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Xiaoying Zhou, Wenting Su, Quanwei Bao, Yu Cui, Xiaoxu Li, Yidong Yang, Chengzhong Yang, Chengyuan Wang, Li Jiao, Dewei Chen, and Jian Huang. Nitric oxide ameliorates the effects of hypoxia in mice by regulating oxygen transport by hemoglobin. High Alt Med Biol. 25:174–185, 2024.—Hypoxia is a common pathological and physiological phenomenon in ischemia, cancer, and strenuous exercise. Nitric oxide (NO) acts as an endothelium-derived relaxing factor in hypoxic vasodilation and serves as an allosteric regulator of hemoglobin (Hb). However, the ultimate effects of NO on the hematological system in vivo remain unknown, especially in extreme environmental hypoxia. Whether NO regulation of the structure of Hb improves oxygen transport remains unclear. Hence, we examined whether NO altered the oxygen affinity of Hb (Hb-O2 affinity) to protect extremely hypoxic mice. Mice were exposed to severe hypoxia with various concentrations of NO, and the survival time, exercise capacity, and other physical indexes were recorded. The survival time was prolonged in the 5 ppm NO (6.09 ± 1.29 minutes) and 10 ppm NO (6.39 ± 1.58 minutes) groups compared with the 0 ppm group (4.98 ± 1.23 minutes). Hypoxia of the brain was relieved, and the exercise exhaustion time was prolonged when mice inhaled 20 ppm NO (24.70 ± 6.87 minutes vs. 20.23 ± 6.51 minutes). In addition, the differences in arterial oxygen saturation (SO2%) (49.64 ± 7.29% vs. 42.90 ± 4.30%) and arteriovenous SO2% difference (25.14 ± 8.95% vs. 18.10 ± 6.90%) obviously increased. In ex vivo experiments, the oxygen equilibrium curve (OEC) left shifted as P50 decreased from 43.77 ± 2.49 mmHg (0 ppm NO) to 40.97 ± 1.40 mmHg (100 ppm NO) and 38.36 ± 2.78 mmHg (200 ppm NO). Furthermore, the Bohr effect of Hb was enhanced by the introduction of 200 ppm NO (−0.72 ± 0.062 vs.−0.65 ± 0.051), possibly allowing Hb to more easily offload oxygen in tissue at lower pH. The crystal structure reveals a greater distance between Asp94β-His146β in nitrosyl -Hb(NO-Hb), NO-HbβCSO93, and S-NitrosoHb(SNO-Hb) compared to tense Hb(T-Hb, 3.7 Å, 4.3 Å, and 5.8 Å respectively, versus 3.5 Å for T-Hb). Moreover, hydrogen bonds were less likely to form, representing a key limitation of relaxed Hb (R-Hb). Upon NO interaction with Hb, hydrogen bonds and salt bridges were less favored, facilitating relaxation. We speculated that NO ameliorated the effects of hypoxia in mice by promoting erythrocyte oxygen loading in the lung and offloading in tissues. [ABSTRACT FROM AUTHOR]

Brain oxygen deprivation causes morphological damage involved in the formation of serious pathological conditions such as stroke and cerebral palsy. Therapeutic methods for post-hypoxia/anoxia injuries are limited and still have deficiencies in terms of safety and efficacy. Recently, clinical studies of stroke have reported the use of drugs containing riboflavin for post-injury clinical rehabilitation, however, the effects of vitamin B2 on exposure to cerebral oxygen deprivation are not completely elucidated. This review aimed to investigate the potential antioxidant, anti-inflammatory and neuroprotective effects of riboflavin in cerebral hypoxia/anoxia. After a systematic search, 21 articles were selected, 8 preclinical and 12 clinical studies, and 1 translational study. Most preclinical studies used B2 alone in models of hypoxia in rodents, with doses of 1–20 mg/kg (in vivo) and 0.5–5 µM (in vitro). Together, these works suggested greater regulation of lipid peroxidation and apoptosis and an increase in neurotrophins, locomotion, and cognition after treatment. In contrast, several human studies have administered riboflavin (5 mg) in combination with other Krebs cycle metabolites, except one study, which used only B2 (20 mg). A reduction in lactic acidosis and recovery of sensorimotor functions was observed in children after treatment with B2, while adults and the elderly showed a reduction in infarct volume and cognitive rehabilitation. Based on findings from preclinical and clinical studies, we conclude that the use of riboflavin alone or in combination acts beneficially in correcting the underlying brain damage caused by hypoxia/anoxia and its inflammatory, oxidative, and behavioral impairments. [ABSTRACT FROM AUTHOR]

Chronic vascular encephalopathy (CVE) is a frequent cause of vascular mild cognitive impairment and dementia, which significantly worsens the quality of life, especially in the elderly population. CVE is a result of chronic cerebral hypoperfusion, characterized by prolonged limited blood flow to the brain. This causes insufficient oxygenation of the brain leading to hypoxia. The latter can trigger a series of events associated with the development of oxidative/reductive stresses and neuroinflammation. Addressing the gap in knowledge regarding oxidative and reductive stresses in the development of vascular disorders and neuroinflammation can give a start to new directions of research in the context of CVE. In this review, we consider the hypoxiainduced molecular challenges involved in the pathophysiology of CVE, focusing on oxidative stress and neuroinflammation, which are combined in a vicious cycle of neurodegeneration. We also briefly describe therapeutic approaches to the treatment of CVE and outline the prospects for the use of sulforaphane, an isothiocyanate common in cruciferous plants, and vitamin D to break the vicious cycle and alleviate the cognitive impairments characteristic of patients with CVE. [ABSTRACT FROM AUTHOR]

Recently, the role of high-concentration oxygen therapy in cerebral hemorrhage has been extensively discussed. This review describes the research progress in high-concentration oxygen therapy after cerebral hemorrhage. High-concentration oxygen therapy can be classified into two treatment methods: hyperbaric and normobaric high-concentration oxygen therapy. Several studies have reported that high-concentration oxygen therapy uses the pathological mechanisms of secondary ischemia and hypoxia after cerebral hemorrhage as an entry point to improve cerebral oxygenation, metabolic rate, cerebral edema, intracranial pressure, and oxidative stress. We also elucidate the mechanisms by which molecules such as Hypoxia-inducible factor 1-alpha (HIF-1α), vascular endothelial growth factor, and erythropoietin (EPO) may play a role in oxygen therapy. Although people are concerned about the toxicity of hyperoxia, combined with relevant literature, the evidence discussed in this article suggests that as long as the duration, concentration, pressure, and treatment interval of patients with cerebral hemorrhage are properly understood and oxygen is administered within the treatment window, it can be effective to avoid hyperoxic oxygen toxicity. Combined with the latest research, we believe that high-concentration oxygen therapy plays an important positive role in injuries and outcomes after cerebral hemorrhage, and we recommend expanding the use of normal-pressure high-concentration oxygen therapy for cerebral hemorrhage. [ABSTRACT FROM AUTHOR]

This article comprehensively reviews how cerebral hypoxia impacts the physiological state of neurons and dendritic spines through a series of molecular changes, and explores the causal relationship between these changes and neuronal functional impairment. As a severe pathological condition, cerebral hypoxia can significantly alter the morphology and function of neurons and dendritic spines. Specifically, dendritic spines, being the critical structures for neurons to receive information, undergo changes such as a reduction in number and morphological abnormalities under hypoxic conditions. These alterations further affect synaptic function, leading to neurotransmission disorders. This article delves into the roles of molecular pathways like MAPK, AMPA receptors, NMDA receptors, and BDNF in the hypoxia-induced changes in neurons and dendritic spines, and outlines current treatment strategies. Neurons are particularly sensitive to cerebral hypoxia, with their apical dendrites being vulnerable to damage, thereby affecting cognitive function. Additionally, astrocytes and microglia play an indispensable role in protecting neuronal and synaptic structures, regulating their normal functions, and contributing to the repair process following injury. These studies not only contribute to understanding the pathogenesis of related neurological diseases but also provide important insights for developing novel therapeutic strategies. Future research should further focus on the dynamic changes in neurons and dendritic spines under hypoxic conditions and their intrinsic connections with cognitive function. [ABSTRACT FROM AUTHOR]

Background: The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. Methods: Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. Results: Individualized limits of autoregulation were computed in 55 patients (mean age 38 years, mean monitoring time 92 h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20 mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14 mm Hg to 79 ± 17 mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6 mm Hg to 21.9 ± 5.6 mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60 min after compared with before an intervention (11% vs. 23%, p = 0.05). Conclusions: Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes. [ABSTRACT FROM AUTHOR]

The mechanisms by which megadose sodium ascorbate improves clinical status in experimental sepsis is unclear. We determined its effects on cerebral perfusion, oxygenation, and temperature, and plasma levels of inflammatory biomarkers, nitrates, nitrites, and ascorbate in ovine Gram-negative sepsis. Sepsis was induced by i.v. infusion of live Escherichia coli for 31 h in unanaesthetised Merino ewes instrumented with a combination sensor in the frontal cerebral cortex to measure tissue perfusion, oxygenation, and temperature. Fluid resuscitation at 23 h was followed by i.v. megadose sodium ascorbate (0.5 g kg−1 over 30 min+0.5 g kg−1 h−1 for 6.5 h) or vehicle (n =6 per group). Norepinephrine was titrated to restore mean arterial pressure (MAP) to 70–80 mm Hg. At 23 h of sepsis, MAP (mean [ sem ]: 85 [2] to 64 [2] mm Hg) and plasma ascorbate (27 [2] to 15 [1] μM) decreased (both P <0.001). Cerebral ischaemia (901 [58] to 396 [40] units), hypoxia (34 [1] to 19 [3] mm Hg), and hyperthermia (39.5 [0.1]°C to 40.8 [0.1]°C) (all P <0.001) developed, accompanied by malaise and lethargy. Sodium ascorbate restored cerebral perfusion (703 [121] units], oxygenation (30 [2] mm Hg), temperature (39.2 [0.1]°C) (all P Treatment <0.05), and the behavioural state to normal. Sodium ascorbate slightly reduced the sepsis-induced increase in interleukin-6, returned VEGF-A to normal (both P GroupxTime <0.01), and increased plasma ascorbate (20 000 [300] μM; P Group <0.001). The effects of sodium ascorbate were not reproduced by equimolar sodium bicarbonate. Megadose sodium ascorbate rapidly reversed sepsis-induced cerebral ischaemia, hypoxia, hyperthermia, and sickness behaviour. These effects were not reproduced by an equimolar sodium load. [ABSTRACT FROM AUTHOR]

Stroke is a leading cause of death worldwide, yet current therapeutic strategies remain limited. Among the neuropathological events underlying this disease are multiple cell death signaling cascades, including autophagy. Recent interest has focused on developing agents that target molecules involved in autophagy to modulate this process under pathological conditions. This study aimed to analyze the role of autophagy in cell death induced by an in vitro ischemia–reperfusion (IR) model and to determine whether nitrones, known for their neuroprotective and antioxidant effects, could modulate this process. We focused on key proteins involved in different phases of autophagy: HIF-1α, BNIP3, and BECN1 for induction and nucleation, LC3 for elongation, and p62 for degradation. Our findings confirmed that the IR model promotes autophagy, initially via HIF-1α activation. Additionally, the neuroprotective effect of three of the selected synthetic nitrones (quinolylnitrones QN6 and QN23, and homo-bis-nitrone HBN6) partially derives from their antiautophagic properties, demonstrated by a downregulation of the expression of molecular markers involved in various phases of autophagy. In contrast, the neuroprotective power of cholesteronitrone ChN2 seems to derive from its promoting effects on the initial phases of autophagy, which could potentially help inhibit other forms of cell death. These results underscore the importance of autophagy modulation in neuroprotection, highlighting the potential of inhibiting prodeath autophagy and promoting prosurvival autophagy as promising therapeutic approaches in treating ischemic stroke clinically. [ABSTRACT FROM AUTHOR]

Background: Sex differences in oxidative stress-associated cognitive decline are influenced by sex hormone levels. Notably, oxidative stress-associated neuronal cell death can be exacerbated through testosterone signaling via membrane androgen receptor AR45, which is complexed with G protein Gaq within plasma membrane-associated lipid rafts. The objective of this study was to elucidate the impact of sex on the expression of AR45 and Gaq in brain regions associated with cognitive function, specifically hippocampus subregions and entorhinal cortex. Additionally, we investigated whether chronic intermittent hypoxia (CIH), an oxidative stressor with sex-specific effects, would modulate AR45 and Gaq expression in these brain regions. Methods: Adult male and female Sprague-Dawley rats were exposed to CIH or normoxia (room air) during their sleep phase for 14 days. We quantified AR45 and Gaq protein expression in various cognition-associated brain regions [dorsal hippocampal CA1, CA3, dentate gyrus (DG), and entorhinal cortex (ETC)] via western blotting. For comparisons, AR45 and Gaq protein expression were also assessed in brain regions outside the hippocampal-ETC circuit [thalamus (TH) and striatum (STR)]. Results: The highest AR45 levels were expressed in the hippocampal CA1 and DG while the lowest expression was observed in the extrahippocampal STR. The highest Gaq levels were expressed in the hippocampal-associated ETC while the lowest expression was observed in the extrahippocampal TH. Females expressed higher levels of AR45 in the hippocampal DG compared to males, while no sex differences in Gaq expression were observed regardless of brain region assessed. Moreover, there was no effect of CIH on AR45 or Gaq expression in any of the brain regions examined. AR45 expression was positively correlated with Gaq expression in the CA1, DG, ETC, TH, and STR in a sex-dependent manner. Conclusion: Our findings reveal enrichment of AR45 and Gaq protein expression within the hippocampal-ETC circuit, which is vulnerable to oxidative stress and neurodegeneration during cognitive decline. Nonetheless, CIH does not modulate the expression of AR45 or Gaq. Importantly, there are sex differences in AR45 expression and its association with Gaq expression in various brain regions, which may underlie sex-specific differences in cognitive and motor functionassociated declines with aging. [ABSTRACT FROM AUTHOR]

Prolonged disorder of consciousness (DoC) is a rising challenge. Pediatric data on diagnosis and prognosis of prolonged DoC were too limited and heterogeneous, making it difficult to define the natural course and evaluate the prognosis. The present study explored the emergence from the Minimally Conscious State (eMCS) incidence at different months postinjury drawing the natural course, and detected the predictors of the incidence in children with prolonged DoC. A hospital-based prospective cohort study was conducted. Kaplan–Meier curves, as well as univariate and multivariate COX regression analysis, were performed. The study enrolled 383 pediatric DoC individuals, including 220 males (57.4%), with an average age of 3.9 (1.9–7.3) years. The median duration between onset and rehabilitation is 30.0 (21.0–46.0) days. At enrollment, the ratio of vegetative state/unresponsive wakefulness syndrome (VS/WUS) to MCS is 78.9%–21.1%. Traumatic brain injury and infection are the major etiologies (36.8% and 37.1%, respectively), followed by hypoxia cerebral injury (12.3%). For children with prolonged DoC, the cumulative incidence of eMCS at months 3, 6, 12, and 24 was 0.510, 0.652, 0.731, 0.784 VS 0.290, 0.418, 0.539, 0.603 in the traumatic VS non-traumatic subgroup, respectively. For children in a persistent vegetative state (PVS), the cumulative incidence of emergence at months in 3, 6, 12, 24, 36 and 48 was testified as 0.439, 0.591, 0.683, 0.724, 0.743 and 0.743 in the traumatic subgroup, and 0.204, 0.349, 0.469, 0.534, 0.589 and 0.620 in the non-traumatic subgroup. Participants who exhibit any of the following four demographical and/or clinical characteristics—namely, older than 4 years at onset, accepted rehabilitation within 28 days of onset, remained MCS at enrollment, or with etiology of traumatic brain injuries—had a significantly positive outcome of consciousness recovery (eMCS). Moreover, both prolongation of the central somatosensory conductive time (CCT) (level 2) and absence of N20 (level 3) independently predict a negative outcome. In children with prolonged DoC, we found that 12 months postinjury was critical to eMCS, and a preferred timepoint to define chronic vegetative state (VS). The characteristics including age, etiology, time before rehabilitation, consciousness state, and SEP results were useful predictors of conscious recovery. Trial registration Registered 06/11/2018, the registration number is chiCTR1800019330 (chictr.org.cn). Registered prospectively. [ABSTRACT FROM AUTHOR]

Background: Acute hypobaric hypoxia-induced brain injury has been a challenge in the health management of mountaineers; therefore, new neuroprotective agents are urgently required. Meldonium, a well-known cardioprotective drug, has been reported to have neuroprotective effects. However, the relevant mechanisms have not been elucidated. We hypothesized that meldonium may play a potentially novel role in hypobaric hypoxia cerebral injury. Methods: We initially evaluated the neuroprotection efficacy of meldonium against acute hypoxia in mice and primary hippocampal neurons. The potential molecular targets of meldonium were screened using drug-target binding Huprot™ microarray chip and mass spectrometry analyses after which they were validated with surface plasmon resonance (SPR), molecular docking, and pull-down assay. The functional effects of such binding were explored through gene knockdown and overexpression. Results: The study clearly shows that pretreatment with meldonium rapidly attenuates neuronal pathological damage, cerebral blood flow changes, and mitochondrial damage and its cascade response to oxidative stress injury, thereby improving survival rates in mice brain and primary hippocampal neurons, revealing the remarkable pharmacological efficacy of meldonium in acute high-altitude brain injury. On the one hand, we confirmed that meldonium directly interacts with phosphoglycerate kinase 1 (PGK1) to promote its activity, which improved glycolysis and pyruvate metabolism to promote ATP production. On the other hand, meldonium also ameliorates mitochondrial damage by PGK1 translocating to mitochondria under acute hypoxia to regulate the activity of TNF receptor-associated protein 1 (TRAP1) molecular chaperones. Conclusion: These results further explain the mechanism of meldonium as an energy optimizer and provide a strategy for preventing acute hypobaric hypoxia brain injury at high altitudes. [ABSTRACT FROM AUTHOR]

Purpose: Applied Behavior Analysis (ABA) tact-training was provided to an adult with post-stroke anomic aphasia, with the main purposes to improve naming of pictures, with a possible generalization to another different setting, through telehealth sessions. Method: The Multiple probe experimental design across behaviors was used. Two sets of stimuli were used (SET 1 and SET 2), including 60 laminated photos, belonging to three different categories for each set. Procedure included the baseline, the intervention phases (face-to-face and telehealth sessions), and the follow-up (1 month after the end of a tact training). Results: For both, SET 1 and SET 2, the mastery criterion (80% correct stimulus tacts, for three consecutive times, simultaneously for all categories) was achieved. No increased percentage of correct picture tacts was found for untrained items. At follow-up, the patient provided 70 to 100% correct responses. For both SET 1 and SET 2, telehealth did not modify the correct response trends. Conclusion: The results of our study seem to suggest that specific tact-training procedures might be successfully carried out in adult and elderly people with post-stroke aphasia. It also appears necessary to arrange protocols providing telehealth sessions, with benefits for both families and the health system. [ABSTRACT FROM AUTHOR]

Objective Hydroxychloroquine (HCQ) has immunomodulatory, antithrombotic, cardiovascular, antimicrobial, and antineoplastic effects. In this study, we aimed to investigate the antiapoptotic and immunomodulator effects of intraperitoneal HCQ on hypoxic–ischemic (HI) injury in newborn rats. Study Design Wistar albino rats, 7 to 10 days old, were randomly divided into three groups: hypoxic–ischemic encephalopathy (HIE) group, HIE treated with HCQ group, and Sham group. Left common carotid artery ligation and hypoxia model were performed in HIE and HCQ groups. The HCQ group was treated with 80 mg/kg intraperitoneal HCQ every 24 hours for 3 days, while Sham and HIE groups were given physiological saline. After 72 hours, rats were decapitated and brain tissues were stained with hematoxylin and eosin, TUNEL, and IL-1β for histopathological grading and neuronal cell injury. Results Neuronal apoptosis was statistically lower in all neuroanatomical areas in the HCQ group compared with the HIE group. IL-1β-stained areas were similar in both HCQ and HIE groups but significantly higher compared with the Sham group. Histopathological grading scores were found to be lower in the HCQ group on the left parietal cortex and hippocampus region. Conclusion In this study, we have shown for the first time that HCQ treatment decreased apoptosis in HI newborn rat model in both hemispheres. HCQ may be a promising adjuvant therapy in neonatal HIE. Key Points HCQ decreased neuronal apoptosis in the ischemic penumbra of the rat brain. HCQ attenuates hypoxia–ischemia-induced brain injury in neonatal rats. HCQ has no anti-inflammatory effect on HI injury. [ABSTRACT FROM AUTHOR]

This study aims to investigate the neuroprotective effects of cannabidiol (CBD) on neurodevelopmental impairments in rats subjected to neonatal hypoxia, specifically examining its potential to mitigate motor and sensory deficits without the confounding effects of ischemia. Neonatal Sprague-Dawley rats were allocated to one of four groups: Control, Control-CBD, Hypoxia, and Hypoxia-CBD. Hypoxia was induced on postnatal days 0 and 1. CBD (50 mg/kg) was administered orally for 14 days starting at postnatal day 0. Neurodevelopmental outcomes were assessed using the Neurodevelopmental Reflex Testing in Neonatal Rat Pups scale and the Revised Neurobehavioral Severity Scale for rodents. Statistical analyses were conducted using two-way and one-way ANOVA, with Tukey's post-hoc tests for group comparisons. Pup weights were recorded on specified postnatal days, with no significant differences observed across the groups (p = 0.1834). Significant neurological impairments due to hypoxia were noted in the Control group compared to the Hypoxia group, particularly in hindlimb grasping on postnatal day 3 (p = 0.0025), posture on postnatal day 12 (p = 0.0073), and in general balance and sound reflex on postnatal day 20 (p = 0.0016 and p = 0.0068, respectively). Additionally, a statistically significant improvement in posture was observed in the Hypoxia-CBD group compared to the Hypoxia group alone (p = 0.0024). Our findings indicate that CBD possesses neuroprotective properties that significantly counteract the neurodevelopmental impairments induced by neonatal hypoxia in rats. This study not only supports the therapeutic potential of CBD in managing conditions characterized by neurodevelopmental challenges due to hypoxia but also underscores the necessity for further investigation into the specific molecular mechanisms driving CBD's neuroprotective effects. Further research is essential to explore CBD's clinical applications and its potential role in treating human neurodevelopmental disorders. [ABSTRACT FROM AUTHOR]

The decision to intubate a patient with acute hypoxemic respiratory failure who is not in apparent respiratory distress is one of the most difficult clinical decisions faced by intensivists. A conservative approach exposes patients to the dangers of hypoxemia, while a liberal approach exposes them to the dangers of inserting an endotracheal tube and invasive mechanical ventilation. To assist intensivists in this decision, investigators have used various thresholds of peripheral or arterial oxygen saturation, partial pressure of oxygen, partial pressure of oxygen-to-fraction of inspired oxygen ratio, and arterial oxygen content. In this review we will discuss how each of these oxygenation indices provides inaccurate information about the volume of oxygen transported in the arterial blood (convective oxygen delivery) or the pressure gradient driving oxygen from the capillaries to the cells (diffusive oxygen delivery). The decision to intubate hypoxemic patients is further complicated by our nescience of the critical point below which global and cerebral oxygen supply become delivery-dependent in the individual patient. Accordingly, intubation requires a nuanced understanding of oxygenation indexes. In this review, we will also discuss our approach to intubation based on clinical observations and physiologic principles. Specifically, we consider intubation when hypoxemic patients, who are neither in apparent respiratory distress nor in shock, become cognitively impaired suggesting emergent cerebral hypoxia. When deciding to intubate, we also consider additional factors including estimates of cardiac function, peripheral perfusion, arterial oxygen content and its determinants. It is not possible, however, to pick an oxygenation breakpoint below which the benefits of mechanical ventilation decidedly outweigh its hazards. It is futile to imagine that decision making about instituting mechanical ventilation in an individual patient can be condensed into an algorithm with absolute numbers at each nodal point. In sum, an algorithm cannot replace the presence of a physician well skilled in the art of clinical evaluation who has a deep understanding of pathophysiologic principles. [ABSTRACT FROM AUTHOR]

Why you should read this article: • To recognise the importance of speaking up in emergency care settings to enhance patient safety • To be aware of the barriers that can prevent nurses from speaking up • To enhance your knowledge of structured assessment and communication frameworks that can support nurses to speak up. Nurses’ competence and confidence in raising concerns with senior clinicians is integral to patient safety and the quality of patient care. If nurses do not speak up when needed it can contribute to incidences of failure to rescue. There are many barriers to nurses speaking up in busy emergency departments and complex major trauma patient cases. Assessment and communication tools such as the SBAR (situation, background, assessment, recommendation) approach and communication techniques such as graded assertiveness can help to overcome some of these barriers. This article uses a case study to discuss how nurses can respectfully but efficiently escalate their concerns to the trauma team leader. It describes barriers to nurses speaking up and tools that can support nurses to speak up, with a focus on graded assertiveness. [ABSTRACT FROM AUTHOR]

Background: The effect of two lung ventilation (TLV) with carbon dioxide artificial pneumothorax on cerebral desaturation and postoperative neurocognitive changes in elderly patients undergoing elective minimally invasive esophagectomy (MIE) is unclear. Objectives: The first aim of this study was to compare the effect of TLV and one lung ventilation (OLV) on cerebral desaturation. The second aim was to assess changes in early postoperative cognitive outcomes of two ventilation methods. Methods: This prospective, randomized, controlled trial enrolled patients 65 and older scheduled for MIE. Patients were randomly assigned (1:1) to TLV group or OLV group. The primary outcome was the incidence of cerebral desaturation events (CDE). Secondary outcomes were the cumulative area under the curve of desaturation for decreases in regional cerebral oxygen saturation (rSO2) values below 20% relative to the baseline value (AUC.20) and the incidence of delayed neurocognitive recovery. Results: Fifty-six patients were recruited between November 2019 and August 2020. TLV group had a lower incidence of CDE than OLV group [3 (10.71%) vs. 13 (48.14%), P = 0.002]. TLV group had a lower AUC.20 [0 (0–35.86) % min vs. 0 (0–0) % min, P = 0.007], and the incidence of delayed neurocognitive recovery [2 (7.4%) vs. 11 (40.7%), P = 0.009] than OLV group. Predictors of delayed neurocognitive recovery on postoperative day 7 were age (OR 1.676, 95% CI 1.122 to 2.505, P = 0.006) and AUC.20 (OR 1.059, 95% CI 1.025 to 1.094, P < 0.001). Conclusion: Compared to OLV, TLV had a lower incidence of CDE and delayed neurocognitive recovery in elderly patients undergoing MIE. The method of TLV combined with carbon dioxide artificial pneumothorax may be an option for these elderly patients. Chinese Clinical Trial Registry (identifier: ChiCTR1900027454). [ABSTRACT FROM AUTHOR]

Dynamic cerebral autoregulation (dCA) is the mechanism that describes how the brain maintains cerebral blood flow approximately constant in response to short‐term changes in arterial blood pressure. This is known to be impaired in many different pathological conditions, including ischaemic and haemorrhagic stroke, dementia and traumatic brain injury. Many different approaches have thus been used both to analyse and to quantify this mechanism in a range of healthy and diseased subjects, including data‐driven models (in both the time and the frequency domain) and biophysical models. However, despite the substantial body of work on both biophysical models and data‐driven models of dCA, there remains little work that links the two together. One of the reasons for this is proposed to be the discrepancies between the time constants that govern dCA in models and in experimental data. In this study, the processes that govern dCA are examined and it is proposed that the application of biophysical models remains limited due to a lack of understanding about the physical processes that are being modelled, partly due to the specific model formulation that has been most widely used (the equivalent electrical circuit). Based on the analysis presented here, it is proposed that the two most important time constants are arterial transit time and feedback time constant. It is therefore time to revisit equivalent electrical circuit models of dCA and to develop a more physiologically realistic alternative, one that can more easily be related to experimental data. Key points: Dynamic cerebral autoregulation is governed by two time constants.The first time constant is the arterial transit time, rather than the traditional 'RC' time constant widely used in previous models.This arterial transit time is approximately 1 s in the brain.The second time constant is the feedback time constant, which is less accurately known, although it is somewhat larger than the arterial transit time.The equivalent electrical circuit model of dynamic cerebral autoregulation should be replaced with a more physiologically representative model. [ABSTRACT FROM AUTHOR]

Brain hypoxia is associated with a wide range of physiological and clinical conditions. Although oxygen is an essential constituent of maintaining brain functions, our understanding of how specific brain cell types globally respond and adapt to decreasing oxygen conditions is incomplete. In this study, we exposed mouse primary neurons, astrocytes, and microglia to normoxia and two hypoxic conditions and obtained genome-wide transcriptional profiles of the treated cells. Analysis of differentially expressed genes under conditions of reduced oxygen revealed a canonical hypoxic response shared among different brain cell types. In addition, we observed a higher sensitivity of neurons to oxygen decline, and dissected cell type-specific biological processes affected by hypoxia. Importantly, this study establishes novel gene modules associated with brain cells responding to oxygen deprivation and reveals a state of profound stress incurred by hypoxia. [ABSTRACT FROM AUTHOR]

Most currently available wearable devices to noninvasively detect hypoxia use the spatially resolved spectroscopy (SRS) method to calculate cerebral tissue oxygen saturation (StO2). This study applies the single source—detector separation (SSDS) algorithm to calculate StO2. Near-infrared spectroscopy (NIRS) data were collected from 26 healthy adult volunteers during a breath-holding task using a wearable NIRS device, which included two source—detector separations (SDSs). These data were used to derive oxyhemoglobin (HbO) change and StO2. In the group analysis, both HbO change and StO2 exhibited significant change during a breath-holding task. Specifically, they initially decreased to minimums at around 10 s and then steadily increased to maximums, which were significantly greater than baseline levels, at 25–30 s (p-HbO < 0.001 and p-StO2 < 0.05). However, at an individual level, the SRS method failed to detect changes in cerebral StO2 in response to a short breath-holding task. Furthermore, the SSDS algorithm is more robust than the SRS method in quantifying change in cerebral StO2 in response to a breath-holding task. In conclusion, these findings have demonstrated the potential use of the SSDS algorithm in developing a miniaturized wearable biosensor to monitor cerebral StO2 and detect cerebral hypoxia. [ABSTRACT FROM AUTHOR]

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury. [ABSTRACT FROM AUTHOR]

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients and prevented the use of oxygen‐related endpoints to evaluate the consequences of respiratory depression. In a community setting when such oxygenation procedures are not immediately available, our model suggests that the higher oxygen demand and reduced cerebrovascular reactivity could make children more susceptible to severe hypoxemia and brain hypoxia, even with the same plasma fentanyl concentration as adults. Our work indicates that when developing intervention strategies to protect children from opioid overdose in a community setting, these pediatric‐specific factors may need to be considered. [ABSTRACT FROM AUTHOR]

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis. [ABSTRACT FROM AUTHOR]

This report delineates the intricate diagnostic journey and therapeutic conundrum presented by a 61-year-old male who exhibited atypical neurological deterioration shortly after lumbar fusion surgery, manifesting clinical and radiological features suggestive of pseudohypoxic encephalopathy, an entity characterized by symptoms mimicking cerebral hypoxia in the absence of a discernible hypoxic insult. Following an initially unremarkable recovery from an elaborate spinal surgery, the patient's postoperative condition was confounded by a perplexing decline in consciousness, unresponsive to conventional therapeutic interventions and devoid of clear etiological indicators on standard neuroimaging. The subsequent diagnostic odyssey unraveled a cerebrospinal fluid leak as the putative reason, positing a nuanced clinical paradigm wherein the cerebrospinal fluid leak engendered a state mimicking pseudohypoxic brain swelling. This report underscores the clinical challenges and emphasizes the need for an astute diagnostic approach in postoperative patients with unexplained neurological symptoms advocating for a comprehensive evaluation to identify underlying cerebrospinal fluid leaks and mitigate potential morbidity. [ABSTRACT FROM AUTHOR]

Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron , Ren et al. 1 identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain. Preterm infants can face lasting neurodevelopmental challenges due to hypoxia-induced injury of the cerebral white matter. In this issue of Neuron , Ren et al. identify microvascular pericytes as unexpected targets for growth hormone signaling, which enhances angiogenesis and remyelination after hypoxic injury in the developing mouse brain. [ABSTRACT FROM AUTHOR]

Objective The objective of this article was to correlate hypotension and cerebral saturation from near-infrared spectroscopy (cNIRS) in neonates on dopamine. Study Design Retrospective review of neonates receiving dopamine between August 2018 and 2019 was performed. Hypotension thresholds included mean arterial pressure (MAP) of postmenstrual age (PMA) ± 5 and 30 mm Hg and gestational age (GA) ± 5 mm Hg. Time below threshold MAP was compared with time with cerebral hypoxia (cNIRS <55%). Results Hypotension occurred 6 to 33% of the time on dopamine in 59 cases. Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes. Hypotensive periods with MAP < GA had fewer corresponding percent time with abnormal cNIRS events (3.7 ± 1.3%) compared with MAP < PMA (11.9 ± 4.9%, p < 0.003) or 30 mm Hg thresholds (12.2 ± 4.7%, p < 0.0001). In most premature infants, mean cNIRS values during hypotension were still within normal range (57 ± 6%). Conclusion cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension. Key Points Hypotension occurred 6 to 33% of the time on dopamine in 59 cases. Hypotension did not correlate with abnormal cNIRS overall, within PMA subgroups or by outcomes. MAP We found no cNIRS difference between IVH grades, mortality, average Hct, lactates, or urine output. cNIRS may be a more clinically relevant measure than MAP for the assessment of neonatal hypotension. [ABSTRACT FROM AUTHOR]

An APGAR score of 0 at 10 minutes is usually associated with high mortality and poor outcomes for the neonate, including lifelong deficits, severe hypoxic brain injury, and even death. Additionally, neonatal exposure to substances such as methamphetamines plays a role in developmental delays and meeting neurobehavioral milestones. In this case of a baby with APGARS of 0 at 1, 5, and 10 minutes, as well as in utero exposure to methamphetamines and complicated delivery, the risk of early demise was high. The aggressive resuscitation at birth and continued care in the NICU resulted in significantly less damage than what was expected. It is important to note that despite multiple factors contributing to the prediction of poor outcomes, early and attentive care of the newborn can play a vital role in recovery and a fighting chance. [ABSTRACT FROM AUTHOR]

Purpose. Glioblastoma is the most aggressive primary brain tumor, characterized by its distinctive intratumoral hypoxia. Sequential preoperative examinations using fluorine-18-fluoromisonidazole (18F-FMISO) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) could depict the degree of glucose metabolism with hypoxic condition. However, molecular mechanism of glucose metabolism under hypoxia in glioblastoma has been unclear. The aim of this study was to identify the key molecules of hypoxic glucose metabolism. Methods. Using surgically obtained specimens, gene expressions associated with glucose metabolism were analyzed in patients with glioblastoma (n = 33) who underwent preoperative 18F-FMISO and 18F-FDG PET to identify affected molecules according to hypoxic condition. Tumor in vivo metabolic activities were semiquantitatively evaluated by lesion-normal tissue ratio (LNR). Protein expression was confirmed by immunofluorescence staining. To evaluate prognostic value, relationship between gene expression and overall survival was explored in another independent nonoverlapping clinical cohort (n = 17) and validated by The Cancer Genome Atlas (TCGA) database (n = 167). Results. Among the genes involving glucose metabolic pathway, mRNA expression of glucose-6-phosphatase 3 (G6PC3) correlated with 18F-FDG LNR (P = 0.03). In addition, G6PC3 mRNA expression in 18F-FMISO high-accumulated glioblastomas was significantly higher than that in 18F-FMISO low-accumulated glioblastomas (P < 0.01). Protein expression of G6PC3 was consistent with mRNA expression, which was confirmed by immunofluorescence analysis. These findings indicated that the G6PC3 expression might be facilitated by hypoxic condition in glioblastomas. Next, we investigated the clinical relevance of G6PC3 in terms of prognosis. Among the glioblastoma patients who received gross total resection, mRNA expressions of G6PC3 in the patients with poor prognosis (less than 1-year survival) were significantly higher than that in the patients who survive more than 3 years. Moreover, high mRNA expression of G6PC3 was associated with poor overall survival in glioblastoma, as validated by TCGA database. Conclusion. G6PC3 was affluently expressed in glioblastoma tissues with coincidentally high 18F-FDG and 18F-FMISO accumulation. Further, it might work as a prognostic biomarker of glioblastoma. Therefore, G6PC3 is a potential key molecule of glucose metabolism under hypoxia in glioblastoma. [ABSTRACT FROM AUTHOR]

Introduction: Severe acute global cerebral hypoxia can lead to significant disability in humans. Although different animal models have been described to study hypoxia, there is no endogenous model that considers hypoxia and its effect on the brain as an independent factor. Thus, we developed a minimally invasive rat model, which is based on the non-depolarizing muscle blocking agent rocuronium in anesthetized animals. This drug causes respiratory insufficiency by paralysis of the striated muscles. Methods: In this study, 14 rats underwent 12 min of hypoxemia with an oxygen saturation of approximately 60% measured by pulse oximetry; thereafter, animals obtained sugammadex to antagonize rocuronium immediately. Results: Compared to controls (14 rats, anesthesia only), hypoxic animals demonstrated significant morphological alterations in the hippocampus (cell decrease in the CA 1 region) and the cerebellum (Purkinje cell decrease), as well as significant changes in hypoxia markers in blood (Hif2α, Il1β, Tgf1β, Tnfα, S100b, cspg2, neuron-specific enolase), hippocampus (Il1β, Tnfα, S100b, cspg2, NSE), and cerebellum (Hif1α, Tnfα, S100b, cspg2, NSE). Effects were more pronounced in females than in males. Discussion: Consequently, this model is suitable to induce hypoxemia with consecutive global cerebral hypoxia. As significant morphological and biochemical changes were proven, it can be used to investigate therapeutic and preventive drugs for global cerebral hypoxia. [ABSTRACT FROM AUTHOR]

This review advances an understanding of several dementias, based on four premises. One is that capillary hemorrhage is prominent in the pathogenesis of the dementias considered (dementia pugilistica, chronic traumatic encephalopathy, traumatic brain damage, Alzheimer's disease). The second premise is that hemorrhage introduces four neurotoxic factors into brain tissue: hypoxia of the tissue that has lost its blood supply, hemoglobin and its breakdown products, excitotoxic levels of glutamate, and opportunistic pathogens that can infect brain cells and induce a cytotoxic immune response. The third premise is that where organisms evolve molecules that are toxic to itself, like the neurotoxicity ascribed to hemoglobin, amyloid- (A), and glutamate, there must be some role for the molecule that gives the organism a selection advantage. The fourth is the known survival-advantage roles of hemoglobin (oxygen transport), of A (neurotrophic, synaptotrophic, detoxification of heme, protective against pathogens) and of glutamate (a major neurotransmitter). From these premises, we propose 1) that the brain has evolved a multi-factor response to intracerebral hemorrhage, which includes the expression of several protective molecules, including haptoglobin, hemopexin and A; and 2) that it is logical, given these premises, to posit that the four neurotoxic factors set out above, which are introduced into the brain by hemorrhage, drive the progression of the capillary-hemorrhage dementias. In this view, A expressed at the loci of neuronal death in these dementias functions not as a toxin but as a first responder, mitigating the toxicity of hemoglobin and the infection of the brain by opportunistic pathogens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Exposure to hypoxic conditions can result in significant brain damage, such as that experienced during an ischemic stroke. Thus, finding ways to mitigate ischemia/hypoxia-induced brain tissue damage is a critical issue that needs addressing. HH-A, a derivative of honokiol, has demonstrated potent pharmacological activities and medicinal properties in treating brain ischemia/reperfusion injury. However, its effect on anti-hypoxic responses during stroke remains largely unexplored. In the present study, we subjected male Sprague-Dawley rats to 24 h of hypoxia (oxygen content at 11%) or to 7 d of permanent middle cerebral artery occlusion. We discovered that both 1 mg/kg (i.v.) and 40 mg/kg (i.g.) of HH-A elevated arterial oxygen saturation after 24 h of hypoxia and significantly reduced the infarct volume after 7 d of ischemia. Furthermore, fluorescence staining with hypoxyprobe-1 indicated that HH-A significantly mitigated the severity of hypoxia in brain tissue. Hematoxylin and eosin staining, along with neuronal nuclei immunofluorescent staining, further revealed that HH-A curbed the death of brain cells. To identify potential protein partners of HH-A, we used a molecular fishing approach based on surface plasmon resonance technology. A high binding affinity was detected between HH-A and the hemoglobin subunit beta, with an estimated binding free energy of -8.7 kcal/mol. These findings suggested that HH-A was capable of enhancing hypoxia tolerance and alleviating brain injury caused by ischemia. [ABSTRACT FROM AUTHOR]

Background: Cerebral ischemia–hypoxia leads to excitotoxicity‐mediated neuronal damage and cognitive dysfunction, especially in the elderly. Excessive intracellular [Cl−]i accumulation weakens γ‐aminobutyric acid (GABA) compensatory effects. Sub‐anesthetic dose of propofol protected the brain against ischemia–hypoxia, which was abolished by blocking Cl− efflux transporter K+/Cl− cotransporter 2 (KCC2). We aimed to determine whether low‐dose anesthetic combined with [Cl−]i regulators could restore the compensatory GABAergic system and improve cognitive function. Methods: Chronic cerebral hypoxia (CCH) model was established by bilateral carotid artery ligation in aged rats. Sub‐dose of anesthetics (propofol and sevoflurane) with or without KCC2 agonist N‐ethylmaleimide (NEM) or Na+/K+/Cl− cotransporter 1 (NKCC1) antagonist bumetanide (BTN) was administered systemically 30 days post‐surgery. Primary rat hippocampal neuronal cultures were subjected to hypoxic injury with or without drug treatment. Memory function, hippocampal neuronal survival, GABAergic system functioning, and brain‐derived neurotrophic factor (BDNF) expressions were evaluated. Results: Sub‐anesthetic dose of combined propofol (1.2 μg mL−1) and sevoflurane [0.7 MAC (minimum alveolar concentration)] did not aggravate the hypoxic brain injury in rats or cell damage in neuronal cultures. Adding either BTN or NEM protected against hypoxic injury, associated with improved cognitive function in vivo, less intracellular accumulation of [Cl−]i, reduced cell death, restored GABAergic compensation, and increased BDNF expression both in vivo and in vitro. Conclusion: Sub‐anesthetic dose of propofol and sevoflurane is a recommended anesthesia regimen in at‐risk patients. Restoration of [Cl−]i homeostasis and GABAergic could further reduce the brain damage caused by ischemia–hypoxia. [ABSTRACT FROM AUTHOR]

The levels and potential role of prolactin (PRL) in the brain under conditions of acute systemic hypoxia were examined, focusing on the accumulation of PRL in cerebrospinal fluid (CSF) and its effects on neuronal activity and injury. The amount of PRL in the brain was investigated using brain tissues from forensic autopsy cases. We counted the number of neurites that formed in human primary neurons (HNs) after the addition of PRL. Furthermore, HNs supplemented with PRL or triiodothyronine (T3) were exposed to hypoxic conditions, and the dead cells were counted. The results showed correlations between brain PRL and CSF PRL levels. Additionally, PRL accumulation in the brain was observed in cases of asphyxia. In vitro experimental findings indicated increased neurite formation in the HNs treated with PRL. Moreover, both PRL and T3 demonstrated neuroprotective effects against hypoxia-induced neuronal cell death, with PRL showing stronger neuroprotective potential than T3. These results suggest that PRL accumulates in the brain during hypoxia, potentially influences neuronal activity, and exhibits neuroprotective properties against hypoxia-induced neuronal injury. [ABSTRACT FROM AUTHOR]

Objectives: Literature on invasive neuromonitoring and bilateral decompressive craniectomies (BDC) in patients with refractory status epilepticus (RSE)-mediated hypoxic-ischemic brain injury (HIBI) is limited. Neuromonitoring can guide decision making and treatment escalation. Methods and results: We report a case of a 17  years-old male who was admitted to our hospital’s intensive care unit for RSE. HIBI was detected on neuroimaging on this patient’s second day of admission after he developed central diabetes insipidus (DI). Invasive neuromonitoring revealed raised intracranial pressure (ICP) and brain hypoxia as measured by reduced brain tissue oxygen tension (PbtO2). Treatments were escalated in a tiered fashion, including administration of hyperosmolar agents, analgesics, sedatives, and a neuromuscular blocking drug. Eventually, BDC was performed as a salvage therapy as a means of controlling refractory ICP crisis in the setting of diffuse cerebral edema (DCE) following HIBI. Discussion: SE-mediated HIBI can result in refractory ICP crisis. Neuromonitoring can help identify secondary brain injury (SBI), guide treatment strategies, including surgical interventions, and may lead to better outcomes. [ABSTRACT FROM AUTHOR]

Summary: Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra‐operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α2‐agonist, dexmedetomidine. We tested the effects of dexmedetomidine on renal and cerebral microcirculatory tissue perfusion, oxygenation and histology in a clinically relevant ovine model. Sixteen sheep were studied while conscious, after induction of anaesthesia and during 2 h of cardiopulmonary bypass. Eight sheep were allocated randomly to receive an intravenous infusion of dexmedetomidine (0.4–0.8 μg.kg‐1.h‐1) from induction of anaesthesia to the end of cardiopulmonary bypass, and eight to receive an equivalent volume of matched placebo (0.9% sodium chloride). Commencement of cardiopulmonary bypass decreased renal medullary tissue oxygenation in the placebo group (mean (95%CI) 5.96 (4.24–7.23) to 1.56 (0.84–2.09) kPa, p = 0.001), with similar hypoxic levels observed in the dexmedetomidine group (6.33 (5.33–7.07) to 1.51 (0.33–2.39) kPa, p = 0.002). While no differences in kidney function (i.e. reduced creatinine clearance) were evident, a greater incidence of histological renal tubular injury was observed in sheep receiving dexmedetomidine (7/8 sheep) compared with placebo (2/8 sheep), p = 0.041. Graded on a semi‐quantitative scale (0–3), median (IQR [range]) severity of histological renal tubular injury was higher in the dexmedetomidine group compared with placebo (1.5 (1–2 [0–3]) vs. 0 (0–0.3 [0–1]) respectively, p = 0.013). There was no difference in cerebral tissue microglial activation (neuroinflammation) between the groups. Dexmedetomidine did not reduce renal medullary hypoxia or cerebral neuroinflammation in sheep undergoing cardiopulmonary bypass. [ABSTRACT FROM AUTHOR]

The following review considers current concepts concerning the characteristics of DRP1-related mitochondrial division in brain cells during hypoxic-ischemic pathology. The functional role of DRP1 in neurons and astroglia in cerebral ischemia conditions was analyzed. We discuss the potential for regulating DRP1 activity through the selective inhibitor of mitochondrial fission, mdivi-1. The article also presents data on DRP1 involvement in astro- and microglia-mediated intercellular mitochondrial transport. Understanding of the molecular mechanisms responsible for mitochondrial fission during hypoxic-ischemic exposure will allow us to consider DRP1 as an effective therapeutic target for treating conditions with a hypoxic component. [ABSTRACT FROM AUTHOR]

Background and purpose: The prognosis of prolonged (28 days to 3 months post‐onset) disorders of consciousness (pDoC) due to anoxic brain injury is uncertain. The present study aimed to evaluate the long‐term outcome of post‐anoxic pDoC and identify the possible predictive value of demographic and clinical information. Method: This is a systematic review and meta‐analysis. The rates of mortality, any improvement in clinical diagnosis, and recovery of full consciousness at least 6 months after severe anoxic brain injury were evaluated. A cross‐sectional approach searched for differences in baseline demographic and clinical characteristics between survivors and non‐survivors, patients improved versus not improved, and patients who recovered full consciousness versus not recovered. Results: Twenty‐seven studies were identified. The pooled rates of mortality, any clinical improvement and recovery of full consciousness were 26%, 26% and 17%, respectively. Younger age, baseline diagnosis of minimally conscious state versus vegetative state/unresponsive wakefulness syndrome, higher Coma Recovery Scale Revised total score, and earlier admission to intensive rehabilitation units were associated with a significantly higher likelihood of survival and clinical improvement. These same variables, except time of admission to rehabilitation, were also associated with recovery of full consciousness. Conclusions: Patients with anoxic pDoC might improve over time up to full recovery of consciousness and some clinical characteristics can help predict clinical improvement. These new insights could support clinicians and caregivers in the decision‐making on patient management. [ABSTRACT FROM AUTHOR]

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterised by recurrent subcortical ischemic events, migraine with aura, dementia and mood disturbance. Strokes are typically lacunar infarcts; however, bilateral multiple subcortical lacunar infarcts have been described only sporadically. Method: We described four CADASIL patients who presented with acute bilateral multiple subcortical infarcts as the first manifestation. We also briefly summarised the case reports detailing the bilateral multiple infarcts in CADASIL. Results: Patient 1 and patient 2 were family members, and they presented with cognitive impairment. Patient 3 and patient 4 presented with slurred speech and hemiparesis. Patients 1, 3 and 4 developed hemodynamic fluctuations before the occurrence of ischemic stroke. Laboratory tests revealed elevated fibrinogen levels in patients 3 and 4. The brain magnetic resonance imaging showed acute bilateral multiple subcortical infarcts on the periventricular white matter in all the patients. Conclusion: CADASIL, with a poor brain hemodynamic reserve, is vulnerable to hemodynamic alterations (e.g. blood pressure fluctuation, dehydration, blood loss and anaemia) and intolerable to ischemia and hypoxia of the brain. Furthermore, blood hypercoagulation may contribute to acute multiple bilateral infarctions in CADASIL. Therefore, it is necessary to avert these predispositions in CADASIL patients in their daily life. [ABSTRACT FROM AUTHOR]

The primary afferent system in the rat's spinal cord starts to develop in the third last week of gestation. First, the pseudounipolar DRG neurons extend their centripetal long primary axons, targeting rostral supra-segmental nuclei in the spinal cord. Meanwhile, the subsequent innervation of the juxta- and intra-segmental spinal levels enables the three subdivisions to commence integrating a complex network with the body periphery. This process may continue to refine and adapt the system life-long. The experimental data elucidated the steps involved in developing the cytoarchitecture by separating the axons of the long and intermediate subdivisions from the short subdivision. Here, we present a blueprint of the features of the long primary afferent axons developing in sequential waves. The pioneering long afferent axons targeted the dorsal gracile nuclei at spring tide and Clarke's nuclei at neap tide in ventrally bent trajectories. The paradigm's myelotomy blocked these pioneering fibers from stepping down the developmental cascade, rendering an unknown phenotype. This reflected a hypothetical transition hub stationed on the assembly line, delineating a critical period. The paradigm also affected the neuropil's ripening independently from the long primary afferent system. The data disclosed that fetal hyposaturation yielded an in vivo genomic engineering capability. Fetal tissue was susceptible to hyposaturation, showing remarkable versatility early in fetal life. The translational impact may favor research into the elusive etiology of clinical syndromes concerning the afferent system relating to fetal hyposaturation. [ABSTRACT FROM AUTHOR]

Cerebral hypoxia is an important cause of secondary brain injury. Improving systemic oxygenation may increase brain tissue oxygenation (PbtO2). The effects of increased positive end-expiratory pressure (PEEP) on PbtO2 and intracranial pressure (ICP) needs to be further elucidated. This is a single center retrospective cohort study (2016–2021) conducted in a 34-bed Department of Intensive Care unit. All patients with acute brain injury under mechanical ventilation who were monitored with intracranial pressure and brain tissue oxygenation (PbtO2) catheters and underwent at least one PEEP increment were included in the study. Primary outcome was the rate of PbtO2 responders (increase in PbtO2 > 20% of baseline) after PEEP increase. ΔPEEP was defined as the difference between PEEP at 1 h and PEEP at baseline; similarly ΔPbtO2 was defined as the difference between PbtO2 at 1 h after PEEP incrementation and PbtO2 at baseline. We included 112 patients who underwent 295 episodes of PEEP increase. Overall, the median PEEP increased form 6 (IQR 5–8) to 10 (IQR 8–12) cmH2O (p = 0.001), the median PbtO2 increased from 21 (IQR 16–29) mmHg to 23 (IQR 18–30) mmHg (p = 0.001), while ICP remained unchanged [from 12 (7–18) mmHg to 12 (7–17) mmHg; p = 0.42]. Of 163 episode of PEEP increments with concomitant PbtO2 monitoring, 34 (21%) were PbtO2 responders. A lower baseline PbtO2 (OR 0.83 [0.73–0.96)]) was associated with the probability of being responder. ICP increased in 142/295 episodes of PEEP increments (58%); no baseline variable was able to identify this response. In PbtO2 responders there was a moderate positive correlation between ΔPbtO2 and ΔPEEP (r = 0.459 [95% CI 0.133–0.696]. The response in PbtO2 and ICP to PEEP elevations in brain injury patients is highly variable. Lower PbtO2 values at baseline could predict a significant increase in brain oxygenation after PEEP increase. [ABSTRACT FROM AUTHOR]

Sepsis induces neuroinflammation, BBB disruption, cerebral hypoxia, neuronal mitochondrial dysfunction, and cell death causing sepsis‐associated encephalopathy (SAE). These pathological consequences lead to short‐ and long‐term neurobehavioural deficits. Till now there is no specific treatment that directly improves SAE and its associated behavioural impairments. In this review, we discuss the underlying mechanisms of sepsis‐induced brain injury with a focus on the latest progress regarding neuroprotective effects of SIRT1 (silent mating type information regulation‐2 homologue‐1). SIRT1 is an NAD+‐dependent class III protein deacetylase. It is able to modulate multiple downstream signals (including NF‐κB, HMGB, AMPK, PGC1α and FoxO), which are involved in the development of SAE by its deacetylation activity. There are multiple recent studies showing the neuroprotective effects of SIRT1 in neuroinflammation related diseases. The proposed neuroprotective action of SIRT1 is meant to bring a promising therapeutic strategy for managing SAE and ameliorating its related behavioural deficits. [ABSTRACT FROM AUTHOR]

Background/Aim. Several serious complications can accompany both spontaneous and post-traumatic subarachnoid hemorrhage (SAH) such as the development of intracranial hypertension, hydrocephalus, re-bleeding, cerebral hypoxia, cerebral vasospasm, impaired pituitary function, electrolyte imbalance, and electrocardiographic (ECG) abnormalities. Although there is a declining trend in mortality, the treatment of SAH and its complications represents a challenge even in imposing neurosurgical centers. The aim of the study was to compare some clinical characteristics and complications between spontaneous and post-traumatic SAH. Methods. The retrospective study included 138 patients treated at the Department of Neurosurgery from January 2018 to January 2023. There were 71 patients with spontaneous and 67 patients with post-traumatic SAH. Results. A predominance of spontaneous SAH in female and post-traumatic SAH in male patients (p < 0.001) was found. There was a statistically significant difference in the frequency of hydrocephalus between groups of spontaneous and post-traumatic SAH patients (p = 0.013). Cerebral vasospasm was significantly more prevalent in patients with spontaneous SAH (p < 0.001). A statistically significant association was also obtained between the thickness of the coagu-lum in these two groups (p < 0.001). Patients with spontaneous SAH were significantly more likely to have a negative T wave in ECG findings (p < 0.001). Furthermore, there was no statistically significant difference regarding electrolyte imbalance in these two groups of patients with SAH. Conclusion. There were statistically significant differences between gender distribution, the frequency of abnormal ECG findings in the form of a negative T wave, greater coagulum thickness, vasospasm occurrence, and a higher rate of hydrocephalus in patients with spontaneous SAH compared to patients with post-traumatic SAH. [ABSTRACT FROM AUTHOR]

Purpose: Cerebral hypoxia may exacerbate the perception of fatigue. We previously demonstrated that exercise-related hypoxemia, a hallmark of fibrotic interstitial lung disease (f-ILD), dose dependently impairs cerebral oxygenation in these patients. It is unknown whether normalizing cerebral oxygenation with O2 supplementation would be associatedwith positive changes in a relevant patient-centered outcome during exercise in f-ILD, such as improved perceived fatigue. Methods: Fourteen patients (12 males, 72 ± 8 yr, 8 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide = 44% ± 13% predicted) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) breathing medical air. Fourteen controls cycled up to Tlim of an age- and sex-matched patient. Patients repeated the test on supplemental O2 (fraction of inspired O2 = 0.41 ± 0.08) for the same duration. Near-infrared spectroscopy and the rating-of-fatigue (ROF) scale assessed prefrontal cortex oxygenation and perceived fatigue, respectively. Results: Patients showed severe exertional hypoxemia (Tlim O2 saturation by pulse oximetry = 80% ± 8%); they had poorer cerebral oxygenation (e.g., oxy-deoxyhemoglobin difference [HbDiff] = -3.5 ± 4.7 [range = -17.6 to +1.9] vs +1.9 ± 1.7 µmol from rest) and greater fatigue (ROF = 6.2 ± 2.0 vs 2.6 ± 2.3) versus controls under air (P < 0.001). Reversal of exertional hypoxemia with supplemental O2 led to improved HbDiff (+1.7 ± 2.4 µmol from rest; no longer differing fromcontrols) and lower ROF scores (3.7 ± 1.2, P < 0.001 vs air) in patients. There was a significant correlation between O2-induced changes inHbDiff and ROF scores throughout exercise in f-ILD (rrepeated-measures correlation = -0.51, P < 0.001). Conclusions: Supplemental O2 improved cerebral oxygenation during exercise in f-ILD, which was moderately associated with lower ratings of perceived fatigue. Reversing cerebral hypoxia with O2 supplementation may thus have positive effects on patients' disablement beyond those expected from lower ventilation and dyspnea in this patient population. [ABSTRACT FROM AUTHOR]

Near-infrared spectroscopy (NIRS) is a noninvasive tool to monitor cerebral regional oxygen saturation. Impairment of microvascular circulation with subsequent cerebral hypoxia during delayed cerebral ischemia (DCI) is associated with poor functional outcome after subarachnoid hemorrhage (SAH). Therefore, NIRS could be useful to predict the risk for DCI and functional outcome. However, only limited data are available on NIRS regional cerebral tissue oxygen saturation (rSO 2) distribution in SAH. The aim of this study was to compare the distribution of NIRS rSO 2 values in patients with nontraumatic SAH with the occurrence of DCI and functional outcome at 2 months. In addition, the predictive value of NIRS rSO 2 was compared with the previously validated SAFIRE grade (derived from Size of the aneurysm, Age, FIsher grade, World Federation of Neurosurgical Societies after REsuscitation). In this study, the rSO 2 distribution of patients with and without DCI after SAH was compared. The optimal cutoff points to predict DCI and outcome were assessed, and its predictive value was compared with the SAFIRE grade. Of 41 patients, 12 developed DCI, and 9 had unfavorable outcome at 60 days. Prediction of DCI with NIRS had an area under the curve of 0.77 (95% confidence interval 0.62–0.92; P = 0.0028) with an optimal cutoff point of 65% (sensitivity 1.00; specificity 0.45). Prediction of favorable outcome with NIRS had an area under the curve of 0.86 (95% confidence interval 0.74–0.98; P = 0.0003) with an optimal cutoff point of 63% (sensitivity 1.00; specificity 0.63). Regression analysis showed that NIRS rSO 2 score is complementary to the SAFIRE grade. NIRS rSO 2 monitoring in patients with SAH may improve prediction of DCI and clinical outcome after SAH. [ABSTRACT FROM AUTHOR]

Introduction: Adequate sedation and analgesia are two crucial factors affecting recovery of intensive care patients. Improper use of sedation and analgesia in intensive care patients may adversely lead to brain oxygen desaturation. This study aims to determine cerebral oxygenation as measured by near-infrared spectroscopy (NIRS) and inotropic interventions received among mechanically ventilated children in the pediatric intensive care unit (PICU). Methods: This study is a nested case − control study in the PICU of Indonesian tertiary hospital. Children aged 1 month to 17 years on mechanical ventilation and were given sedation and analgesia were included in the study. Subjects were divided into two groups according to the protocol of the main study (Clinical Trial ID NCT04788589). Cerebral oxygenation was measured by NIRS at five time points (before sedation, 5-min, 1, 6, and 12 h after sedation). Results: Thirty-nine of the 69 subjects were categorized into the protocol group and the rest were in the control group. A decrease of >20% NIRS values was found among subjects in the protocol group at 5-min (6.7%), 1-h (11.1%), 6-h (26.3%), and 12-h (23.8%) time-point. The mean NIRS value was lower and the inotropic intervention was more common in the control group (without protocol), although not statistically significant. Conclusion: This study found that mechanically ventilated children who received sedation and analgesia based on the protocol had a greater decrease of >20% NIRS values compared to the other group. The use of sedation and analgesia protocols must be applied in selected patients after careful consideration. [ABSTRACT FROM AUTHOR]

This is the case of a 26-year-old male who developed Anton Babinski syndrome (ABS), quadriplegia, and delayed post-hypoxic leukoencephalopathy (DPHL) after an opioid overdose. He exhibited cortical blindness, visual anosognosia, and confabulation upon awakening. Several days later, he experienced acute psychosis and agitation. T2-FSE MRI revealed extensive supratentorial leukoencephalopathy involving both cerebral hemispheres, extending to the posterior corpus callosum due to cerebral anoxia. This case report will discuss different types of encephalopathy from opioid abuse, ABS, visual anosognosia, and confabulation's pathogenic mechanisms. It underscores the necessity of researching substance-induced neuropsychiatric disorders and their pathogenic mechanisms for effective treatments. [ABSTRACT FROM AUTHOR]

COVID-19 is a pandemic disease in which most patients have pulmonary symptoms. However, several cases of CNS involvement associated with COVID-19 have been reported. Acute necrotizing encephalopathy of childhood (ANEC) is a rare CNS complication of viral infections such as influenza, herpes virus, and COVID-19, leading to high mortality and morbidity rates. Several cases of COVID-19-associated acute necrotizing encephalopathy (ANE) have been reported since March 2020 in adults, with just a few cases in pediatrics. This article reports a 5-month-old child who presented with seizures, with the final diagnosis of ANE as a complication of COVID-19. MRI findings of ANEC, as reported in most COVID-19-associated ANEC case reports, involve bilateral, symmetric, multifocal lesions in the central thalami. Moreover, the brainstem, cerebral white matter, and cerebellum could be affected. The prognosis of COVID-19-associated ANE is poor, leading to neurologic dysfunction or mortality. COVID-19-associated ANE cases must be reported, especially in pediatrics, with detailed clinical history, laboratory data, and radiologic findings to introduce diagnostic criteria, prognosis, and a management protocol. [ABSTRACT FROM AUTHOR]