Septic encephalopathy: does inflammation drive the brain crazy?

Sepsis and the multiorgan dysfunction syndrome are among the most common reasons for admission to an intensive care unit, and are a leading cause of death. During sepsis, the central nervous system (CNS) is one of the first organs affected, and this is clinically manifested as sepsis-associated encephalopathy (SAE). It is postulated that the common final pathway that leads to SAE symptoms is the deregulation of neurotransmitters, mainly acetylcholine. Thus, it is supposed that inflammation can affect neurotransmitters, which is associated with SAE development. In this review, we will cover the current evidence (or lack thereof) for the mechanisms by which systemic inflammation interferes with the metabolism of major CNS neurotransmitters, trying to explain how systemic inflammation drives the brain crazy.

Disfunção cerebral associada à sepse: papel das estatinas na prevenção do dano cognitivo em modelo de sepse experimental / Brain dysfunction associated with sepsis: role of statins in the reversal of cognitive impairment in experimental sepsis model

A sepse é um dos mais graves problemas de saúde pública mundial, apresentando uma estimativa de 19 milhões de casos por ano. [...] A disfunção no sistema nervoso central se manifesta tipicamente por delirium, déficit de atenção e dano cognitivo. As estatinas são fármacos que têm a capacidade de bloquear a enzima HMG-CoA redutase,reduzindo a síntese de colesterol endógeno. Recentemente, foi observado que asestatinas, apresentam efeitos anti-inflamatórios, com potencial para prevenir a disfunção cerebral em modelo experimental de malária cerebral. Objetivamos neste estudo avaliar a capacidade do tratamento das estatinas em reduzir a neuroinflamação e proteger do dano cognitivo no modelo (ISC) de sepse. Para isso,foi coletado o conteúdo cecal, diluído em solução salina, e centrifugado, sendo sobrenadante recolhido para administração nos animais por via (i.p.) na dose de 5mg/g (0,5 mL) (n = 5-8/grupo). Os controles receberam 0,5 mL de solução salina. Os animais foram tratados 6, 24 e 48 h após a indução da sepse com imipenem (30mg/kg de peso corporal, por via subcutânea – s.c.) e 1,0 ml de solução salina (s.c.).As estatinas (atorvastatina e sinvastatina) foram administrados v.o. 1 hora antes e 6,24 e 48 h após a infecção (20 mg/kg). A mortalidade foi observada por 96 h e um escore de gravidade avaliado. O perfil de citocinas inflamatórias, o dano oxidativo e os níveis de mieloperoxidase foram determinados em 6 e 24 h. Além disso, foramavaliados a adesão e rolamento de leucócitos foram avaliados no cérebro dos animais a ativação da microglia, a disfunção da barreira hematoencefálica e alterações na microcirculação vascular cerebral...

Sepsis is one of the most serious problems in worldwide public health, with anestimated 19 million cases a year. [...] Thedysfunction in the central nervous system (CNS) is typically manifested by delirium,cognitive impairment and attention deficit. The statins are drugs with the ability toinhibit the HMG-CoA reductase enzymatic activity, reducing endogenous cholesterolsynthesis. Recently, it was observed that statins have anti-inflammatory effects, withthe potential to prevent brain dysfunction in an experimental model of cerebralmalaria. We aimed in this study to evaluate the capacity of statins to reduceneuroinflammation and protect from cognitive impairment in an experimental modelof sepsis (CSI). For this purpose, the cecal content was collected, diluted in salinesolution and centrifuged, and the supernatant collected for administration in animals(i.p.) at a dose of 5 mg/g (0.5 mL) (n= 5-8/grupo). The controls received 0.5 mL ofsaline. The animals received antibiotic therapy 6, 24 and 48 hours after induction ofsepsis with imipenem (30 mg/kg, subcutaneously - s.c.) and 1.0 ml of saline (s.c.).Statins (atorvastatin and simvastatin) were administered orally 1 h before and 6, 24and 48 h post-infection (20 mg/kg). Mortality was observed for 96 h and a clinicalscore reported. The profile of cytokines, oxidative stress and myeloperoxidase levelswere determined at 6 and 24 h. Moreover, adhesion and rolling of leukocytes inbrain, microglial activation, dysfunction of the blood brain barrier (BBB) and vascularchanges in the cerebral microcirculation were assessed. After 15 days we analyzedthe cognitive impairment using behavioral tests of inhibitory avoidance task andMorris Water Maze...

Biomarcadores na encefalopatia séptica: revisão sistemática dos estudos clínicos / Biomarkers in septic encephalopathy: a systematic review of clinical studies

OBJETIVO: O objetivo deste estudo foi revisar sistematicamente a importância da enolase específica neuronal e S100B para diagnóstico e monitorização da encefalopatia séptica. MÉTODOS: Foi realizada uma busca no banco de dados PubMed selecionando estudos que avaliaram níveis séricos de S 100 B e enolase específica neuronal em pacientes com sepse, publicados entre Janeiro de 2000 e Abril de 2012. Apenas estudos em humanos e que utilizaram um método adicional de avaliação neurológica foram selecionados. RESULTADOS: Foram identificados nove estudos, dos quais sete associaram concentrações elevadas de S100 beta e enolase específica neuronal ao desenvolvimento de encefalopatia séptica; quatro também as associaram ao aumento de mortalidade. Entretanto, dois trabalhos não encontraram essa associação quando avaliaram S100 beta e um deles não observou correlação entre a enolase específica neuronal e encefalopatia séptica. CONCLUSÃO: A S100 beta e enolase específica neuronal são biomarcadores promissores para diagnóstico e monitorização de pacientes com encefalopatia séptica, mas é necessária uma maior investigação.

OBJECTIVE: The aim of this study was to systematically review the importance of neuron-specific enolase and S100 beta for diagnosing and monitoring septic encephalopathy. METHODS: A PubMed database search was performed to identify studies that evaluated S100 beta and neuron-specific enolase serum levels in patients with sepsis and that were published between January 2000 and April 2012. Only human studies that employed an additional method of neurological assessment were selected. RESULTS: Nine studies were identified, seven of which associated high concentrations of S100 beta and neuron-specific enolase with the development of septic encephalopathy. Four studies also associated these concentrations with increased mortality. However, two studies did not find such an association when they evaluated S100 beta levels, and one of these studies did not observe a correlation between neuron-specific enolase and septic encephalopathy. CONCLUSION: S100 beta and neuron-specific enolase are promising biomarkers for diagnosing and monitoring patients with septic encephalopathy, but more research is necessary.