Sepsis-Associated Encephalopathy: From Delirium to Dementia?
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ABSTRACT:
SUBMITTER: Chung HY
PROVIDER: S-EPMC7141293 | biostudies-literature | 2020 Mar
REPOSITORIES: biostudies-literature
Publications
Sepsis-Associated Encephalopathy: From Delirium to Dementia?
Chung Ha-Yeun HY Wickel Jonathan J Brunkhorst Frank M FM Geis Christian C
Journal of clinical medicine 20200305 3
Sepsis is a major cause of death in intensive care units worldwide. The acute phase of sepsis is often accompanied by sepsis-associated encephalopathy, which is highly associated with increased mortality. Moreover, in the chronic phase, more than 50% of surviving patients suffer from severe and long-term cognitive deficits compromising their daily quality of life and placing an immense burden on primary caregivers. Due to a growing number of sepsis survivors, these long-lasting deficits are incr ...[more]
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Project description:Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.
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Project description:IntroductionThe pathophysiology of sepsis-associated delirium is not completely understood and the data on cerebral perfusion in sepsis are conflicting. We tested the hypothesis that cerebral perfusion and selected serum markers of inflammation and delirium differ in septic patients with and without sepsis-associated delirium.MethodsWe investigated 23 adult patients with sepsis, severe sepsis, or septic shock with an extracranial focus of infection and no history of intracranial pathology. Patients were investigated after stabilisation within 48 hours after admission to the intensive care unit. Sepsis-associated delirium was diagnosed using the confusion assessment method for the intensive care unit. Mean arterial pressure (MAP), blood flow velocity (FV) in the middle cerebral artery using transcranial Doppler, and cerebral tissue oxygenation using near-infrared spectroscopy were monitored for 1 hour. An index of cerebrovascular autoregulation was calculated from MAP and FV data. C-reactive protein (CRP), interleukin-6 (IL-6), S-100beta, and cortisol were measured during each data acquisition.ResultsData from 16 patients, of whom 12 had sepsis-associated delirium, were analysed. There were no significant correlations or associations between MAP, cerebral blood FV, or tissue oxygenation and sepsis-associated delirium. However, we found a significant association between sepsis-associated delirium and disturbed autoregulation (P = 0.015). IL-6 did not differ between patients with and without sepsis-associated delirium, but we found a significant association between elevated CRP (P = 0.008), S-100beta (P = 0.029), and cortisol (P = 0.011) and sepsis-associated delirium. Elevated CRP was significantly correlated with disturbed autoregulation (Spearman rho = 0.62, P = 0.010).ConclusionIn this small group of patients, cerebral perfusion assessed with transcranial Doppler and near-infrared spectroscopy did not differ between patients with and without sepsis-associated delirium. However, the state of autoregulation differed between the two groups. This may be due to inflammation impeding cerebrovascular endothelial function. Further investigations defining the role of S-100beta and cortisol in the diagnosis of sepsis-associated delirium are warranted.Trial registrationClinicalTrials.gov NCT00410111.
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Project description:Sepsis-associated delirium (SAD) increases morbidity in septic patients and, therefore, factors contributing to SAD should be further characterized. One possible mechanism might be the impairment of cerebrovascular autoregulation (AR) by sepsis, leading to cerebral hypo- or hyperperfusion in these haemodynamically unstable patients. Therefore, the present study investigates the relationship between the incidence of SAD and the status of AR during sepsis.Cerebral blood flow velocity was measured using transcranial Doppler sonography and was correlated with the invasive arterial blood pressure curve to calculate the index of AR Mx (Mx>0.3 indicates impaired AR). Mx was measured daily during the first 4 days of sepsis. Diagnosis of a SAD was performed using the confusion assessment method for ICU (CAM-ICU) and, furthermore the predominant brain electrical activity in electroencephalogram (EEG) both at day 4 after reduction of sedation to RASS >-2.30 critically ill adult patients with severe sepsis or septic shock (APACHE II 32 ± 6) were included. AR was impaired at day 1 in 60%, day 2 in 59%, day 3 in 41% and day 4 in 46% of patients; SAD detected by CAM-ICU was present in 76 % of patients. Impaired AR at day 1 was associated with the incidence of SAD at day 4 (p = 0.035).AR is impaired in the great majority of patients with severe sepsis during the first two days. Impaired AR is associated with SAD, suggesting that dysfunction of AR is one of the trigger mechanisms contributing to the development of SAD.clinicalTrials.gov ID NCT01029080.
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Project description:Brain dysfunction is frequently observed in sepsis as a consequence of changes in cerebral structure and metabolism, resulting in worse outcome and reduced life-quality of surviving patients. However, the mechanisms of sepsis-associated encephalopathy development and a better characterization of this syndrome in vivo are lacking. Here, we used magnetic resonance imaging (MRI) techniques to assess brain morphology and metabolism in a murine sepsis model (cecal ligation and puncture, CLP). Sham-operated and CLP mice were subjected to a complete MRI session at baseline, 6 and 24 h after surgery. Accumulation of vasogenic edematic fluid at the base of the brain was observed in T(2)-weighted image at 6 and 24 h after CLP. Also, the water apparent diffusion coefficients in both hippocampus and cortex were decreased, suggesting a cytotoxic edema in brains of nonsurvival septic animals. Moreover, the N-acetylaspartate/choline ratio was reduced in brains of septic mice, indicating neuronal damage. In conclusion, noninvasive assessment by MRI allowed the identification of new aspects of brain damage in sepsis, including cytotoxic and vasogenic edema as well as neuronal damage. These findings highlight the potential applications of MRI techniques for the diagnostic and therapeutic studies in sepsis.
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Project description:Sepsis-associated encephalopathy (SAE) is a major and frequent complication in patients with sepsis resulting in delirium and premature death. Sepsis survivors commonly suffer from long-term cognitive impairment causing immense burden on patients, caregivers, and economic health systems. Underlying pathophysiology of SAE related cognitive deficits is largely unresolved, Thus treatment options are missing. We report that experimental polymicrobial sepsis in mice induces synaptic pathology in the central nervous system underlying defective long-term potentiation and cognitive dysfunction. Analysis of differentially expressed genes revealed severely affected downregulation of genes related to neuronal and synaptic signaling in the brain, e.g. of the activity-regulated cytoskeleton-associated protein (Arc ), of the transcription-regulatory EGR family, and of the dual-specificity phosphatase 6 (Dusp6). On the protein level, ARC expression and mitogen-activated protein (MAP) kinase signaling in the brain was disturbed during SAE. For targeted rescue of dysregulated synaptic signaling and plasticity, we overexpressed ARC in the hippocampus by bilateral in-vivo stereotactic microinjection of an adeno-associated virus containing a neuron-specific plasmid of the Arc transgene. Hereby, defective synaptic plasticity and signaling in the hippocampus were restored and memory function improved. Accordingly, synaptic plasticity, neuronal spine pathology, and memory dysfunction also improved when post-septic mice were subjected to enriched environment demonstrating the potential for activity-induced recovery of long-term cognitive dysfunction. Together, we identified synaptic pathology of neurocognitive dysfunction after severe systemic infection and provide a proof-of-concept approach to interfere with SAE pathomechanisms leading to cognitive improvement.
2021-02-27 | GSE167610 | GEO
Project description:Sepsis associated encephalopathy (SAE), appears often indicates the deterioration of the sepsis disease and which have high risk of death. Although several mechanism and hypotheses have been proposed and studied, there is no breakthrough in the treatment of SAE. We performed a systematic research to evaluate the effect of intraperitoneal pressure on SAE. A mice model of sepsis was established by intraperitoneal injection of endotoxin. A total of 48 female BALB/c mouse (30 days old) were randomly divided into a control group (n?=?12) and an injection of endotoxin referred to bacterial lipopolysaccharide (LPS) group (n?=?12). Intraperitoneal hypertension (IAH) referred to IAH group (n?=?12), and LPS?+?IAH group (n?=?12). Following sepsis induction, diagnosis, the brains were analyzed for both function and ultrastructural morphology.We determined that IAH exacerbated sepsis induces sepsis-associated encephalopathy when examining low score of neurological function and more delta wave in EEG, increased neuronal edema in LPS?+?IAH group, as well as an escalation of Bax and Cleaved-caspase-3, Cleaved-parp, and reduction of Bcl-2 and Mfsd2a in LPS?+?IAH group. Therefore, IAH can exacerbate and increase incident rate of sepsis-related encephalopathy in sepsis mice by promoting neuronal apoptosis and destruction of the blood-brain barrier.
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