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Common eye movement abnormalities. Spontaneous eye movements rarely have localizing value and are most commonly seen in hypoxic- ischemic coma. a Roving, without particular significance. b Periodic alternating gaze: predominantly in hepatic encephalopathy, bilateral midbrain or vermis lesions. c Ping-pong: bihemispheric alterations. d Convergence nystagmus: lesions in the mesencephalon. e Bobbing: rapid downward conjugate movement with slower return to baseline position is found mostly in pontine lesions (primary due
Source publication
Sepsis-associated delirium is a common and poorly understood neurological complication of sepsis. This review provides an update of the diagnostic criteria and treatment strategies and the current knowledge about the mechanisms involved in sepsis associated brain dysfunction.
Articles published between 1981 and 2006 were identified through a Medlin...
Citations
... 6 Thus, the diagnosis of SAE is relatively challenging. 7 As previously reported, Sequential Organ Failure Assessment (SOFA) and quick SOFA scores have been widely used as prognostic tools for sepsis and treatment of other infections in clinical practice. 8,9 However, these still have limitations in terms of discriminative power and predictive accuracy. ...
Objective
We identified predictive factors and developed a novel machine learning (ML) model for predicting mortality risk in patients with sepsis-associated encephalopathy (SAE).
Methods
In this retrospective cohort study, data from the Medical Information Mart for Intensive Care IV (MIMIC-IV) and eICU Collaborative Research Database were used for model development and external validation. The primary outcome was the in-hospital mortality rate among patients with SAE; the observed in-hospital mortality rate was 14.74% (MIMIC IV: 1112, eICU: 594). Using the least absolute shrinkage and selection operator (LASSO), we built nine ML models and a stacking ensemble model and determined the optimal model based on the area under the receiver operating characteristic curve (AUC). We used the Shapley additive explanations (SHAP) algorithm to determine the optimal model.
Results
The study included 9943 patients. LASSO identified 15 variables. The stacking ensemble model achieved the highest AUC on the test set (0.807) and 0.671 on external validation. SHAP analysis highlighted Glasgow Coma Scale (GCS) and age as key variables. The model (https://sic1.shinyapps.io/SSAAEE/) can predict in-hospital mortality risk for patients with SAE.
Conclusions
We developed a stacked ensemble model with enhanced generalization capabilities using novel data to predict mortality risk in patients with SAE.
... Our data reveals a 55% incidence of delirium among these patients, in contrast to the 17.7 to 48% range reported in intensive care units (ICU) for sepsis-associated delirium (SAD) (9), with some studies indicating rates up to 70% (19). Additionally, another multicenter study documented acute mental status changes in 307 of 1,333 patients with severe sepsis (23%) (20). The variation in reported incidence rates may stem from differences in patient demographics, severity of sepsis, delirium diagnostic criteria, and methods of data collection and analysis. ...
Background
This study aims to explore the value of the Lymphocyte-to-Monocyte Ratio (LMR) in predicting delirium among older adult patients with sepsis.
Methods
Retrospective data were obtained from the MIMIC-IV database in accordance with the STROBE guidelines. Patients aged 65 and above, meeting the Sepsis 3.0 criteria, were selected for this study. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU). Demographic information, comorbid conditions, severity of illness scores, vital sign measurements, and laboratory test results were meticulously extracted. The prognostic utility of the Lymphocyte-to-Monocyte Ratio (LMR) in predicting delirium was assessed through logistic regression models, which were carefully adjusted for potential confounding factors.
Results
In the studied cohort of 32,971 sepsis patients, 2,327 were identified as meeting the inclusion criteria. The incidence of delirium within this subgroup was observed to be 55%. A univariate analysis revealed a statistically significant inverse correlation between the Lymphocyte-to-Monocyte Ratio (LMR) and the risk of delirium (p < 0.001). Subsequent multivariate analysis, which accounted for comorbidities and illness severity scores, substantiated the role of LMR as a significant predictive marker. An optimized model, achieving the lowest Akaike Information Criterion (AIC), incorporated 17 variables and continued to demonstrate LMR as a significant prognostic factor (p < 0.01). Analysis of the Receiver Operating Characteristic (ROC) curve indicated a significant enhancement in the Area Under the Curve (AUC) upon the inclusion of LMR (p = 0.035).
Conclusion
The Lymphocyte-to-Monocyte Ratio (LMR) serves as a significant, independent prognostic indicator for the occurrence of delirium in older adult patients with sepsis. Integrating LMR into existing predictive models markedly improves the identification of patients at elevated risk, thereby informing and potentially guiding early intervention strategies.
... Sepsis-associated encephalopathy (SAE), which commonly accompanies severe systemic infection, is defined as a diffuse cerebral dysfunction in the absence of a direct central nervous system (CNS) infection, structural abnormalities, or other types of encephalopathy (Iacobone et al., 2009;Gofton and Young, 2012). Neurological dysfunction during SAE ranges from mild confusion and lethargy to disturbed cognitive functions and coma (Ebersoldt et al., 2007). Although SAE is considered a reversible syndrome, mild to moderate neurological symptoms, including memory alterations, depression, anxiety, and cognitive disturbances, may persist in up to 40% of patients one year after hospital discharge (Semmler et al., 2013). ...
We investigated the influences of sepsis on central synaptic plasticity in vitro. Cecal ligation and puncture (CLP) was performed by creating rat sepsis models, which were divided into early and late sepsis groups (8 and 16 h after CLP, respectively). In the CA1 of the rat hippocampal slices, orthodromically elicited population spikes (PSs) and field excitatory postsynaptic potentials (fEPSPs) were simultaneously recorded, and their long-term potentiation (LTP) was induced by theta burst stimulation (TBS). TBS induced LTPs of PSs and fEPSPs in all groups. In the sham and early sepsis groups, there was no significant difference in LTPs between PSs and fEPSPs. However, in the late sepsis group, the LTP of PSs was greater than that of fEPSPs (p < 0.05) and was greater than the LTPs of PSs in the sham and early sepsis groups (p < 0.05). Superoxide dismutase, administered immediately before CLP, inhibited the enhancement of LTP in PS, as observed in the late sepsis group. The initial rapid potentiation component of LTP in fEPSPs was suppressed or reduced in all groups that underwent CLP. The results indicate that CLP-induced sepsis modulates hippocampal synaptic plasticity, depressing excitatory synaptic transmissions and facilitating somatic excitability, which is induced by septic oxygen superoxide.
... Finally, we examined the routine blood characteristics of ICU patients, from which no significant differences were observed between both groups (Table 2). 11.5 ± 4.6 11.5 ± 3.2 0.489 Leucocytes (/nL) 11.5 ± 4. 6 13.2 ± 7.3 0.259 ...
Patients with sepsis-associated delirium (SAD) show severe neurological impairment, often require an intensive care unit (ICU) stay and have a high risk of mortality. Hence, useful biomarkers for early detection of SAD are urgently needed. Extracellular vesicles (EVs) and their cargo are known to maintain normal physiology but also have been linked to numerous disease states. Here, we sought to identify differentially expressed proteins in plasma EVs from SAD patients as potential biomarkers for SAD. Plasma EVs from 11 SAD patients and 11 age-matched septic patients without delirium (non-SAD) were isolated by differential centrifugation, characterized by nanoparticle tracking analysis, transmission electron microscopy and Western blot analysis. Differential EV protein expression was determined by mass spectrometry and the resulting proteomes were characterized by Gene Ontology term and between-group statistics. As preliminary results because of the small group size, five distinct proteins showed significantly different expression pattern between SAD and non-SAD patients (p ≤ 0.05). In SAD patients, upregulated proteins included paraoxonase-1 (PON1), thrombospondin 1 (THBS1), and full fibrinogen gamma chain (FGG), whereas downregulated proteins comprised immunoglobulin (IgHV3) and complement subcomponent (C1QC). Thus, plasma EVs of SAD patients show significant changes in the expression of distinct proteins involved in immune system regulation and blood coagulation as well as in lipid metabolism in this pilot study. They might be a potential indicator for to the pathogenesis of SAD and thus warrant further examination as potential biomarkers, but further research is needed to expand on these findings in longitudinal study designs with larger samples and comprehensive polymodal data collection.
... This brain malfunction frequently manifests as an alteration in consciousness (known as encephalopathy), which can vary from a change in consciousness, often known as encephalopathy, ranging from confusion and delirium to coma. Otherwise, Focal neurological symptoms may be obvious and should prompt one to consider a localized brain lesion, often ischemic in nature [32] . The term "brain dysfunction" is used by the writers because "encephalopathy" is too limited. ...
... Sepsis-associated encephalopathy (SAE) is one of the most common organ dysfunctions in sepsis and is also associated with significantly higher mortality rates [12,[16][17][18]. The term SAE is derived from human post-mortem studies and animal models. ...
... Due to inconsistent diagnostic criteria in clinical studies and diverging daily clinical practice, the estimated prevalence of delirium in SAE varies from 9 to 71% in sepsis patients [16]. As an example, a multicenter study including 2513 patients identified cerebral dysfunction due to SAE in approximately 50% of sepsis patients on the ICU [18]. ...
Sepsis is the most common cause of admission to intensive care units worldwide. Sepsis patients frequently suffer from sepsis-associated encephalopathy (SAE) reflecting acute brain dysfunction. SAE may result in increased mortality, extended length of hospital stay, and long-term cognitive dysfunction. The diagnosis of SAE is based on clinical assessments, but a valid biomarker to identify and confirm SAE and to assess SAE severity is missing. Several blood-based biomarkers indicating neuronal injury have been evaluated in sepsis and their potential role as early diagnosis and prognostic markers has been studied. Among those, the neuroaxonal injury marker neurofilament light chain (NfL) was identified to potentially serve as a prognostic biomarker for SAE and to predict long-term cognitive impairment. In this review, we summarize the current knowledge of biomarkers, especially NfL, in SAE and discuss a possible future clinical application considering existing limitations.
... Recognition memory is hippocampus-dependent (Barker and Warburton, 2011;Stanley et al., 2012), and lesions in this region impair recognition memory (Clark et al., 2000). Loss of short-term memory and spatial recognition indicate that sepsis compromises the brain (Ebersoldt et al., 2007). Besides, the hippocampus is vulnerable and susceptible to inflammation due to sepsis (Lynch et al., 2004;Annane, 2009). ...
Introduction: Sepsis is defined as a multifactorial debilitating condition with high risks of death. The intense inflammatory response causes deleterious effects on the brain, a condition called sepsis-associated encephalopathy. Neuroinflammation or pathogen recognition are able to stress cells, resulting in ATP (Adenosine Triphosphate) release and P2X7 receptor activation, which is abundantly expressed in the brain. The P2X7 receptor contributes to chronic neurodegenerative and neuroinflammatory diseases; however, its function in long-term neurological impairment caused by sepsis remains unclear. Therefore, we sought to evaluate the effects of P2X7 receptor activation in neuroinflammatory and behavioral changes in sepsis-surviving mice.
Methods: Sepsis was induced in wild-type (WT), P2X7−/−, and BBG (Brilliant Blue G)-treated mice by cecal ligation and perforation (CLP). On the thirteenth day after the surgery, the cognitive function of mice was assessed using the novel recognition object and Water T-maze tests. Acetylcholinesterase (AChE) activity, microglial and astrocytic activation markers, and cytokine production were also evaluated.
Results: Initially, we observed that both WT and P2X7−/− sepsis-surviving mice showed memory impairment 13 days after surgery, once they did not differentiate between novel and familiar objects. Both groups of animals presented increased AChE activity in the hippocampus and cerebral cortex. However, the absence of P2X7 prevented partly this increase in the cerebral cortex. Likewise, P2X7 absence decreased ionized calcium-binding protein 1 (Iba⁻¹) and glial fibrillary acidic protein (GFAP) upregulation in the cerebral cortex of sepsis-surviving animals. There was an increase in GFAP protein levels in the cerebral cortex but not in the hippocampus of both WT and P2X7−/− sepsis-surviving animals. Pharmacological inhibition or genetic deletion of P2X7 receptor attenuated the production of Interleukin-1β (IL-1β), Tumor necrosis factor-α (TNF-α), and Interleukin-10 (IL-10).
Conclusion: The modulation of the P2X7 receptor in sepsis-surviving animals may reduce neuroinflammation and prevent cognitive impairment due to sepsis-associated encephalopathy, being considered an important therapeutic target.
... SAE manifests itself as a spectrum of disturbed cerebral function from mild delirium, through confusion, to coma. Due to this wide range of clinical presentations, however, incidence remains difficult to define [36][37][38]. Based on 2513 septic patients in 12 French ICUs (from 1997-2014), Sonneville et al. reported an SAE incidence of 53% derived HMGB1 is a major alarmin that disrupts homeostasis by triggering complex signaling, processes leading to inflammation. ...
... SAE manifests itself as a spectrum of disturbed cerebral function from mild delirium, through confusion, to coma. Due to this wide range of clinical presentations, however, incidence remains difficult to define [36][37][38]. Based on 2513 septic patients in 12 French ICUs (from 1997-2014), Sonneville et al. reported an SAE incidence of 53% derived from Coma Glasgow Scale < 15, together with abnormal neuropsychological findings consistent with delirium (i.e., inattention, disorientation, altered thinking, psychomotor slowing and/or agitation) [37]. ...
... Based on 2513 septic patients in 12 French ICUs (from 1997-2014), Sonneville et al. reported an SAE incidence of 53% derived from Coma Glasgow Scale < 15, together with abnormal neuropsychological findings consistent with delirium (i.e., inattention, disorientation, altered thinking, psychomotor slowing and/or agitation) [37]. SAE is also associated with a higher risk of developing longterm cognitive impairment in survivors of sepsis and a higher susceptibility to developing neuropsychiatric diseases such as dementia, depression, anxiety and post-traumatic stress disorder [38][39][40]. ...
Sepsis-associated encephalopathy (SAE) remains a challenge for intensivists that is exacerbated by lack of an effective diagnostic tool and an unambiguous definition to properly identify SAE patients. Risk factors for SAE development include age, genetic factors as well as pre-existing neuropsychiatric conditions. Sepsis due to certain infection sites/origins might be more prone to encephalopathy development than other cases. Currently, ICU management of SAE is mainly based on non-pharmacological support. Pre-clinical studies have described the role of the alarmin high mobility group box 1 (HMGB1) in the complex pathogenesis of SAE. Although there are limited data available about the role of HMGB1 in neuroinflammation following sepsis, it has been implicated in other neurologic disorders, where its translocation from the nucleus to the extracellular space has been found to trigger neuroinflammatory reactions and disrupt the blood–brain barrier. Negating the inflammatory cascade, by targeting HMGB1, may be a strategy to complement non-pharmacologic interventions directed against encephalopathy. This review describes inflammatory cascades implicating HMGB1 and strategies for its use to mitigate sepsis-induced encephalopathy.
... According to the National Institute of Health, sepsis-associated encephalopathy (SAE) is an acute diffuse neurological deficit caused by severe sepsis without signs of direct infection of the brain. It is characterized by systemic inflammation, disturbance of the blood-brain barrier (BBB), and changes in consciousness that can range from confusion to delirium or even lead to coma induction (Ebersoldt et al., 2007). SAE is one of the main manifestations of sepsis, which can manifest as the first organ dysfunction and contribute to a worse prognosis in patients with sepsis. ...
... In ICU, sedatives are frequently used to improve the comfort and safety of patient, aid in the synchronization of patients with mechanical ventilation, and prevent accidental extubation (Devlin et al., 2001;Chen et al., 2022). However, the use of sedatives may have some side effects, such as excessive sedation leading to inability to awaken the patient even if the sedative is stopped or awakening accompanied by agitation, both of which will interfere with the judgment of the patient's mental status (Ebersoldt et al., 2007;Van Rompaey et al., 2009;Lahariya et al., 2014;Junior et al., 2022). Therefore, before making a judgment, the sedation state should be evaluated through the Richmond Restlessness and Sedation Scale (RASS), which demonstrates excellent interrater reliability and criterion, construct, and face validity (Ely et al., 2003). ...
... Despite more than 20 years of research, the role of electrophysiological examination in the diagnosis of SAE remains unclear, and most studies have significant limitations (Hosokawa et al., 2014). Sharshar et al. (2007) showed that an "MRI of SAE included multiple ischemic strokes and white matter lesions at the level of the centrum semiovale, mainly surrounding Virchow-Robin spaces, ranging from small multiple areas to diffuse lesions, and characterized by hyperintensity on FLAIR images. The major lesions were also characterized by reduced signal on diffusion isotropic images and increased apparent diffusion coefficient" (Sharshar et al., 2007). ...
Sepsis-associated encephalopathy (SAE) is an acute neurological deficit caused by severe sepsis without signs of direct brain infection, characterized by the systemic inflammation and disturbance of the blood–brain barrier. SAE is associated with a poor prognosis and high mortality in patients with sepsis. Survivors may exhibit long-term or permanent sequelae, including behavioral changes, cognitive impairment, and decreased quality of life. Early detection of SAE can help ameliorate long-term sequelae and reduce mortality. Half of the patients with sepsis suffer from SAE in the intensive care unit, but its physiopathological mechanism remains unknown. Therefore, the diagnosis of SAE remains a challenge. The current clinical diagnosis of SAE is a diagnosis of exclusion; this makes the process complex and time-consuming and delays early intervention by clinicians. Furthermore, the scoring scales and laboratory indicators involved have many problems, including insufficient specificity or sensitivity. Thus, a new biomarker with excellent sensitivity and specificity is urgently needed to guide the diagnosis of SAE. MicroRNAs have attracted attention as putative diagnostic and therapeutic targets for neurodegenerative diseases. They exist in various body fluids and are highly stable. Based on the outstanding performance of microRNAs as biomarkers for other neurodegenerative diseases, it is reasonable to infer that microRNAs will be excellent biomarkers for SAE. This review explores the current diagnostic methods for sepsis-associated encephalopathy (SAE). We also explore the role that microRNAs could play in SAE diagnosis and if they can be used to make the SAE diagnosis faster and more specific. We believe that our review makes a significant contribution to the literature because it summarizes some of the important diagnostic methods for SAE, highlighting their advantages and disadvantages in clinical use, and could benefit the field as it highlights the potential of miRNAs as SAE diagnostic markers.
... SAE is also referred to as sepsis-induced brain dysfunction (SIBD) (Orhun et al. 2019), sepsis-associated Dumbuya et al. Molecular Medicine (2023) 29:27 brain dysfunction (SABD) (Crippa et al. 2018;, or sepsis-associated delirium (SAD) (Ebersoldt et al. 2007;Chaudhry and Duggal 2014), depending on the context it is being used. However, they are not entirely synonymous per se. ...
... In addition to its feasibility and accessibility in most ICU tertiary institutions, EEG has high sensitivity in diagnosing SAE patients and its associated complications; it is also valuable for excluding non-convulsive status epilepticus in critically ill patients caused by altered sensorium (Pantzaris et al. 2021). However, its specificity is very low and hampered by sedatives, making its interpretation inconclusive in severe cases (Ebersoldt et al. 2007;Ehler et al. 2017). EEG manoeuvre is also very challenging, especially in ventilated children. ...
... The mRNA expression of TNF-α and its receptor, TNFR1, is upregulated following LPS induction in the septic encephalopathy model (Alexander et al. 2008). IL-1β activates afferent vagal fibres in the nucleus tractus solitarius, further causing (Ebersoldt et al. 2007). TNF-α and IL-1β activation can induce IL-6, cyclooxygenase 2 (COX2), implicated in activating the HPA axis (Cotena and Piazza 2012). ...
Sepsis-associated encephalopathy (SAE) is one of the most common types of organ dysfunction without overt central nervous system (CNS) infection. It is associated with higher mortality, low quality of life, and long-term neurological sequelae, its mortality in patients diagnosed with sepsis, progressing to SAE, is 9% to 76%. The pathophysiology of SAE is still unknown, but its mechanisms are well elaborated, including oxidative stress, increased cytokines and proinflammatory factors levels, disturbances in the cerebral circulation, changes in blood–brain barrier permeability, injury to the brain’s vascular endothelium, altered levels of neurotransmitters, changes in amino acid levels, dysfunction of cerebral microvascular cells, mitochondria dysfunction, activation of microglia and astrocytes, and neuronal death. The diagnosis of SAE involves excluding direct CNS infection or other types of encephalopathies, which might hinder its early detection and appropriate implementation of management protocols, especially in paediatric patients where only a few cases have been reported in the literature. The most commonly applied diagnostic tools include electroencephalography, neurological imaging, and biomarker detection. SAE treatment mainly focuses on managing underlying conditions and using antibiotics and supportive therapy. In contrast, sedative medication is used judiciously to treat those showing features such as agitation. The most widely used medication is dexmedetomidine which is neuroprotective by inhibiting neuronal apoptosis and reducing a sepsis-associated inflammatory response, resulting in improved short-term mortality and shorter time on a ventilator. Other agents, such as dexamethasone, melatonin, and magnesium, are also being explored in vivo and ex vivo with encouraging results. Managing modifiable factors associated with SAE is crucial in improving generalised neurological outcomes. From those mentioned above, there are still only a few experimentation models of paediatric SAE and its treatment strategies. Extrapolation of adult SAE models is challenging because of the evolving brain and technical complexity of the model being investigated. Here, we reviewed the current understanding of paediatric SAE, its pathophysiological mechanisms, diagnostic methods, therapeutic interventions, and potential emerging neuroprotective agents.
