BACKGROUND A pathophysiological feature of septic organ failure is endothelial dysfunction in sepsis (EDS). The physiological and pathological mechanism of sepsis is considered to be vascular leakage caused by endothelial dysfunction. These pathological changes lead to systemic organ injury. However, an analysis using bibliometric methods has not yet been conducted in the field of EDS. This study was conducted to provide an overview of knowledge structure and research trends in the field of EDS.

METHODS Based on previous research, a literature search was performed in the Web of Science Core Collection (WoSCC) for publications associated with EDS published between the year 2003 and 2023. Various types of data from the publications, such as citation frequency, authorship, keywords and highly cited articles, were extracted. The "Create Citation Report" feature in the WoSCC was employed to calculate the Hirsch index (h-index) and average citations per item (ACI) of authors, institutions, and countries. To conduct bibliometric and visualization analyses, three bibliometric tools were used, including R-bibliometrix, CiteSpace (co-citation analysis of references), and VOSviewer (co-authorship analysis of institutions, co-authorship analysis of authors, co-occurrence analysis of keywords).

RESULTS After excluding invalid records, the study finaly included 4,536 publications with 135,386 citations. Most of these publications originated in the USA, China, Germany, Canada, and Japan. Harvard University emerged as the most prolific institution, while professor Jong-Sup Bae and his research team at Kyungpook National University emerged as authors with the greatest influence. The "protein C", "tissue factor", "thrombin", "glycocalyx", “acute kidney injury”, “syndecan-1” and “biomarker” were identified as prominent areas of research. Future research may focus on molecular mechanisms (such as as vascular endothelial [VE]-cadherin regulation) and therapeutic interventions to enhance endothelial repair and function.

CONCLUSION Our findings show a growing interest in EDS research. Key areas for future research include signaling pathways, molecular mechanisms, endothelial repair, and interactions between endothelial cells and other cell types in sepsis.

BACKGROUND Sepsis is one of the main causes of mortality in intensive care units (ICUs). Early prediction is critical for reducing injury. As approximately 36% of sepsis occur within 24 h after emergency department (ED) admission in Medical Information Mart for Intensive Care (MIMIC-IV), a prediction system for the ED triage stage would be helpful. Previous methods such as the quick Sequential Organ Failure Assessment (qSOFA) are more suitable for screening than for prediction in the ED, and we aimed to find a light-weight, convenient prediction method through machine learning.

METHODS We accessed the MIMIC-IV for sepsis patient data in the EDs. Our dataset comprised demographic information, vital signs, and synthetic features. Extreme Gradient Boosting (XGBoost) was used to predict the risk of developing sepsis within 24 h after ED admission. Additionally, SHapley Additive exPlanations (SHAP) was employed to provide a comprehensive interpretation of the model's results. Ten percent of the patients were randomly selected as the testing set, while the remaining patients were used for training with 10-fold cross-validation.

RESULTS For 10-fold cross-validation on 14,957 samples, we reached an accuracy of 84.1%±0.3% and an area under the receiver operating characteristic (ROC) curve of 0.92±0.02. The model achieved similar performance on the testing set of 1,662 patients. SHAP values showed that the five most important features were acuity, arrival transportation, age, shock index, and respiratory rate.

CONCLUSION Machine learning models such as XGBoost may be used for sepsis prediction using only a small amount of data conveniently collected in the ED triage stage. This may help reduce workload in the ED and warn medical workers against the risk of sepsis in advance.

BACKGROUND: This study aimed to evaluate the discriminatory performance of 11 vital sign-based early warning scores (EWSs) and three shock indices in early sepsis prediction in the emergency department (ED).

METHODS: We performed a retrospective study on consecutive adult patients with an infection over 3 months in a public ED in Hong Kong. The primary outcome was sepsis (Sepsis-3 definition) within 48 h of ED presentation. Using c-statistics and the DeLong test, we compared 11 EWSs, including the National Early Warning Score 2 (NEWS2), Modified Early Warning Score, and Worthing Physiological Scoring System (WPS), etc., and three shock indices (the shock index [SI], modified shock index [MSI], and diastolic shock index [DSI]), with Systemic Inflammatory Response Syndrome (SIRS) and quick Sequential Organ Failure Assessment (qSOFA) in predicting the primary outcome, intensive care unit admission, and mortality at different time points.

RESULTS: We analyzed 601 patients, of whom 166 (27.6%) developed sepsis. NEWS2 had the highest point estimate (area under the receiver operating characteristic curve [AUROC] 0.75, 95%CI 0.70-0.79) and was significantly better than SIRS, qSOFA, other EWSs and shock indices, except WPS, at predicting the primary outcome. However, the pooled sensitivity and specificity of NEWS2 ≥ 5 for the prediction of sepsis were 0.45 (95%CI 0.37-0.52) and 0.88 (95%CI 0.85-0.91), respectively. The discriminatory performance of all EWSs and shock indices declined when used to predict mortality at a more remote time point.

CONCLUSION: NEWS2 compared favorably with other EWSs and shock indices in early sepsis prediction but its low sensitivity at the usual cut-off point requires further modification for sepsis screening.

BACKGROUND: Disseminated intravascular coagulation (DIC) is associated with increased mortality in sepsis patients. In this study, we aimed to assess the clinical ability of sepsis-induced coagulopathy (SIC) and sepsis-associated coagulopathy (SAC) criteria in identifying overt-DIC and pre-DIC status in sepsis patients.
METHODS: Data from 419 sepsis patients were retrospectively collected from July 2018 to December 2022. The performances of the SIC and SAC were assessed to identify overt-DIC on days 1, 3, 7, or 14. The SIC status or SIC score on day 1, the SAC status or SAC score on day 1, and the sum of the SIC or SAC scores on days 1 and 3 were compared in terms of their ability to identify pre-DIC. The SIC or SAC status on day 1 was evaluated as a pre-DIC indicator for anticoagulant initiation.
RESULTS: On day 1, the incidences of coagulopathy according to overt-DIC, SIC and SAC criteria were 11.7%, 22.0% and 31.5%, respectively. The specificity of SIC for identifying overt-DIC was significantly higher than that of the SAC criteria from day 1 to day 14 (P<0.05). On day 1, the SIC score with a cut-off value > 3 had a significantly higher sensitivity (72.00%) and area under the curve (AUC) (0.69) in identifying pre-DIC than did the SIC or SAC status (sensitivity: SIC status 44.00%, SAC status 52.00%; AUC: SIC status 0.62, SAC status 0.61). The sum of the SIC scores on days 1 and 3 had a higher AUC value for identifying the pre-DIC state than that of SAC (0.79 vs. 0.69, P<0.001). Favorable effects of anticoagulant therapy were observed in SIC (adjusted hazard ratio [HR]=0.216, 95% confidence interval [95% CI]: 0.060-0.783, P=0.018) and SAC (adjusted HR=0.146, 95% CI: 0.041-0.513, P=0.003).
CONCLUSION: The SIC and SAC seem to be valuable for predicting overt-DIC. The sum of SIC scores on days 1 and 3 has the potential to help identify pre-DIC.

BACKGROUND: Sepsis-related acute respiratory distress syndrome (ARDS) has a high mortality rate, and no effective treatment is available currently. Quercetin is a natural plant product with many pharmacological activities, such as antioxidative, anti-apoptotic, and anti-inflammatory effects. This study aimed to elucidate the protective mechanism of quercetin against sepsis-related ARDS.

METHODS: In this study, network pharmacology and in vitro experiments were used to investigate the underlying mechanisms of quercetin against sepsis-related ARDS. Core targets and signaling pathways of quercetin against sepsis-related ARDS were screened and were verified by in vitro experiments.

RESULTS: A total of 4,230 targets of quercetin, 360 disease targets of sepsis-related ARDS, and 211 intersection targets were obtained via database screening. Among the 211 intersection targets, interleukin-6 (IL-6), tumor necrosis factor (TNF), albumin (ALB), AKT serine/threonine kinase 1 (AKT1), and interleukin-1β (IL-1β) were identified as the core targets. A Gene Ontology (GO) enrichment analysis revealed 894 genes involved in the inflammatory response, apoptosis regulation, and response to hypoxia. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis identified 106 pathways. After eliminating and generalizing, the hypoxia-inducible factor-1 (HIF-1), TNF, nuclear factor-κB (NF-κB), and nucleotide-binding and oligomerization domain (NOD)-like receptor signaling pathways were identified. Molecular docking revealed that quercetin had good binding activity with the core targets. Moreover, quercetin blocked the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways in lipopolysaccharide (LPS)-induced murine alveolar macrophage (MH-S) cells. It also suppressed the inflammatory response, oxidative reactions, and cell apoptosis.

CONCLUSION: Quercetin ameliorates sepsis-related ARDS by binding to its core targets and blocking the HIF-1, TNF, NF-κB, and NOD-like receptor signaling pathways to reduce inflammation, cell apoptosis, and oxidative stress.

BACKGROUND: The molecular mechanism of sepsis-associated acute kidney injury (SA-AKI) is unclear. We analyzed co-differentially expressed genes (co-DEGs) to elucidate the underlying mechanism and intervention targets of SA-AKI.

METHODS: The microarray datasets GSE65682, GSE30718, and GSE174220 were downloaded from the Gene Expression Omnibus (GEO) database. We identified the co-DEGs and constructed a gene co-expression network to screen the hub genes. We analyzed immune correlations and disease correlations and performed functional annotation of the hub genes. We also performed single-cell and microenvironment analyses and investigated the enrichment pathways and the main transcription factors. Finally, we conducted a correlation analysis to evaluate the role of the hub genes.

RESULTS: Interleukin 32 (IL32) was identified as the hub gene in SA-AKI, and the main enriched signaling pathways were associated with hemopoiesis, cellular response to cytokine stimulus, inflammatory response, and regulation of kidney development. Additionally, IL32 was significantly associated with mortality in SA-AKI patients. Monocytes, macrophages, T cells, and NK cells were closely related to IL32 and were involved in the immune microenvironment in SA-AKI patients. IL32 expression increased significantly in the kidney of septic mouse. Toll-like receptor 2 (TLR2) was significantly and negatively correlated with IL32.

CONCLUSION: IL32 is the key gene involved in SA-AKI and is significantly associated with prognosis. TLR2 and relevant immune cells are closely related to key genes.

BACKGROUND: Xuebijing (XBJ) can alleviate the inflammatory response, improve organ function, and shorten the intensive care unit (ICU) stay in patients with pyogenic liver abscess (PLA) complicated with sepsis, but the molecular mechanisms have not been elucidated. This study aimed to explore the molecular mechanism of XBJ in treating PLA complicated with sepsis using a network pharmacology approach.
METHODS: The active ingredients and targets of XBJ were retrieved from the ETCM database. Potential targets related to PLA and sepsis were retrieved from the GeneCards, PharmGKB, DisGeNet, Online Mendelian Inheritance in Man (OMIM), Therapeutic Targets Database (TTD), and DrugBank databases. The targets of PLA complicated with sepsis were mapped to the targets of XBJ to identify potential treatment targets. Protein-protein interaction networks were analyzed using the STRING database. Potential treatment targets were imported into the Metascape platform for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Molecular docking was performed to validate the interactions between active ingredients and core targets.
RESULTS: XBJ was found to have 54 potential treatment targets for PLA complicated with sepsis. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF) were identified as core targets. KEGG enrichment analysis revealed important pathways, including the interleukin-17 (IL-17) signaling pathway, the TNF signaling pathway, the nuclear factor-kappa B (NF-κB) signaling pathway, and the Toll-like receptor (TLR) signaling pathway. Molecular docking experiments indicated stable binding between XBJ active ingredients and core targets.
CONCLUSION: XBJ may exert therapeutic effects on PLA complicated with sepsis by modulating signaling pathways, such as the IL-17, TNF, NF-κB, and TLR pathways, and targeting IL-1β, IL-6, and TNF.

BACKGROUND: Emergency patients with sepsis or septic shock are at high risk of death. Despite increasing attention to microhemodynamics, the clinical use of advanced microcirculatory assessment is limited due to its shortcomings. Since blood gas analysis is a widely used technique reflecting global oxygen supply and consumption, it may serve as a surrogate for microcirculation monitoring in septic treatment.

METHODS: We performed a search using PubMed, Web of Science, and Google scholar. The studies and reviews that were most relevant to septic microcirculatory dysfunctions and blood gas parameters were identified and included.

RESULTS: Based on the pathophysiology of oxygen metabolism, the included articles provided a general overview of employing blood gas analysis and its derived set of indicators for microhemodynamic monitoring in septic care. Notwithstanding flaws, several parameters are linked to changes in the microcirculation. A comprehensive interpretation of blood gas parameters can be used in order to achieve hemodynamic optimization in septic patients.

CONCLUSION: Blood gas analysis in combination with clinical performance is a reliable alternative for microcirculatory assessments. A deep understanding of oxygen metabolism in septic settings may help emergency physicians to better use blood gas analysis in the evaluation and treatment of sepsis and septic shock.

BACKGROUND: Sepsis-associated encephalopathy (SAE) is a critical disease caused by sepsis. In addition to high mortality, SAE can also adversely affect life quality and lead to significant socioeconomic costs. This review aims to explore the development of evaluation animal models of SAE, giving insight into the direction of future research in terms of its pathophysiology and therapy.
METHODS: We performed a literature search from January 1, 2000, to December 31, 2022, in MEDLINE, PubMed, EMBASE, and Web of Science using related keywords. Two independent researchers screened all the accessible articles based on the inclusion and exclusion criteria and collected the relevant data of the studies.
RESULTS: The animal models for sepsis are commonly induced through cecal ligation and puncture (CLP) or lipopolysaccharide (LPS) injection. SAE can be evaluated using nervous reflex scores and sepsis evaluation during the acute phase, or through Morris water maze (MWM), open-field test, fear condition (FC) test, inhibitory avoidance, and other tests during the late phase.
CONCLUSION: CLP and LPS injection are the most common methods for establishing SAE animal models. Nervous reflexs cores, MWM, FC test, and inhibitory avoidance are widely used in SAE model analysis. Future research should focus on establishing a standardized system for SAE development and analysis.

BACKGROUND: To determine the protective role of mesencephalic astrocyte-derived neurotrophic factor (MANF) in regulating sepsis-associated acute kidney injury (S-AKI).
METHODS: A total of 96 mice were randomly divided into the control group, control+MANF group, S-AKI group, and S-AKI+MANF group. The S-AKI model was established by injecting lipopolysaccharide (LPS) at 10 mg/kg intraperitoneally. MANF (200 μg/kg) was administered to the control+MANF and S-AKI+MANF groups. An equal dose of normal saline was administered daily intraperitoneally in the control and S-AKI groups. Serum and kidney tissue samples were obtained for biochemical analysis. Western blotting was used to detect the protein expression of MANF in the kidney, and enzyme-linked immunosorbent assay (ELISA) was used to determine expression of MANF in the serum, pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α] and interleukin-6 [IL-6]). Serum creatinine (SCr), and blood urea nitrogen (BUN) were examined using an automatic biochemical analyzer. In addition, the kidney tissue was observed for pathological changes by hematoxylin-eosin staining. The comparison between two groups was performed by unpaired Student’s t-test, and statistics among multiple groups were carried out using Tukey’s post hoc test following one-way analysis of variance (ANOVA). A P-value <0.05 was considered statistically significant.
RESULTS: At the early stage of S-AKI, MANF in the kidney tissue was up-regulated, but with the development of the disease, it was down-regulated. Renal function was worsened in the S-AKI group, and TNF-α and IL-6 were elevated. The administration of MANF significantly alleviated the elevated levels of SCr and BUN and inhibited the expression of TNF-α and IL-6 in the kidney. The pathological changes were more extensive in the S-AKI group than in the S-AKI+MANF group.
CONCLUSION: MANF treatment may significantly alleviate renal injury, reduce the inflammatory response, and alleviate or reverse kidney tissue damage. MANF may have a protective effect on S-AKI, suggesting a potential treatment for S-AKI.

BACKGROUND: This study aims to evaluate the effect of continuous renal replacement therapy (CRRT) on inflammation-related anemia, iron metabolism, and the prognosis in sepsis patients with acute kidney injury (AKI).

METHODS: Sepsis patients with AKI were prospectively enrolled and randomized into the CRRT and control groups. The clinical and laboratory data on days 1, 3 and 7 after intensive care unit (ICU) admission were collected. The serum interleukin (IL)-6, hepcidin, erythropoietin, ferritin, and soluble transferrin receptor (sTfR) were determined by enzyme-linked immunosorbent assay. The Sequential Organ Failure Assessment (SOFA) score and 28-day mortality were recorded. Data were analyzed using Pearson’s Chi-square test or Fisher’s exact test (categorical variables), and Mann-Whitney U-test or t-test (continuous variables).

RESULTS: The hemoglobin and serum erythropoietin levels did not significantly differ between the CRRT and control groups though gradually decreased within the first week of ICU admission. On days 3 and 7, the serum IL-6, hepcidin, ferritin, and red blood cell distribution width significantly decreased in the CRRT group compared to the control group (all P<0.05). On day 7, the serum iron was significantly elevated in the CRRT group compared to the control group (P<0.05). However, the serum sTfR did not significantly differ between the groups over time. In addition, the SOFA scores were significantly lower in the CRRT group compared to the control group on day 7. The 28-day mortality did not significantly differ between the control and CRRT groups (38.0% vs. 28.2%, P=0.332).

CONCLUSION: CRRT might have beneficial effects on the improvement in inflammation-related iron metabolism and disease severity during the first week of ICU admission but not anemia and 28-day mortality in sepsis patients with AKI.

BACKGROUND: This study aimed to explore the changes of programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) expression on antigen-presenting cells (APCs) and evaluate their association with organ failure and mortality during early sepsis.

METHODS: In total, 40 healthy controls and 198 patients with sepsis were included in this study. Peripheral blood was collected within the first 24 h after the diagnosis of sepsis. The expression of PD-L1 and PD-1 was determined on APCs, such as B cells, monocytes, and dendritic cells (DCs), by flow cytometry. Cytokines in plasma, such as interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), IL-6, IL-10, and IL-17A were determined by Luminex assay.

RESULTS: PD-1 expression decreased significantly on B cells, monocytes, myeloid DCs (mDCs), and plasmacytoid DCs (pDCs) as the severity of sepsis increased. PD-1 expression was also markedly decreased in non-survivors compared with survivors. In contrast, PD-L1 expression was markedly higher on mDCs, pDCs, and monocytes in patients with sepsis than in healthy controls and in non-survivors than in survivors. The PD-L1 expression on APCs (monocytes and DCs) was weakly related to organ dysfunction and inflammation. The area under the receiver operating characteristic curve (AUC) of the PD-1 percentage of monocytes (monocyte PD-1%)+APACHE II model (0.823) and monocyte PD-1%+SOFA model (0.816) had higher prognostic value than other parameters alone. Monocyte PD-1% was an independent risk factor for 28-day mortality.

CONCLUSION: The severity of sepsis was correlated with PD-L1 or PD-1 over-expression on APCs. PD-L1 in monocytes and DCs was weakly correlated with inflammation and organ dysfunction during early sepsis. The combination of SOFA or APACHE II scores with monocyte PD-1% could improve the prediction ability for mortality.

BACKGROUND: Endothelial dysfunction in sepsis is a pathophysiological feature of septic organ failure. Endothelial cells (ECs) exhibit specific metabolic traits and release metabolites to adapt to the septic state in the blood to maintain vascular homeostasis.

METHODS: Web of Science and PubMed were searched from inception to October 1, 2022. The search was limited to the English language only. Two reviewers independently identified studies related to EC metabolism in sepsis. The exclusion criteria were duplicate articles according to multiple search criteria.

RESULTS: Sixty articles were included, and most of them were cell and animal studies. These studies reported the role of glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism in EC homeostasis. including glycolysis, oxidative phosphorylation, fatty acid metabolism and amino acid metabolism. However, dysregulation of EC metabolism can contribute to sepsis progression.

CONCLUSION: There are few clinical studies on EC metabolism in sepsis. Related research mainly focuses on basic research, but some scientific problems have also been clarified. Therefore, this review may provide an overall comprehension and novel aspects of EC metabolism in sepsis.

BACKGROUND: The latest sepsis definition includes both infection and organ failure, as evidenced by the sequential organ failure assessment (SOFA) score. However, the applicability of the pediatric SOFA score (pSOFA) is not yet determined. This study evaluated the effectiveness of both pSOFA and system inflammatory reaction syndrome (SIRS) scores in predicting sepsis-related pediatric deaths.

METHODS: This is a retrospective multi-center cohort study including hospitalized patients <18 years old with diagnosed or not-yet-diagnosed infections. Multivariate analyses were carried out to evaluate risk factors for in-hospital mortality. According to Youden index (YI), three sub-categories of pSOFA were screened out and a new simplified pSOFA score (spSOFA) was formed. The effectiveness and accuracy of prediction of pSOFA, SIRS and spSOFA was retrieved from the area under the receiver operating characteristic curve (AUROC) and Delong’s test.

RESULTS: A total of 1,092 participants were eligible for this study, and carried a 23.4% in-hospital mortality rate. The 24-h elevated pSOFA score (24 h-pSOFA), bloodstream infection, and mechanical ventilation (MV) requirement were major risk factors associated with sepsis-related deaths. The AUROC analysis confirmed that the spSOFA provided good predictive capability in sepsis-related pediatric deaths, relative to the 24 h-pSOFA and SIRS.

CONCLUSIONS: The pSOFA score performed better than SIRS in diagnosing infected children with high mortality risk. However, it is both costly and cumbersome. We, therefore, proposed spSOFA to accurately predict patient outcome, without the disadvantages. Nevertheless, additional investigations, involving a large sample population, are warranted to confirm the conclusion of this study.

BACKGROUND: Patients with sepsis often exhibit an acute inflammatory response, followed by an immunosuppressive phase with a poor immune response. However, the underlying mechanisms have not been fully elucidated.

METHODS: We sought to comprehensively characterize the transcriptional changes in neutrophils of patients with sepsis by transcriptome sequencing. Additionally, we conducted a series of experiments, including real-time quantitative polymerase chain reaction (RT-qPCR) and flow cytometry to investigate the role of arginase-1 signaling in sepsis.

RESULTS: Through the analysis of gene expression profiles, we identified that the negative regulation of T cell activation signaling was enriched, and the expression of arginase-1 was high in neutrophils from patients with sepsis. Furthermore, we conducted flow cytometry and found that the function of CD8⁺ T cells in septic patients was impaired. Moreover, neutrophils from septic patients inhibited the percentage of polyfunctional effector CD8⁺ T cells through arginase-1. Additionally, the proportions of granzyme B⁺IFN^-γ⁺CD8⁺ T and TNF^-α⁺IFN^-γ⁺CD8⁺ T cells increased after inhibition of arginase-1 signaling.

CONCLUSION: The impaired effector function of CD8⁺ T cells could be restored by blocking arginase-1 signaling in patients with sepsis.