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Objectives: We aimed to evaluate the association between β-blocker therapy and mortality in patients with sepsis., Methods: Patients with sepsis were selected from the Medical Information Mart for Intensive Care (MIMIC)-III. Propensity score matching (PSM) was used to balance the baseline differences. A multivariate Cox regression model was used to assess the relationship between β-blocker therapy and mortality. The primary outcome was the 28-day mortality., Results: A total of 12,360 patients were included in the study, involving 3,895 who received β-blocker therapy and 8,465 who did not. After PSM, 3,891 pairs of patients were matched. The results showed that β-blockers were associated with improved 28- (hazards ratio (HR) 0.78) and 90-day (HR 0.84) mortality. Long-acting β-blockers were associated with improved 28-day survival (757/3627 [20.9%] vs. 583/3627 [16.1%], P < 0.001, HR0.76) and 90-day survival (1065/3627 [29.4%] vs.921/3627 [25.4%], P < 0.001, HR 0.77). Short-acting β-blocker treatment did not reduce the 28-day and 90-day mortality (61/264 [23.1%] vs. 63/264 [23.9%], P = 0.89 and 83/264 [31.4%] vs. 89/264 [31.7%], P = 0.8, respectively)., Conclusions: β-blockers were associated with improved 28- and 90-day mortality in patients with sepsis and septic shock. Long-acting β-blocker therapy may have a protective role in patients with sepsis, reducing the 28-day and 90-day mortality. However, short-acting β-blocker (esmolol) treatment did not reduce the mortality in sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ge, Zhang, Ai, Chen, Ye, Zou and Peng.)

Aims: Sepsis-associated encephalopathy (SAE) often leads to cognitive impairments. However, the pathophysiology of SAE is complex and unclear. Here, we investigated the role of hippocampus (HPC)-prefrontal cortex (PFC) in cognitive dysfunction in sepsis induced by cecal ligation puncture (CLP) in mice., Methods: The neural projections from the HPC to PFC were first identified via retrograde tracing and viral expression. Chemogenetic activation of the HPC-PFC pathway was shown via immunofluorescent staining of c-Fos-positive neurons in PFC. Morris Water Maze (MWM) and Barnes maze (BM) were used to evaluate cognitive function. Western blotting analysis was used to determine the expression of glutamate receptors and related molecules in PFC and HPC., Results: Chemogenetic activation of the HPC-PFC pathway enhanced cognitive dysfunction in CLP-induced septic mice. Glutamate receptors mediated the effects of HPC-PFC pathway activation in CLP mice. The activation of the HPC-PFC pathway resulted in significantly increased levels of NMDAR, AMPAR, and downstream signaling molecules including CaMKIIa, pCREB, and BDNF in PFC. However, inhibition of glutamate receptors using 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F)quinoxaline (NBQX), which is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR inhibitor), or D-2-amino-5-phosphonopentanoate (D-AP5), which is an NMDA receptor antagonist abolished this increase., Conclusion: Our study reveals the important role of the HPC-PFC pathway in improving cognitive dysfunction in a mouse model of CLP sepsis and provides a novel pathogenetic mechanism for SAE., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Emerged evidence has indicated that immunosuppression is involved in the occurrence and development of sepsis. To provide clinical practice recommendations on the immune function in sepsis, an expert consensus focusing on the monitoring and treatment of sepsis-induced immunosuppression was developed. Literature related to the immune monitoring and treatment of sepsis were retrieved from PubMed, Web of Science, and Chinese National Knowledge Infrastructure to design items and expert opinions were collected through an online questionnaire. Then, the Delphi method was used to form consensus opinions, and RAND appropriateness method was developed to provide consistency evaluation and recommendation levels for consensus opinions. This consensus achieved satisfactory results through two rounds of questionnaire survey, with 2 statements rated as perfect consistency, 13 as very good consistency, and 9 as good consistency. After summarizing the results, a total of 14 strong recommended opinions, 8 weak recommended opinions and 2 non-recommended opinions were produced. Finally, a face-to-face discussion of the consensus opinions was performed through an online meeting, and all judges unanimously agreed on the content of this consensus. In summary, this expert consensus provides a preliminary guidance for the monitoring and treatment of immunosuppression in patients with sepsis., (© 2022. The Author(s).)

Background: Sepsis and sepsis-associated encephalopathy (SAE) are common intensive care unit (ICU) diseases; the morbidity and mortality are high. The present study analyzed the sensitivity of different diagnostic criteria of sepsis 1.0 and 3.0, epidemiological characteristics of sepsis and SAE, and explored its risk factors for death, short-term, and long-term prognosis., Methods: The retrospective study included patients in ICU from January 2015 to June 2016. After excluding 58 patients, 175 were assigned to either an SAE or a non-SAE group (patients with sepsis but no encephalopathy). The sensitivity of the diagnostic criteria was compared between sepsis 1.0 and 3.0, respectively. Between-group differences in baseline data, Acute Physiology and Chronic Health Evaluation II score (APACHE II score), Sequential Organ Failure Assessment score (SOFA score), etiological data, biochemical indicators, and 28-day and 180-day mortality rates were analyzed. Survival outcomes and long-term prognosis were observed, and risk factors for death were analyzed through 180-day follow-up., Results: The sensitivity did not differ significantly between the diagnostic criteria of sepsis 1.0 and 3.0 ( P = .286). The 42.3% incidence of SAE presented a significantly high APACHE II and SOFA scores as well as 28-day mortality and 180-day mortality (all P < .001). The incidence of death was 37.1%. The multivariate stepwise regression analysis demonstrated that the risk of death in SAE group was significantly higher than the non-SAE group ( P < .001). Sepsis-associated encephalopathy is a risk factor for sepsis-related death (relative risk [RR] = 2.868; 95% confidence interval: 1.730-4.754; P < .001). Although males showed a significantly high rate of 28-day and 180-day mortality ( P = .035 and .045), it was not an independent risk factor for sepsis-related death ( P = .072). The long-term prognosis of patients with sepsis was poor with decreased quality of life. No significant difference was observed in prognosis between the SAE and non-SAE groups ( P > .05)., Conclusion: Both diagnostic criteria cause misdiagnosis, and the sensitivity did not differ significantly. The incidence of SAE was high, and 28-day and 180-day mortality rates were significantly higher than those without SAE. Sepsis-associated encephalopathy is a risk factor for poor outcome. The overall long-term prognosis of patients with sepsis was poor, and the quality of life decreased.

Background: The CD38/cADPR pathway has been found to play roles in various inflammatory conditions. However, whether CD38 plays a protective or detrimental effect in the central nervous system (CNS) is controversial. The aim of this study was to determine the effect of CD38/cADPR pathway in sepsis associated brain injury., Materials and Methods: Male Sprague-Dawley rats were undergone cecal ligation and puncture (CLP) or sham laparotomies. NAD + , cADPR and CD38 were measured in the hippocampus of septic rats at 0, 6, 12, 24, and 48h after CLP surgery. Rats were divided into the sham, CLP group, CLP+ CD38 expression lentivirus (CLP+ CD38 LV), CLP+ CD38 interference lentivirus (CLP+ CD38 Ri), CLP+ negative control lentivirus (CLP+NC) and the CLP+8-Br-cADPR groups. The Western blots of Bcl-2, Bax and iNOS, TUNEL assays, malondialdehyde (MDA) and superoxide dismutase (SOD) assays, transmission electron microscope analysis were performed in the hippocampus of rats., Results: NAD + , cADPR and CD38 levels increased significantly in the hippocampus of septic rats as early as 12-24h after CLP surgery. CD38 knockdown or blocking cADPR with 8-Br-cADPR significantly reduced apoptosis, MDA and SOD activity, iNOS expression and ultrastructural morphology damages in the hippocampus of septic rats., Conclusions: In this study, we found that the CD38/cADPR pathway was activated in sepsis associated brain injury. Blocking this pathway protected the hippocampus from apoptosis, oxidative stress and ultrastructural morphology damages in septic rats., (Copyright © 2017. Published by Elsevier B.V.)

Sepsis causes many early deaths; both macrophage mitochondrial damage and oxidative stress responses are key factors in its pathogenesis. Although the exact mechanisms responsible for sepsis-induced mitochondrial damage are unknown, the nuclear transcription factor, interferon regulatory factor-1 (IRF-1) has been reported to cause mitochondrial damage in several diseases. Previously, we reported that in addition to promoting systemic inflammation, IRF-1 promoted the apoptosis of and inhibited autophagy in macrophages. In the present study, we hypothesized that lipopolysaccharide (LPS)-induced IRF-1 activation in macrophages may promote mitochondrial damage and oxidative stress. In vitro, LPS was found to promote IRF-1 activation, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) depletion, superoxide dismutase (SOD) consumption, malondialdehyde (MDA) accumulation and mitochondrial depolarization in macrophages in a time- and dose-dependent manner. These effects were abrogated in cells in which IRF-1 was knocked down. Furthermore, IRF-1 overexpression increased LPS-induced oxidative stress responses and mitochondrial damage. In vivo, peritoneal macrophages obtained from IRF-1 knockout (KO) mice produced less ROS and had less mitochondrial depolarization and damage following the administration of LPS, when compared to their wild-type (WT) counterparts. In addition, IRF-1 KO mice exhibited a decreased release of mitochondrial DNA (mtDNA) following the administration of LPS. Thus, IRF-1 may be a critical factor in augmenting LPS-induced oxidative stress and mitochondrial damage in macrophages.

Background: Acute lung injury (ALI) is a common complication of sepsis that is associated with high mortality. Intracellular Ca2+ overload plays an important role in the pathophysiology of sepsis-induced ALI, and cyclic adenosine diphosphate ribose (cADPR) is an important regulator of intracellular Ca2+ mobilization. The cluster of differentiation 38 (CD38)/cADPR pathway has been found to play roles in multiple inflammatory processes but its role in sepsis-induced ALI is still unknown. This study aimed to investigate whether the CD38/cADPR signaling pathway is activated in sepsis-induced ALI and whether blocking cADPR-mediated calcium overload attenuates ALI., Methods: Septic rat models were established by cecal ligation and puncture (CLP). Rats were divided into the sham group, the CLP group, and the CLP+ 8-bromo-cyclic adenosine diphosphate ribose (8-Br-cADPR) group. Nicotinamide adenine dinucleotide (NAD+), cADPR, CD38, and intracellular Ca2+ levels in the lung tissues were measured at 6, 12, 24, and 48 h after CLP surgery. Lung histologic injury, tumor necrosis factor (TNF)-μ, malondialdehyde (MDA) levels, and superoxide dismutase (SOD) activities were measured., Results: NAD+, cADPR, CD38, and intracellular Ca2+ levels in the lungs of septic rats increased significantly at 24 h after CLP surgery. Treatment with 8-Br-cADPR, a specific inhibitor of cADPR, significantly reduced intracellular Ca2+ levels (P = 0.007), attenuated lung histological injury (P = 0.023), reduced TNF-μ and MDA levels (P < 0.001 and P = 0.002, respectively) and recovered SOD activity (P = 0.031) in the lungs of septic rats., Conclusions: The CD38/cADPR pathway is activated in the lungs of septic rats, and blocking cADPR-mediated calcium overload with 8-Br-cADPR protects against sepsis-induced ALI.

Background: Although the nicotinamide adenine dinucleotide (NAD(+))/CD38/cyclic ADP ribose (cADPR)/Ca(2+) signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD(+)/CD38/cADPR/Ca(2+) signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage., Materials and Methods: Male Sprague-Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD(+), cADPR, CD38, and intracellular Ca(2+) levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin-eosin-stained and assayed for malondialdehyde and superoxide dismutase activities., Results: NAD(+), cADPR, CD38, and intracellular Ca(2+) levels increased in the hearts, livers, and kidneys of septic rats as early as 6-24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca(2+) mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats., Conclusions: The NAD(+)/CD38/cADPR/Ca(2+) signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To determine the role of neuroglobin in the pathology of sepsis-associated encephalopathy and ascertain if neuroglobin has any protective effects against sepsis-associated encephalopathy., Design: Randomized laboratory animal study., Setting: Research university animal laboratory., Subjects: Two hundred and forty adult male Sprague-Dawley rats., Interventions: Rats received cecal puncture and ligation (or sham) surgery to induce sepsis, then broken up into groups based on whether or not the rat developed sepsis-associated encephalopathy as determined by electroencephalograph and evoked potential recordings. The rats were then left untreated to examine the effect of sepsis-associated encephalopathy on neuroglobin, treated with a neuroglobin antisense nucleotide to block gene expression, or given hemin, a neuroglobin inducer., Measurements and Main Results: Following sepsis induction, diagnosis, and treatment, the brains were analyzed for both gross and ultrastructural morphology. Also, neuronal neuroglobin immunoreactivity and apoptosis (via terminal uridine nucleotide end-labeling) were examined. Blood serum levels were then analyzed for neuroglobin, superoxide dismutase, and malondialdehyde levels. We determined that sepsis-associated encephalopathy induces damage evident when examining both gross and ultrastructural morphology, as well as induces neuronal neuroglobin expression. Also, blockade of neuroglobin expression via antisense treatment will exacerbate these pathological effects, while increasing neuroglobin levels via hemin will ameliorate them. Blood analysis found that levels of superoxide dismutase and malondialdehyde mirrored the level of pathology found in the brain, while plasma neuroglobin levels reflected the amount of neuronal neuroglobin immunoreactivity., Conclusions: We conclude that neuroglobin is involved in the pathogenesis of sepsis-associated encephalopathy and has neuroprotective effects. We also determined that hemin has protective effects against sepsis-associated encephalopathy as well, most probably due to its effect on neuroglobin.

Objective: To investigate the effect of ulinastatin (UTI) on the levels of immune regulatory cells,pro-inflammatory mediators, and the expression of human leukocyte antigen-DR (HLA-DR) in CD14⁺ monocytes., Methods: A total of sixty patients with severe sepsis who were admitted to intensive care unit (ICU) during October 2011 to October 2012 were enrolled. The patients were randomly divided into two groups: routine treatment group (n=30, received routine bundle treatment) and UTI group (n=30, received 30 kU UTI three times per day in addition to routine bundle treatment). A course of treatment consisted of 5 days in both groups. The peripheral blood was collected, and the expression of CD4⁺CD25⁺⁻ regulatory T cell (Treg), help T cell 17 (Th17), interleukin (IL-17, IL-6, IL-10) and HLA-DR were determined before and 5 days after treatment, in order to observe the effect of UTI., Results: There was no significant difference in all indexes before treatment between two groups. Compared with routine treatment group, UTI could reduce the abnormal expression of Treg and Th17 in patients with severe sepsis [Treg: (9.05 ± 1.27)% vs. (11.83 ± 1.30)%, Th17:(3.20 ± 0.33)% vs. (4.42 ± 0.35)%, both P<0.01], and decrease the ratio of Treg/Th17 (2.22 ± 0.28 vs. 2.82 ± 0.29, P<0.01) more effectively. UTI could also reduce the abnormal expression of IL-17, IL-6 and IL-10 compared with routine treatment group (IL-17: 98.35 ± 12.23 ng/L vs. 118.20 ± 15.97 ng/L, IL-6: 24.17 ± 6.72 ng/L vs. 29.27 ± 8.13 ng/L, IL-10: 33.17 ± 7.24 ng/L vs. 37.34 ± 8.49 ng/L, P<0.05 or P<0.01). In addition UTI could ameliorate the immune status, improve the expression of HLA-DR compared with routine treatment group [(49.34 ± 11.34)% vs. (36.44 ± 8.14)%, P<0.01]. The 28-day mortality in UTI group showed a tendency of lowering compared with routine treatment group, but the difference between two groups was not significant(18.2% vs. 20.1%, P>0.05)., Conclusions: UTI can decrease in the expression of Treg and Th17, inverse the ratio of Treg/Th17, decrease in the expression of IL-17, IL-6 and IL-10, ameliorate the immune status, and improve the expression of HLA-DR. UTI is expected to improve the prognosis of patients with severe sepsis.

Objective: To investigate the protective effects of polydatin on sepsis-induced acute liver injury (ALI) in mice, and to preliminarily study its mechanisms., Methods: The sepsis model was established using cecal ligation and puncture (CLP).A sham-operation control group was also set up. Polydatin (50, 100, and 300 mg/kg, respectively) was administrated to mice 1 h before CLP. The survival and liver injury were evaluated subsequently per 6 h after CLP. The survived mice were scarified 24 h later. The serum and the liver tissue sample were collected. The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by colorimetric method. The content of tumor necrosis factor-alpha (TNF-alpha) was assayed by ELISA. The cyclooxygenase-2 (COX-2) expression in the liver tissue was detected by Western blot. The pathological changes of the hepatic tissue were analyzed by hematoxylin and eosin stain., Results: The mortality of mice reached as high as 50% at 24 h after CLP. The biochemical indices and the pathological changes of the liver tissue showed obvious lesion. The success rate of modeling was 90%. Compared with the sham-operation control group, the serum ALT,AST activity, the TNF-alpha content, and the hepatic COX-2 protein expression markedly increased in the CLP group (P < 0.01). Polydatin improved the sepsis-induced mortality dose-dependently, inhibited increased ALT, AST activity and TNF-alpha, decreased the hepatic COX-2 protein expression, and attenuated the pathological injury of the liver (P < 0.05)., Conclusion: Polydatin could effectively protect sepsis-induced ALI, which might be achieved possibly through inhibiting serum TNF-alpha production and hepatic COX-2 expression.

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., Methods: Our retrospective study included all patients with sepsis admitted to our intensive care unit from 2008 to 2011. After excluding 91 patients, 232 patients were assigned to either a sepsis-associated encephalopathy group or sepsis without encephalopathy group. Between-group differences in baseline patient data including vital signs, disease severity, pathogens, sites of infection, biochemical indicators, and time on a mechanical ventilator, intensive care unit (ICU) stay, and 28-day mortality rate were analyzed., Results: The incidence of sepsis-associated encephalopathy was 17.7%. The sepsis-associated encephalopathy group had significantly higher 28-day mortality (56.1% vs. 35.1%; P=0.013), spent a significantly longer time on a ventilator ((8.2±2.2) days vs. (2.9±0.4) days; P=0.021), and had a significantly longer ICU stay ((12.4±2.4) days vs. (7.1±0.6) days; P=0.042). Acute physiology and chronic health evaluation II score, Glasgow coma scale, heart rate, blood lactate, serum sodium, platelets, serum albumin, and pH values were related to the presence of encephalopathy. Patients with biliary tract infections and intestinal infections caused by Staphylococcus aureus, Enterococcus faecium, Acinetobacter spp, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia, were more prone to develop sepsis-associated encephalopathy., Conclusions: Encephalopathy increases mortality rate in septic patients. Clinical intervention to reduce risk factors and thereby morbidity and mortality depends on a correct understanding of the differences between patients with sepsis and patients with both sepsis and encephalopathy.

Objective: To investigate the therapeutic effect of low molecular weight heparin (LMWH) therapy on sepsis., Methods: Forty sepsis patients were randomly divided into two groups: routine treatment group and LMWH treatment group. Score of acute physiology and chronic health evaluation II (APACHE II), the days in intensive care unit (ICU) and mortality rate in 28 days were observed, and the levels of interleukin-6 (IL-6), malondialdehyde (MDA), superoxide dismutase (SOD), coagulation function and platelet count (PLT) were determined before and after treatment in the two groups., Results: Both APACHE II and IL-6 levels in LMWH group decreased with passage of time, the differences were significant between the results on day 7 and that of pretreatment (both P<0.05). In the routine treatment group, APACHE II and IL-6 levels decreased first and then increased, and they were higher than those in LMWH group 7 days after treatment (both P<0.05). In LMWH group, the time of stay in ICU was (9.92+/-6.81)days, the mortality rate in 28 days was 40.9%, and they all were lower than those in routine treatment group [(12.85+/-9.14)days and 50.0%], but the difference was not statistically significant (both P>0.05). After treatment SOD level elevated [(159.13+/-99.31) kU/L vs.(318.38+/-284.29) kU/L] and MDA level lowered [(17.72+/-14.89) micromol/L vs.(6.62+/-5.53) micromol/L] in LMWH group. The changes in MDA and SOD in routine treatment were reverse to those of the LMWH group [SOD: (180.99+/-169.40) kU/L vs. (135.16+/-107.73) kU/L; MDA: (17.25+/-15.74) micromol/L vs. (20.77+/-16.87) micromol/L]. The difference was significant between the two groups after treatment (both P<0.05). The difference in coagulation function and PLT was not significant between the two groups., Conclusion: LMWH can ameliorate sepsis by down-regulating the levels of pro-inflammatory cytokines, and suppressing the release of oxygen-derived free radicals. It is a promising treatment measure in sepsis patient with safety and no severe side effects.