR and gene enrichment analysis confirmed the expression and correlation of its potential target, Nurr1, as an essential gene involved in the synergistic effect of the UCB+EPO combination. The results indicated the remarkable activation of Wnt/ß-catenin signaling by reducing the infarct size by UCB+EPO treatment, accompanied by Nurr1 activity. In conclusion, these findings suggest that the regulation of Nurr1 through the Wnt/ß-catenin pathway exerts a synergistic neuroprotective effect in UCB and EPO combination treatment.

Medium-chain Triglyceride Ketogenic Diet as a Treatment Strategy for Adult Super-refractory Status Epilepticus.

How to cite this article: Dutta K, Satishchandra P, Borkotokey M. Medium-chain Triglyceride Ketogenic Diet as a Treatment Strategy for Adult Super-refractory Status Epilepticus. Indian J Crit Care Med 2022;26(1):139-140.

Sex specific correlation between GABAergic disruption in the dorsal hippocampus and flurothyl seizure susceptibility after neonatal hypoxic-ischemic brain injury.

Since neonatal hypoxia-ischemia (HI) disrupts the hippocampal (Hp) GABAergic network in the mouse and Hp injury in this model correlates with flurothyl seizure susceptibility only in male mice, we hypothesized that GABAergic disruption correlates with flurothyl seizure susceptibility in a sex-specific manner. C57BL6 mice were exposed to HI (Vannucci model) versus sham procedures at P10, randomized to normothermia (NT) or therapeutic hypothermia (TH), and subsequently underwent flurothyl seizure testing at P18. Only in male mice, Hp atrophy correlated with seizure susceptibility. The number of Hp parvalbumin positive interneurons (PV+INs) decreased after HI in both sexes, but TH attenuated this deficit only in females. In males only, seizure susceptibility directly correlated with the number of PV+INs, but not somatostatin or calretinin expressing INs. Hp GABAB receptor subunit levels were decreased after HI, but unrelated to later seizure susceptibility. In contrast, Hp GABAA receptor α1 subunit (GABAARα1) levels were increased after HI. Adjusting the number of PV+ INs for their GABAARα1 expression strengthened the correlation with seizure susceptibility in male mice. Thus, we identified a novel Hp sex-specific GABA-mediated mechanism of compensation after HI that correlates with flurothyl seizure susceptibility warranting further study to better understand potential clinical translation.

Sevoflurane Post-Conditioning Ameliorates Neuronal Deficits and Axon Demyelination After Neonatal Hypoxic Ischemic Brain Injury: Role of Microglia/Macrophage.

Microglia/macrophages have been identified to be highly polarized after ischemia. Interestingly, the polarization of these microglia/macrophages varies immensely under differing disease conditions. Post-conditioning using sevoflurane, a volatile anesthetic, could provide long-term neuroprotection to neonatal rats after hypoxic-ischemic brain injury (HIBI). Thus, the current study aimed at investigating the effects of sevoflurane post-conditioning (SPC) on microglia/macrophage polarization after HIBI induction in neonatal rats. Additionally, we aimed at identifying the underpinning mechanisms specifically related to autophagy and lysosomal protease enzyme, cathepsin B. To develop a HIBI model, 7-day-old Sprague-Dawley rats underwent left common carotid artery ligation followed by 2 h of hypoxia. The role of microglia/macrophages in the neuroprotection conferred by SPC was examined by left-side intra-cerebroventricular injection with adenovirus vector carrying catB-GFP or rapamycin. The number of interleukin (IL)-1ß+ cells, cathepsin B+ cells, light chain 3B positive (LC3B+) cells among ionized calcium binding adaptor molecule 1(Iba1+)cells to investigate microglia polarization, neuronal apoptosis to assess neuronal death in the acute phase were tested at 24 h after HIBI. Behavioral tests including suspension test, Morris water maze tests were performed to investigate the long-term effects of SPC, at 21 to 34 days post HIBI. Nissl staining and myelin basic protein (MBP) immunostaining to assess the long-term neuronal and myelin damage were performed at 34 days after HIBI. Based on the obtained results post HIBI, we observed the cells that were positive for IL-1ß, cathepsin B, and LC3B among Iba1 positive cell population in the hippocampus were significantly decreased after SPC treatment. SPC significantly attenuated the HIBI-induced increase in neuronal apoptosis, improved long-term cognitive function, and attenuated HI-induced decrease of Nissl-positive cells and MBP expression. However, these trends were reversed by injection of adenovirus vector carrying catB-GFP and rapamycin. SPC attenuated microglia polarization towards neurotoxic phenotypes, alleviates neuronal death and axon demyelination after HIBI in neonatal rats by regulating microglia autophagy and cathepsin B expression, and therefore provided long-term cognitive, learning and memory protection.