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BACKGROUND: Acute brain dysfunction during sepsis, which manifests as delirium or coma, is common and is associated with multiple adverse outcomes, including longer periods of mechanical ventilation, prolonged hospital stays, and increased mortality. Delirium and coma during sepsis may be manifestations of alteration in systemic metabolism. Because access to brain mitochondria is a limiting factor, measurement of peripheral platelet bioenergetics offers a potential opportunity to understand metabolic changes associated with acute brain dysfunction during sepsis. RESEARCH QUESTION: Are altered platelet mitochondrial bioenergetics associated with acute brain dysfunction during sepsis? STUDY DESIGN AND METHODS: We assessed participants with critical illness in the ICU for the presence of delirium or coma via validated assessment measures. Blood samples were collected and processed to isolate and measure platelet mitochondrial oxygen consumption. We used Seahorse extracellular flux to measure directly baseline, proton leak, maximal oxygen consumption rate, and extracellular acidification rate. We calculated adenosine triphosphate-linked, spare respiratory capacity, and nonmitochondrial oxygen consumption rate from the measured values. RESULTS: Maximum oxygen consumption was highest in patients with coma, as was spare respiratory capacity and extracellular acidification rate in unadjusted analysis. After adjusting for age, sedation, modified Sequential Organ Failure Assessment score without the neurologic component, and preexisting cognitive function, increased spare respiratory capacity remained associated with coma. Delirium was not associated with any platelet mitochondrial bioenergetics. INTERPRETATION: In this single-center exploratory prospective cohort study, we found that increased platelet mitochondrial spare respiratory capacity was associated with coma in patients with sepsis. Future studies powered to determine any relationship between delirium and mitochondrial respiration bioenergetics are needed.
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Although COVID-19 affects the respiratory system, extrapulmonary manifestations frequently occur, including encephalopathy and liver damage. Here, we want to call attention to a possible connection between liver and brain dysfunctions, in which ammonia can play a role targeting astrocytes. Importantly, astrocyte dysfunction can produce future and/or long-term neurological consequences.
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Background: Neurogranin (Ng) concentrates at dendritic spines. In patients with Alzheimer disease Ng levels are elevated. The role of Ng in delirium development has not been assessed, therefore we hypothesized that Ng levels are associated with delirium in critically ill patients. Materials & methods: From 94 critically ill patients, 47 developed delirium and 47 controls were included. Blood was collected during the first 24 h of intensive care unit (ICU) admission, and on the day of delirium diagnoses. Ng and IL-1ß were determined. Results: Ng and IL-1ß levels were higher in the delirium group at ICU admission and on the day of delirium diagnoses. IL-1ß and Ng were independently associated with delirium occurrence. Conclusion: Ng levels are associated with delirium development in ICU patients.
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Estado Terminal , Delírio/sangue , Neurogranina/sangue , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Background: Several different mechanisms have been proposed to explain long-term cognitive impairment in sepsis survivors. The role of persisting mitochondrial dysfunction is not known. We thus sought to determine whether stimulation of mitochondrial dynamics improves mitochondrial function and long-term cognitive impairment in an experimental model of sepsis.Methods: Sepsis was induced in adult Wistar rats by cecal ligation and perforation (CLP). Animals received intracerebroventricular injections of either rosiglitazone (biogenesis activator), rilmenidine, rapamycin (autophagy activators), or n-saline (sham control) once a day on days 7-9 after the septic insult. Cognitive impairment was assessed by inhibitory avoidance and object recognition tests. Animals were killed 24 h, 3 and 10 days after sepsis with the hippocampus and prefrontal cortex removed to determine mitochondrial function.Results: Sepsis was associated with both acute (24 h) and late (10 days) brain mitochondrial dysfunction. Markers of mitochondrial biogenesis, autophagy and mitophagy were not up-regulated during these time points. Activation of biogenesis (rosiglitazone) or autophagy (rapamycin and rilmenidine) improved brain ATP levels and ex vivo oxygen consumption and the long-term cognitive impairment observed in sepsis survivors.Conclusion: Long-term impairment of brain function is temporally related to mitochondrial dysfunction. Activators of autophagy and mitochondrial biogenesis could rescue animals from cognitive impairment.
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Disfunção Cognitiva/complicações , Disfunção Cognitiva/patologia , Mitocôndrias/patologia , Sepse/complicações , Sepse/patologia , Animais , Autofagia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dinâmica Mitocondrial/efeitos dos fármacos , Ratos Wistar , Rilmenidina/farmacologia , Rosiglitazona/farmacologia , Sirolimo/farmacologia , Análise de Sobrevida , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
The presence of autoantibodies against neuronal cell surface or synaptic proteins and their relationship to autoimmune encephalitis have recently been characterized. These autoantibodies have been also reported in other pathologic conditions; however, their role during sepsis is not known. This study detected the presence of autoantibodies against neuronal cell surface or synaptic proteins in the serum of septic patients and determined their relationship to the occurrence of brain dysfunction and mortality. This prospective, observational cohort study was performed in four Brazilian intensive care units (ICUs). Sixty patients with community-acquired severe sepsis or septic shock admitted to the ICU were included. Blood samples were collected from patients within 24 h of ICU admission. Antibodies to six neuronal proteins were assessed, including glutamate receptors (types NMDA, AMPA1, and AMPA2); voltage-gated potassium channel complex (VGKC) proteins, leucine-rich glioma-inactivated protein 1 (LGI1), and contactin-associated protein-2 (Caspr2), as well as the GABAB1 receptor. There was no independent association between any of the measured autoantibodies and the occurrence of brain dysfunction (delirium or coma). However, there was an independent and significant relationship between anti-NMDAR fluorescence intensity and hospital mortality. In conclusion, anti-NMDAR was independently associated with hospital mortality but none of the measured antibodies were associated with brain dysfunction in septic patients.
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Hepatic encephalopathy (HE) represents a brain dysfunction caused by both acute and chronic liver failures, and its severity deeply affects the prognosis of patients with impaired liver function. In its pathophysiology, ammonia levels and glutamatergic system hyperactivity seem to play a pivotal role in the disruption of brain homeostasis. Here, we investigate important outcomes involved in behavioral performance, electroencephalographic patterns, and neurochemical parameters to better characterize the well-accepted animal model of acute liver failure (ALF) induced by subtotal hepatectomy (92% removal of tissue) that produces ALF. This study was divided into three cohorts: (1) rats clinically monitored after hepatectomy every 6â¯h for 96â¯h or until death; (2) rats tested in an open-field task (OFT) before and after surgery and had blood, cerebrospinal fluid, and brain tissue collected after the last OFT; and (3) rats that had continuous EEGs recorded before and after surgery for 3â¯days. The hepatectomized rats presented significant motor behavioral changes accompanied by important abnormalities in classical blood laboratory parameters of ALF, and EEG features suggestive of HE and deep disturbances in the brain glutamatergic system. Using an animal model of ALF induced via subtotal hepatectomy, this work provides a comprehensive and reliable experimental model that increases the opportunity for studying the effects of new treatment strategies to be explored in an unprecedented way. It also presents insights into the pathophysiology of HE in a reproducible model of ALF, which correlates important neurochemical and EEG aspects of the syndrome.
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Encéfalo/fisiopatologia , Comportamento Exploratório , Encefalopatia Hepática/fisiopatologia , Falência Hepática Aguda/fisiopatologia , Animais , Modelos Animais de Doenças , Eletroencefalografia , Hepatectomia , Encefalopatia Hepática/sangue , Falência Hepática Aguda/sangue , Masculino , Atividade Motora/fisiologia , Malformações do Sistema Nervoso , Ratos , Ratos WistarRESUMO
Alzheimer's disease (AD) is associated to depressed brain energy supply and impaired cortical and hippocampal synaptic function. It was previously reported in McGill-R-Thy1-APP transgenic (Tg(+/+)) rats that Aß deposition per se is sufficient to cause abnormalities in glucose metabolism and neuronal connectivity. These data support the utility of this animal model as a platform for the search of novel AD biomarkers based on bioenergetic status. Recently, it has been proposed that energy dysfunction can be dynamically tested in platelets (PLTs) of nonhuman primates. PLTs are good candidates to find peripheral biomarkers for AD because they may reflect in periphery the bioenergetics deficits and the inflammatory and oxidative stress processes taking place in AD brain. In the present study, we carried out a PLTs bioenergetics screening in advanced-age (12-14 months old) control (WT) and Tg(+/+) rats. Results indicated that thrombin-activated PLTs of Tg(+/+) rats showed a significantly lower respiratory rate, as compared to that measured in WT animals, when challenged with the same dose of FCCP (an uncoupler of oxidative phosphorylation). In summary, our results provide original evidence that PLTs bioenergetic profiling may reflect brain bioenergetics dysfunction mediated by Aß plaque accumulation. Further studies on human PLTs from control and AD patients are required to validate the usefulness of PLTs bioenergetics as a novel blood-based biomarker for AD.
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Doença de Alzheimer/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Plaquetas/metabolismo , Metabolismo Energético/fisiologia , Hipocampo/metabolismo , Placa Amiloide/metabolismo , Animais , Mitocôndrias/metabolismo , Ratos , Ratos TransgênicosRESUMO
El periodo neonatal corresponde a una etapa en el desarrollo en el que las convulsiones constituyen la expresión clínica de disfunción del sistema nervioso central. Estas se manifiestan por una alteración en la función neurológica que puede ser motora, autonómica, de la conducta o una combinación de ellas. Dado que en este periodo el desarrollo anatómico, bioquímico y fisiológico, presentan características muy diferentes al desarrollo del niño mayor, las convulsiones pueden ser muy difíciles de identificar y pueden confundirse con eventos clínicos paroxísticos no epilépticos del recién nacido. Lo anterior se explica porque las convulsiones presentan patrones poco organizados, suelen no ser bien definidas y el registro electroencefalográfico es diferente al del niño mayor. En su mayoría las CN son secundarias a una etiología específica, por lo que es indispensable encontrar la causa lo cual se encuentra fuertemente relacionado al pronóstico. También es necesario diferenciar los eventos no epilépticos, para un óptimo manejo.
The neonatal period corresponds to a developmental stage in which seizures are the clinical expression of central nervous system dysfunction. These are manifested by a change in neurological function that can be motor, autonomic, behavior or a combination of them.Given that in this period the anatomical, biochemical and physiological development present with very different characteristics to those of the older child, seizures can be very difficult to identify, and can be confused with paroxysmal non epileptic clinical events of the newborn. This is explains why seizures have little organized patterns are often not well defined and the Electroencephalographic record is different from that found in the older child. For the most part, neonatal seizures are secondary to a specific etiology, so it is essential to find the cause, which is strongly related to the prognosis. It is also necessary to differentiate non-epileptic events, for optimal handling.
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Humanos , Recém-Nascido , Convulsões/terapia , Convulsões/diagnóstico por imagem , Eletroencefalografia/métodosRESUMO
There are different theories about the pathophysiology of sepsis-associated encephalopathy (SAE), and the majority of our knowledge was derived from critically ill patients. 7In less severe sepsis, it is probable that neuroinflammation can be a major aspect of SAE development. We hypothesized that in non-severe septic patients, blood biomarkers of inflammation, endothelial activation, coagulation, and brain function would be different when compared to patients with and without brain dysfunction. A total of 30 patients presenting with community-acquired pneumonia (CAP)-induced sepsis were included of which 10 (33 %) developed SAE. Eight medical patients admitted to the general ward, except due to sepsis or infection, which developed delirium were included as delirium, non-sepsis group. From all measured biomarkers, only brain-derived neurotrophic factor (BDNF), regulated upon activation normal T cell expressed, and presumably secreted (RANTES), and interleukin (IL)-10 where significantly different when compared to SAE and sepsis groups. In addition, SAE patients presented higher levels of BDNF, vascular cellular adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), platelet-derived growth factor (PDGF)-AB/BB and RANTES when compared to delirium patients. In conclusion, the profile of biomarkers differs between SAE, sepsis, and delirium patients, suggesting that pathways related to SAE are different from delirium and from sepsis itself.
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Infecções Comunitárias Adquiridas/sangue , Delírio/sangue , Mediadores da Inflamação/sangue , Pneumonia/sangue , Sepse/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Infecções Comunitárias Adquiridas/diagnóstico , Infecções Comunitárias Adquiridas/epidemiologia , Delírio/diagnóstico , Delírio/epidemiologia , Feminino , Humanos , Tempo de Internação/tendências , Masculino , Pessoa de Meia-Idade , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Fatores de Risco , Sepse/diagnóstico , Sepse/epidemiologiaRESUMO
Abstract Objective: Hyperprolinemia type I (HPI) is a rare and inherited autosomal recessive disorder caused by proline oxidase deficiency. Hyperprolinemia type 1 is biochemically defined as high plasma proline levels without urinary ?-1-pyrroline-5-carboxylate excretion. Hyperprolinemia type 1 has been considered a benign metabolic disorder, but a relationship with neurological disorders has recently been suggested. Study Design: We retrospectively analyzed plasma amino acid values obtained by amino acid analysis from 10 030 children admitted for neurological reasons during the years 1996 to 2010 at the Regional Sicilian Centre for Metabolic Diseases. Patients with proline levels above the normal range of 129 to 245 ?M were identified. Results: Only 2 children showed high levels of proline (450-480 ?M and 380-470 ?M, respectively), but their disorders (tubercular neuroencephalitis and progressive mitochondrial encephalopathy) did not seem to be related to hyperprolinemia as a causative factor. Conclusion: The question of HPI as benign metabolic anomaly or as a direct cause of brain damage is still open. Since HPI is rare, other observations on this regard are necessary.
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Las alteraciones del estado de conciencia constituyen una emergencia neurológica y/o neuroquirúrgica, que se presenta frecuentemente en la Sala o Departamento de Emergencia. La habilidad para establecer un diagnóstico correcto y manejar adecuadamente al paciente con una afectación neurológica de este tipo, requiere la actuación de un médico clínico entrenado, lo que va a impactar en una disminución de la morbimortalidad de estos pacientes. Se trata de un tema complejo, con riesgo vital inmediato, que impone un rápido diagnóstico clínico, concomitantemente al inicio del sostén de sistemas fisiológico mayores e implementación de métodos diagnósticos específicos destinados a valorar la etiología y eventual tratamiento específico. En esta revisión, se analizarán los aspectos fisiopatológicos, clínicos, terapéuticos y pronósticos de esta situación clínica, poniendo énfasis en sus aspectos prácticos con vistas a realizar un adecuado manejo sistemático inicial de este tipo de pacientes.
The altered state of consciousness is a neurological and / or neurosurgical emergency, which occurs frequently in the Emergency Department. The ability to establish a correct diagnosis and properly management of the patient with such a neurological impairment, requires the performance of a trained clinician, which will impact in a reduction in morbidity and mortality of these patients. This is a complex and life-threatening issue, which requires a rapid clinical diagnosis with the concomitant start of major physiological systems support and the implementation of specific diagnostic methods, designed to assess the possible etiology and specific treatment. In this review, we discuss the pathophysiological, clinical, therapeutic and prognostic issues of patients with acute disorders of consciousness, emphasizing practical aspects in order to perform an adequate initial management of these patients.
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Las alteraciones del estado de conciencia constituyen una emergencia neurológica y/o neuroquirúrgica, que se presenta frecuentemente en la Sala o Departamento de Emergencia. La habilidad para establecer un diagnóstico correcto y manejar adecuadamente al paciente con una afectación neurológica de este tipo, requiere la actuación de un médico clínico entrenado, lo que va a impactar en una disminución de la morbimortalidad de estos pacientes. Se trata de un tema complejo, con riesgo vital inmediato, que impone un rápido diagnóstico clínico, concomitantemente al inicio del sostén de sistemas fisiológico mayores e implementación de métodos diagnósticos específicos destinados a valorar la etiología y eventual tratamiento específico. En esta revisión, se analizarán los aspectos fisiopatológicos, clínicos, terapéuticos y pronósticos de esta situación clínica, poniendo énfasis en sus aspectos prácticos con vistas a realizar un adecuado manejo sistemático inicial de este tipo de pacientes.
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Humanos , Transtornos da Consciência/diagnóstico , Transtornos da Consciência/etiologia , Transtornos da Consciência/terapia , Administração de Caso , Medicina de Emergência , Doenças do Sistema Nervoso/complicações , Coma , Transtornos da Consciência/fisiopatologiaRESUMO
Introducción: La alteración focal aguda de la función cerebral en el adulto permite diagnosticar un accidente vascular encefálico (AVE) e iniciar precozmente el rescate de tejido cerebral. En los niños, las diferencias clínicas de esta patología en relación al adulto generan atraso, subdiagnóstico e impiden el tratamiento en la etapa aguda. Objetivo: Describir la presentación clínica y factores de riesgo del AVE isquémico en 156 niños, comparar la presentación clínica según edad y tipo de AVE. Pacientes y Método: Se analiza un registro de AVE isquémico, confirmado con imágenes cerebrales, en población menor de 18 años, iniciado en Enero 2003. Resultados: La mediana de edad: 4,9 meses (33 por ciento recién nacidos, 46 por ciento menores 6 años y 21 por ciento mayor de 6 años), 64 por ciento fueron hombres. Los infartos arteriales correspondieron al 85 por ciento y el resto fueron trombosis de senos venosos. Predominaron los signos difusos (67 por ciento) en menores de 6 años (p = 0,001). Las convulsiones fueron observadas en el 61 por ciento de los niños menores de 6 años (p = 0,03), el 33 por ciento presentó signos focales. Los factores de riesgo más frecuentes fueron patologías sistémicas agudas y cardiopatías. En 14,7 por ciento no se encontraron factores de riesgo. Conclusiones: La búsqueda de signos focales agudos de AVE no tiene utilidad diagnóstica en el niño, a diferencia de los adultos, pues su ausencia no excluye patología vascular isquémica focal. La patología sistémica aguda fue el factor de riesgo más frecuente para AVE.
Introduction: Acute focal brain dysfunction in adults serves to diagnose and to provide early rescue of the brain tissue. In children, the clinical differences of this condition compared to adults results in delayed diagnosis and treatment. Objective: To describe the clinical presentation and risk factors of CVA in 156 children and related to age and type of CVA. Patients and Method: A CVA registry of newborn to 18 years old was started in January 2003 were analized. Diagnosis was confirmed by brain imaging. Results: The median of age was 4.9 month (33 percent was newborn, 46 percent < 6 years old, 21 percent > 6 years old); 64 percent were males. Arterial ischemic stroke represented 85 percent, the rest were cerebral sinovenous thrombosis. In the clinical manifestations the diffuse signs were more frequently seen (67 percent) in children < 6 years of age (p 0.001). Seizures were observed in 61 percent in children < 6 years old (p = 0.03), 33 percent presented focal signs. The most common risk factors were acute systemic diseases and heart disease. 14.7 percent of the patients did not present risk factors. Conclusions: Acute focus signals of CVA in children have no diagnostic value, unlike adults; however absence doesn't exclude focal ischemic vascular disease. The acute systemic disease was the most common risk factor for stroke.