Effect of Thiamine Supplementation on Mortality in Septic Patients: A Meta-Analysis of Randomized Controlled Trials

Effect of Thiamine Supplementation on Mortality in Septic Patients: A 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 Effect of Thiamine Supplementation on Mortality in Septic Patients: A Meta-Analysis of Randomized Controlled Trials Chenglin Zhao, Qingyu Du, Chunling Sun, Shaohua Du, Xiangwen Zhang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6639223/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background Sepsis is a life-threatening condition characterized by a dysregulated host response to infection and leads to high mortality rates. Thiamine has been proposed as a potential therapeutic agent in sepsis. However, the effect of thiamine on mortality in septic patients remains inconclusive. Existing trials on thiamine's efficacy in sepsis show conflicting results, necessitating a comprehensive meta-analysis. Objective This meta-analysis aims to evaluate the impact of thiamine supplementation on mortality, sequential organ failure assessment (SOFA) scores and the likelihood of requiring renal replacement therapy (RRT) in patients with sepsis. Methods We systematically searched PubMed, Embase, Web of Science, CNKI, and the Cochrane Library for randomized, double-blind, controlled trials up to October 2024. The mortality rate, SOFA scores and the probability of requiring RRT in patients with sepsis were assessed. Results Thiamine supplementation did not significantly reduce overall mortality of patients with sepsis compared to placebo ( RR = 1.10, 95% CI : 0.89–1.37, P = 0.38). Similarly, thiamine showed no significant effect on SOFA scores ( SMD = -0.69, 95% CI : -1.63-0.25, P = 0.15). However, in septic patients with baseline thiamine deficiency, thiamine supplementation significantly reduced 28-day mortality ( RR = 0.70, 95% CI : 0.52–0.90, P = 0.01). Additionally, thiamine reduced the probability of requiring RRT ( RR = 0.75, 95% CI : 0.61–0.93, P = 0.001). Conclusion Thiamine supplementation could reduce the need for RRT and did not reduce overall mortality of patients with sepsis. However, thiamine supplementation offers survival benefits in patients with baseline thiamine deficiency. Thiamine Mortality Sepsis Randomized controlled trials Meta-Analysis Renal replacement therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Sepsis is a life-threatening condition characterized by a dysregulated host response to infection. Sepsis is a major global health concern and leads to high mortality rates worldwide [ 1 ] . Despite advancements were made in critical care in recent years, the mortality rate of sepsis remains unacceptably high. The complex pathophysiology of sepsis involves a dysregulated immune response to infection and widespread inflammation, mitochondrial dysfunction, and multi-organ failure [ 2 ][ 3 ] . So far, there is still a lack of effective drugs for the treatment of sepsis in clinical practice. Thiamine (vitamin B1), an essential coenzyme in carbohydrate metabolism, plays a crucial role in mitochondrial function and energy production. Thiamine deficiency is common in critically ill patients due to increased metabolic demands, inadequate intake and losses secondary to diuresis or dialysis [ 4 ] . This deficiency exacerbates cellular dysfunction and oxidative stress, potentially worsening outcomes in sepsis [ 5 ] . It has been hypothesized that thiamine supplementation may improve outcomes in sepsis by enhancing cellular energy production and reducing oxidative stress [ 6 ] . Previous clinical trials have reported inconsistent results regarding the effects of thiamine supplementation in sepsis. Some studies suggested beneficial effects on mortality, organ function and renal outcomes of thiamine supplementation in the patients with sepsis [ 5 – 7 ] . while others showed there was no significant impact of thiamine supplementation in sepsis [ 8 – 11 ] . A recent hypothesis posited that the benefits of thiamine may be more pronounced in patients with baseline deficiency or those at higher risk for acute kidney injury (AKI) [ 5 , 12 ] . Additionally, emerging evidence indicated that thiamine supplementation may reduce the need for renal replacement therapy (RRT) by mitigating kidney injury through improved cellular energy metabolism and reduced oxidative stress [ 7 ] . Thus, it is needed to perform a meta-analysis to clarify the effects of thiamine supplementation on mortality, organ dysfunction and RRT requirement in septic patients. Methods Search Strategy We conducted a comprehensive literature search of PubMed, Embase, Web of Science, Embase, CNKI and the Cochrane Library databases from inception to October 2024. The search terms included "thiamine", "vitamin B1", "sepsis", "septic shock", "mortality", "randomized controlled trial". Boolean operators "AND" and "OR" were used to combine terms. No language restrictions were applied. We also manually searched the reference lists of relevant articles to identify additional studies. Inclusion and Exclusion Criteria Inclusion Criteria : Studies must be randomized, double-blind, placebo-controlled trials. Participants are adult patients (≥ 18 years old) who diagnosed with sepsis or septic shock based on established criteria. Septic shock was defined according to the Survival Sepsis Campaign 2012 and Sepsis-3 criteria [ 13 ][ 14 ][ 15 ] . Intervention group received thiamine supplementation in addition to standard care. Control group received placebo alongside standard care. Reported outcomes include mortality rates and/or SOFA scores. Exclusion Criteria : Non-randomized studies, observational studies, case reports and reviews. Studies lacking a control group or not using a placebo. Studies without sufficient data to extract outcomes. Duplicate publications or overlapping data. Data Extraction and Quality Assessment Two independent reviewers (CLZ and QYD) extracted data using a standardized data extraction form, including study characteristics, patient demographics, intervention details (dosage, route, duration), and outcomes. Disagreements were resolved by a third reviewer (CLS). The quality of included studies was assessed using the Cochrane Risk of Bias tool, evaluating sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other biases [ 16 – 18 ] . Statistical Analysis Statistical analyses were performed using Stata 18.0. Relative risks (RR) were calculated for dichotomous outcomes, and standardized mean differences (SMD) were calculated for continuous outcomes [ 16 ] . A random-effects model was applied due to moderate to high heterogeneity ( I² > 50%) [ 16 ]-[ 17 ] . Sensitivity analysis was conducted by sequentially removing individual studies. Funnel plots and Bgger's test were used to assess publication bias [ 19 – 21 ] . Results Study Selection A total of 1850 articles were identified through database searches. After removing duplicates and screening titles and abstracts, 34 full-text articles were assessed for eligibility. Finally, five studies met the inclusion criteria and were included in the meta-analysis (Fig. 1 ) [ 5 – 9 ] . Study Characteristics The five included studies comprised 451 patients, with sample sizes ranging from 40 to 158. All studies were randomized, double-blind, trials conducted in intensive care settings. Thiamine dosages varied, with most studies administering 200 mg intravenously. Patient characteristics, intervention details, and outcome measures are summarized in Table 1 . Table 1 Characteristics of included studies. Author Study design Sample size Male (%) Treatment regimen Comparator Outcome Vine et al 2024 Randomized controlled trial 158 46.20% thiamine (There is no specific dose) placebo In-hospital survival Pereira AG et al 2023 Randomized controlled trial 115 54.78% 200 mg of intravenous thiamine placebo survival at 28-days Nandhini N et al 2022 Randomized controlled trial 50 52.00% 2 mg/kg of intravenous (IV) thiamine placebo In-hospital mortality Gayathri R et al 2022 Randomized controlled trial 40 65.00% 200 mg of THIA MINE per day, 12 hourly, for 5 days placebo In-hospital mortality Donnino MW et al 2016 Randomized controlled trial 88 59.09% 200 mg of thiamine, dissolved in 50 mL of 5% glucose solution, administered twice daily for 7 days or until discharge placebo In-hospital mortality Risk of Bias Assessment Overall, the included fiver studies demonstrated low to moderate risk of bias. Random sequence generation and allocation concealment were adequately described in all studies. Blinding of participants, personnel, and outcome assessors was maintained. However, one study had incomplete outcome data due to loss to follow-up (Fig. 2 ). Overall Mortality The pooled analysis showed that thiamine supplementation did not significantly reduce mortality compared to placebo ( RR = 1.10, 95% CI : 0.89–1.37, P = 0.38). Heterogeneity was moderate ( I² = 53.4%), and a random-effects model was used (Fig. 3 a). Sensitivity analysis which removed one study at a time did not significantly alter the results (Fig. 3 b). Further subgroup analysis was performed according to the patients with baseline thiamine deficiency, and our results revealed that thiamine supplementation significantly reduced mortality in patients with baseline thiamine deficiency. In septic patients with thiamine deficiency at baseline, thiamine supplementation significantly reduced 28-day mortality ( RR = 0.70, 95% CI : 0.52–0.90, P = 0.01) (Fig. 3 c). SOFA Scores Thiamine supplementation did not result in a statistically significant reduction in SOFA scores ( SMD = -0.69, 95% CI : -1.63 to 0.25, P = 0.15). Heterogeneity was high ( I² = 92.6%), indicating substantial variability among studies (Fig. 4 a). Sensitivity analysis did not significantly alter the results (Fig. 4 b). Effect of Thiamine on the Probability of RRT Treatment Our analysis showed that thiamine supplementation significantly reduced the probability of patients requiring renal replacement therapy (RRT). Pooled data from five studies demonstrated a significant reduction in the need for RRT in the thiamine group compared to the placebo group. The pooled relative risk (RR) was 0.75 (95% CI : 0.61–0.93, P = 0.001), and there was no significant heterogeneity( I² = 0.0%) (Fig. 5 a). Sensitivity analysis did not significantly alter the results (Fig. 5 b). Publication Bias No significant publication bias was observed for mortality (Begg’s test, P = 0.22) or SOFA scores (Begg’s test, P = 0.35), as demonstrated by symmetrical funnel plots (Figs. 6 a and b). Discussion Sepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality worldwide. The high mortality rate of sepsis is attributable to multiple factors, including persistent inflammation, immune suppression and mitochondrial dysfunction, which collectively impair organ function and exacerbate patient outcomes. Thiamine, an essential B-vitamin, plays a crucial role in cellular metabolism and energy production. Its supplementation has been hypothesized to confer therapeutic benefits in sepsis through several mechanisms, including anti-inflammatory effects, enhancement of mitochondrial function, and reduction of lactate levels [ 17 ] . However, the effects of thiamine supplementation in sepsis are still in debate. In this meta-analysis, our results showed that 1) thiamine supplementation did not significantly reduce overall mortality in the general septic population. 2)Thiamine supplementation could reduce the need for RRT in patients with sepsis. 3) thiamine supplementation offers survival benefits in patients with baseline thiamine deficiency. Overall mortality is one of the important indicators for predicting the prognosis of sepsis which has a high mortality in worldwide, and it is in debate that thiamine supplementation could reduce the overall mortality in sepsis. In our results of meta-analysis, the thiamine could not reduce overall mortality in the general septic population. However, our subgroup analysis revealed a significant mortality reduction in patients with baseline thiamine deficiency. This finding suggests that thiamine may exert a targeted therapeutic effect in septic patients who are deficient. This discrepancy underscores the importance of individualized treatment approaches in sepsis management. Routine thiamine administration may not be beneficial for all septic patients, but screening for thiamine deficiency could identify those who are more likely to benefit from supplementation. Targeting interventions based on patients' nutritional and metabolic status, such as thiamine levels, may optimize therapeutic outcomes and resource utilization [ 22 ] . RRT is a critical intervention for managing acute kidney injury (AKI) in septic patients, aiming to support renal function and maintain fluid and electrolyte balance. The need for RRT is associated with increased morbidity, prolonged hospital stays, and higher healthcare costs. Recent studies have failed to demonstrate a significant impact of thiamine on RRT necessity, with some reporting no clear association between thiamine supplementation and improved renal outcomes [ 23 ] . This discrepancy highlights the ongoing debate and underscores the need for further research to clarify thiamine’s role in renal protection in sepsis. In our analysis, thiamine supplementation significantly reduced the probability of requiring RRT. This protective effect may be attributed to thiamine’s role in improving mitochondrial function and reducing oxidative stress, thereby preserving renal tissue integrity and function. Additionally, by modulating inflammatory responses, thiamine may help prevent the progression of sepsis-induced kidney damage. These findings highlight the potential of thiamine supplementation to improve renal outcomes in septic patients, reducing the reliance on RRT and its associated complications. The SOFA score is a widely used tool to assess the extent of organ dysfunction in the patient with sepsis, which can help to guide clinical decision-making and prognostication.. Several studies in the existing literature suggest that thiamine supplementation may play a role in improving organ function. For instance, by Paul et al found that thiamine administration in patients with septic shock was associated with a reduction in SOFA scores and improved clinical outcome [ 24 ] . However, in this meta-analysis, thiamine supplementation did not lead to a significant improvement in SOFA scores across the general septic population. However, the substantial heterogeneity was observed. The high variability may stem from differences in patient demographics, variations in standard care practices and inconsistent timing of SOFA score assessments across studies. Thiamine's potential benefits on organ function, particularly in patients with deficiency, may not be uniformly captured in the overall SOFA score. Future studies should consider standardized assessment protocols and focus on specific organ systems to better elucidate the impact of thiamine on organ dysfunction in sepsis. This study has several limitations. The small number of included trials and patients limits the statistical power to detect significant effects, and the heterogeneity in thiamine dosing regimens, durations of treatment and variability in patients' baseline thiamine status are not neglected. Significant heterogeneity among studies restricts the generalizability of our findings. Additionally, the lack of individual patient data precluded more detailed subgroup analyses that could identify specific populations benefiting from thiamine supplementation. Variations in thiamine dosing regimens, treatment durations, and timing of administration further contribute to the observed heterogeneity. Future large-scale, well-designed randomized controlled trials are necessary to confirm these findings. It is crucial to assess baseline thiamine levels and focus on patients with documented deficiency to determine the efficacy of supplementation in this subgroup. Standardizing thiamine dosing regimens and administration timing will enhance comparability across studies and provide clearer insights into its therapeutic potential in sepsis. Additionally, exploring the mechanistic pathways through which thiamine influences sepsis outcomes may uncover novel therapeutic targets and strategies. Conclusion Thiamine supplementation does not significantly reduce overall mortality or improve SOFA scores in the general septic population. However, our analysis showed that thiamine supplementation offers a significant survival benefit in patients with baseline thiamine deficiency. Additionally, thiamine supplementation significantly reduces the probability of requiring RRT in septic patients. Given the limitations and heterogeneity of current evidence, routine use of thiamine in sepsis cannot be recommended for all patients. Future research should focus on patients with confirmed thiamine deficiency to determine whether targeted supplementation offers clinical benefits, particularly in reducing mortality and improving renal outcomes. Standardization of dosing regimens and timing of administration, along with the inclusion of larger, more homogenous study populations, will be critical in further clarifying thiamine's role in sepsis management. Declarations Ethical Approval and Consent to participate : Not applicable. This meta-analysis utilized publicly available data from published studies. Ethical approval and patient consent were obtained in all original studies, as reported in their respective publications. Therefore, no additional ethical approval was required for this secondary analysis. Clinical Trial : Not applicable. This is a meta-analysis of existing published studies. Consent for publication :Not applicable. This manuscript contains no individual person’s data. Availability of supporting data : The datasets analyzed during this study are available in the following repositories: PubMed (https://pubmed.ncbi.nlm.nih.gov/) Embase (https://www.embase.com/) Web of Science (https://www.webofscience.com/) CNKI (https://www.cnki.net/) Cochrane Library (https://www.cochranelibrary.com/) The full search strategy and PRISMA checklist are provided as Additional Files. Competing interests :The authors declare that they have no competing interests. Funding :This research received no specific funding. Authors' contributions : Conceptualization: XWZ, GZ Methodology: CLZ, QYD, CLS, SHD Formal analysis: CLZ, QYD, CLS, XWZ, GZ Data curation: CLZ, QYD, CLS, SHD, XWZ, GZ Writing original draft: CLZ, QYD, CLS – Writing review & editing: All authors Supervision: XWZ, GZ All authors read and approved the final manuscript. Acknowledgements: We thank the contributors to the original studies included in this meta-analysis. References Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181–247. 10.1007/s00134-021-06506-y . World Health Organization. Report on the Burden of Endemic Health Care-Associated Infection Worldwide. Geneva: WHO; 2011. Rhee C, Jones TM, Hamad Y, et al. Prevalence, underlying causes, and preventabilityof sepsis-associated mortality in US acute care hospitals. JAMA Netw Open. 2022;5(6):e2215832. 10.1001/jamanetworkopen.2022.15832 . Garcia-Alvarez M, Marik P, Bellomo R. Sepsis-associated hyperlactatemia. Crit Care. 2014;18:503. 10.1186/s13054-014-0503-3 . Vine J, Lee JH, Kravitz MS, et al. Thiamine administration in septic shock: a post hoc analysis of two randomized trials. Crit Care. 2024;28:41. 10.1186/s13054-024-04818-1 . Pereira AG, Costa NA, Amancio SCP, et al. Effect of thiamine on clinical outcomes in septic shock patients: a randomized, double-blinded pilot study. Am J Respir Crit Care Med. 2023;208(5):616–8. 10.1164/rccm.202208-1583LE . Nandhini N, Malviya D, Parashar S, et al. Comparison of the effects of vitamin C and thiamine on refractory hypotension in patients with sepsis: a randomized controlled trial. Int J Crit Illn Inj Sci. 2022;12(3):138–45. 10.4103/ijciis.ijciis_107_21 . Ap GR, Daga MK, Mawari G, et al. Effect of supplementation of vitamin C and thiamine on the outcome in sepsis: South East Asian region. J Assoc Physicians India. 2022;70(3):11–2. PMID:35438278. Donnino MW, Andersen LW, Chase M, et al. Randomized, double-blind, placebo-controlled trial of thiamine as a metabolic resuscitator in septic shock: a pilot study. Crit Care Med. 2016;44(2):360–7. 10.1097/CCM.0000000000001572 . Donnino MW, Carney E, Cocchi MN, et al. Thiamine deficiency in critically ill patients with sepsis. J Crit Care. 2010;25(4):576–81. 10.1016/j.jcrc.2010.03.003 . Miyamoto Y, Aso S, Iwagami M, et al. Thiamine supplementation in septic shock. Crit Care Med. 2020;48(8):1135–9. 10.1097/CCM.0000000000004394 . Moskowitz A, Andersen LW, Cocchi MN, et al. Thiamine as a renal protective agent in septic shock: a secondary analysis. Ann Am Thorac Soc. 2017;14(5):737–41. 10.1513/AnnalsATS.201611-887BC . Stewart LA, Clarke M, Rovers M, et al. Preferred reporting items for systematic review and meta-analyses of individual participant data: the PRISMA-IPD statement. JAMA. 2015;313(16):1657–65. 10.1001/jama.2015.3656 . Dellinger RP, Levy MM, Rhodes A, et al. Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580–637. 10.1097/CCM.0b013e31827e83af . Singer M, Deutschman CS, Seymour CW, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):801–10. 10.1001/jama.2016.0287 . DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. 10.1016/0197-2456(86)90046-2 . Higgins JPT, Altman DG, Gøtzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 10.1136/bmj.d5928 . Sterne JA, Hernán MA, Reeves BC, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. 10.1136/bmj.i4919 . Sterne JA, Egger M. Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis. J Clin Epidemiol. 2001;54(10):1046–55. 10.1016/s0895- . Begg CB, Berlin JA. Publication bias and dissemination of clinical research. J Natl Cancer Inst. 1989;81(2):107–15. 10.1093/jnci/81.2.107 . Egger M, Smith GD. Bias in location and selection of studies. BMJ. 1998;316(7124):61–6. 10.1136/bmj.316.7124.61 . Woolum JA, Abner EL, Kelly A, et al. Effect of thiamine administration on lactate clearance and mortality in patients with septic shock. Crit Care Med. 2018;46(11):1747–52. 10.1097/CCM.0000000000003311 . Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA. 2021;325(8):742–50. 10.1001/jama . 2020.24505. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospectivebefore-after study. Chest. 2017;151(6):1229–38. 10.1016/j.chest.2016.11.036 . Additional Declarations No competing interests reported. Supplementary Files AdditionalFile1PRISMAChecklist.docx AdditionalFile2SearchStrategy.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 15 Jun, 2025 Reviewers agreed at journal 14 Jun, 2025 Reviewers invited by journal 06 Jun, 2025 Editor invited by journal 19 May, 2025 Editor assigned by journal 16 May, 2025 Submission checks completed at journal 16 May, 2025 First submitted to journal 11 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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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-6639223","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":467745121,"identity":"e8ef3316-adc9-4f9f-95ed-acfdaccbe963","order_by":0,"name":"Chenglin Zhao","email":"","orcid":"","institution":"Central Hospital of Dalian University of Technology, Dalian Municipal Central Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Chenglin","middleName":"","lastName":"Zhao","suffix":""},{"id":467745122,"identity":"c631097c-1099-4480-b309-029a7ab5f868","order_by":1,"name":"Qingyu Du","email":"","orcid":"","institution":"Central 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3","display":"","copyAsset":false,"role":"figure","size":167544,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots and sensitivity analysis for overall mortality\u003c/p\u003e\n\u003cp\u003e(a) Primary analysis of thiamine vs. placebo (random-effects model, \u003cem\u003eRR\u003c/em\u003e = 1.10, 95% \u003cem\u003eCI\u003c/em\u003e: 0.89–1.37);\u003c/p\u003e\n\u003cp\u003e(b) Sensitivity analysis with sequential exclusion of individual studies;\u003c/p\u003e\n\u003cp\u003e(c) Subgroup analysis in patients with baseline thiamine deficiency (\u003cem\u003eRR\u003c/em\u003e = 0.70, 95% \u003cem\u003eCI\u003c/em\u003e: 0.52–0.90).\u003c/p\u003e","description":"","filename":"Figure3MortalityForestPlot.png","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/cad29fbc18e35a6792380a0f.png"},{"id":84306365,"identity":"1738a659-6518-4976-b3a5-0e2cb7a05044","added_by":"auto","created_at":"2025-06-10 11:24:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":785816,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots and sensitivity analysis for SOFA scores\u003c/p\u003e\n\u003cp\u003e(a) Primary analysis (\u003cem\u003eSMD\u003c/em\u003e = -0.69, 95% \u003cem\u003eCI\u003c/em\u003e: -1.63–0.25)\u003c/p\u003e\n\u003cp\u003e(b) Sensitivity analysis after excluding outlier studies.\u003c/p\u003e","description":"","filename":"Figure4SOFAScoreForestPlot.png","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/cb38ffc3de4c1ff0b06487cc.png"},{"id":84306179,"identity":"60008686-d47a-41a7-8ab4-664cbb127ba6","added_by":"auto","created_at":"2025-06-10 11:24:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":368656,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots and sensitivity analysis for RRT requirement\u003c/p\u003e\n\u003cp\u003e(a) Primary analysis (\u003cem\u003eRR\u003c/em\u003e = 0.75, 95% \u003cem\u003eCI\u003c/em\u003e: 0.61–0.93)\u003c/p\u003e\n\u003cp\u003e(b) Sensitivity analysis stratified by study quality.\u003c/p\u003e","description":"","filename":"Figure5RRTRequirementForestPlot.png","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/98c51e9147923f1dc9af5153.png"},{"id":84306274,"identity":"d12a93b3-1ab8-40f1-8bce-fa3c7c0876c1","added_by":"auto","created_at":"2025-06-10 11:24:42","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":573746,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plots for publication bias assessment: (a) Mortality; (b) SOFA scores\u003c/p\u003e","description":"","filename":"Figure6RiskOfBias.png","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/43cc5b9a1b9d66a4e4620f60.png"},{"id":84306961,"identity":"5c5c6025-a39c-4feb-bcc0-38a3b24bb468","added_by":"auto","created_at":"2025-06-10 11:32:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4102670,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/51819be3-df29-4506-9ecf-b42b1806f29e.pdf"},{"id":84306176,"identity":"3f79b8bd-28b4-47dc-9618-dcf84dbb073c","added_by":"auto","created_at":"2025-06-10 11:24:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":274378,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile1PRISMAChecklist.docx","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/4365f8f1f6224a575f2e5550.docx"},{"id":84306233,"identity":"f0a24e60-f96c-4993-a67e-9414a293648d","added_by":"auto","created_at":"2025-06-10 11:24:40","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":10751,"visible":true,"origin":"","legend":"","description":"","filename":"AdditionalFile2SearchStrategy.docx","url":"https://assets-eu.researchsquare.com/files/rs-6639223/v1/e147c1b78d16ed3c3cc1416f.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effect of Thiamine Supplementation on Mortality in Septic Patients: A Meta-Analysis of Randomized Controlled Trials","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSepsis is a life-threatening condition characterized by a dysregulated host response to infection. Sepsis is a major global health concern and leads to high mortality rates worldwide\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Despite advancements were made in critical care in recent years, the mortality rate of sepsis remains unacceptably high. The complex pathophysiology of sepsis involves a dysregulated immune response to infection and widespread inflammation, mitochondrial dysfunction, and multi-organ failure\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e][\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. So far, there is still a lack of effective drugs for the treatment of sepsis in clinical practice.\u003c/p\u003e \u003cp\u003eThiamine (vitamin B1), an essential coenzyme in carbohydrate metabolism, plays a crucial role in mitochondrial function and energy production. Thiamine deficiency is common in critically ill patients due to increased metabolic demands, inadequate intake and losses secondary to diuresis or dialysis\u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. This deficiency exacerbates cellular dysfunction and oxidative stress, potentially worsening outcomes in sepsis\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. It has been hypothesized that thiamine supplementation may improve outcomes in sepsis by enhancing cellular energy production and reducing oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Previous clinical trials have reported inconsistent results regarding the effects of thiamine supplementation in sepsis. Some studies suggested beneficial effects on mortality, organ function and renal outcomes of thiamine supplementation in the patients with sepsis\u003csup\u003e[\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. while others showed there was no significant impact of thiamine supplementation in sepsis\u003csup\u003e[\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. A recent hypothesis posited that the benefits of thiamine may be more pronounced in patients with baseline deficiency or those at higher risk for acute kidney injury (AKI)\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Additionally, emerging evidence indicated that thiamine supplementation may reduce the need for renal replacement therapy (RRT) by mitigating kidney injury through improved cellular energy metabolism and reduced oxidative stress\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Thus, it is needed to perform a meta-analysis to clarify the effects of thiamine supplementation on mortality, organ dysfunction and RRT requirement in septic patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch Strategy\u003c/h2\u003e \u003cp\u003eWe conducted a comprehensive literature search of PubMed, Embase, Web of Science, Embase, CNKI and the Cochrane Library databases from inception to October 2024. The search terms included \"thiamine\", \"vitamin B1\", \"sepsis\", \"septic shock\", \"mortality\", \"randomized controlled trial\". Boolean operators \"AND\" and \"OR\" were used to combine terms. No language restrictions were applied. We also manually searched the reference lists of relevant articles to identify additional studies.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003e \u003cb\u003eInclusion Criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eStudies must be randomized, double-blind, placebo-controlled trials.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eParticipants are adult patients (\u0026ge;\u0026thinsp;18 years old) who diagnosed with sepsis or septic shock based on established criteria.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eSeptic shock was defined according to the Survival Sepsis Campaign 2012 and Sepsis-3 criteria\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e][\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e][\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eIntervention group received thiamine supplementation in addition to standard care. Control group received placebo alongside standard care.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eReported outcomes include mortality rates and/or SOFA scores.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e \u003cp\u003e \u003cb\u003eExclusion Criteria\u003c/b\u003e:\u003c/p\u003e \u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eNon-randomized studies, observational studies, case reports and reviews. Studies lacking a control group or not using a placebo.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eStudies without sufficient data to extract outcomes. Duplicate publications or overlapping data.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e\n\u003ch3\u003eData Extraction and Quality Assessment\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers (CLZ and QYD) extracted data using a standardized data extraction form, including study characteristics, patient demographics, intervention details (dosage, route, duration), and outcomes. Disagreements were resolved by a third reviewer (CLS).\u003c/p\u003e \u003cp\u003eThe quality of included studies was assessed using the Cochrane Risk of Bias tool, evaluating sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting and other biases\u003csup\u003e[\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using Stata 18.0. Relative risks (RR) were calculated for dichotomous outcomes, and standardized mean differences (SMD) were calculated for continuous outcomes\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. A random-effects model was applied due to moderate to high heterogeneity (\u003cem\u003eI\u0026sup2;\u003c/em\u003e \u0026gt; 50%)\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]-[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Sensitivity analysis was conducted by sequentially removing individual studies. Funnel plots and Bgger's test were used to assess publication bias\u003csup\u003e[\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy Selection\u003c/h2\u003e \u003cp\u003eA total of 1850 articles were identified through database searches. After removing duplicates and screening titles and abstracts, 34 full-text articles were assessed for eligibility. Finally, five studies met the inclusion criteria and were included in the meta-analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e)\u003csup\u003e[\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy Characteristics\u003c/h3\u003e\n\u003cp\u003eThe five included studies comprised 451 patients, with sample sizes ranging from 40 to 158. All studies were randomized, double-blind, trials conducted in intensive care settings. Thiamine dosages varied, with most studies administering 200 mg intravenously. Patient characteristics, intervention details, and outcome measures are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAuthor\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStudy design\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTreatment regimen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eComparator\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVine et al 2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e158\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46.20%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003ethiamine\u003c/p\u003e \u003cp\u003e(There is no specific\u003c/p\u003e \u003cp\u003edose)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eplacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIn-hospital\u003c/p\u003e \u003cp\u003esurvival\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePereira AG et al 2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54.78%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e200 mg of\u003c/p\u003e \u003cp\u003eintravenous thiamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eplacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003esurvival at\u003c/p\u003e \u003cp\u003e28-days\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNandhini N et al 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52.00%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2 mg/kg of\u003c/p\u003e \u003cp\u003eintravenous\u003c/p\u003e \u003cp\u003e(IV) thiamine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eplacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGayathri R et al 2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e65.00%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e200 mg of THIA MINE per day, 12 hourly, for 5 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eplacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDonnino MW et al 2016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRandomized controlled trial\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e59.09%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e200 mg of thiamine, dissolved\u003c/p\u003e \u003cp\u003ein 50 mL of 5% glucose\u003c/p\u003e \u003cp\u003esolution, administered twice daily for 7 days or until\u003c/p\u003e \u003cp\u003edischarge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eplacebo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIn-hospital mortality\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eRisk of Bias Assessment\u003c/h3\u003e\n\u003cp\u003eOverall, the included fiver studies demonstrated low to moderate risk of bias. Random sequence generation and allocation concealment were adequately described in all studies. Blinding of participants, personnel, and outcome assessors was maintained. However, one study had incomplete outcome data due to loss to follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eOverall Mortality\u003c/h2\u003e \u003cp\u003eThe pooled analysis showed that thiamine supplementation did not significantly reduce mortality compared to placebo (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.10, 95% \u003cem\u003eCI\u003c/em\u003e: 0.89\u0026ndash;1.37, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.38). Heterogeneity was moderate (\u003cem\u003eI\u0026sup2;\u003c/em\u003e = 53.4%), and a random-effects model was used (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea). Sensitivity analysis which removed one study at a time did not significantly alter the results (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003eFurther subgroup analysis was performed according to the patients with baseline thiamine deficiency, and our results revealed that thiamine supplementation significantly reduced mortality in patients with baseline thiamine deficiency. In septic patients with thiamine deficiency at baseline, thiamine supplementation significantly reduced 28-day mortality (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.70, 95% \u003cem\u003eCI\u003c/em\u003e: 0.52\u0026ndash;0.90, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ec).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSOFA Scores\u003c/h2\u003e \u003cp\u003eThiamine supplementation did not result in a statistically significant reduction in SOFA scores (\u003cem\u003eSMD\u003c/em\u003e = -0.69, 95% \u003cem\u003eCI\u003c/em\u003e: -1.63 to 0.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15). Heterogeneity was high (\u003cem\u003eI\u0026sup2;\u003c/em\u003e = 92.6%), indicating substantial variability among studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Sensitivity analysis did not significantly alter the results (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eEffect of Thiamine on the Probability of RRT Treatment\u003c/h2\u003e \u003cp\u003eOur analysis showed that thiamine supplementation significantly reduced the probability of patients requiring renal replacement therapy (RRT). Pooled data from five studies demonstrated a significant reduction in the need for RRT in the thiamine group compared to the placebo group. The pooled relative risk (RR) was 0.75 (95% \u003cem\u003eCI\u003c/em\u003e: 0.61\u0026ndash;0.93, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and there was no significant heterogeneity(\u003cem\u003eI\u0026sup2;\u003c/em\u003e = 0.0%) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). Sensitivity analysis did not significantly alter the results (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003ePublication Bias\u003c/h2\u003e \u003cp\u003eNo significant publication bias was observed for mortality (Begg\u0026rsquo;s test, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.22) or SOFA scores (Begg\u0026rsquo;s test, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.35), as demonstrated by symmetrical funnel plots (Figs.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea and b).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSepsis, a life-threatening organ dysfunction caused by a dysregulated host response to infection, remains a leading cause of mortality worldwide. The high mortality rate of sepsis is attributable to multiple factors, including persistent inflammation, immune suppression and mitochondrial dysfunction, which collectively impair organ function and exacerbate patient outcomes. Thiamine, an essential B-vitamin, plays a crucial role in cellular metabolism and energy production. Its supplementation has been hypothesized to confer therapeutic benefits in sepsis through several mechanisms, including anti-inflammatory effects, enhancement of mitochondrial function, and reduction of lactate levels\u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. However, the effects of thiamine supplementation in sepsis are still in debate. In this meta-analysis, our results showed that 1) thiamine supplementation did not significantly reduce overall mortality in the general septic population. 2)Thiamine supplementation could reduce the need for RRT in patients with sepsis. 3) thiamine supplementation offers survival benefits in patients with baseline thiamine deficiency.\u003c/p\u003e \u003cp\u003eOverall mortality is one of the important indicators for predicting the prognosis of sepsis which has a high mortality in worldwide, and it is in debate that thiamine supplementation could reduce the overall mortality in sepsis. In our results of meta-analysis, the thiamine could not reduce overall mortality in the general septic population. However, our subgroup analysis revealed a significant mortality reduction in patients with baseline thiamine deficiency. This finding suggests that thiamine may exert a targeted therapeutic effect in septic patients who are deficient. This discrepancy underscores the importance of individualized treatment approaches in sepsis management. Routine thiamine administration may not be beneficial for all septic patients, but screening for thiamine deficiency could identify those who are more likely to benefit from supplementation. Targeting interventions based on patients' nutritional and metabolic status, such as thiamine levels, may optimize therapeutic outcomes and resource utilization\u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRRT is a critical intervention for managing acute kidney injury (AKI) in septic patients, aiming to support renal function and maintain fluid and electrolyte balance. The need for RRT is associated with increased morbidity, prolonged hospital stays, and higher healthcare costs. Recent studies have failed to demonstrate a significant impact of thiamine on RRT necessity, with some reporting no clear association between thiamine supplementation and improved renal outcomes\u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e. This discrepancy highlights the ongoing debate and underscores the need for further research to clarify thiamine\u0026rsquo;s role in renal protection in sepsis. In our analysis, thiamine supplementation significantly reduced the probability of requiring RRT. This protective effect may be attributed to thiamine\u0026rsquo;s role in improving mitochondrial function and reducing oxidative stress, thereby preserving renal tissue integrity and function. Additionally, by modulating inflammatory responses, thiamine may help prevent the progression of sepsis-induced kidney damage. These findings highlight the potential of thiamine supplementation to improve renal outcomes in septic patients, reducing the reliance on RRT and its associated complications.\u003c/p\u003e \u003cp\u003eThe SOFA score is a widely used tool to assess the extent of organ dysfunction in the patient with sepsis, which can help to guide clinical decision-making and prognostication.. Several studies in the existing literature suggest that thiamine supplementation may play a role in improving organ function. For instance, by Paul et al found that thiamine administration in patients with septic shock was associated with a reduction in SOFA scores and improved clinical outcome\u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e. However, in this meta-analysis, thiamine supplementation did not lead to a significant improvement in SOFA scores across the general septic population. However, the substantial heterogeneity was observed. The high variability may stem from differences in patient demographics, variations in standard care practices and inconsistent timing of SOFA score assessments across studies. Thiamine's potential benefits on organ function, particularly in patients with deficiency, may not be uniformly captured in the overall SOFA score. Future studies should consider standardized assessment protocols and focus on specific organ systems to better elucidate the impact of thiamine on organ dysfunction in sepsis.\u003c/p\u003e \u003cp\u003eThis study has several limitations. The small number of included trials and patients limits the statistical power to detect significant effects, and the heterogeneity in thiamine dosing regimens, durations of treatment and variability in patients' baseline thiamine status are not neglected. Significant heterogeneity among studies restricts the generalizability of our findings. Additionally, the lack of individual patient data precluded more detailed subgroup analyses that could identify specific populations benefiting from thiamine supplementation. Variations in thiamine dosing regimens, treatment durations, and timing of administration further contribute to the observed heterogeneity.\u003c/p\u003e \u003cp\u003eFuture large-scale, well-designed randomized controlled trials are necessary to confirm these findings. It is crucial to assess baseline thiamine levels and focus on patients with documented deficiency to determine the efficacy of supplementation in this subgroup. Standardizing thiamine dosing regimens and administration timing will enhance comparability across studies and provide clearer insights into its therapeutic potential in sepsis. Additionally, exploring the mechanistic pathways through which thiamine influences sepsis outcomes may uncover novel therapeutic targets and strategies.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThiamine supplementation does not significantly reduce overall mortality or improve SOFA scores in the general septic population. However, our analysis showed that thiamine supplementation offers a significant survival benefit in patients with baseline thiamine deficiency. Additionally, thiamine supplementation significantly reduces the probability of requiring RRT in septic patients. Given the limitations and heterogeneity of current evidence, routine use of thiamine in sepsis cannot be recommended for all patients. Future research should focus on patients with confirmed thiamine deficiency to determine whether targeted supplementation offers clinical benefits, particularly in reducing mortality and improving renal outcomes. Standardization of dosing regimens and timing of administration, along with the inclusion of larger, more homogenous study populations, will be critical in further clarifying thiamine's role in sepsis management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp skip=\"true\"\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e: Not applicable. This meta-analysis utilized publicly available data from published studies. Ethical approval and patient consent were obtained in all original studies, as reported in their respective publications. Therefore, no additional ethical approval was required for this secondary analysis.\u003c/p\u003e\n\u003cp skip=\"true\"\u003e\u003cstrong\u003eClinical Trial\u003c/strong\u003e: Not applicable. This is a meta-analysis of existing published studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e:Not applicable. This manuscript contains no individual person\u0026rsquo;s data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe datasets analyzed during this study are available in the following repositories: \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePubMed (https://pubmed.ncbi.nlm.nih.gov/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEmbase (https://www.embase.com/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWeb of Science (https://www.webofscience.com/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCNKI (https://www.cnki.net/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCochrane Library (https://www.cochranelibrary.com/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe full search strategy and PRISMA checklist are provided as Additional Files. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:The authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:This research received no specific funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eConceptualization: XWZ, GZ\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMethodology: CLZ, QYD, CLS, SHD\u003c/p\u003e\n\u003cp\u003eFormal analysis: CLZ, QYD, CLS, XWZ, GZ\u003c/p\u003e\n\u003cp\u003eData curation: CLZ, QYD, CLS, SHD, XWZ, GZ\u003c/p\u003e\n\u003cp\u003eWriting original draft: CLZ, QYD, CLS \u0026ndash;\u003c/p\u003e\n\u003cp\u003eWriting review \u0026amp; editing: All authors\u003c/p\u003e\n\u003cp\u003eSupervision: XWZ, GZ\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003eWe thank the contributors to the original studies included in this meta-analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eEvans L, Rhodes A, Alhazzani W, et al. 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Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospectivebefore-after study. Chest. 2017;151(6):1229\u0026ndash;38. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.chest.2016.11.036\u003c/span\u003e\u003cspan address=\"10.1016/j.chest.2016.11.036\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Thiamine, Mortality, Sepsis, Randomized controlled trials, Meta-Analysis, Renal replacement therapy","lastPublishedDoi":"10.21203/rs.3.rs-6639223/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6639223/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSepsis is a life-threatening condition characterized by a dysregulated host response to infection and leads to high mortality rates. Thiamine has been proposed as a potential therapeutic agent in sepsis. However, the effect of thiamine on mortality in septic patients remains inconclusive. Existing trials on thiamine's efficacy in sepsis show conflicting results, necessitating a comprehensive meta-analysis.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis meta-analysis aims to evaluate the impact of thiamine supplementation on mortality, sequential organ failure assessment (SOFA) scores and the likelihood of requiring renal replacement therapy (RRT) in patients with sepsis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe systematically searched PubMed, Embase, Web of Science, CNKI, and the Cochrane Library for randomized, double-blind, controlled trials up to October 2024. The mortality rate, SOFA scores and the probability of requiring RRT in patients with sepsis were assessed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThiamine supplementation did not significantly reduce overall mortality of patients with sepsis compared to placebo (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.10, 95% \u003cem\u003eCI\u003c/em\u003e: 0.89\u0026ndash;1.37, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.38). Similarly, thiamine showed no significant effect on SOFA scores (\u003cem\u003eSMD\u003c/em\u003e = -0.69, 95% \u003cem\u003eCI\u003c/em\u003e: -1.63-0.25, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.15). However, in septic patients with baseline thiamine deficiency, thiamine supplementation significantly reduced 28-day mortality (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.70, 95% \u003cem\u003eCI\u003c/em\u003e: 0.52\u0026ndash;0.90, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.01). Additionally, thiamine reduced the probability of requiring RRT (\u003cem\u003eRR\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.75, 95% \u003cem\u003eCI\u003c/em\u003e: 0.61\u0026ndash;0.93, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThiamine supplementation could reduce the need for RRT and did not reduce overall mortality of patients with sepsis. However, thiamine supplementation offers survival benefits in patients with baseline thiamine deficiency.\u003c/p\u003e","manuscriptTitle":"Effect of Thiamine Supplementation on Mortality in Septic Patients: A Meta-Analysis of Randomized Controlled Trials","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 11:24:10","doi":"10.21203/rs.3.rs-6639223/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-06-15T13:46:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"153523465165140833318780729105192446076","date":"2025-06-14T07:13:52+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-06-06T06:51:56+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-05-19T08:04:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-16T07:47:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-16T07:45:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Infectious Diseases","date":"2025-05-11T10:59:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-infectious-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"infd","sideBox":"Learn more about [BMC Infectious Diseases](http://bmcinfectdis.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/infd","title":"BMC Infectious Diseases","twitterHandle":"#bmcinfectdis","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"708b7bb0-57f0-43a3-aafa-05ecf91bdf58","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-06-10T11:24:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-10 11:24:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6639223","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6639223","identity":"rs-6639223","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}