Post-cardiac Arrest Brain Injury Research Articles

LncRNA MSTRG.13,871/miR155-5p/Grip1 network involved in the post-cardiac arrest brain injury

Post-cardiac arrest brain (PCABI) is a severe medical condition characterized by a significant risk of neurological impairment and death. Nevertheless, the specific process and essential molecules responsible for its development are not fully understood. Profiling based on competing endogenous RNAs (ceRNA) has been implicated in the onset and progression of neurological disorders, yet its role in PCABI remains unclear. In this study, we performed RNA transcriptome sequencing analysis to identify differentially expressed genes in the rat model for cardiac arrest and cardiopulmonary resuscitation (CA/CPR). A hub ceRNA regulatory network was constructed using miRWalk 2.0 and Cytohubba plug-in in Cytoscape. Subsequently, real-time quantitative reverse transcription-polymerase chain reaction and dual-luciferase activity assays validated MSTRG.13,871, miR-155-5p, and Grip1 as differentially expressed in CA/CPR group, with MSTRG.13,871 capable of targeting both miR-155-5p and Grip1. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed the ceRNA network enrichment in immunoregulation mechanisms such as mitochondrion, apoptotic process, and negative regulation cell death. Our research highlights the mechanism of PCABI by revealing a critical regulatory axis involving MSTRG.13,871-miR-155-5p-Grip1 in the hippocampus CA1 region after CA/CPR in rats, proposing a feasible controlled mechanism, which may serve as a theoretical basis for designing innovative therapies.

Liver protects neuron viability and electrocortical activity in post-cardiac arrest brain injury

Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.

Perioperative cardiopulmonary resuscitation in a prone position: A case report

Post-cardiac arrest brain injury remains a major cause of mortality in perioperative cardiac arrest, although intraoperative events are uncommon due to pre-procedural preparations, risk-benefit anticipation, and a controlled working environment. Herein, we describe the successful cardiopulmonary resuscitation of a 57-year-old male with a C2-C3 schwannoma who experienced intraoperative cardiac arrest due to massive blood loss during a C2-C3 laminectomy and excision of tumor while in a prone position. The intricacies and effectiveness of resuscitation in a prone position, as well as neuroprotective strategies in the perioperative setting to optimize functional outcomes, will be discussed.

Combination of Hydrogen Inhalation and Hypothermic Temperature Control After Out-of-Hospital Cardiac Arrest: A Post hoc Analysis of the Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During PostCardiac Arrest Care II Trial.

The Efficacy of Inhaled Hydrogen on Neurologic Outcome Following Brain Ischemia During Post-Cardiac Arrest Care (HYBRID) II trial (jRCTs031180352) suggested that hydrogen inhalation may reduce post-cardiac arrest brain injury (PCABI). However, the combination of hypothermic target temperature management (TTM) and hydrogen inhalation on outcomes is unclear. The aim of this study was to investigate the combined effect of hydrogen inhalation and hypothermic TTM on outcomes after out-of-hospital cardiac arrest (OHCA). Post hoc analysis of a multicenter, randomized, controlled trial. Fifteen Japanese ICUs. Cardiogenic OHCA enrolled in the HYBRID II trial. Hydrogen mixed oxygen (hydrogen group) versus oxygen alone (control group). TTM was performed at a target temperature of 32-34°C (TTM32-TTM34) or 35-36°C (TTM35-TTM36) per the institutional protocol. The association between hydrogen + TTM32-TTM34 and 90-day good neurologic outcomes was analyzed using generalized estimating equations. The 90-day survival was compared between the hydrogen and control groups under TTM32-TTM34 and TTM35-TTM36, respectively. The analysis included 72 patients (hydrogen [ n = 39] and control [ n = 33] groups) with outcome data. TTM32-TTM34 was implemented in 25 (64%) and 24 (73%) patients in the hydrogen and control groups, respectively ( p = 0.46). Under TTM32-TTM34, 17 (68%) and 9 (38%) patients achieved good neurologic outcomes in the hydrogen and control groups, respectively (relative risk: 1.81 [95% CI, 1.05-3.66], p < 0.05). Hydrogen + TTM32-TTM34 was independently associated with good neurologic outcomes (adjusted odds ratio 16.10 [95% CI, 1.88-138.17], p = 0.01). However, hydrogen + TTM32-TTM34 did not improve survival compared with TTM32-TTM34 alone (adjusted hazard ratio: 0.22 [95% CI, 0.05-1.06], p = 0.06). Hydrogen + TTM32-TTM34 was associated with improved neurologic outcomes after cardiogenic OHCA compared with TTM32-TTM34 monotherapy. Hydrogen inhalation is a promising treatment option for reducing PCABI when combined with TTM32-TTM34.

Improving Outcomes After Post–Cardiac Arrest Brain Injury: A Scientific Statement From the International Liaison Committee on Resuscitation

This scientific statement presents a conceptual framework for the pathophysiology of post–cardiac arrest brain injury, explores reasons for previous failure to translate preclinical data to clinical practice, and outlines potential paths forward. Post–cardiac arrest brain injury is characterized by 4 distinct but overlapping phases: ischemic depolarization, reperfusion repolarization, dysregulation, and recovery and repair. Previous research has been challenging because of the limitations of laboratory models; heterogeneity in the patient populations enrolled; overoptimistic estimation of treatment effects leading to suboptimal sample sizes; timing and route of intervention delivery; limited or absent evidence that the intervention has engaged the mechanistic target; and heterogeneity in postresuscitation care, prognostication, and withdrawal of life-sustaining treatments. Future trials must tailor their interventions to the subset of patients most likely to benefit and deliver this intervention at the appropriate time, through the appropriate route, and at the appropriate dose. The complexity of post–cardiac arrest brain injury suggests that monotherapies are unlikely to be as successful as multimodal neuroprotective therapies. Biomarkers should be developed to identify patients with the targeted mechanism of injury, to quantify its severity, and to measure the response to therapy. Studies need to be adequately powered to detect effect sizes that are realistic and meaningful to patients, their families, and clinicians. Study designs should be optimized to accelerate the evaluation of the most promising interventions. Multidisciplinary and international collaboration will be essential to realize the goal of developing effective therapies for post–cardiac arrest brain injury.

Cardiac arrest, stony heart, and cardiopulmonary resuscitation: An updated revisit.

The post-resuscitation period is recognized as the main predictor of cardiopulmonary resuscitation (CPR) outcomes. The first description of post-resuscitation syndrome and stony heart was published over 50 years ago. Major manifestations may include but are not limited to, persistent precipitating pathology, systemic ischemia/reperfusion response, post-cardiac arrest brain injury, and finally, post-cardiac arrest myocardial dysfunction (PAMD) after successful resuscitation. Why do some patients initially survive successful resuscitation, and others do not? Also, why does the myocardium response vary after resuscitation? These questions have kept scientists busy for several decades since the first successful resuscitation was described. By modifying the conventional modalities of resuscitation together with new promising agents, rescuers will be able to salvage the jeopardized post-resuscitation myocardium and prevent its progression to a dismal, stony heart. Community awareness and staff education are crucial for shortening the resuscitation time and improving short- and long-term outcomes. Awareness of these components before and early after the restoration of circulation will enhance the resuscitation outcomes. This review extensively addresses the underlying pathophysiology, management, and outcomes of post-resuscitation syndrome. The pattern, management, and outcome of PAMD and post-cardiac arrest shock are different based on many factors, including in-hospital cardiac arrest vs out-of-hospital cardiac arrest (OHCA), witnessed vs unwitnessed cardiac arrest, the underlying cause of arrest, the duration, and protocol used for CPR. Although restoring spontaneous circulation is a vital sign, it should not be the end of the game or lone primary outcome; it calls for better understanding and aggressive multi-disciplinary interventions and care. The development of stony heart post-CPR and OHCA remain the main challenges in emergency and critical care medicine.

Aberrant brain-heart coupling is associated with the severity of post cardiac arrest brain injury.

To investigate autonomic nervous system activity measured by brain-heart interactions in comatose patients after cardiac arrest in relation to the severity and prognosis of hypoxic-ischemic brain injury. Strength and complexity of bidirectional interactions between EEG frequency bands (delta, theta, and alpha) and ECG heart rate variability frequency bands (low frequency, LF and high frequency, HF) were computed using a synthetic data generation model. Primary outcome was the severity of brain injury, assessed by (i) standardized qualitative EEG classification, (ii) somatosensory evoked potentials (N20), and (iii) neuron-specific enolase levels. Secondary outcome was the 3-month neurological status, assessed by the Cerebral Performance Category score [good (1-2) vs. poor outcome (3-4-5)]. Between January 2007 and July 2021, 181 patients were admitted to ICU for a resuscitated cardiac arrest. Poor neurological outcome was observed in 134 patients (74%). Qualitative EEG patterns suggesting high severity were associated with decreased LF/HF. Severity of EEG changes were proportional to higher absolute values of brain-to-heart coupling strength (p < 0.02 for all brain-to-heart frequencies) and lower values of alpha-to-HF complexity (p = 0.049). Brain-to-heart coupling strength was significantly higher in patients with bilateral absent N20 and correlated with neuron-specific enolase levels at Day 3. This aberrant brain-to-heart coupling (increased strength and decreased complexity) was also associated with 3-month poor neurological outcome. Our results suggest that autonomic dysfunctions may well represent hypoxic-ischemic brain injury post cardiac arrest pathophysiology. These results open avenues for integrative monitoring of autonomic functioning in critical care patients.

Neurological outcomes and quality of life in post-cardiac arrest patients with return of spontaneous circulation supported by ECMO: A retrospective case series.

Post-cardiac arrest brain injury constitutes a significant contributor to morbidity and mortality, leading to cognitive impairment and subsequent disability. Individuals within this patient cohort grapple with uncertainty regarding the potential advantages of extracorporeal life support (ECMO) cannulation. This study elucidates the neurological outcomes and quality of life of post-cardiac arrest patients who attained spontaneous circulation and underwent ECMO cannulation. This is a retrospective case study within a local context, the research involved 32 patients who received ECMO support following an intrahospital cardiac arrest with return of spontaneous circulation (ROSC). An additional 32 patients experienced cardiac arrest with ROSC before undergoing cannulation. The average age was 41 years, with the primary causes of cardiac arrest identified as acute coronary syndrome (46.8%), pulmonary thromboembolism (21.88%), and hypoxemia (18.7%). The most prevalent arrest rhythm was asystole (37.5%), followed by ventricular fibrillation (34.4%). The mean SOFA score was 7 points (IQR 6.5-9), APACHE II score was 12 (IQR 9-16), RESP score was -1 (IQR -1 to -4) in cases of respiratory ECMO, and SAVE score was -3 (IQR -5 to 2) in cases of cardiac ECMO. Overall survival was 71%, and at 6 months, the Barthel score was 75 points, modified Rankin score was 2, cerebral performance categories score was 1, and the SF-12 had an average score of 30. Notably, there were no significant associations between the time, cause, or rhythm of cardiac arrest and neurological outcomes. Importantly, cardiac arrest is not a contraindication for ECMO cannulation. A meticulous assessment of candidates who have achieved spontaneous circulation after cardiac arrest, considering the absence of early signs of poor neurological prognosis, is crucial in patient selection. Larger prospective studies are warranted to validate and extend these findings.

Modulation of mitochondrial function with near-infrared light reduces brain injury in a translational model of cardiac arrest

BackgroundBrain injury is a leading cause of morbidity and mortality in patients resuscitated from cardiac arrest. Mitochondrial dysfunction contributes to brain injury following cardiac arrest; therefore, therapies that limit mitochondrial dysfunction have the potential to improve neurological outcomes. Generation of reactive oxygen species (ROS) during ischemia–reperfusion injury in the brain is a critical component of mitochondrial injury and is dependent on hyperactivation of mitochondria following resuscitation. Our previous studies have provided evidence that modulating mitochondrial function with specific near-infrared light (NIR) wavelengths can reduce post-ischemic mitochondrial hyperactivity, thereby reducing brain injury during reperfusion in multiple small animal models.MethodsIsolated porcine brain cytochrome c oxidase (COX) was used to investigate the mechanism of NIR-induced mitochondrial modulation. Cultured primary neurons from mice expressing mitoQC were utilized to explore the mitochondrial mechanisms related to protection with NIR following ischemia–reperfusion. Anesthetized pigs were used to optimize the delivery of NIR to the brain by measuring the penetration depth of NIR to deep brain structures and tissue heating. Finally, a model of out-of-hospital cardiac arrest with CPR in adult pigs was used to evaluate the translational potential of NIR as a noninvasive therapeutic approach to protect the brain after resuscitation.ResultsMolecular evaluation of enzyme activity during NIR irradiation demonstrated COX function was reduced in an intensity-dependent manner with a threshold of enzyme inhibition leading to a moderate reduction in activity without complete inhibition. Mechanistic interrogation in neurons demonstrated that mitochondrial swelling and upregulation of mitophagy were reduced with NIR treatment. NIR therapy in large animals is feasible, as NIR penetrates deep into the brain without substantial tissue heating. In a translational porcine model of CA/CPR, transcranial NIR treatment for two hours at the onset of return of spontaneous circulation (ROSC) demonstrated significantly improved neurological deficit scores and reduced histologic evidence of brain injury after resuscitation from cardiac arrest.ConclusionsNIR modulates mitochondrial function which improves mitochondrial dynamics and quality control following ischemia/reperfusion. Noninvasive modulation of mitochondria, achieved by transcranial treatment of the brain with NIR, mitigates post-cardiac arrest brain injury and improves neurologic functional outcomes.Graphical abstract

Managing Post Cardiac Arrest Syndrome

Four conditions occur after cardiac arrest resuscitation and are referred to as the post-cardiac arrest syndrome. Moreover, post-cardiac arrest brain injury has the greatest impact on outcomes. Brain injury can be primary as a result of global cerebral ischemia during cardiac arrest. It may be secondary(reperfusion injury)after initiation of cardiopulmonary resuscitation. After cardiac arrest resuscitation, the patient must be managed in the intensive care unit, and it is recommended to avoid hypotension(MAP<65 mmHg), hypoxemia, and hyperoxemia. Oxygen saturation should be maintained at 94%-98%, normal ventilation(35 mmHg-45 mmHg), and body temperature below 37.5℃ for 72 h after resuscitation. The administration of anticonvulsants for abnormal electroencephalograms did not significantly affect the outcome. Prognosis should be predicted within 24 h to 72 h combining physical examination, biomarkers, electrophysiology, and imaging being predictive of poor outcomes.

Indoleamine 2,3-Dioxygenase Deletion to Modulate Kynurenine Pathway and to Prevent Brain Injury after Cardiac Arrest in Mice.

The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase. Wild-type and indoleamine 2,3-dioxygenase-deleted (IDO-/-) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements. IDO-/- mice showed higher survival compared to wild-type mice (IDO-/- 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO-/- mice than in wild-type mice after cardiac arrest (IDO-/- 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO-/- 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO-/- 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO-/- mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO-/- (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO-/- 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving l-kynurenine (apparent diffusion coefficient, μm2/ms: wild-type, 0.48 ± 0.07; IDO-/-, 0.59 ± 0.02; IDO-/- and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6). The kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.

Interpretable machine learning model for imaging-based outcome prediction after cardiac arrest

IntroductionEarly identification of brain injury patterns in computerized tomography (CT) imaging is crucial for post-cardiac arrest prognostication. Lack of interpretability of machine learning prediction reduces trustworthiness by clinicians and prevents translation to clinical practice. We aimed to identify CT imaging patterns associated with prognosis with interpretable machine learning. MethodsIn this IRB-approved retrospective study, we included consecutive comatose adult patients hospitalized at a single academic medical center after resuscitation from in- and out-of-hospital cardiac arrest between August 2011 and August 2019 who underwent unenhanced CT imaging of the brain within 24 hours of their arrest. We decomposed the CT images into subspaces to identify interpretable and informative patterns of injury, and developed machine learning models to predict patient outcomes (i.e., survival and awakening status) using the identified imaging patterns. Practicing physicians visually examined the imaging patterns to assess clinical relevance. We evaluated machine learning models using 80%-20% random data split and reported AUC values to measure the model performance. ResultsWe included 1284 subjects of whom 35% awakened from coma and 34% survived hospital discharge. Our expert physicians were able to visualize decomposed image patterns and identify those believed to be clinically relevant on multiple brain locations. For machine learning models, the AUC was 0.710 ± 0.012 for predicting survival and 0.702 ± 0.053 for predicting awakening, respectively. DiscussionWe developed an interpretable method to identify patterns of early post-cardiac arrest brain injury on CT imaging and showed these imaging patterns are predictive of patient outcomes (i.e., survival and awakening status).

Duration of cardiopulmonary resuscitation and phenotype of post-cardiac arrest brain injury

BackgroundPatients resuscitated from cardiac arrest have variable severity of primary hypoxic ischemic brain injury (HIBI). Signatures of primary HIBI on brain imaging and electroencephalography (EEG) include diffuse cerebral edema and burst suppression with identical bursts (BSIB). We hypothesize distinct phenotypes of primary HIBI are associated with increasing cardiopulmonary resuscitation (CPR) duration. MethodsWe identified from our prospective registry of both in-and out-of-hospital CA patients treated between January 2010 to January 2020 for this cohort study. We abstracted CPR duration, neurological examination, initial brain computed tomography gray to white ratio (GWR), and initial EEG pattern. We considered four phenotypes on presentation: awake; comatose with neither BSIB nor cerebral edema (non-malignant coma); BSIB; and cerebral edema (GWR ≤ 1.20). BSIB and cerebral edema were considered as non-mutually exclusive outcomes. We generated predicted probabilities of brain injury phenotype using localized regression. ResultsWe included 2,440 patients, of whom 545 (23%) were awake, 1,065 (44%) had non-malignant coma, 548 (23%) had BSIB and 438 (18%) had cerebral edema. Only 92 (4%) had both BSIB and edema. Median CPR duration was 16 [IQR 8–28] minutes. Median CPR duration increased in a stepwise manner across groups: awake 6 [3–13] minutes; non-malignant coma 15 [8–25] minutes; BSIB 21 [13–31] minutes; cerebral edema 32 [22–46] minutes. Predicted probability of phenotype changes over time. ConclusionsBrain injury phenotype is related to CPR duration, which is a surrogate for severity of HIBI. The sequence of most likely primary HIBI phenotype with progressively longer CPR duration is awake, coma without BSIB or edema, BSIB, and finally cerebral edema.

Inflammatory responses involved in post-cardiac arrest brain injury: mechanisms, regulation, and therapeutic potential

Neuroinflammation plays a key role in the pathogenesis of post-cardiac arrest (CA) brain injury. Innate immune cells sense a variety of danger signals through pattern-recognition receptors and evoke rapidly after ischemic challenge, triggering inflammatory responses and amplifying brain damage. A programmed cell death (PCD) pathway is activated after ischemic and/or inflammatory stimuli, leading to the elimination of the damaged cells. However, PCD also regulates inflammatory responses flexibly. The present review aimed to summarize the mechanisms of inflammatory responses, including the biology of immune cells, the innate immune recognition that initiates the inflammation, and the immunomodulatory effects of PCD following CA. Promising therapeutic approaches of targeting inflammatory responses to alleviate brain injury and improve neurological outcomes after CA are also reviewed.

Neuroprotective Effect of miR-483-5p Against Cardiac Arrest-Induced Mitochondrial Dysfunction Mediated Through the TNFSF8/AMPK/JNK Signaling Pathway

Substantial morbidity and mortality are associated with postcardiac arrest brain injury (PCABI). MicroRNAs(miRNAs) are essential regulators of neuronal metabolism processes and have been shown to contribute to alleviated neurological injury after cardiac arrest. In this study, we identified miRNAs related to the prognosis of patients with neurological dysfunction after cardiopulmonary resuscitation based on data obtained from the Gene Expression Omnibus (GEO) database. Then, we explored the effects of miR-483-5p on mitochondrial biogenesis, mitochondrial-dependent apoptosis, and oxidative stress levels after ischemia‒reperfusion injury in vitro and in vivo. MiR-483-5p was downregulated in PC12 cells and hippocampal samples compared with that in normal group cells and hippocampi. Overexpression of miR-483-5p increased the viability of PC12 cells after ischemia‒reperfusion injury and reduced the proportion of dead cells. A western blot analysis showed that miR-483-5p increased the protein expression of PCG-1, NRF1, and TFAM and reduced the protein expression of Bax and cleaved caspase 3, inhibiting the release of cytochrome c from mitochondria and alleviating oxidative stress injury by inhibiting the production of ROS and reducing MDA activity. We confirmed that miR-483-5p targeted TNFSF8 to regulate the AMPK/JNK pathway, thereby playing a neuroprotective role after cardiopulmonary resuscitation. Hence, this study provides further insights into strategies for inhibiting neurological impairment after cardiopulmonary resuscitation and suggests a potential therapeutic target for PCABI.

Implementation of neurocritical care in Thailand.

Dedicated neurointensive care units and neurointensivists are rarely available in Thailand, a developing country, despite the high burden of life-threatening neurologic illness, including strokes, post-cardiac arrest brain injury, status epilepticus, and cerebral edema from various etiologies. Therefore, the implementation of neurocritical care is essential to improve patient outcomes. With the resource-limited circumstances, the integration of neurocritical care service by collaboration between intensivists, neurologists, neurosurgeons, and other multidisciplinary care teams into the current institutional practice to take care of critically-ill neurologic patients is more suitable than building a new neurointensive care unit since this approach can promptly be made without reorganization of the hospital system. Providing neurocritical care knowledge to internal medicine and neurology residents and critical care fellows and developing a research system will lead to sustainable quality improvement in patient care. This review article will describe our current situation and strategies to implement neurocritical care in Thailand.

Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway–mediated antioxidant defense in a mouse model of cardiac arrest

ObjectiveThe aim of this study was to investigate the effect of the ketogenic diet (KD) on post-cardiac arrest brain injury in a mouse model of cardiac arrest and cardiopulmonary resuscitation. MethodsMice were fed a KD for 4 wk and then subjected to cardiac arrest and cardiopulmonary resuscitation. The HT22 cells after β-hydroxybutyrate (β-OHB) treatment were exposed to oxygen-glucose deprivation/reoxygenation. Survival and neurologic function were measured after return of spontaneous circulation. Positron emission tomography/computed tomography scanning, 13C-magnetic resonance spectroscopy analysis, and seahorse assay were performed to explore the mechanism underlying the phenotype. ResultsResults of this study demonstrated that KD improved neurologic function and reduced apoptotic neurons in cardiac arrest and cardiopulmonary resuscitation mice. With no alteration of glucose uptake, KD suppressed glucose oxidation in mouse brain. Consistently, the glycolytic capacity of the HT22 cells was also downregulated by β-OHB treatment. Moreover, KD increased nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate and reduced glutathione/oxidized glutathione couples and reduced reactive oxygen species in the brain, probably due to activation of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. Pharmacologic inhibition of pentose phosphate pathway totally abolished the influence of β-OHB on glycolysis, and post–oxygen-glucose deprivation/reoxygenation cell viability and reactive oxygen species production in HT22 cells. ConclusionKD improved survival and attenuated post-cardiac arrest brain injury, which was mediated by upregulation of pentose phosphate pathway and related antioxidant defense system.

A novel global ischemia-reperfusion rat model with asymmetric brain damage simulating post-cardiac arrest brain injury

BackgroundPost-cardiac arrest brain injury (PCABI) is a major cause of disability and death in patients with post-cardiac arrest syndrome (PCAS). However, there have been no suitable animal models with characteristic behaviors and cerebral damage adequately mimicking clinical PCABI. New methodWe established a chimeric model by increasing transient middle cerebral artery occlusion-mediated ipsilateral hemisphere damage in the 4-vessel occlusion (4VO) model, thereby inducing global forebrain asymmetric hemisphere ischemia. Severity of brain damage was then evaluated by behavioral and histological approaches. Neuroprotection was assessed by performing targeted temperature management (TTM) for two hours. ResultsComatose behaviors were observed in both groups. Compared to the 4VO group, the chimeric group exhibited a higher neurological deficit score (NDS) (70.5 ± 17.6 vs. 139.5 ± 16.8, p = 0.0002), decreased brain cell viability (88.6 ± 18.0% vs. 5.7 ± 2.7%, p < 0.0001), and increased inflammation in the cortex (10.3 ± 1.6% vs. 16.9 ± 1.1%, p = 0.0061). After TTM neuroprotection, the chimeric-TTM group showed improvement in NDS (139.5 ± 16.8 vs. 0.0 ± 0.0, p < 0.0001), cortex and hippocampus cell viability (5.7 ± 2.7% vs. 72.8 ± 10.0%, p < 0.0001; and 2.5 ± 1.5% vs. 75.5 ± 10.3%, p < 0.0001, respectively) and inflammation (16.9 ± 1.1% vs. 11.0 ± 2.3%, p = 0.190; and 30.9 ± 1.7% vs. 16.6 ± 1.2%, p < 0.0001, respectively) compared to the chimeric group. Comparison with existing methodUnlike the extensive brain damage found in clinical PCAS settings, the existing 4VO models showed only global forebrain damage involving CA1 lesions on both hippocampi. Our model induced global forebrain and additional asymmetric hemisphere ischemic damages, which resulted in simulating PCABI-specific clinical manifestations than conventional models. ConclusionsOur model adequately simulates clinical PCABI and reflects appropriate neuroprotective effects of TTM.

Baclofen attenuates cognitive deficits in post-cardiac arrest brain injury

Between 30% and 50% of survivors of cardiac arrest (CA) suffer from cognitive deficits. However, no effective medical intervention is available to alleviate cognitive deficits. Baclofen is known to protect damaged neurons, but researchers have still not clearly whether baclofen alleviates CA-induced cognitive deficits. The present study aimed to investigate whether baclofen protects against post-CA cognitive deficits and to reveal the protective mechanism of baclofen. Rats underwent 10 min of asphyxia to establish CA models. Intriguingly, our results indicated that baclofen improved spatial memory 72 h after CA. Baclofen increased plasticity-related protein (PSD95, and GAP43) expression in the brain after CA. Baclofen reduced microglial number and the release of inflammatory factors (IL-1β and IL-18). Furthermore, baclofen significantly reduced the expression of pyroptosis-related molecules after CA. Notably, activation of NLRP3 abolished the anti-pyroptosis effect of baclofen and reduced the expression of synaptic plasticity-related proteins after CA. Taken together, this study first shows that baclofen attenuates cognitive deficits induced by brain injury after CA. The mechanism is at least partially attributed to baclofen regulating pyroptosis by inhibition of NLRP3 activation.

Inhaled gases as novel neuroprotective therapies in the postcardiac arrest period.

The purpose of this review is to summarize recent advances about inhaled gases as novel neuroprotective agents in the postcardiac arrest period. Inhaled gases, as nitric oxide (NO) and molecular hydrogen (H2), and noble gases as xenon (Xe) and argon (Ar) have shown neuroprotective properties after resuscitation. In experimental settings, the protective effect of these gases has been demonstrated in both in-vitro studies and animal models of cardiac arrest. They attenuate neuronal degeneration and improve neurological function after resuscitation acting on different pathophysiological pathways. Safety of both Xe and H2 after cardiac arrest has been reported in phase 1 clinical trials. A randomized phase 2 clinical trial showed the neuroprotective effects of Xe, combined with targeted temperature management. Xe inhalation for 24 h after resuscitation preserves white matter integrity as measured by fractional anisotropy of diffusion tensor MRI. Inhaled gases, as Xe, Ar, NO, and H2 have consistently shown neuroprotective effects in experimental studies. Ventilation with these gases appears to be well tolerated in pigs and in preliminary human trials. Results from phase 2 and 3 clinical trials are needed to assess their efficacy in the treatment of postcardiac arrest brain injury.