Efficacy and safety of Chinese tonic medicines for treating sepsis or septic shock: a protocol for a systematic review and Bayesian network meta-analysis of randomized controlled trials

Efficacy and safety of Chinese tonic medicines for treating sepsis or septic shock: a protocol for a systematic review and Bayesian network meta-analysis of randomized controlled trials | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of Chinese tonic medicines for treating sepsis or septic shock: a protocol for a systematic review and Bayesian network meta-analysis of randomized controlled trials Rui Yang, Cheng Hu, Yuxin Zhuo, Wen Wang, Qingyuan Tan, Yuxin Shen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4163266/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 26 Dec, 2024 Read the published version in Systematic Reviews → Version 1 posted 5 You are reading this latest preprint version Abstract Background Sepsis is a life-threatening organ dysfunction with high morbidity and mortality. Various studies have demonstrated the effectiveness of Chinese tonic medicines (CTMs) in treating sepsis or septic shock. However, trials direct comparing the efficacy and safety of different CTMs for sepsis or septic shock are still lacking. To identify the most optimal CTMs for treating sepsis or septic shock, we plan to perform a systematic review and network meta-analysis of various CTMs used for sepsis or septic shock patients. Methods Randomized controlled trials (RCTs) that investigated the efficacy and safety of CTMs for patients with sepsis or septic shock will be systematically searched in Pubmed, Embase, Cochrane Central Register of Controlled Trials, CBM, CNKI, Wanfang, and VIP database from inception to November 2023. The quality of the included studies will be assessed using the Cochrane Risk of Bias V.2.0. tool. The confidence of evidence will be evaluated through the CINeMA (Confidence in Network Meta-Analysis) web application. Primary outcomes include the delta Sequential Organ Failure Assessment (△SOFA) score at day 7 after interventions and 28-day mortality. Secondary outcomes comprise delta serum lactate levels (△Lac) and delta mean arterial pressure (△MAP) at day 7 after interventions as well as total dose and duration of vasoactive drugs. Safety outcome includes adverse drug reactions or adverse drug events (ADRs/ADEs). The Bayesian network meta-analysis will be conducted using the “BUGSnet” package in R version 4.2.2. The surface under the cumulative ranking curve (SUCRA) values will be used to rank each treatment. Statistical inconsistency assessment, publication bias assessment, heterogeneity analysis, sensitivity analysis, and subgroup analysis will be performed. Discussion This study will provide new insights into the efficacy and safety of various CTMs used in sepsis or septic shock patients, providing help for future clinical practice and research. Systematic review registration CRD42023482572 sepsis septic shock Chinese tonic medicines delta Sequential Organ Failure Assessment mortality Introduction Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection [ 1 ]. A subset of patients with sepsis may progress to septic shock, increasing the risk of mortality to 23.6% [ 2 , 3 ]. Sepsis or septic shock is recognized as a primary health threat by the World Health Organization [ 4 ]. Despite substantial advances over the past two decades, the management of this disorder remains largely unchanged [ 5 , 6 ]. Novel adjuvant therapies that are effective, safe, and economical for improving organ function, reducing mortality, and alleviating the financial burden of sepsis are urgently needed. A new consensus termed Sepsis-3 requires the Sequential Organ Failure Assessment (SOFA) score to define sepsis [ 1 ]. Changes of SOFA score (△SOFA ) have been identified as an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis [ 7 , 8 ]. It is worth using △SOFA score as the primary outcome to assess the performance of each adjuvant therapy. In recent years, Chinese herbal medicines, especially Chinese tonic medicines (CTMs), have been widely used in China as adjuvant treatments for sepsis or septic shock, and have demonstrated efficacy in reducing mortality [ 9 – 14 ]. However, trials directly comparing the efficacy and safety of different CTMs for sepsis or septic shock are still lacking. Consequently, we plan to systematically search all randomized controlled trials (RCTs) of CTMs for treating sepsis or septic shock, perform a network meta-analysis, and, more importantly, use △SOFA as a crucial evaluation index to assess the efficacy and safety of different CTMs, hoping to provide more evidence for clinical practice. Methods Study registration This systematic review and network meta-analysis has been registered in the International Prospective Registry of Systematic Reviews (PROSPERO, CRD42023482572). The protocol followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol statement [15]. The PRISMA-P checklist is provided in Supplementary Table 1. Any modifications to this protocol will be reported in our full reviews if needed. Eligibility criteria Types of studies We will include RCTs, whether placebo-controlled or head-to-head trials, without restrictions on language or publication date. Non-randomized trials, observational studies, reviews, meta-analysis commentary articles, and studies with unavailable full text will be excluded. Types of participants We will include adults (aged ≥18 years) diagnosed with sepsis or septic shock[1,16,17] and exclude studies exclusively involving the elderly. Types of interventions We will include studies investigating the efficacy and safety of CTMs for treating sepsis or septic shock. The control groups received one of the following treatments: CTMs combined with western medicine (WM), a placebo combined with WM, or only WM. The experimental groups were treated with different types of CTMs combined with WM. WM includes antibiotics, fluid resuscitation, vasopressors, mechanical ventilation, and other necessary therapies [5,6,18–20]. CTMs are defined as medicines aimed at reinforcing the body and preventing diseases. We specified that CTMs should be administered orally or intravenously, with no restriction on dosage, frequency, or course of intervention. Types of outcome measures Primary outcomes We chose the △SOFA score at day 7 after interventions and 28-day mortality as the primary outcomes. The △SOFA score is calculated by subtracting the SOFA score at enrollment from the corresponding value at day 7 after interventions. Secondary outcomes 1. Delta serum lactate levels (△Lac) at day 7 after interventions. 2. Delta mean arterial pressure (△MAP) at day 7 after interventions. 3. Total dose and duration of vasoactive drugs. Safety outcome Adverse drug reactions or adverse drug events (ADRs/ADEs). Search strategy There were no restrictions on language or publication date. The Pubmed, Embase (via Ovid), Cochrane Central Register of Controlled Trials (via Ovid), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang, and VIP database will be searched by two investigators (Rui Yang and Cheng Hu). We will search the following MeSH terms, keywords, abstracts or titles: “sepsis”, “septic shock”, “traditional Chinese medicine”, or “Chinese herbal medicine”. The detailed search strategies are provided in Supplementary Table 2. Selection process Zotero 6.0.23 software will be used to collect citations and remove duplicate articles. Two investigators (Rui Yang and Cheng Hu) will independently screen based on title and abstract first. The full text of all potentially relevant studies will be collected for subsequent assessment. In the presence of duplicate data, only studies with a larger sample size and longer follow-up time will be included. Any disagreements will be resolved by the third investigator (Lihui Deng). The process of study selection is shown in Supplementary figure 1. Data collection process Two investigators (Rui Yang and Cheng Hu) will independently extract the following data: study information (study design, first author name, publication year, study country), characteristics of participants (inclusion/exclusion criteria, size, age, sex), intervention and control (type of drug, administration, dose, frequency, and duration), outcomes (before and after the interventions). All the data will undergo cross-checking after extraction, and any disagreement will be resolved by the third investigator (Lihui Deng). In addition, we will send emails to researchers to obtain any missing data. Assessment of risk of bias The risk of bias for the included studies will be assessed by two investigators (Rui Yang and Cheng Hu) independently using the Cochrane Risk of Bias V.2.0. tool [21]. The assessments will be conducted across 5 domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in the measurement of the outcome and (5) bias in the selection of reported result. Each domain will be classified as high, moderate (some concerns), or low risk of bias, and studies will be given an overall classification of high, moderate (some concerns) or low risk of bias. Any disagreements will be resolved with the third investigator (Lihui Deng). Data synthesis and analysis If quantitative analysis is feasible, R version 4.2.2 and STATA 15.0 software will be used for statistical analysis. In case quantitative analysis cannot be conducted, the results will be described narratively. For binary outcomes, the pooled effects will be calculated as risk ratio (RR) with 95% confidence intervals (CIs). For continuous outcomes, if the scales of outcomes are uniform, mean difference (MD) with 95% CIs will be used, otherwise, standardized mean difference (SMD) with 95% CIs will be applied. Median and interquartile ranges (IQRs) will be transformed to mean and standard deviation (SD) [22]. We will construct a Bayesian network meta-analysis for each outcome to compare the individual CTMs used for sepsis or septic shock patients using the “BUGSnet” (Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis) package[23] in R. Both fixed-effects and random-effects model will be fitted, and we will use the more suitable model. Model fit will be assessed using deviance information criterion (DIC) [24]. After selecting the appropriate model, we will evaluate model convergence using the trace and density plots, as well as Gelman-Rubin’s potential scale reduction factor [25]. The network plot will be created to visualize direct and indirect comparisons between different treatments. League tables will be generated to estimate relative effects of different treatments. Surface under the cumulative ranking curve (SUCRA) values will be utilized to rank each treatment [26]. A larger SUCRA value indicates a better rank of treatment. Both global and local approaches will be used to assess inconsistency between direct and indirect evidence. We will use the Chi-square test to assess the global inconsistency. If closed loops exist, the node-splitting approach[27] will be used to examine the local inconsistency. Also, we will use a comparison-adjusted funnel plot to identify small study effects and assess potential publication bias in the outcomes with 10 or more RCTs. Heterogeneity will be assessed using the I 2 . A sensitivity analysis will be performed to test the robustness of results by eliminating each study. If feasible, subgroup analysis will be performed for the primary outcomes based on the severity of the disease and the diagnostic criteria. Certainty of Evidence Assessment The quality of evidence for each outcome will be assessed using the CINeMA (Confidence in Network Meta-Analysis) web application [28,29]. The CINeMA includes 6 domains: (1) within-study bias, (2) across-studies bias, (3) indirectness, (4) imprecision, (5) heterogeneity and (6) incoherence. The certainty of evidence will be classified as high, moderate, low, or very low. Discussion Our study will be among the pioneering efforts to evaluate the △SOFA score for assessing various CTMs in the treatment of sepsis or septic shock. Furthermore, we will assess the protective effect of different CTMs on organ perfusion by examining △Lac, △MAP, total dose and duration of vasoactive drugs. We hope that the results of this network meta-analysis will provide additional insights into the efficacy and safety of various CTMs used in sepsis or septic shock patients, providing help for future clinical practice and research. Abbreviations CTMs: Chinese tonic medicines; WM: western medicine; RCTs: Randomized controlled trials; △SOFA: delta Sequential Organ Failure Assessment; △Lac: delta serum lactate levels; △MAP: delta mean arterial pressure; ADRs/ADEs: adverse drug reactions or adverse drug events; SUCRA: surface under the cumulative ranking curve; CBM: Chinese Biomedical Literature Database; CNKI: China National Knowledge Infrastructure; RR: risk ratio; CIs: confidence intervals; MD: mean difference; SMD: standardized mean difference; IQRs: standardized mean difference; SD: standard deviation; BUGSnet: Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis; DIC: deviance information criterion; CINeMA: Confidence in Network Meta-Analysis; PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol. Declarations Dissemination The results of the final analysis will be published and disseminated at the university and across various social media platforms. Additionally, the results will be presented at a conference, and the research findings will be submitted to a peer-reviewed journal. Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article Competing interests The authors declare that they have no competing interests Funding This study was supported by the National Natural Science Foundation of China (No.82104715, Cheng Hu; No.82074230, Lihui Deng), and the Sichuan Provincial Administration of Traditional Chinese Medicine (No.2023ZD04, Qing Xia). Authors’ contributions Rui Yang and Cheng Hu contributed equally to this work and shared co-first authorship. Qing Xia and Lihui Deng defined the research topic and study design. Xin Sun, Wen Wang and Kun Jiang provided advice on the statistical analysis. Rui Yang and Cheng Hu performed the protocol registration. Yuxin Zhuo, Yuxin Shen and Qingyuan Tan elaborated the search strategy. Rui Yang and Cheng Hu performed the literature search and wrote the manuscript. Qing Xia and Lihui Deng revised the manuscript. All authors read and approved the final manuscript. Acknowledgements Not applicable. References Singer Mervyn, Deutschman Clifford S, Seymour Christopher Warren, Shankar-Hari Manu, Annane Djillali, Bauer Michael, et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA, 2016, 315(8): 801. Rhee Chanu, Dantes Raymund, Epstein Lauren, Murphy David J, Seymour Christopher W, Iwashyna Theodore J, et al., Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014, JAMA, 2017, 318(13): 1241. Seymour Christopher W, Gesten Foster, Prescott Hallie C, Friedrich Marcus E, Iwashyna Theodore J, Phillips Gary S, et al., Time to Treatment and Mortality during Mandated Emergency Care for Sepsis, New England Journal of Medicine, 2017, 376(23): 2235–2244. Reinhart Konrad, Daniels Ron, Kissoon Niranjan, Machado Flavia R, Schachter Raymond D, Finfer Simon, Recognizing Sepsis as a Global Health Priority—A WHO Resolution, New England Journal of Medicine, Massachusetts Medical Society, 2017, 377(5): 414–417. Dellinger R Phillip, Carlet Jean M, Masur Henry, Gerlach Herwig, Calandra Thierry, Cohen Jonathan, et al., Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock, Intensive Care Medicine, 2004, 30(4): 536–555. Evans Laura, Rhodes Andrew, Alhazzani Waleed, Antonelli Massimo, Coopersmith Craig M, French Craig, et al., Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021, Intensive Care Medicine, 2021, 47(11): 1181–1247. Karakike Eleni, Kyriazopoulou Evdoxia, Tsangaris Iraklis, Routsi Christina, Vincent Jean-Louis, Giamarellos-Bourboulis Evangelos J, The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through a derivation and a validation cohort, Critical Care, 2019, 23(1): 387. De Grooth Harm-Jan, Geenen Irma L, Girbes Armand R, Vincent Jean-Louis, Parienti Jean-Jacques, Oudemans-van Straaten Heleen M, SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis, Critical Care, 2017, 21(1): 38. Huang P, Chen Y, Zhang H, Chen B, Zhao S, Feng Y, et al., Comparative Efficacy of Chinese Herbal Injections for Septic Shock: A Bayesian Network Meta-Analysis of Randomized Controlled Trials., Frontiers in Pharmacology, 2020, 13: 850221. Xiao L, Niu L, Xu X, Zhao Y, Yue L, Liu X, et al., Comparative Efficacy of Tonic Chinese Herbal Injections for Treating Sepsis or Septic Shock: A Systematic Review and Bayesian Network Meta-Analysis of Randomized Controlled Trials, Frontiers in Pharmacology, 2022, 13: 830030. Huang P, Guo Y, Feng S, Zhao G, Li B, Liu Q, Efficacy and safety of Shenfu injection for septic shock: A systematic review and meta-analysis of randomized controlled trials., The American Journal of Emergency Medicine, 2019, 37(12): 2197–2204. Sun Y, Liu Y, Li L, Xue B, Cao Y, Adjuvant Application of Shenmai Injection for Sepsis: A Systematic Review and Meta-Analysis., Evidence-based complementary and alternative medicine: eCAM, 2022: 3710672. Li X, Huang F, Zhu L, Luo T, Zhang Y, Gu H, et al., Effects of combination therapy with Shenfu Injection in critically ill patients with septic shock receiving mechanical ventilation: A multicentric, real-world study., Frontiers in Pharmacology, 2022, 13: 1041326. Liao J, Qin C, Wang Z, Gao L, Zhang S, Feng Y, et al., Effect of shenfu injection in patients with septic shock: A systemic review and meta-analysis for randomized clinical trials, Journal of Ethnopharmacology, 2023: 117431. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al., Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation, BMJ, British Medical Journal Publishing Group, 2015, 349(jan02 1): g7647–g7647. Levy Mitchell M, Fink Mitchell P, Marshall John C, Abraham Edward, Angus Derek, Cook Deborah, et al., 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, Intensive Care Medicine, 2003, 29(4): 530–538. Bone Roger C, Balk Robert A, Cerra Frank B, Dellinger R Phillip, Fein Alan M, Knaus William A, et al., Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis, Chest, 1992, 101(6): 1644–1655. Rhodes Andrew, Evans Laura E, Alhazzani Waleed, Levy Mitchell M, Antonelli Massimo, Ferrer Ricard, et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016, Intensive Care Medicine, 2017, 43(3): 304–377. Dellinger R P, Levy Mitchell M, Rhodes Andrew, Annane Djillali, Gerlach Herwig, Opal Steven M, et al., Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012, Intensive Care Medicine, 2013, 39(2): 165–228. Dellinger R Phillip, Levy Mitchell M, Carlet Jean M, Bion Julian, Parker Margaret M, Jaeschke Roman, et al., Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008, Intensive Care Medicine, 2008, 34(1): 17–60. Sterne Jonathan A C, Savović Jelena, Page Matthew J, Elbers Roy G, Blencowe Natalie S, Boutron Isabelle, et al., RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ, British Medical Journal Publishing Group, 2019, 366: l4898. Hozo Stela Pudar, Djulbegovic Benjamin, Hozo Iztok, Estimating the mean and variance from the median, range, and the size of a sample, BMC Medical Research Methodology, 2005, 5(1): 13. Béliveau Audrey, Boyne Devon J, Slater Justin, Brenner Darren, Arora Paul, BUGSnet: an R package to facilitate the conduct and reporting of Bayesian network Meta-analyses, BMC Medical Research Methodology, 2019, 19(1): 196. Dias Sofia, Sutton Alex J, Ades A E, Welton Nicky J, Evidence Synthesis for Decision Making 2, Medical Decision Making, SAGE Publications Inc STM, 2013, 33(5): 607–617. Hamra Ghassan, MacLehose Richard, Richardson David, Markov Chain Monte Carlo: an introduction for epidemiologists, International Journal of Epidemiology, 2013, 42(2): 627–634. Mbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, et al., Approaches to interpreting and choosing the best treatments in network meta-analyses, Systematic Reviews, 2017, 6(1): 79. Van Valkenhoef Gert, Dias Sofia, Ades A E, Welton Nicky J, Automated generation of node‐splitting models for assessment of inconsistency in network meta‐analysis, Research Synthesis Methods, 2016, 7(1): 80–93. Nikolakopoulou Adriani, Higgins Julian P T, Papakonstantinou Theodoros, Chaimani Anna, Del Giovane Cinzia, Egger Matthias, et al., CINeMA: An approach for assessing confidence in the results of a network meta-analysis, PLOS Medicine, Public Library of Science, 2020, 17(4): e1003082. Papakonstantinou Theodoros, Nikolakopoulou Adriani, Higgins Julian P T, Egger Matthias, Salanti Georgia, CINeMA: Software for semiautomated assessment of the confidence in the results of network meta‐analysis, Campbell Systematic Reviews, 2020, 16(1): e1080. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4163266","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":328295761,"identity":"060547a0-8bfc-4106-8451-5c8bbf493cfe","order_by":0,"name":"Rui 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A subset of patients with sepsis may progress to septic shock, increasing the risk of mortality to 23.6% [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Sepsis or septic shock is recognized as a primary health threat by the World Health Organization [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Despite substantial advances over the past two decades, the management of this disorder remains largely unchanged [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Novel adjuvant therapies that are effective, safe, and economical for improving organ function, reducing mortality, and alleviating the financial burden of sepsis are urgently needed.\u003c/p\u003e \u003cp\u003eA new consensus termed Sepsis-3 requires the Sequential Organ Failure Assessment (SOFA) score to define sepsis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Changes of SOFA score (△SOFA ) have been identified as an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. It is worth using △SOFA score as the primary outcome to assess the performance of each adjuvant therapy.\u003c/p\u003e \u003cp\u003eIn recent years, Chinese herbal medicines, especially Chinese tonic medicines (CTMs), have been widely used in China as adjuvant treatments for sepsis or septic shock, and have demonstrated efficacy in reducing mortality [\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, trials directly comparing the efficacy and safety of different CTMs for sepsis or septic shock are still lacking. Consequently, we plan to systematically search all randomized controlled trials (RCTs) of CTMs for treating sepsis or septic shock, perform a network meta-analysis, and, more importantly, use △SOFA as a crucial evaluation index to assess the efficacy and safety of different CTMs, hoping to provide more evidence for clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis systematic review and network meta-analysis has been registered in the International Prospective Registry of Systematic Reviews (PROSPERO, CRD42023482572). The protocol followed the guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol statement\u0026nbsp;[15]. The PRISMA-P checklist is provided in Supplementary Table 1. Any modifications to this protocol will be reported in our full reviews if needed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEligibility criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTypes of studies\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will include RCTs, whether placebo-controlled or head-to-head trials, without restrictions on language or publication date. Non-randomized trials, observational studies, reviews, meta-analysis commentary articles, and studies with unavailable full text will be excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTypes of participants\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will include adults (aged ≥18 years) diagnosed with sepsis or septic shock[1,16,17]\u0026nbsp;and exclude studies exclusively involving the elderly.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTypes of interventions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will include studies investigating the efficacy and safety of CTMs for treating sepsis or septic shock. The control groups received one of the following treatments: CTMs combined with western medicine (WM), a placebo combined with WM, or only WM. The experimental groups were treated with different types of CTMs combined with WM. WM includes antibiotics, fluid resuscitation, vasopressors, mechanical ventilation, and other necessary therapies\u0026nbsp;[5,6,18–20]. CTMs are defined as medicines aimed at reinforcing the body and preventing diseases. We specified that CTMs should be administered orally or intravenously, with no restriction on dosage, frequency, or course of intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTypes of outcome measures\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrimary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe chose the\u0026nbsp;△SOFA score at day 7 after interventions and 28-day mortality as the primary outcomes. The\u0026nbsp;△SOFA score is calculated by subtracting the SOFA score at enrollment from the corresponding value at day 7 after interventions.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e1. Delta serum lactate levels (△Lac) at day 7 after interventions.\u003c/p\u003e\n\u003cp\u003e2. Delta mean arterial pressure (△MAP) at day 7 after interventions.\u003c/p\u003e\n\u003cp\u003e3. Total dose and duration of vasoactive drugs.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSafety outcome\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAdverse drug reactions or adverse drug events (ADRs/ADEs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eSearch strategy\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were no restrictions on language or publication date. The Pubmed, Embase (via Ovid), Cochrane Central Register of Controlled Trials (via Ovid), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang, and VIP database will be searched by two investigators (Rui Yang and Cheng Hu). We will search the following MeSH terms, keywords, abstracts or titles: “sepsis”, “septic shock”, “traditional Chinese medicine”, or “Chinese herbal medicine”. The detailed search strategies are provided in Supplementary Table 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSelection process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZotero 6.0.23 software will be used to collect citations and remove duplicate articles. Two investigators (Rui Yang and Cheng Hu) will independently screen based on title and abstract first. The full text of all potentially relevant studies will be collected for subsequent assessment. In the presence of duplicate data, only studies with a larger sample size and longer follow-up time will be included. Any disagreements will be resolved by the third investigator (Lihui Deng). The process of study selection is shown in Supplementary figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection process\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwo investigators (Rui Yang and Cheng Hu) will independently extract the following data: study information (study design, first author name, publication year, study country), characteristics of participants (inclusion/exclusion criteria, size, age, sex), intervention and control (type of drug, administration, dose, frequency, and duration), outcomes (before and after the interventions). All the data will undergo cross-checking after extraction, and any disagreement will be resolved by the third investigator (Lihui Deng). In addition, we will send emails to researchers to obtain any missing data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssessment of risk of bias\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe risk of bias for the included studies will be assessed by two investigators (Rui Yang and Cheng Hu) independently using the Cochrane Risk of Bias V.2.0. tool\u0026nbsp;[21]. The assessments will be conducted across 5 domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in the measurement of the outcome and (5) bias in the selection of reported result. Each domain will be classified as high, moderate (some concerns), or low risk of bias, and studies will be given an overall classification of high, moderate (some concerns) or low risk of bias. Any disagreements will be resolved with the third investigator (Lihui Deng).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData synthesis and analysis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIf quantitative analysis is feasible, R version 4.2.2 and STATA 15.0 software will be used for statistical analysis. In case quantitative analysis cannot be conducted, the results will be described narratively. For binary outcomes, the pooled effects will be calculated as risk ratio (RR) with 95% confidence intervals (CIs). For continuous outcomes, if the scales of outcomes are uniform, mean difference (MD) with 95% CIs will be used, otherwise, standardized mean difference (SMD) with 95% CIs will be applied. Median and interquartile ranges (IQRs) will be transformed to mean and standard deviation (SD)\u0026nbsp;[22].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe will construct a Bayesian network meta-analysis for each outcome to compare the individual CTMs used for sepsis or septic shock patients using the “BUGSnet” (Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis) package[23]\u0026nbsp;in R. Both fixed-effects and random-effects model will be fitted, and we will use the more suitable model. Model fit will be assessed using deviance information criterion (DIC)\u0026nbsp;[24]. After selecting the appropriate model, we will evaluate model convergence using the trace and density plots, as well as Gelman-Rubin’s potential scale reduction factor\u0026nbsp;[25]. The network plot will be created to visualize direct and indirect comparisons between different treatments. League tables will be generated to estimate relative effects of different treatments. Surface under the cumulative ranking curve (SUCRA) values will be utilized to rank each treatment\u0026nbsp;[26]. A larger SUCRA value indicates a better rank of treatment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBoth global and local approaches will be used to assess inconsistency between direct and indirect evidence. We will use the Chi-square test to assess the global inconsistency. If closed loops exist, the node-splitting approach[27]\u0026nbsp;will be used to examine the local inconsistency. Also, we will use a comparison-adjusted funnel plot to identify small study effects and assess potential publication bias in the outcomes with 10 or more RCTs. Heterogeneity will be assessed using the \u003cem\u003eI\u0026nbsp;\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e. A sensitivity analysis will be performed to test the robustness of results by eliminating each study. If feasible, subgroup analysis will be performed for the primary outcomes based on the severity of the disease and the diagnostic criteria.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCertainty of Evidence Assessment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe quality of evidence for each outcome will be assessed using the CINeMA (Confidence in Network Meta-Analysis) web application\u0026nbsp;[28,29]. The CINeMA includes 6 domains: (1) within-study bias, (2) across-studies bias, (3) indirectness, (4) imprecision, (5) heterogeneity and (6) incoherence. The certainty of evidence will be classified as high, moderate, low, or very low.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur study will be among the pioneering efforts to evaluate the △SOFA score for assessing various CTMs in the treatment of sepsis or septic shock. Furthermore, we will assess the protective effect of different CTMs on organ perfusion by examining △Lac, △MAP, total dose and duration of vasoactive drugs. We hope that the results of this network meta-analysis will provide additional insights into the efficacy and safety of various CTMs used in sepsis or septic shock patients, providing help for future clinical practice and research.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCTMs: Chinese tonic medicines; WM: western medicine; RCTs: Randomized controlled trials;\u0026nbsp;△SOFA: delta Sequential Organ Failure Assessment;\u0026nbsp;△Lac: delta serum lactate levels;\u0026nbsp;△MAP: delta mean arterial pressure; ADRs/ADEs: adverse drug reactions or adverse drug events; SUCRA: surface under the cumulative ranking curve; CBM: Chinese Biomedical Literature Database; CNKI: China National Knowledge Infrastructure; RR: risk ratio; CIs: confidence intervals; MD: mean difference; SMD: standardized mean difference; IQRs: standardized mean difference; SD: standard deviation; BUGSnet: Bayesian inference Using Gibbs Sampling to conduct a Network meta-analysis; DIC: deviance information criterion; CINeMA: Confidence in Network Meta-Analysis; PRISMA-P: Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the final analysis will be published and disseminated at the university and across various social media platforms. Additionally, the results will be presented at a conference, and the research findings will be submitted to a peer-reviewed journal.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China (No.82104715, Cheng Hu; No.82074230, Lihui Deng), and the Sichuan Provincial Administration of Traditional Chinese Medicine (No.2023ZD04, Qing Xia).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRui Yang and Cheng Hu contributed equally to this work and shared co-first authorship. Qing Xia and Lihui Deng defined the research topic and study design. Xin Sun, Wen Wang and Kun Jiang provided advice on the statistical analysis. Rui Yang and Cheng Hu performed the protocol registration. Yuxin Zhuo, Yuxin Shen and Qingyuan Tan elaborated the search strategy. Rui Yang and Cheng Hu performed the literature search and wrote the manuscript. Qing Xia and Lihui Deng revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eSinger Mervyn, Deutschman Clifford S, Seymour Christopher Warren, Shankar-Hari Manu, Annane Djillali, Bauer Michael, et al., The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), JAMA, 2016, 315(8): 801.\u003c/li\u003e\n \u003cli\u003eRhee Chanu, Dantes Raymund, Epstein Lauren, Murphy David J, Seymour Christopher W, Iwashyna Theodore J, et al., Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014, JAMA, 2017, 318(13): 1241.\u003c/li\u003e\n \u003cli\u003eSeymour Christopher W, Gesten Foster, Prescott Hallie C, Friedrich Marcus E, Iwashyna Theodore J, Phillips Gary S, et al., Time to Treatment and Mortality during Mandated Emergency Care for Sepsis, New England Journal of Medicine, 2017, 376(23): 2235\u0026ndash;2244.\u003c/li\u003e\n \u003cli\u003eReinhart Konrad, Daniels Ron, Kissoon Niranjan, Machado Flavia R, Schachter Raymond D, Finfer Simon, Recognizing Sepsis as a Global Health Priority\u0026mdash;A WHO Resolution, New England Journal of Medicine, Massachusetts Medical Society, 2017, 377(5): 414\u0026ndash;417.\u003c/li\u003e\n \u003cli\u003eDellinger R Phillip, Carlet Jean M, Masur Henry, Gerlach Herwig, Calandra Thierry, Cohen Jonathan, et al., Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock, Intensive Care Medicine, 2004, 30(4): 536\u0026ndash;555.\u003c/li\u003e\n \u003cli\u003eEvans Laura, Rhodes Andrew, Alhazzani Waleed, Antonelli Massimo, Coopersmith Craig M, French Craig, et al., Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021, Intensive Care Medicine, 2021, 47(11): 1181\u0026ndash;1247.\u003c/li\u003e\n \u003cli\u003eKarakike Eleni, Kyriazopoulou Evdoxia, Tsangaris Iraklis, Routsi Christina, Vincent Jean-Louis, Giamarellos-Bourboulis Evangelos J, The early change of SOFA score as a prognostic marker of 28-day sepsis mortality: analysis through a derivation and a validation cohort, Critical Care, 2019, 23(1): 387.\u003c/li\u003e\n \u003cli\u003eDe Grooth Harm-Jan, Geenen Irma L, Girbes Armand R, Vincent Jean-Louis, Parienti Jean-Jacques, Oudemans-van Straaten Heleen M, SOFA and mortality endpoints in randomized controlled trials: a systematic review and meta-regression analysis, Critical Care, 2017, 21(1): 38.\u003c/li\u003e\n \u003cli\u003eHuang P, Chen Y, Zhang H, Chen B, Zhao S, Feng Y, et al., Comparative Efficacy of Chinese Herbal Injections for Septic Shock: A Bayesian Network Meta-Analysis of Randomized Controlled Trials., Frontiers in Pharmacology, 2020, 13: 850221.\u003c/li\u003e\n \u003cli\u003eXiao L, Niu L, Xu X, Zhao Y, Yue L, Liu X, et al., Comparative Efficacy of Tonic Chinese Herbal Injections for Treating Sepsis or Septic Shock: A Systematic Review and Bayesian Network Meta-Analysis of Randomized Controlled Trials, Frontiers in Pharmacology, 2022, 13: 830030.\u003c/li\u003e\n \u003cli\u003eHuang P, Guo Y, Feng S, Zhao G, Li B, Liu Q, Efficacy and safety of Shenfu injection for septic shock: A systematic review and meta-analysis of randomized controlled trials., The American Journal of Emergency Medicine, 2019, 37(12): 2197\u0026ndash;2204.\u003c/li\u003e\n \u003cli\u003eSun Y, Liu Y, Li L, Xue B, Cao Y, Adjuvant Application of Shenmai Injection for Sepsis: A Systematic Review and Meta-Analysis., Evidence-based complementary and alternative medicine: eCAM, 2022: 3710672.\u003c/li\u003e\n \u003cli\u003eLi X, Huang F, Zhu L, Luo T, Zhang Y, Gu H, et al., Effects of combination therapy with Shenfu Injection in critically ill patients with septic shock receiving mechanical ventilation: A multicentric, real-world study., Frontiers in Pharmacology, 2022, 13: 1041326.\u003c/li\u003e\n \u003cli\u003eLiao J, Qin C, Wang Z, Gao L, Zhang S, Feng Y, et al., Effect of shenfu injection in patients with septic shock: A systemic review and meta-analysis for randomized clinical trials, Journal of Ethnopharmacology, 2023: 117431.\u003c/li\u003e\n \u003cli\u003eShamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al., Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation, BMJ, British Medical Journal Publishing Group, 2015, 349(jan02 1): g7647\u0026ndash;g7647.\u003c/li\u003e\n \u003cli\u003eLevy Mitchell M, Fink Mitchell P, Marshall John C, Abraham Edward, Angus Derek, Cook Deborah, et al., 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference, Intensive Care Medicine, 2003, 29(4): 530\u0026ndash;538.\u003c/li\u003e\n \u003cli\u003eBone Roger C, Balk Robert A, Cerra Frank B, Dellinger R Phillip, Fein Alan M, Knaus William A, et al., Definitions for Sepsis and Organ Failure and Guidelines for the Use of Innovative Therapies in Sepsis, Chest, 1992, 101(6): 1644\u0026ndash;1655.\u003c/li\u003e\n \u003cli\u003eRhodes Andrew, Evans Laura E, Alhazzani Waleed, Levy Mitchell M, Antonelli Massimo, Ferrer Ricard, et al., Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016, Intensive Care Medicine, 2017, 43(3): 304\u0026ndash;377.\u003c/li\u003e\n \u003cli\u003eDellinger R P, Levy Mitchell M, Rhodes Andrew, Annane Djillali, Gerlach Herwig, Opal Steven M, et al., Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012, Intensive Care Medicine, 2013, 39(2): 165\u0026ndash;228.\u003c/li\u003e\n \u003cli\u003eDellinger R Phillip, Levy Mitchell M, Carlet Jean M, Bion Julian, Parker Margaret M, Jaeschke Roman, et al., Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008, Intensive Care Medicine, 2008, 34(1): 17\u0026ndash;60.\u003c/li\u003e\n \u003cli\u003eSterne Jonathan A C, Savović Jelena, Page Matthew J, Elbers Roy G, Blencowe Natalie S, Boutron Isabelle, et al., RoB 2: a revised tool for assessing risk of bias in randomised trials, BMJ, British Medical Journal Publishing Group, 2019, 366: l4898.\u003c/li\u003e\n \u003cli\u003eHozo Stela Pudar, Djulbegovic Benjamin, Hozo Iztok, Estimating the mean and variance from the median, range, and the size of a sample, BMC Medical Research Methodology, 2005, 5(1): 13.\u003c/li\u003e\n \u003cli\u003eB\u0026eacute;liveau Audrey, Boyne Devon J, Slater Justin, Brenner Darren, Arora Paul, BUGSnet: an R package to facilitate the conduct and reporting of Bayesian network Meta-analyses, BMC Medical Research Methodology, 2019, 19(1): 196.\u003c/li\u003e\n \u003cli\u003eDias Sofia, Sutton Alex J, Ades A E, Welton Nicky J, Evidence Synthesis for Decision Making 2, Medical Decision Making, SAGE Publications Inc STM, 2013, 33(5): 607\u0026ndash;617.\u003c/li\u003e\n \u003cli\u003eHamra Ghassan, MacLehose Richard, Richardson David, Markov Chain Monte Carlo: an introduction for epidemiologists, International Journal of Epidemiology, 2013, 42(2): 627\u0026ndash;634.\u003c/li\u003e\n \u003cli\u003eMbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, et al., Approaches to interpreting and choosing the best treatments in network meta-analyses, Systematic Reviews, 2017, 6(1): 79.\u003c/li\u003e\n \u003cli\u003eVan Valkenhoef Gert, Dias Sofia, Ades A E, Welton Nicky J, Automated generation of node‐splitting models for assessment of inconsistency in network meta‐analysis, Research Synthesis Methods, 2016, 7(1): 80\u0026ndash;93.\u003c/li\u003e\n \u003cli\u003eNikolakopoulou Adriani, Higgins Julian P T, Papakonstantinou Theodoros, Chaimani Anna, Del Giovane Cinzia, Egger Matthias, et al., CINeMA: An approach for assessing confidence in the results of a network meta-analysis, PLOS Medicine, Public Library of Science, 2020, 17(4): e1003082.\u003c/li\u003e\n \u003cli\u003ePapakonstantinou Theodoros, Nikolakopoulou Adriani, Higgins Julian P T, Egger Matthias, Salanti Georgia, CINeMA: Software for semiautomated assessment of the confidence in the results of network meta‐analysis, Campbell Systematic Reviews, 2020, 16(1): e1080.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"sepsis, septic shock, Chinese tonic medicines, delta Sequential Organ Failure Assessment, mortality","lastPublishedDoi":"10.21203/rs.3.rs-4163266/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4163266/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSepsis is a life-threatening organ dysfunction with high morbidity and mortality. Various studies have demonstrated the effectiveness of Chinese tonic medicines (CTMs) in treating sepsis or septic shock. However, trials direct comparing the efficacy and safety of different CTMs for sepsis or septic shock are still lacking. To identify the most optimal CTMs for treating sepsis or septic shock, we plan to perform a systematic review and network meta-analysis of various CTMs used for sepsis or septic shock patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRandomized controlled trials (RCTs) that investigated the efficacy and safety of CTMs for patients with sepsis or septic shock will be systematically searched in Pubmed, Embase, Cochrane Central Register of Controlled Trials, CBM, CNKI, Wanfang, and VIP database from inception to November 2023. The quality of the included studies will be assessed using the Cochrane Risk of Bias V.2.0. tool. The confidence of evidence will be evaluated through the CINeMA (Confidence in Network Meta-Analysis) web application. Primary outcomes include the delta Sequential Organ Failure Assessment (△SOFA) score at day 7 after interventions and 28-day mortality. Secondary outcomes comprise delta serum lactate levels (△Lac) and delta mean arterial pressure (△MAP) at day 7 after interventions as well as total dose and duration of vasoactive drugs. Safety outcome includes adverse drug reactions or adverse drug events (ADRs/ADEs). The Bayesian network meta-analysis will be conducted using the “BUGSnet” package in R version 4.2.2. The surface under the cumulative ranking curve (SUCRA) values will be used to rank each treatment. Statistical inconsistency assessment, publication bias assessment, heterogeneity analysis, sensitivity analysis, and subgroup analysis will be performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiscussion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study will provide new insights into the efficacy and safety of various CTMs used in sepsis or septic shock patients, providing help for future clinical practice and research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSystematic review registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCRD42023482572\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Chinese tonic medicines for treating sepsis or septic shock: a protocol for a systematic review and Bayesian network meta-analysis of randomized controlled trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-12 02:21:26","doi":"10.21203/rs.3.rs-4163266/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2024-09-19T09:55:36+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2024-08-05T06:44:44+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-17T13:27:47+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-27T06:35:46+00:00","index":"","fulltext":""},{"type":"submitted","content":"Systematic Reviews","date":"2024-03-25T08:30:45+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"systematic-reviews","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"sysr","sideBox":"Learn more about [Systematic Reviews](http://systematicreviewsjournal.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/sysr/default.aspx","title":"Systematic Reviews","twitterHandle":"@MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7a2357e6-a2bc-47b4-bc81-fbd50c8fc5fd","owner":[],"postedDate":"August 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-12-30T16:01:17+00:00","versionOfRecord":{"articleIdentity":"rs-4163266","link":"https://doi.org/10.1186/s13643-024-02736-5","journal":{"identity":"systematic-reviews","isVorOnly":false,"title":"Systematic Reviews"},"publishedOn":"2024-12-26 15:57:28","publishedOnDateReadable":"December 26th, 2024"},"versionCreatedAt":"2024-08-12 02:21:26","video":"","vorDoi":"10.1186/s13643-024-02736-5","vorDoiUrl":"https://doi.org/10.1186/s13643-024-02736-5","workflowStages":[]},"version":"v1","identity":"rs-4163266","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4163266","identity":"rs-4163266","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}