Xuebijing injection, a Chinese patent medicine, against severe pneumonia: Current research progress and future perspectives.
Journal of integrative medicine
Severe pneumonia is one of the most common infectious diseases and the leading cause of sepsis and septic shock. Preventing infection, balancing the patient's immune status, and anti-coagulation therapy are all important elements in the treatment of severe pneumonia. As multi-target agents, Xuebijing injection (XBJ) has shown unique advantages in targeting complex conditions and saving the lives of patients with severe pneumonia. This review outlines progress in the understanding of XBJ's anti-inflammatory, endotoxin antagonism, and anticoagulation effects. From the hundreds of publications released over the past few years, the key results from representative clinical studies of XBJ in the treatment of severe pneumonia were selected and summarized. XBJ was observed to effectively suppress the release of pro-inflammatory cytokines, counter the effects of endotoxin, and assert an anticoagulation effect in most clinical trials, which are consistent with experimental studies. Collectively, this evidence suggests that XBJ could play an important and expanding role in clinical medicine, especially for sepsis, septic shock and severe pneumonia. Please cite this article as: Zhang M, Zheng R, Liu WJ, Hou JL, Yang YL, Shang HC. Xuebijing injection, a Chinese patent medicine, against severe pneumonia: Current research progress and future perspectives. J Integr Med. 2023; 21(5): 413-422.
10.1016/j.joim.2023.08.004
[Advancement in the research of mechanism of immune dysfunction in sepsis and the regulatory effects of Xuebijing injection].
Gao Yu-lei,Chai Yan-fen,Yao Yong-ming
Zhonghua shao shang za zhi = Zhonghua shaoshang zazhi = Chinese journal of burns
Sepsis is a systemic inflammatory response syndrome resulting from a host response to infection. The early stage of sepsis is characterized by excessive inflammatory response, accompanied by immune dysfunction characterized by aggravating cellular immunosuppression. The vast majority of patients with sepsis survive the initial excessive inflammatory response, but die of hospital-acquired infection, opportunistic pathogenic bacteria infection, latent virus reactivation, and multiple organ dysfunction syndrome. These facts indicate that immunosuppression may be a significant cause of exacerbation of the illness even death of the septic patients. The primary cellular mechanisms in inducing immune dysfunction include immune dysfunction of T lymphocytes, negative regulation of regulatory T lymphocytes and dendritic cells, and damage of intestinal mucosa associated lymphoid tissue. Xuebijing injection is a complex Chinese patent medicine, which is widely used in the treatment of sepsis. It has a potential immunoregulation ability, as well as effects on bacteriostasis, anti-endotoxin and anti-inflammation. Its target and mechanism of action need to be explored further.
Efficacy and safety of Xuebijing injection (a Chinese patent) for sepsis: A meta-analysis of randomized controlled trials.
Li Chengyu,Wang Ping,Zhang Li,Li Min,Lei Xiang,Liu Si,Feng Zhiqiao,Yao Yongming,Chang Bai,Liu Baoshan,Shang Hongcai
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Xuebijing injection (XBJ), a Chinese patent medicine that was approved for treating sepsis in China in 2004, consists of Carthamus tinctorius L. (Carthami Flos, hong hua), Paeonia lactiflora Pall. (Paeoniae Radix Rubra, chi shao), Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, chuan xiong), Salvia miltiorrhiza Bge. (Salviae Miltiorrhizae Radix Et Rhizoma, dan shen) and Angelica sinensis (Oliv.) Diels (Angelicae Sinensis Radix, dang gui). AIM OF THE STUDY:This study aimed to assess the efficacy and safety of XBJ combined with routine treatment (RT) for treating sepsis through systematic review and meta-analysis. MATERIALS AND METHODS:Databases including Embase, PubMed, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journal Database (VIP) and the Wanfang database were searched from inception to June 6, 2017 to collect relevant RCTs comparing XBJ combined with RT and RT alone for sepsis. The primary clinical outcomes were 28-day mortality and mortality during treatment. The secondary outcomes of our study included APACHE Ⅱ scores, WBC counts, body temperature, and adverse events or reactions. We excluded low-quality studies (Jadad score < 3) and calculated risk ratios (RR) for primary outcomes with fixed effects models. We assessed quality of evidence using the grading of recommendations assessment, development, and evaluation (GRADE) approach. RESULTS:We identified 1602 records, and 16 RCTs (1144 patients) were included. Moderate-quality evidence suggested that combined therapy reduced 28-day mortality (934/1144, RR 0.62, 95% CI 0.51-0.76 P < 0.000 01, I = 0%), APACHE Ⅱ scores (792/1144, MD -3.53, 95% CI -4.49 to -2.54; P < 0.000 01, I = 59%) and body temperature (362/1144, MD -0.43, 95% CI -0.55 to -0.31; P < 0.000 01, I = 0%). Very low-quality evidence showed that WBC count improved with combined medication at high dosages (one study included, 40/1144, MD -8.00, 95% CI -10.18 to -5.82), but there was no reduction at moderate dosages (230/1144, MD -2.38, 95% CI -5.01 to 0.25; P = 0.08, I = 70%). However, moderate-quality evidence indicated positive results with low dosages (142/1144, MD -2.88, 95% CI -3.79 to -1.96; P < 0.000 01, I = 0%). Nevertheless, due to the insufficient number of studies and the poor quality of the current evidence, more studies of dose-effect relationships and safety concerns of XBJ are needed. Low-quality evidence showed no risk difference for mortality during treatment (210/1144, RR 0.65, 95% CI 0.36-1.17; P = 0.15, I = 0%). CONCLUSIONS:This study suggested that supplementation with XBJ in addition to regular treatment may improve the 28-day mortality rate, APACHE Ⅱ scores, WBC count and body temperature of sepsis patients without serious adverse events, but it may not reduce mortality during treatment, revealing a specific, remote effect of traditional Chinese medicine. However, given the high risk of bias and the low quality of the included trials, we may be unable to draw any conclusions about its routine use. Rigorously designed, multicentre, large-scale, methodologically sound trials are warranted.
10.1016/j.jep.2018.05.043
The effects of Xuebijing injection combined with ulinastatin as adjunctive therapy on sepsis: An overview of systematic review and meta-analysis.
Medicine
BACKGROUND:Xuebijing injection (XBJ) has increasingly been used for sepsis in China. We aimed to evaluate the methodological quality and summarize the evidence regarding the effectiveness of XBJ combined with ulinastatin (UTI) for sepsis from systematic reviews/meta-analyses (SRs/MAs). METHODS:From the inception to May 23, 2021, eight databases were searched to screen the SRs/MAs of XBJ combined with UTI in the treatment of sepsis. Methodology Quality of Systematic Reviews 2 (AMSTAR-2) was used to evaluate the quality of the methods. Grading of Recommendation,Assessment, Development, and Evaluation (GRADE) was used in the assessment of evidence quality. RESULTS:Seven SRs/MAs on XBJ combined with UTI treatment for sepsis were included. The AMSTAR-2 showed that the methodological quality of all included SRs/MAs was rated as critically low. According to the evaluation results of GRADE, 30% (13/44), 30% (13/44), and 40% (18/44) were rated to be of moderate, low, and critically low quality, respectively. Descriptive analysis results showed that XBJ combined with UTI was an effective treatment modality for sepsis. CONCLUSIONS:All included SRs/MAs showed that XBJ combined with UTI was more effective than UTI alone in the treatment of sepsis on the basis of conventional treatment, but the reliability of the results was limited due to the disadvantages of lower methodological quality and higher risk of bias in the included SRs/MAs. Further high-quality clinical studies and SRs/MAs are recommended to verify whether XBJ combined with UTI is more effective than UTI alone.
10.1097/MD.0000000000031196
Network pharmacology to explore the anti-inflammatory mechanism of Xuebijing in the treatment of sepsis.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Xuebijing (XBJ) is a traditional Chinese patent medicine for sepsis. However, the mechanism of action (MoA) of XBJ on sepsis remain unclear. PURPOSE:Elucidate the MoA of XBJ for treating sepsis based on network pharmacology. STUDY DESIGN:Integrate computational prediction, experimental validation and literature reported clinical results analysis based on network pharmacology. METHODS:Computationally, representative compounds of XBJ were characterized by LC-MS/MS and the target profiles of each compound were identified using network-based method. Compounds from XBJ were compared with FDA approved drugs or experimental agents for sepsis by hierarchical clustering of target profile. Key biological functional modules of XBJ for treating sepsis were identified by enrichment analysis. Differential expressed analysis for each biological functional module was conducted from sepsis related public omics datasets. Herb-biological functional module network was constructed to reveal part of the traditional combinatorial rules of herbs for modules. Experimentally, the action of XBJ compounds on genes in biological functional module was validated by detecting quantitative transcriptional profiling and sepsis animal model. Clinically, combined with the clinical results recorded in literature, computational and experimental results were used to interpret the anti-inflammatory effect of XBJ for treating sepsis. RESULTS:The target profiles of compound cover most of the compound's related biomolecules reported in literature, which can characterize the comprehensive function of compound. XBJ has similar pharmacological effect as FDA approved drugs or experimental agents. Four key biological functional modules including inflammation, immune, cell apoptosis and coagulation of XBJ for treating sepsis were identified. Cell line experimental results show that part of ingredients in XBJ regulate the expression of genes in inflammation modules as predicted. Animal experiments show that compounds from XBJ could reduce the expression level of IL-1β. Combined with literature reported clinical results, XBJ was found to exert anti-inflammatory effect through regulating the NF-kappa B signaling pathway. CONCLUSION:The network pharmacology framework integrating computational prediction, experimental validation and literature reported clinical results analysis provides a novel approach for analyzing MoA of XBJ for treating sepsis.
10.1016/j.phymed.2021.153543
The current evidence for the treatment of sepsis with Xuebijing injection: Bioactive constituents, findings of clinical studies and potential mechanisms.
Li Chengyu,Wang Ping,Li Min,Zheng Rui,Chen Shiqi,Liu Si,Feng Zhiqiao,Yao Yongming,Shang Hongcai
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Xuebijing (XBJ) injection is a Chinese medicine containing extracts from Carthamus tinctorius L. (Carthami Flos, hong hua, Asteraceae), Paeonia lactiflora Pall. (Paeoniae radix rubra, chi shao, Ranunculaceae), Ligusticum chuanxiong Hort. (Chuanxiong Rhizoma, chuan xiong, Umbelliferae), Salvia miltiorrhiza Bge. (Salviae miltiorrhizae Radix Et Rhizoma, dan shen, Labiatae) and Angelica sinensis (Oliv.) Diels (Angelicae sinensis Radix, dang gui, Umbelliferae). It has been approved for the treatment of sepsis in China since 2004 and has been widely used as an add-on treatment for sepsis or septic shock with few side effects. AIM OF THE STUDY:The aim of the present review was to analyse up-to-date information related to the treatment of sepsis with XBJ, including the bioactive constituents, clinical studies and potential mechanisms, and to discuss possible scientific gaps, to provide a reliable reference for future studies. MATERIALS AND METHODS:Scientific resources concentrating on treating sepsis with XBJ were searched through PubMed, the Chinese National Knowledge Infrastructure (CNKI) and WanFang databases from inception to November 2018. Dissertations were also searched, and eligible dissertations were selected. Studies related to the identification of constituents, bioactive components and their targets of action or pathways, clinical trials, and animal or cellular experiments that explored pharmacological mechanisms were manually selected. The quality of reporting and methodology of the included pharmacological experiments were assessed using the Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines and the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)'s risk of bias tool. RESULTS:A total of 108 relative studies were eventually included, containing 12 bioactivity research studies, 10 systematic reviews on clinical trials and 86 animal or cellular experiments. We noted that as identification methods progressed, further constituents could be detected in XBJ. XBJ was also found to have "multi-ingredient, multi-target and multi-pathway" effects. The systematic review revealed that XBJ could improve the 28-day mortality and other indexes, such as the APACHE II score, body temperature, and white blood cell (WBC) count, to some extent. A major organ protection effect was demonstrated in septic rats. Pharmacological investigations suggested that XBJ acts in both the early and late stages of sepsis by anti-inflammatory, anti-coagulation, immune regulation, vascular endothelial protection, anti-oxidative stress and other mechanisms. However, most of the included studies were poorly reported, and the risk of bias was unclear. CONCLUSIONS:With respect to the multiple therapeutic mechanisms contributing to both the early and late stages of sepsis, the multiple effective constituents detected and randomized controlled trials (RCTs) performed to prove its efficacy, XBJ is a promising therapy for the treatment of sepsis. However, although XBJ has shown some efficacy for the treatment of sepsis, there are currently some scientific gaps. More studies concerning the pharmacokinetics, interactions with antibiotics, real-world efficacy and safety, pharmacological mechanisms of the bioactive components and large-scale clinical trials should be conducted in the future.
10.1016/j.jep.2020.113301
Xuebijing injection inhibited neutrophil extracellular traps to reverse lung injury in sepsis mice reducing Gasdermin D.
Frontiers in pharmacology
The mortality of sepsis and septic shock remains high worldwide. Neutrophil extracellular traps (NETs) release is a major cause of organ failure and mortality in sepsis. Targeting Gasdermin D (GSDMD) can restrain NETs formation, which is promising for sepsis management. However, no medicine is identified without severe safety concerns for this purpose. Xuebijing injection (XBJ) has been demonstrated to alleviate the clinical symptoms of COVID-19 and sepsis patients, but there are not enough animal studies to reveal its mechanisms in depth. Therefore, we wondered whether XBJ relieved pulmonary damage in sepsis by suppressing NETs formation and adopted a clinically relevant polymicrobial infection model to test this hypothesis. Firstly, XBJ effectively reversed lung injury caused by sepsis and restrained neutrophils recruitment to lung by down-regulating proinflammatory chemokines, such as CSF-3, CXCL-2, and CXCR-2. Strikingly, we found that XBJ significantly reduced the expressions of NETs component proteins, including citrullinated histone H3 (CitH3), myeloperoxidase (MPO), and neutrophil elastase (NE). GSDMD contributes to the production of NETs in sepsis. Notably, XBJ exhibited a reduced effect on the expressions of GSDMD and its upstream regulators. Besides, we also revealed that XBJ reversed NETs formation by inhibiting the expressions of GSDMD-related genes. Collectively, we demonstrated XBJ protected against sepsis-induced lung injury by reversing GSDMD-related pathway to inhibit NETs formation.
10.3389/fphar.2022.1054176
Xuebijing Administration Alleviates Pulmonary Endothelial Inflammation and Coagulation Dysregulation in the Early Phase of Sepsis in Rats.
Journal of clinical medicine
ETHNOPHARMACOLOGICAL RELEVANCE:Xuebijing injection is a Chinese herbal-derived drug composed of radix paeoniaerubra, rhizomachuanxiong, Salvia miltiorrhiza, floscarthami, and Angelica sinensis. This study aimed to investigate the effects of Xuebijing administration on pulmonary endothelial injury and coagulation dysfunction in a cecal ligation and puncture (CLP)-induced sepsis rat model. MATERIALS AND METHODS:A CLP-induced sepsis rat model was established. The CLP rats were treated with a vehicle or Xuebijing via intravenous infusion and sacrificed at 2, 4, 6, 8, or 12 h after CLP for lung tissue and blood sample collection. The mean arterial pressure (MAP) was monitored. Transmission microscopy examination and H&E staining were performed to observe pulmonary structural alterations. Enzyme linked immunosorbent assay (ELISA) was performed to measure the plasma levels of epithelial markers, proinflammatory cytokines, and coagulation-related proteins. RESULTS:Compared with vehicle treatment, Xuebijing administration maintained the MAP in the normal range until 11 h after CLP. Transmission microscopy and H&E staining revealed that Xuebijing administration alleviated alveolar-capillary barrier impairments and lung inflammation in CLP rats. ELISA showed that Xuebijing administration effectively reversed CLP-induced elevations in the plasma levels of epithelial markers endothelin-1 and von Willebrand factor, starting 6 and 8 h after CLP, respectively. Xuebijing administration also significantly abolished CLP-induced rises in circulating proinflammatory cytokines interleukin 6 (IL-6) at 6 h after CLP, IL-1β at 2 and 12 h after CLP, and TNF-α at 2, 4, 6, 8, and 12 h after CLP. In addition, Xuebijing administration strongly reversed CLP-induced alterations in circulating active protein C and tissue-type plasminogen activator, starting 4 h and 2 h after CLP, respectively. CONCLUSIONS:Xuebijing ameliorates pulmonary endothelial injury, systemic inflammation, and coagulation dysfunction in early sepsis.
10.3390/jcm11226696
Xuebijing injection protects sepsis induced myocardial injury by mediating TLR4/NF-κB/IKKα and JAK2/STAT3 signaling pathways.
Aging
OBJECTIVE:Compelling evidence has demonstrated that Xuebijing (XBJ) exerted protective effects against SIMI. The aims of this study were to investigate whether TLR4/IKKα-mediated NF-κB and JAK2/STAT3 pathways were involved in XBJ's cardio-protection during sepsis and the mechanisms. METHODS:In this study, rats were randomly assigned to three groups: Sham group; CLP group; XBJ group. Rats were treated with XBJ or sanitary saline after CLP. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1β, IL-6 and TNF-α in serum were measured using ELISA kits. Cardiomyocyte apoptosis were tested by TUNEL staining. The protein levels of Bax, Bcl-2, Bcl-xl, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3 in the myocardium were assayed by western blotting. And finally, immunofluorescence was used to assess the level of p-JAK2 and p-STAT3 in heart tissue. RESULTS:The results of echocardiography, myocardial enzyme and HE test showed that XBJ could significantly improve SIMI. The IL-1β, IL-6 and TNF-α levels in the serum were markedly lower in the XBJ group than in the CLP group (<0.05). TUNEL staining's results showed that XBJ ameliorated CLP-induced cardiomyocyte apoptosis. Meanwhile, XBJ downregulated the protein levels of Bax, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3, as well as upregulated the protein levels of Bcl-2, Bcl-xl ( <0.05). CONCLUSIONS:In here, we observed that XBJ's cardioprotective advantages may be attributable to its ability to suppress inflammation and apoptosis via inhibiting the TLR4/ IKKα-mediated NF-κB and JAK2/STAT3 pathways during sepsis.
10.18632/aging.204990
Performances of disseminated intravascular coagulation scoring systems in septic shock patients.
Helms Julie,Severac François,Merdji Hamid,Clere-Jehl Raphaël,François Bruno,Mercier Emmanuelle,Quenot Jean-Pierre,Meziani Ferhat,
Annals of intensive care
BACKGROUND:There is no gold standard to diagnose septic shock-induced disseminated intravascular coagulation (DIC). The objective of our multicenter prospective study was to assess the performances of the different major scoring systems in terms of mortality prediction and DIC diagnosis. The JAAM-DIC 2016 score, the ISTH overt-DIC 2001 score, the associations of sepsis-induced coagulopathy (SIC) score with JAAM-DIC 2016 or ISTH overt-DIC scores were tested in patients within 12 h of their admission in ICU for septic shock (day 1) and at day 2. RESULTS:582 patients were enrolled in the study. 182/567 (32.1%) were diagnosed with DIC according to ISTH overt-DIC score, and 193/561 (34.4%) according to JAAM-DIC score; 486/577 patients (84.2%) were diagnosed with a coagulopathy according to SIC score. A moderate concordance was observed between ISTH overt-DIC and JAAM-DIC [κ = 0.67 (0.60, 0.73), p < 0.001]. The delay of positivity of the scores for early DIC patients was not different between JAAM-DIC and ISTH overt-DIC scores. Although it was positive earlier, SIC score had worse diagnosis specificity, as 84.2% of the patients with septic shock were diagnosed with "coagulopathy". The specificity of SIC score alone to predict mortality was very low [0.18 (0.15; 0.22)], compared to the ones of JAAM-DIC score [0.71 (0.67; 0.75)], and of ISTH overt-DIC score [0.76 (0.72; 0.80)], p < 0.001. The sensitivity of SIC score to predict mortality was 0.95 [0.89; 0.98], and the ones of JAAM-DIC score and ISTH overt-DIC score were 0.61 [0.50; 0.70] and 0.68 [0.58; 0.77], respectively. There was no benefit in sensitivity and specificity in combining SIC score to JAAM-DIC score or to ISTH overt-DIC score, compared to JAAM-DIC score or ISTH overt-DIC score alone. CONCLUSIONS:Our data suggest that the added value of SIC score alone or combined with other scores is limited, and that both JAAM-DIC score and ISTH overt-DIC score can be used in septic shock patients. Trial registration clinicaltrial; Trial registration number: NCT02391792; Date of registration: 18/03/2015; URL of trial registry record: https://clinicaltrials.gov/ct2/show/NCT02391792?term=meziani&draw=4&rank=1.
10.1186/s13613-020-00704-5
Early Detection of Disseminated Intravascular Coagulation During Septic Shock: A Multicenter Prospective Study.
Delabranche Xavier,Quenot Jean-Pierre,Lavigne Thierry,Mercier Emmanuelle,François Bruno,Severac François,Grunebaum Lélia,Mehdi Madah,Zobairi Fatiha,Toti Florence,Meziani Ferhat,Boisramé-Helms Julie,
Critical care medicine
OBJECTIVES:Inadequate stratification of septic shock patients may result in inappropriate treatment allocation in randomized clinical trials, especially regarding anticoagulant. We previously reported that endothelial-derived microparticles are relevant biomarkers of sepsis-induced disseminated intravascular coagulation. In this validation cohort, we assess microparticles as surrogates of cell activation to improve early disseminated intravascular coagulation diagnosis and patient stratification. DESIGN:Prospective observational study in septic shock patients. SETTINGS:Four medical ICUs in university hospitals. PATIENTS AND METHODS:Two hundred sixty-five patients with septic shock from four ICUs were consecutively enrolled. Disseminated intravascular coagulation was diagnosed according to Japanese Association for Acute Medicine 2006 score. Endothelial- and leukocyte-derived circulating procoagulant microparticles were isolated and quantified by prothrombinase assay at admission, day 3, and day 7. INTERVENTION:None. MEASUREMENTS AND MAIN RESULTS:Two hundred fifty-nine patients were analyzed. Sixty-one had disseminated intravascular coagulation at admission, and 32 developed disseminated intravascular coagulation during the first 24 hours after admission. Multiple logistic regression model confirmed that endothelial cell-derived microparticles were associated with disseminated intravascular coagulation: CD105-microparticles (odds ratio, 2.13) and CD31-microparticles (odds ratio, 0.65) (p < 0.05). Furthermore, CD11a-microparticles to leukocyte ratio evidenced leukocyte activation (odds ratio, 1.59; p < 0.05). Prediction of disseminated intravascular coagulation was also analyzed after exclusion of patients with disseminated intravascular coagulation at admission. A new multiple logistic regression analysis demonstrated the association of CD105-microparticles (> 0.60 nM eq. PhtdSer; odds ratio, 1.67; p < 0.01), platelets count (≤ 127 g/L; odds ratio, 0.99; p < 0.01), and prothrombin time (≤ 58%; odds ratio, 0.98; p < 0.05) with disseminated intravascular coagulation. A combining score at admission is predictive of the absence of disseminated intravascular coagulation (area under the curve, 72.9%; specificity, 71.2%; sensitivity, 71.0%, with a negative predictive value of 93.1% and a positive predictive value of 31.0%). CONCLUSIONS:Procoagulant microparticles from endothelial cells and leukocytes reflect a vascular injury during sepsis-induced disseminated intravascular coagulation that precedes obvious activation of coagulation. A combination of prothrombin time, endothelium-derived CD105-microparticles, and platelet count at admission could predict the absence of disseminated intravascular coagulation and allow a better stratification in future randomized clinical trials.
10.1097/CCM.0000000000001836
Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.
Rhodes Andrew,Evans Laura E,Alhazzani Waleed,Levy Mitchell M,Antonelli Massimo,Ferrer Ricard,Kumar Anand,Sevransky Jonathan E,Sprung Charles L,Nunnally Mark E,Rochwerg Bram,Rubenfeld Gordon D,Angus Derek C,Annane Djillali,Beale Richard J,Bellinghan Geoffrey J,Bernard Gordon R,Chiche Jean-Daniel,Coopersmith Craig,De Backer Daniel P,French Craig J,Fujishima Seitaro,Gerlach Herwig,Hidalgo Jorge Luis,Hollenberg Steven M,Jones Alan E,Karnad Dilip R,Kleinpell Ruth M,Koh Younsuck,Lisboa Thiago Costa,Machado Flavia R,Marini John J,Marshall John C,Mazuski John E,McIntyre Lauralyn A,McLean Anthony S,Mehta Sangeeta,Moreno Rui P,Myburgh John,Navalesi Paolo,Nishida Osamu,Osborn Tiffany M,Perner Anders,Plunkett Colleen M,Ranieri Marco,Schorr Christa A,Seckel Maureen A,Seymour Christopher W,Shieh Lisa,Shukri Khalid A,Simpson Steven Q,Singer Mervyn,Thompson B Taylor,Townsend Sean R,Van der Poll Thomas,Vincent Jean-Louis,Wiersinga W Joost,Zimmerman Janice L,Dellinger R Phillip
Critical care medicine
OBJECTIVE:To provide an update to "Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012." DESIGN:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. METHODS:The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. RESULTS:The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. CONCLUSIONS:Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.
10.1097/CCM.0000000000002255
Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study.
Lancet (London, England)
BACKGROUND:Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. METHODS:We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990-2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. FINDINGS:In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9-62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1-12·0) sepsis-related deaths were reported, representing 19·7% (18·2-21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8-54·5) and mortality decreased by 52·8% (47·7-57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. INTERPRETATION:Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. FUNDING:The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.
10.1016/S0140-6736(19)32989-7
The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey.
Xie Jianfeng,Wang Hongliang,Kang Yan,Zhou Lixin,Liu Zhongmin,Qin Bingyu,Ma Xiaochun,Cao Xiangyuan,Chen Dechang,Lu Weihua,Yao Chen,Yu Kaijiang,Yao Xiaoqing,Shang Hongcai,Qiu Haibo,Yang Yi,
Critical care medicine
OBJECTIVES:We performed a national cross-sectional survey to determine the epidemiologic characteristics of patients with sepsis in ICU in China. DESIGN:A cross-section survey study. SETTING:Forty-four hospitals in mainland China from December 1, 2015, to January 31, 2016. PATIENTS:All septic patients diagnosed according sepsis-1 criteria admitted to participating ICU. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:We recorded demographic, physiologic, and microbiological data with follow-up for 90 days or death, if sooner. The frequency of sepsis and 90-day mortality rate were computed, and the relationship with gross domestic product determined. Multivariate logistic regression analysis was used to determine risk factors for 90-day mortality in patients with sepsis. Two-thousand three-hundred twenty-two patients with sepsis were included in the analysis, of whom 786 patients (33.9%) had hospital-acquired sepsis. The most common infection site was the lung (68.2%), followed by abdomen (26.6%) and bloodstream (7.8%). The frequency of sepsis in the ICU was 20.6 cases per 100 ICU admissions (95% CI, 15.8-25.4) with a 90-day mortality of 35.5%. The proportion of sepsis, severe sepsis, and septic shock were 3.10%, 43.6%, and 53.3% with a 90-day mortality of 2.78%, 17.69%, and 51.94%, respectively. Older age, low body weight, higher Sequential Organ Failure Assessment score, the number of systemic inflammatory response syndrome criteria, comorbid with heart failure, hematologic cancer, immunosuppression, higher level of lactate, infection site (pneumonia and bloodstream) were associated with 90-day mortality. CONCLUSIONS:Sepsis affects a fifth of patients admitted to ICUs in mainland China with a 90-day mortality rate of 35.5%. Our findings indicate that a large burden of sepsis, and we need to focus on sepsis as a quality improvement target in China given the high mortality. In addition, further studies are needed to delineate the epidemiology of sepsis outside the ICU.
10.1097/CCM.0000000000004155
Xuebijing injection in septic rats mitigates kidney injury, reduces cortical microcirculatory disorders, and suppresses activation of local inflammation.
Journal of ethnopharmacology
ETHNOPHARMACOLOGICAL RELEVANCE:Xuebijing injections originate from the traditional Chinese medicine (TCM) prescription XuefuZhuyu Decoction. It is composed of five Chinese herbal extracts; Carthami flos, Paeoniae radix rubra, Chuanxiong rhizoma, Salviae miltiorrhizae, and Angelicae Sinensis radix. The China Food and Drug Administration approved Xuebijing injections as a TCM preparation for the adjuvant treatment of sepsis. AIM OF THE STUDY:This study aims to determine the effects of Xuebijing injections as an adjuvant to antibiotics for the treatment of renal microcirculatory dysfunction and renal inflammation in rats with sepsis. MATERIALS AND METHODS:The rats received a sham operation (Sham), sham operation followed by Xuebijign injection (Sxbj), cecal ligation and puncture (CLP), or CLP followed by Xuebijing injection (Cxbj). Renal microvascular perfusion in the cortex and oxygenation were assessed at different times after sepsis induction. Renal levels of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and high mobility group box (HMGB)-1 were measured. Urinary TIMP-2 × IGFBP-7 and neutrophil gelatinase-associated lipocalin (NGAL) were measured as kidney biomarkers, and serum creatinine (SCr) was used to assess kidney injury. Tissue samples were stained for histologic evaluation. RESULTS:The induction of sepsis increased local inflammation and decreased renal microvascular perfusion and oxygenation. Compared with the CLP group, the Cxbj group displayed improvements in microvascular perfusion and oxygenation (p < 0.05). The CLP group had significant increases in renal inflammatory biomarkers (IL-1β, IL-6, TNF-α, and HMGB-1; p < 0.05) and Xuebijing injection reduced the levels of these markers. The levels of urinary TIMP-2 × IGFBP-7, NAGL, and SCr were lower in the Cxbj group than in the CLP group (p < 0.05), and the CLP group had a higher Paller score than the Cxbj group (p < 0.05). However, the CLP and Cxbj groups had no significant difference in mortality. CONCLUSIONS:This study into the early stages of sepsis in a rat model indicated that as an adjuvant therapy to antibiotics, Xuebijing injection improved renal perfusion and oxygenation, suppressed renal inflammation, and ameliorated kidney dysfunction. However, Xuebijing injection had no impact on mortality.
10.1016/j.jep.2021.114199
Sepsis assessment and management in critically Ill adults: A systematic review.
PloS one
BACKGROUND:Early assessment and management of patients with sepsis can significantly reduce its high mortality rates and improve patient outcomes and quality of life. OBJECTIVES:The purposes of this review are to: (1) explore nurses' knowledge, attitude, practice, and perceived barriers and facilitators related to early recognition and management of sepsis, (2) explore different interventions directed at nurses to improve sepsis management. METHODS:A systematic review method according to the PRISMA guidelines was used. An electronic search was conducted in March 2021 on several databases using combinations of keywords. Two researchers independently selected and screened the articles according to the eligibility criteria. RESULTS:Nurses reported an adequate of knowledge in certain areas of sepsis assessment and management in critically ill adult patients. Also, nurses' attitudes toward sepsis assessment and management were positive in general, but they reported some misconceptions regarding antibiotic use for patients with sepsis, and that sepsis was inevitable for critically ill adult patients. Furthermore, nurses reported they either were not well-prepared or confident enough to effectively recognize and promptly manage sepsis. Also, there are different kinds of nurses' perceived barriers and facilitators related to sepsis assessment and management: nurse, patient, physician, and system-related. There are different interventions directed at nurses to help in improving nurses' knowledge, attitudes, and practice of sepsis assessment and management. These interventions include education sessions, simulation, decision support or screening tools for sepsis, and evidence-based treatment protocols/guidelines. DISCUSSION:Our findings could help hospital managers in developing continuous education and staff development training programs on assessing and managing sepsis in critical care patients. CONCLUSION:Nurses have poor to good knowledge, practices, and attitudes toward sepsis as well as report many barriers related to sepsis management in adult critically ill patients. Despite all education interventions, no study has collectively targeted critical care nurses' knowledge, attitudes, and practice of sepsis management.
10.1371/journal.pone.0270711
Sepsis, a 2020 review for the internist.
Purcarea Adrian,Sovaila Silvia
Romanian journal of internal medicine = Revue roumaine de medecine interne
Sepsis is an overwhelming reaction to infection that comes with high morbidity and mortality, which requires urgent interventions in order to improve outcomes. Surviving Sepsis is an international campaign that aims to improve sepsis outcomes. The 2016 guideline modifies the previous definition of sepsis and proposes some specific diagnostic and therapeutic measures, such as the protocolized use of fluid resuscitation and antibiotics. We aim to summarize the main recommendations of the 2016 guideline that are relevant to the internist and evidence-base update them to the year 2020. In the current context, this review doesn't address patients affected by SARS-COV2 induced disease.
10.2478/rjim-2020-0012
Advances in Immune Monitoring Approaches for Sepsis-Induced Immunosuppression.
Frontiers in immunology
Sepsis represents a life-threatening organ dysfunction due to an aberrant host response. Of note is that majority of patients have experienced a severe immune depression during and after sepsis, which is significantly correlated with the occurrence of nosocomial infection and higher risk of in-hospital death. Nevertheless, the clinical sign of sepsis-induced immune paralysis remains highly indetectable and ambiguous. Given that, specific yet robust biomarkers for monitoring the immune functional status of septic patients are of prominent significance in clinical practice. In turn, the stratification of a subgroup of septic patients with an immunosuppressive state will greatly contribute to the implementation of personalized adjuvant immunotherapy. In this review, we comprehensively summarize the mechanism of sepsis-associated immunosuppression at the cellular level and highlight the recent advances in immune monitoring approaches targeting the functional status of both innate and adaptive immune responses.
10.3389/fimmu.2022.891024
Immune Activation in Sepsis.
Conway-Morris Andrew,Wilson Julie,Shankar-Hari Manu
Critical care clinics
Sepsis is caused by a dysregulated host response to infection. Immune responses determine the characteristics of sepsis. The body's protection against infection involves danger signal surveillance and recognition from nonself, effector functions in response to sensing danger signals, homeostatic regulation, and generation of immunologic memory. During sepsis, the immune system is activated by pathogen-associated and host-derived molecular patterns. Detecting these molecular patterns generates multisystem responses. Impaired organ function remote to the site of infection is the unifying feature. The processes by which an appropriate response to a microbial invader change from adaptive to maladaptive and dysregulated remain unclear.
10.1016/j.ccc.2017.08.002
Lactate and Immunosuppression in Sepsis.
Nolt Benjamin,Tu Fei,Wang Xiaohui,Ha Tuanzhu,Winter Randi,Williams David L,Li Chuanfu
Shock (Augusta, Ga.)
Serum lactate levels are traditionally interpreted as a marker of tissue hypoxia and often used clinically as an indicator of severity and outcome of sepsis/septic shock. Interestingly, recent studies involving the effects of tumor-derived lactate suggest that lactate itself may have an immunosuppressive effect in its local environment. This finding adds to the recent advances in immunometabolism that shed light on the importance of metabolism and metabolic intermediates in the regulation of innate immune and inflammatory responses in sepsis. In this article, we summarize recent studies, showing that the activation of immune cells requires aerobic glycolytic metabolism and that lactate produced by aerobic glycolysis may play an immunosuppressive role in sepsis.
10.1097/SHK.0000000000000958
The new normal: immunomodulatory agents against sepsis immune suppression.
Hutchins Noelle A,Unsinger Jacqueline,Hotchkiss Richard S,Ayala Alfred
Trends in molecular medicine
Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections. Recent studies from animal sepsis models and patient samples suggest that cytokines such as interleukin-7 (IL-7), IL-15, granulocyte macrophage colony-stimulating factor (GM-CSF), as well as co-inhibitory molecule blockade, such as anti-programmed cell death receptor-1 (anti-PD-1) and anti-B and T lymphocyte attenuator (anti-BTLA), may have utility in alleviating the clinical morbidity associated with sustained sepsis. This review discusses some of these novel immunomodulatory agents and evaluates their potential use as therapeutics.
10.1016/j.molmed.2014.01.002
IMMUNE CELL PHENOTYPE AND FUNCTION IN SEPSIS.
Shock (Augusta, Ga.)
Cells of the innate and adaptive immune systems play a critical role in the host response to sepsis. Moreover, their accessibility for sampling and their capacity to respond dynamically to an acute threat increases the possibility that leukocytes might serve as a measure of a systemic state of altered responsiveness in sepsis.The working group of the 14th Acute Dialysis Quality Initiative (ADQI) conference sought to obtain consensus on the characteristic functional and phenotypic changes in cells of the innate and adaptive immune system in the setting of sepsis. Techniques for the study of circulating leukocytes were also reviewed and the impact on cellular phenotypes and leukocyte function of nonextracorporeal treatments and extracorporeal blood purification therapies proposed for sepsis was analyzed.A large number of alterations in the expression of distinct neutrophil and monocyte surface markers have been reported in septic patients. The most consistent alteration seen in septic neutrophils is their activation of a survival program that resists apoptotic death. Reduced expression of HLA-DR is a characteristic finding on septic monocytes, but monocyte antimicrobial function does not appear to be significantly altered in sepsis. Regarding adaptive immunity, sepsis-induced apoptosis leads to lymphopenia in patients with septic shock and it involves all types of T cells (CD4, CD8, and Natural Killer) except T regulatory cells, thus favoring immunosuppression. Finally, numerous promising therapies targeting the host immune response to sepsis are under investigation. These potential treatments can have an effect on the number of immune cells, the proportion of cell subtypes, and the cell function.
10.1097/SHK.0000000000000495
Sepsis-Induced Immunosuppression.
Annual review of physiology
Sepsis is expected to have a substantial impact on public health and cost as its prevalence increases. Factors contributing to increased prevalence include a progressively aging population, advances in the use of immunomodulatory agents to treat a rising number of diseases, and immune-suppressing therapies in organ transplant recipients and cancer patients. It is now recognized that sepsis is associated with profound and sustained immunosuppression, which has been implicated as a predisposing factor in the increased susceptibility of patients to secondary infections and mortality. In this review, we discuss mechanisms of sepsis-induced immunosuppression and biomarkers that identify a state of impaired immunity. We also highlight immune-enhancing strategies that have been evaluated in patients with sepsis, as well as therapeutics under current investigation. Finally, we describe future challenges and the need for a new treatment paradigm, integrating predictive enrichment with patient factors that may guide the future selection of tailored immunotherapy.
10.1146/annurev-physiol-061121-040214
The immune system's role in sepsis progression, resolution, and long-term outcome.
Delano Matthew J,Ward Peter A
Immunological reviews
Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after "recovery" from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.
10.1111/imr.12499
Biomarkers of sepsis.
Faix James D
Critical reviews in clinical laboratory sciences
Sepsis is an unusual systemic reaction to what is sometimes an otherwise ordinary infection, and it probably represents a pattern of response by the immune system to injury. A hyper-inflammatory response is followed by an immunosuppressive phase during which multiple organ dysfunction is present and the patient is susceptible to nosocomial infection. Biomarkers to diagnose sepsis may allow early intervention which, although primarily supportive, can reduce the risk of death. Although lactate is currently the most commonly used biomarker to identify sepsis, other biomarkers may help to enhance lactate's effectiveness; these include markers of the hyper-inflammatory phase of sepsis, such as pro-inflammatory cytokines and chemokines; proteins such as C-reactive protein and procalcitonin which are synthesized in response to infection and inflammation; and markers of neutrophil and monocyte activation. Recently, markers of the immunosuppressive phase of sepsis, such as anti-inflammatory cytokines, and alterations of the cell surface markers of monocytes and lymphocytes have been examined. Combinations of pro- and anti-inflammatory biomarkers in a multi-marker panel may help identify patients who are developing severe sepsis before organ dysfunction has advanced too far. Combined with innovative approaches to treatment that target the immunosuppressive phase, these biomarkers may help to reduce the mortality rate associated with severe sepsis which, despite advances in supportive measures, remains high.
10.3109/10408363.2013.764490
Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options.
Military Medical Research
Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.
10.1186/s40779-022-00422-y
The immunopathology of sepsis and potential therapeutic targets.
van der Poll Tom,van de Veerdonk Frank L,Scicluna Brendon P,Netea Mihai G
Nature reviews. Immunology
Sepsis is defined as a life-threatening organ dysfunction that is caused by a dysregulated host response to infection. In sepsis, the immune response that is initiated by an invading pathogen fails to return to homeostasis, thus culminating in a pathological syndrome that is characterized by sustained excessive inflammation and immune suppression. Our understanding of the key mechanisms involved in the pathogenesis of sepsis has increased tremendously, yet this still needs to be translated into novel targeted therapeutic strategies. Pivotal for the clinical development of new sepsis therapies is the selection of patients on the basis of biomarkers and/or functional defects that provide specific insights into the expression or activity of the therapeutic target.
10.1038/nri.2017.36