RESUMEN

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.

Asunto(s)

Espinas Dendríticas , Neuronas , Espinas Dendríticas/metabolismo , Espinas Dendríticas/patología , Animales , Humanos , Neuronas/metabolismo , Neuronas/patología , Hipoxia Encefálica/patología , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/fisiopatología

RESUMEN

Hypoxic hypoxia arises from an inadequate oxygen supply to the blood, resulting in reduced arterial oxygen partial pressure and a consequent decline in oxygen diffusion into tissue cells for utilization. This condition is characterized by diminished oxygen content in the blood, while the supply of other nutrients within the blood remains normal. The brain is particularly sensitive to oxygen deficiency, with varying degrees of hypoxic hypoxia resulting in different levels of neural functional disorder. Since the brain has a specific threshold range for the perception of hypoxic hypoxia, mild hypoxic hypoxia can trigger compensatory protective responses in the brain without affecting neural function. These hypoxic compensatory responses enable the maintenance of an adequate oxygen supply and energy substrates for neurons, thereby ensuring normal physiological functions. To further understand the hypoxic compensatory mechanisms of the central nervous system (CNS), this article explores the structural features of the brain's neurovascular unit model, hypoxic signal transduction, and compensatory mechanisms.

Asunto(s)

Encéfalo , Acoplamiento Neurovascular , Transducción de Señal , Humanos , Transducción de Señal/fisiología , Animales , Encéfalo/metabolismo , Acoplamiento Neurovascular/fisiología , Hipoxia/fisiopatología , Hipoxia/metabolismo , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/fisiopatología

RESUMEN

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.

Asunto(s)

Hipoxia Encefálica , Vaina de Mielina , Pericitos , Pericitos/metabolismo , Vaina de Mielina/metabolismo , Animales , Hipoxia Encefálica/metabolismo , Ratones , Humanos , Animales Recién Nacidos , Encéfalo/metabolismo

Asunto(s)

Paro Cardíaco , Hipoxia Encefálica , Choque Cardiogénico , Humanos , Choque Cardiogénico/epidemiología , Choque Cardiogénico/etiología , Paro Cardíaco/epidemiología , Incidencia , Hipoxia Encefálica/epidemiología , Hipoxia Encefálica/complicaciones , Hipoxia Encefálica/etiología , Masculino , Femenino , Persona de Mediana Edad , Anciano

RESUMEN

This critique evaluates a letter to the editor discussing the role of brain tissue oxygen partial pressure (PbtO2) monitoring in the prognosis of patients with traumatic brain injury (TBI). The meta-analysis aims to synthesize existing evidence, highlighting the potential of PbtO2 monitoring as an early indicator of cerebral hypoxia and its correlation with improved patient outcomes. Despite these promising findings, the analysis is constrained by significant methodological variability among the included studies, potential publication bias, and the practical challenges of implementing PbtO2 monitoring widely. The letter emphasizes the need for standardized protocols and further research to solidify the clinical utility of PbtO2 monitoring and integrate it with other monitoring strategies for comprehensive TBI management.

Asunto(s)

Lesiones Traumáticas del Encéfalo , Encéfalo , Oxígeno , Humanos , Lesiones Traumáticas del Encéfalo/diagnóstico , Lesiones Traumáticas del Encéfalo/terapia , Oxígeno/metabolismo , Pronóstico , Monitoreo Fisiológico/métodos , Hipoxia Encefálica/diagnóstico , Presión Parcial

RESUMEN

RATIONALE: Argon gas poisoning is an often overlooked yet critical public health concern with the potential for severe and persistent neurological consequences. Current treatment protocols primarily focus on acute-phase management, but a comprehensive understanding of the long-term neurological effects remains incomplete. PATIENT CONCERNS: A 22-year-old male worker was found unconscious in the furnace room of an argon production facility. After regaining consciousness, he presented with symptoms of dizziness, headache, fatigue, and irritability. Neurological examination revealed impairments in both recent and remote memory, notably pronounced short-term memory deficits and reduced arithmetic skills. DIAGNOSIS: Argon gas poisoning, hypoxic encephalopathy, and mild hepatic and renal dysfunction. INTERVENTIONS: Upon admission, symptomatic supportive measures included oxygen therapy via nasal cannula (3 L/min), daily hyperbaric oxygen therapy (1.5 ATA, 60 minutes), oral neurotrophic methylcobalamin (0.5 mg, 3 times daily), and intravenous vitamin C infusion (2 g daily) to scavenge oxygen free radicals. OUTCOME: A 2-year telephone follow-up indicated persistent short-term memory impairment, particularly with memorizing numbers. In a memory test, he achieved a digit span forward of 5 but a digit span backward of 2, indicating impairment. Despite these challenges, his daily life and work performance remained largely unaffected. LESSON: This case offers valuable insights into the biological mechanisms underlying prolonged neurological sequelae following asphyxiating gas exposure, specifically the persistent impairment of hippocampal function.

Asunto(s)

Argón , Trastornos de la Memoria , Humanos , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/terapia , Adulto Joven , Oxigenoterapia Hiperbárica/métodos , Hipoxia Encefálica/inducido químicamente , Hipoxia Encefálica/terapia

RESUMEN

BACKGROUND: Hypothermia is a neuroprotective strategy during cardiopulmonary bypass. Rewarming entailing a rapid rise in cerebral metabolism might lead to secondary neurological sequelae. In this pilot study, we aimed to validate the hypothesis that a slower rewarming rate would lower the risk of cerebral hypoxia and seizures in infants. METHODS: This is a prospective, clinical, single-center study. Infants undergoing cardiac surgery in hypothermia were rewarmed either according to the standard (+1°C in < 5 minutes) or a slow (+1°C in > 5-8 minutes) rewarming strategy. We monitored electrocortical activity via amplitude-integrated electroencephalography (aEEG) and cerebral oxygenation by near-infrared spectroscopy during and after surgery. RESULTS: Fifteen children in the standard rewarming group (age: 13 days [5-251]) were cooled down to 26.6°C (17.2-29.8) and compared with 17 children in the slow-rewarming group (age: 9 days [4-365]) with a minimal temperature of 25.7°C (20.1-31.4). All neonates in both groups (n = 19) exhibited suppressed patterns compared with 28% of the infants > 28 days (p < 0.05). During rewarming, only 26% of the children in the slow-rewarming group revealed suppressed aEEG traces (vs. 41%; p = 0.28). Cerebral oxygenation increased by a median of 3.5% in the slow-rewarming group versus 1.5% in the standard group (p = 0.9). Our slow-rewarming group revealed no aEEG evidence of any postoperative seizures (0 vs. 20%). CONCLUSION: These results might indicate that a slower rewarming rate after hypothermia causes less suppression of electrocortical activity and higher cerebral oxygenation during rewarming, which may imply a reduced risk of postoperative seizures.

Asunto(s)

Puente Cardiopulmonar , Electroencefalografía , Hipotermia Inducida , Recalentamiento , Convulsiones , Espectroscopía Infrarroja Corta , Humanos , Lactante , Estudios Prospectivos , Proyectos Piloto , Masculino , Factores de Tiempo , Recién Nacido , Femenino , Resultado del Tratamiento , Hipotermia Inducida/efectos adversos , Factores de Riesgo , Convulsiones/fisiopatología , Convulsiones/diagnóstico , Convulsiones/etiología , Convulsiones/prevención & control , Puente Cardiopulmonar/efectos adversos , Ondas Encefálicas , Hipoxia Encefálica/prevención & control , Hipoxia Encefálica/etiología , Hipoxia Encefálica/fisiopatología , Hipoxia Encefálica/diagnóstico , Factores de Edad , Monitorización Neurofisiológica Intraoperatoria , Encéfalo/metabolismo , Encéfalo/fisiopatología , Encéfalo/irrigación sanguínea , Circulación Cerebrovascular

RESUMEN

This column is the first of a 3-part series illustrating the importance of medical knowledge, including clinical pharmacology, in a forensic context. This first case involved an 18-year-old high school student who suffered an anoxic brain injury and remained in a state of permanent decorticate posture, unresponsive except for grunts and primitive movements until he died several years later. Our investigation began by ruling out plausible causes that were suggested by the defense in the malpractice suit. Once those possibilities were eliminated, the focus was on what accounted for the damage to the patient using general medical knowledge and clinical pharmacology. The 4 Ds of forensic psychiatry (duty, damages, dereliction, and direct cause) are the 4 elements that the plaintiff is required to prove in civil court to prevail in a malpractice suit and are applied to this case with a special focus on dereliction and direct cause. This catastrophic outcome was due to 3 factors. First, the patient had physiologically significant dehydration to the point that he had developed a reflex tachycardia to maintain his blood pressure. Second, the patient had been switched from extended to immediate-release quetiapine, resulting in a doubling of the peak concentration of the drug, which produced higher occupancy of alpha-1 adrenergic, histamine-1, and dopamine-2 receptors, causing a further drop in his blood pressure as well as increased sedation and impairment of his gag reflex. These effects occurred quickly because of the faster absorption of the IR formulation of the drug. Third, the patient had gone to sleep in a reclining chair so that his brain was above his heart and his lower extremities were below his heart, resulting in an increased "steal" of cardiac output going to his brain. These 3 factors together led the patient to aspirate and suffer a hypoxic brain injury after an episode of vomitus. This column explains the process by which the cause of this sad outcome was determined, how it was related to a dereliction of duty to the patient, and how other proposed causes were ruled out.

Asunto(s)

Trastorno Depresivo Mayor , Hipoxia Encefálica , Humanos , Adolescente , Masculino , Trastorno Depresivo Mayor/tratamiento farmacológico , Psiquiatría Forense , Mala Praxis/legislación & jurisprudencia

RESUMEN

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

Asunto(s)

Mutismo Acinético , Imagen de Difusión Tensora , Trastornos Neurológicos de la Marcha , Leucoencefalopatías , Humanos , Mutismo Acinético/etiología , Mutismo Acinético/fisiopatología , Masculino , Leucoencefalopatías/etiología , Leucoencefalopatías/fisiopatología , Leucoencefalopatías/complicaciones , Leucoencefalopatías/diagnóstico por imagen , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/fisiopatología , Hipoxia Encefálica/complicaciones , Hipoxia Encefálica/diagnóstico por imagen , Persona de Mediana Edad , Adulto

Asunto(s)

Hipoxia Encefálica , Diálisis Renal , Humanos , Diálisis Renal/efectos adversos , Hipoxia Encefálica/etiología , Masculino , Fallo Renal Crónico/terapia , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/psicología , Trastornos del Conocimiento/etiología , Femenino , Persona de Mediana Edad , Disfunción Cognitiva/etiología , Pronóstico , Anciano

RESUMEN

BACKGROUND/AIM: Chronic cerebral hypoxia often leads to brain damage and inflammation. Propofol is suggested to have neuroprotective effects under anaesthesia. MATERIALS AND METHODS: This study used rat models with carotid artery coarctation or closure. Four groups of rats were compared: a control group, a propofol-treated group, a group with bilateral common carotid artery blockage (BCAO), and a BCAO group treated with propofol post-surgery. RESULTS: The Morris water maze test indicated cognitive impairment in BCAO rats, which also showed hippocampal structure changes, oxidative stress markers alteration, and reduced Klotho expression. Propofol treatment post-BCAO surgery improved these outcomes, suggesting its potential in mitigating chronic cerebral hypoxia effects. CONCLUSION: Propofol may increase klotho levels and reduce apoptosis and inflammation linked to oxidative stress in cognitively impaired mice.

Asunto(s)

Modelos Animales de Enfermedad , Glucuronidasa , Hipocampo , Hipoxia Encefálica , Proteínas Klotho , Estrés Oxidativo , Propofol , Animales , Propofol/farmacología , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/patología , Ratas , Proteínas Klotho/metabolismo , Masculino , Estrés Oxidativo/efectos de los fármacos , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/patología , Hipoxia Encefálica/etiología , Glucuronidasa/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Apoptosis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Enfermedad Crónica

RESUMEN

Hypoxia stabilizes hypoxia-inducible factors (HIFs), facilitating adaptation to hypoxic conditions. Appropriate hypoxia is pivotal for neurovascular regeneration and immune cell mobilization. However, in central nervous system (CNS) injury, prolonged and severe hypoxia harms the brain by triggering neurovascular inflammation, oxidative stress, glial activation, vascular damage, mitochondrial dysfunction, and cell death. Diminished hypoxia in the brain improves cognitive function in individuals with CNS injuries. This review discusses the current evidence regarding the contribution of severe hypoxia to CNS injuries, with an emphasis on HIF-1α-mediated pathways. During severe hypoxia in the CNS, HIF-1α facilitates inflammasome formation, mitochondrial dysfunction, and cell death. This review presents the molecular mechanisms by which HIF-1α is involved in the pathogenesis of CNS injuries, such as stroke, traumatic brain injury, and Alzheimer's disease. Deciphering the molecular mechanisms of HIF-1α will contribute to the development of therapeutic strategies for severe hypoxic brain diseases.

Asunto(s)

Hipoxia Encefálica , Subunidad alfa del Factor 1 Inducible por Hipoxia , Animales , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Hipoxia Encefálica/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mitocondrias/metabolismo , Estrés Oxidativo

RESUMEN

BACKGROUND: Controlled donation after circulatory death (cDCD) in post-anoxic brain injury is a valuable source of organs that is still underused in some countries. We assessed the number of potential cDCD donors after out-of-hospital cardiac arrest (OHCA) in Paris and its suburbs and extrapolated the results to the French population. METHODS: Using the large regional registry of the Great Paris area, we prospectively included all consecutive adults with OHCA with a stable return of spontaneous circulation (ROSC) who ultimately died in the intensive care unit (ICU) after withdrawal of life-sustaining treatments (WLST) due to post anoxic brain injury. The primary endpoint was potential for organ donation by cDCD in this population. The number of potential cDCD donors was calculated and extrapolated to the entire French population. RESULTS: Between 2011 and 2018, 4638 patients with stable ROSC were admitted to ICUs after OHCA, and 3170 died in ICU, of which 1034 died after WLST due to post-anoxic brain injury. When considering French criteria, 421/1034 patients (41%) would have been potential cDCD donors (55 patients per year in a 4.67 million population). After standardization for age and sex, the potential for cDCD was 515 (95% CI 471-560) patients per year in France corresponding to an annual incidence of 1.18 per 100 000 inhabitants per year. CONCLUSIONS: Organ donation by cDCD after cardiac arrest could provide a large pool of donors in France.

Asunto(s)

Paro Cardíaco Extrahospitalario , Sistema de Registros , Obtención de Tejidos y Órganos , Humanos , Masculino , Femenino , Paro Cardíaco Extrahospitalario/mortalidad , Paro Cardíaco Extrahospitalario/terapia , Persona de Mediana Edad , Obtención de Tejidos y Órganos/estadística & datos numéricos , Obtención de Tejidos y Órganos/métodos , Anciano , Estudios Prospectivos , Donantes de Tejidos/estadística & datos numéricos , Francia/epidemiología , Paris/epidemiología , Unidades de Cuidados Intensivos/estadística & datos numéricos , Adulto , Hipoxia Encefálica/etiología

RESUMEN

The progression of human degenerative and hypoxic/ischemic diseases is accompanied by widespread cell death. One death process linking iron-catalyzed reactive species with lipid peroxidation is ferroptosis, which shows hallmarks of both programmed and necrotic death in vitro. While evidence of ferroptosis in neurodegenerative disease is indicated by iron accumulation and involvement of lipids, a stable marker for ferroptosis has not been identified. Its prevalence is thus undetermined in human pathophysiology, impeding recognition of disease areas and clinical investigations with candidate drugs. Here, we identified ferroptosis marker antigens by analyzing surface protein dynamics and discovered a single protein, Fatty Acid-Binding Protein 5 (FABP5), which was stabilized at the cell surface and specifically elevated in ferroptotic cell death. Ectopic expression and lipidomics assays demonstrated that FABP5 drives redistribution of redox-sensitive lipids and ferroptosis sensitivity in a positive-feedback loop, indicating a role as a functional biomarker. Notably, immunodetection of FABP5 in mouse stroke penumbra and in hypoxic postmortem patients was distinctly associated with hypoxically damaged neurons. Retrospective cell death characterized here by the novel ferroptosis biomarker FABP5 thus provides first evidence for a long-hypothesized intrinsic ferroptosis in hypoxia and inaugurates a means for pathological detection of ferroptosis in tissue.

Asunto(s)

Biomarcadores , Proteínas de Unión a Ácidos Grasos , Ferroptosis , Proteínas de Neoplasias , Proteínas de Unión a Ácidos Grasos/metabolismo , Animales , Humanos , Biomarcadores/metabolismo , Ratones , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/patología , Ratones Endogámicos C57BL , Peroxidación de Lípido , Masculino

RESUMEN

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

Asunto(s)

Anestésicos , Hipoxia Encefálica , Pregnanodionas , Tortugas , Animales , Tortugas/fisiología , Receptores de GABA-A/metabolismo , Células Piramidales/metabolismo , Hipoxia/metabolismo , Anestésicos/farmacología , Mamíferos

RESUMEN

Consciousness is lost within seconds upon cessation of cerebral blood flow. The brain cannot store oxygen, and interruption of oxidative phosphorylation is fatal within minutes. Yet only rudimentary knowledge exists regarding cortical partial oxygen tension (Po2) dynamics under physiological conditions. Here we introduce Green enhanced Nano-lantern (GeNL), a genetically encoded bioluminescent oxygen indicator for Po2 imaging. In awake behaving mice, we uncover the existence of spontaneous, spatially defined "hypoxic pockets" and demonstrate their linkage to the abrogation of local capillary flow. Exercise reduced the burden of hypoxic pockets by 52% compared with rest. The study provides insight into cortical oxygen dynamics in awake behaving animals and concurrently establishes a tool to delineate the importance of oxygen tension in physiological processes and neurological diseases.

Asunto(s)

Corteza Cerebral , Circulación Cerebrovascular , Hipoxia Encefálica , Mediciones Luminiscentes , Saturación de Oxígeno , Oxígeno , Animales , Ratones , Corteza Cerebral/irrigación sanguínea , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Oxígeno/sangre , Oxígeno/metabolismo , Presión Parcial , Hipoxia Encefálica/sangre , Hipoxia Encefálica/diagnóstico por imagen , Hipoxia Encefálica/metabolismo , Vasodilatación , Mediciones Luminiscentes/métodos , Luciferasas/genética , Luciferasas/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipercapnia/sangre , Hipercapnia/diagnóstico por imagen , Hipercapnia/metabolismo

RESUMEN

BACKGROUND: Our objective was to assess the utility of the 1-h suppression ratio (SR) as a biomarker of cerebral injury and neurologic prognosis after cardiac arrest (CA) in the pediatric hospital setting. METHODS: Prospectively, we reviewed data from children presenting after CA and monitored by continuous electroencephalography (cEEG). Patients aged 1 month to 21 years were included. The SR, a quantitative measure of low-voltage cEEG (≤ 3 µV) content, was dichotomized as present or absent if there was > 0% suppression for one continuous hour. A multivariate logistic regression analysis was performed including age, sex, type of CA (i.e., in-hospital or out-of-hospital), and the presence of SR as a predictor of global anoxic cerebral injury as confirmed by magnetic resonance imaging (MRI). RESULTS: We included 84 patients with a median age of 4 years (interquartile range 0.9-13), 64% were male, and 49% (41/84) had in-hospital CA. Cerebral injury was seen in 50% of patients, of whom 65% had global injury. One-hour SR presence, independent of amount, predicted cerebral injury with 81% sensitivity (95% confidence interval (CI) (66-91%) and 98% specificity (95% CI 88-100%). Multivariate logistic regression analyses indicated that SR was a significant predictor of both cerebral injury (ß = 6.28, p < 0.001) and mortality (ß = 3.56, p < 0.001). CONCLUSIONS: The SR a sensitive and specific marker of anoxic brain injury and post-CA mortality in the pediatric population. Once detected in the post-CA setting, the 1-h SR may be a useful threshold finding for deployment of early neuroprotective strategies prior or for prompting diagnostic neuroimaging.

Asunto(s)

Electroencefalografía , Paro Cardíaco , Humanos , Masculino , Femenino , Niño , Preescolar , Electroencefalografía/métodos , Paro Cardíaco/etiología , Lactante , Adolescente , Diagnóstico Precoz , Adulto Joven , Estudios Prospectivos , Hipoxia Encefálica/etiología , Hipoxia Encefálica/fisiopatología , Hipoxia Encefálica/diagnóstico , Sensibilidad y Especificidad , Imagen por Resonancia Magnética

RESUMEN

In comparison to other stroke types, subarachnoid hemorrhage (SAH) is characterized by an early age of onset and often results in poor prognosis. The inadequate blood flow at the site of the lesion leads to localized oxygen deprivation, increased level of hypoxia-inducible factor-1α (HIF-1α), and triggers inflammatory responses and oxidative stress, ultimately causing hypoxic brain damage. Despite the potential benefits of oxygen (O2) administration, there is currently a lack of efficient focal site O2 delivery following SAH. Conventional clinical O2 supply methods, such as transnasal oxygenation and hyperbaric oxygen therapy, do not show the ideal therapeutic effect in severe SAH patients. The perfluorocarbon oxygen carrier (PFOC) demonstrates efficacy in transporting O2 and responding to elevated levels of CO2 at the lesion site. Through cellular experiments, we determined that PFOC oxygenation serves as an effective therapeutic approach in inhibiting hypoxia. Furthermore, our animal experiments showed that PFOC oxygenation outperforms O2 breathing, leading to microglia phenotypic switching and the suppression of inflammatory response via the inhibition of HIF-1α. Therefore, as a new type of O2 therapy after SAH, PFOC oxygenation can effectively reduce hypoxic brain injury and improve neurological function.

Asunto(s)

Lesiones Encefálicas , Fluorocarburos , Hipoxia Encefálica , Hemorragia Subaracnoidea , Animales , Humanos , Oxígeno , Fluorocarburos/uso terapéutico , Hipoxia Encefálica/terapia

Asunto(s)

Lesiones Encefálicas , Paro Cardíaco , Hipoxia Encefálica , Mioclonía , Humanos , Mioclonía/etiología , Paro Cardíaco/complicaciones , Hipoxia Encefálica/complicaciones , Hipoxia Encefálica/diagnóstico por imagen

RESUMEN

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

Asunto(s)

Hipoxia Encefálica , Sobredosis de Opiáceos , Masculino , Humanos , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Femenino , Etanol , Comercio , Fentanilo , Naloxona/uso terapéutico