Comparison between sepsis-induced coagulopathy and sepsis-associated coagulopathy criteria in identifying sepsis-associated disseminated intravascular coagulation

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 preDIC 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.

Sepsis-associated liver injury:Mechanisms and potential therapeutic targets

In this editorial,we examined a recent article in the World Journal of Gastroenterology that focused on sepsis-associated liver injury(SLI)and its treatment.SLI is a serious complication of sepsis,primarily caused by microcirculatory disturbances,the gut-liver axis,and inflammatory responses.Specific treatment recommendations for SLI are lacking.The gut-liver axis represents a potential therapeutic target,with metformin showing promise in modulating the gut microbiome and enhancing intestinal barrier function.Although immunomodulatory therapies are being explored,anti-tumor necrosis factor agents and interleukin-1 receptor antagonists have not demonstrated significant clinical benefits.Statins may reduce liver inflammation and prevent injury in sepsis,but their clinical application is limited.Reduced D-related human leucocyte antigen expression on monocytes and lymphocytes suggests immune suppression in patients,indicating that corticosteroids could reverse clinical deterioration in severe infections and address adrenal cortical insufficiency.Current large-scale studies on glucocorticoid therapy for sepsis have yielded mixed results,likely due to inadequate assessment of the immune status of the host.Future research should prioritize the development of personalized immunotherapy tailored to patients’immune profiles,focusing on identifying novel indicators of immune status and advancing immunomodulatory targets and therapeutics for septic patients.

Establishment and evaluation of animal models of sepsis-associated encephalopathy

BACKGROUND:Sepsis-associated encephalopathy(SAE) is a critical disease caused by sepsis.In addition to high mortality,SAE can also adversely aff ect 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),openfield 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.

Effects of mesencephalic astrocyte-derived neurotrophic factor on sepsis-associated acute kidney injury

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.

Is rosuvastatin protective against sepsis-associated encephalopathy? A secondary analysis of the SAILS trial

BACKGROUND:Sepsis is a common cause of death in emergency departments and sepsis-associated encephalopathy(SAE)is a major complication.Rosuvastatin may play a neuroprotective role due to its protective effects on the vascular endothelium and its anti-inflammatory functions.Our study aimed to explore the potential protective function of rosuvastatin against SAE.METHODS:Sepsis patients without any neurological dysfunction on admission were prospectively enrolled in the“Rosuvastatin for Sepsis-Associated Acute Respiratory Distress Syndrome”study(SAILS trial,ClinicalTrials.gov number:NCT00979121).Patients were divided into rosuvastatin and placebo groups.This is a secondary analysis of the SAILS dataset.Baseline characteristics,therapy outcomes,and adverse drug events were compared between groups.RESULTS:A total of 86 patients were eligible for our study.Of these patients,51 were treated with rosuvastatin.There were significantly fewer cases of SAE in the rosuvastatin group than in the placebo group(32.1%vs.57.1%,P=0.028).However,creatine kinase levels were significantly higher in the rosuvastatin group than in the placebo group(233[22-689]U/L vs.79[12-206]U/L,P=0.034).CONCLUSION:Rosuvastatin appears to have a protective role against SAE but may result in a higher incidence of adverse events.

Risk factors for sepsis-associated encephalopathy

Sepsis-associated encephalopathy （SAE） is a diffuse and acute cerebral dysfunction caused by sepsis. Many sepsis patients exhibit acute deterioration in mental status during the early stage of disease, and central nervous system dysfunction has been shown to increase patient mortality. The present study selected 284 sepsis patients who were admitted to the Intensive Care Unit of Beijing Friendship Hospital, Capital Medical University, from January to December 2009. The patients were assigned to SAE and non-SAE patient groups according to SAE occurrence. SAE incidence was 37.68%, and mortality was significantly greater in SAE patients compared with non-SAE patients （41.12% vs. 17.51%, P 〈 0.01）. Univariate analysis and multivariate logistic regression analysis indicated lower arterial partial pressure of oxygen and greater alanine aminotransferase and Acute Physiology and Chronic Health Evaluation II scores in the SAE group compared with the non-SAE group. Arterial partial pressure of oxygen, alanine aminotransferase, and Acute Physiology and Chronic Health Evaluation II scores were determined to be potential risk factors for SAE.

Effects of Hydrogen Sulfide on a Rat Model of Sepsis-associated Encephalopathy

To investigate the interaction and involvement of sodium hydrosulfide （NaHS）, a H2S donor, on hippocampus of rats suffering from sepsis-associated encephalopathy, rats were subjected to cecal ligation and puncture （CLP）-induced sepsis. Adult male Sprague-Dawley rats were randomly divided into four groups： Sham group, CLP group, CLP＋NaHS group and CLP＋aminooxyacetic acid （AOAA, an inhibitor of H2S formation） group. The four groups were observed at 3, 6, 9, 12 h after treatment. We examined hippocampal H2S synthesis and the expression of cystathionine-β-synthetase （CBS）, a major enzyme involved in the H2S synthesis in hippocampus. CBS expression was detected by reverse transcription polymerase chain reaction （RT-PCR）. The concentrations of inflammatory cytokines （TNF-α, IL-1β） were determined in hippocampus by using enzyme-linked immunosorbent assay （ELISA）. Neuronal damage was studied by histological examination of hippocampus. In CLP group, H2S synthesis was significantly increased in hippocampus compared with sham group and it peaked 3 h after CLP （P〈0.05）. Sepsis also resulted in a significantly upregulated CBS mRNA in hippocampus. The levels of TNF-α and IL-1β in the hippocampus were substantially elevated at each time point of measurement （P〈0.05）, and they also reached a peak value at about 3 h. Administration of NaHS significantly aggravated sepsis-associated hippocampus inflammation, as evidenced by TNF-α and IL-1β activity and histological changes in hippocampus. In septic rats pretreated with AOAA, sepsis-associated hippocampus inflammation was reduced. It is concluded that the rats subjected to sepsis may suffer from brain injury and elevated pro-inflammatory cytokines are responsible for the process. Furthermore, administration of H2S can increase injurious effects and treatment with AOAA can protect the brain from injury.

Novel Time-dependent Multi-omics Integration in Sepsis-associated Liver Dysfunction

The recently developed technologies that allow the analysis of each single omics have provided an unbiased insight into ongoing disease processes.However,it remains challenging to specify the study design for the subsequent integration strategies that can associate sepsis pathophysiology and clinical outcomes.Here,we conducted a time-dependent multi-omics integration(TDMI)in a sepsis-associated liver dysfunction(SALD)model.We successfully deduced the relation of the Toll-like receptor 4(TLR4)pathway with SALD.Although TLR4 is a critical factor in sepsis progression,it is not specified in single-omics analyses but only in the TDMI analysis.This finding indicates that the TDMI-based approach is more advantageous than single-omics analyses in terms of exploring the underlying pathophysiological mechanism of SALD.Furthermore,TDMI-based approach can be an ideal paradigm for insightful biological interpretations of multi-omics datasets that will potentially reveal novel insights into basic biology,health,and diseases,thus allowing the identification of promising candidates for therapeutic strategies.

Epidemiological features and risk factors of sepsis-associated encephalopathy in intensive care unit patients： 2008-2011

Background Encephalopathy is a common complication of sepsis, and its onset can occur at any stage of sepsis and implies worse prognosis. However, the incidence, epidemiology, and pathogenesis of sepsis-associated encephalopathy remain controversial. The purpose of this study was to investigate the epidemiological features and risk factors for sepsis-associated encephalopathy.

Psychometric hepatic encephalopathy score for diagnosis of minimal hepatic encephalopathy in China

AIM:To construct normal values for the tests of the psychometric hepatic encephalopathy score(PHES)and to evaluate its usefulness in the diagnosis of minimal hepatic encephalopathy(MHE)among Chinese individuals with cirrhosis.METHODS:The five tests of PHES,number connection test-A(NCT-A),number connection test-B,serial dotting test,line tracing test and digit symbol test(DST),were administered to all enrolled subjects in a quiet room with sufficient light.Cirrhotic subjects with overt HE were excluded by the West-Haven criteria and a detailed neurological examination.Based on the nomograms of healthy volunteers,the patients were classified as having MHE when their PHES was less than-4.RESULTS:In total,146 healthy volunteers completed all the PHES tests.Age and education years were confirmed to be predictors of all five tests.In total,53patients with liver cirrhosis completed the PHES.Of the patients with liver cirrhosis,24(45.3%),22(41.5%)and 7(13.2%)had Child-Pugh grades A,B and C,respectively.MHE was diagnosed in 26 patients(49.1%).Compared with compensated cirrhotic patients(Child A),decompensated cirrhotic patients(Child B and C)had a higher proportion of MHE(65.5%vs 29.2%).No differences in age and education years were found between the MHE and non-MHE groups.NCT-A and DST were able to diagnose MHE with a sensitivity of 76.9%and a specificity of 96.3%(AUC=0.866,K=0.735).CONCLUSION:The proportion of MHE is associated with liver function.NCT-A and DST are simple tools that can be used for the diagnosis of MHE in China.

Diagnostic and Predictive Levels of Calcium-binding Protein A8 and Tumor Necrosis Factor Receptor-associated Factor 6 in Sepsis-associated Encephalopathy： A Prospective Observational Study

Background： Despite its high prevalence, morbidity, and mortality, sepsis-associated encephalopathy （SAE） is still poorly understood. The aim of this prospective and observational study was to investigate the clinical significance of calcium-binding protein A8 （S 100AS） in serum and tumor necrosis factor receptor-associated factor 6 （TRAF6） in peripheral blood mononuclear cells （PBMCs） in diagnosing SAE and predicting its prognosis. Methods： Data of septic patients were collected within 24 h after Intensive Care Unit admission fi-om July 2014 to March 2015. Healthy medical personnel served as the control group. SAE was defined as cerebral dysfhnction in the presence of sepsis that fulfilled the exclusion criteria. The biochemical indicators, Glasgow Coma Scale, Acute Physiology and Chronic Health Evaluation score II, TRAF6 in PBMC, serum S 100A8, S 10013, and neuron-specific enolase were evaluated in SAE patients afresh. TRAF6 and S 100A8 were also measured in the control group. Results： Of the 57 enrolled patients, 29 were diagnosed with SAE. The S 100A8 and TRAF6 concentrations in SAE patients were both significantly higher than that in no-encephalopathy （NE） patients, and higher in NE than that in controls （3.74 ± 3.13 vs. 1.08 ± 0.75 vs. 0.37 ± 0.14 ng/ml, P 〈 0.01 ; 3.18 ± 1.55 vs. 1.02 ± 0.63 vs. 0.47 ± 0.10, P 〈 0.01）. S 100A8 levels of 1.93 ng/ml were diagnostic of SAE with 92.90% specificity and 69.00% sensitivity in the receiver operating characteristic （ROC） curve, and the area under the curve was 0.86 （95% confidence interval [CI]： 0.76-0.95）. TRAF6-relative levels of 1.44 were diagnostic of SAE with 85.70% specificity and 86.20% sensitivity, and the area under the curve was 0.94 （95% CI： 0.88-0.99）. In addition, S 100A8 levels of 2.41 ng/ml predicted 28-day mortality of SAE with 90.00% specificity and 73.70% sensitivity in the ROC curve, and the area under the curve was 0.88. TRAF6 relative levels of 2.94 predicted 28-day mortality of SAE with 80.00% specificity and 68.40% sensitivity, and the area under the curve was 0.77. Compared with TRAF6, the specificity of serum S 100A8 in diagnosing SAE and predicting mortality was higher, although the sensitivity was low. In contrast, the TRAF6 had higher sensitivity for diagnosis. Conclusions： Peripheral blood levels of S 100A8 and TRAF6 in SAE patients were elevated and might be related to the severity of SAE and predict the outcome of SAE. The efficacy and specificity of S 100A8 for SAE diagnosis were superior, despite its weak sensitivity. S100A8 might be a better biomarker for diagnosis of SAE and predicting prognosis.

Effects of sepsis on hippocampal volume and memory function

BACKGROUND:This study aimed to determine the effects of sepsis on brain integrity,memory,and executive function.METHODS:Twenty sepsis patients who were not diagnosed with sepsis-associated encephalopathy(SAE)but had abnormal electroencephalograms(EEGs)were included.The control group included twenty healthy persons.A neuropsychological test of memory and executive function and a brain magnetic resonance imaging scan were performed.The volumes of cortex and subcortex were measured using the FreeSurfer software.Acute Physiology and Chronic Health Evaluation II(APACHE II)score was used to determine the disease severity.RESULTS:In the sepsis group,the levels of immediate free recall,immediate cued recall,and delayed cued recall in the California Verbal Learning Test-II(CVLT-II)were significantly lower;the explicit memory(recollection process)in the process dissociation procedure test was lower;and the volumes of the left and right hippocampi were significantly lower compared with the control group.The volume of the presubiculum in the hippocampus of sepsis patients showed statistically signifi cant decrease.In the sepsis group,the volumes of the left and right hippocampi were negatively correlated with the APACHE II score and positively with immediate free recall,immediate cued recall,and delayed cued recall in the CVLT-II;moreover,the hippocampal volume was significantly correlated with recollection but not with familiarity.CONCLUSIONS:Patients with abnormal EEGs during hospitalization but with no SAE still have reduced hippocampal volume and memory defi cits.This fi nding indicates that sepsis leads to damage to specifi c parts of the hippocampus.

Basic research and clinical progress of sepsis-associated encephalopathy

Sepsis-associated encephalopathy(SAE),a major cerebral complication of sepsis,occurs in 70%of patients admitted to the intensive care unit(ICU).This condition can cause serious impairment of consciousness and is associated with a high mortality rate.Thus far,several experimental screenings and radiological techniques(e.g.,electroencephalography)have been used for the non-invasive assessment of the structure and function of the brain in patients with SAE.Nevertheless,the pathogenesis of SAE is complicated and remains unclear.In the present article,we reviewed the currently available literature on the epidemiology,clinical manifestations,pathology,diagnosis,and management of SAE.However,currently,there is no ideal pharmacological treatment for SAE.Treatment targeting mitochondrial dysfunction may be useful in the management of SAE.

A Study on the Mechanism of the Protective Effect of GuangeFang on Sepsis-Associated Acute Kidney Injury

Objective:The objective of this study was to explore the mechanism of Guan Gefang(GGF);raw rhubarb 30 g,cassia arboreal 30 g,raw oyster 30 g,ground elm 60 g,and dandelion 30 g.kidney protection.Materials and Methods:Thirty-six Sprague Dawley rats were randomly divided into a control group(Group N),a sepsis control group(Group S),and a sepsis+GGF group(Group G).For Group N,8 ml/kg 0.9%NaCl was used as an enema;for Group S,cecal ligation and puncture(CLP)method was used for modeling and 8 ml/kg 0.9%NaCl was used as an enema;and Group G,CLP was used for modeling and 8 ml/kg GGF was used as an enema.All of the enemas were applied once daily for 4 days.The indices of serum creatinine(SCr),blood urea nitrogen(BUN),uric acid(UA),mammalian target of rapamycin(mTOR),Janus kinase 2(JAK2)were compared across each group.Results:Compared to Group S,Group G had lower levels of SCr,BUN,and UA(P<0.05),while the activities of mTOR and JAK2 were significantly inhibited.Conclusion:GGF may have inhibited the JAK2 or mTOR signaling pathways to protect the rats’kidneys,which had sepsis-associated acute kidney injury.

Complementary and alternative medicine on cognitive defects and neuroinflammation after sepsis

Sepsis-associated encephalopathy(SAE)is a common manifestation of sepsis,ranging from mild confusion and delirium to severe cognitive impairment and deep coma.SAE is associated with higher mortality and long-term outcomes,particularly substantial declines in cognitive function.The mechanisms of SAE probably include neuroinflammation that is mediated by systemic inflammation and ischemic lesions in the brain,a disrupted blood–brain barrier,oxidative stress,neurotransmitter dysfunction,and severe microglial activation.Increasing evidence suggests that complementary and alternative medicine,especially Traditional Chinese Medicine(TCM),is favorable in alleviating cognitive decline after sepsis.Here,we summarized the studies of traditional herbal remedies,TCM formulas and acupuncture therapy in animal models of neurological dysfunctions after sepsis in recent decades and reviewed their potential mechanisms.

Recent advances in the study of sepsis-induced depression

Progress in medicine such as the use of anti-infective drugs and development of the advanced life support equipment has greatly improved the survival rate of patients with sepsis.However,the incidence of sepsis-relateddiseases is increasing.These include severe neurologic and psychologic disorders,cognitive decline,anxiety,depression,and post-traumatic stress disorder.Cerebral dysfunction occurs via multiple interacting mechanisms,with different causative pathogens having distinct effects.Because sepsis-related diseases place a substantial burden on patients and their families,it is important to elucidate the underlying pathophysiologic mechanisms todevelop effective treatments.