{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T15:39:13Z","timestamp":1772465953433,"version":"3.50.1"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>To evaluate the efficacy and safety of hydrocortisone combined with fludrocortisone in the treatment of septic shock in adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched PubMed, Embase, Web of Science, and the Cochrane Library for studies on hydrocortisone combined with fludrocortisone in the treatment of septic shock in adults. Two investigators independently screened studies, extracted data, and assessed the risk of bias of the included studies. A meta-analysis was performed using RevMan 5.3 and STATA 17.0 software.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of eight studies (5 RCTs and 3 N-RCTs) were included. Stratified analysis by study design and comparator type revealed that in the HC\u202f+\u202fFC vs. Placebo subgroup (derived solely from RCTs), the combination significantly reduced 28-day mortality [RR 0.84; 95% CI (0.76, 0.94);\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.002], 90-day mortality [RR 0.82; 95% CI (0.71, 0.94);\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.006], and in-hospital mortality [RR 0.85; 95% CI (0.77, 0.94);\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.002]. In contrast, for the HC\u202f+\u202fFC vs. HC alone subgroup (addressing incremental benefit), no significant survival advantage was observed in either RCTs (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f553) or N-RCTs (\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f88,666, 28-day mortality RR 0.99,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.79). Regarding safety, HC\u202f+\u202fFC was associated with a higher reinfection rate compared to placebo (RR 1.13,\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.03) but not when compared to HC alone (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f=\u202f0.19). No significant increase in gastrointestinal bleeding or reduction in ICU\/hospital length of stay was identified across all tiers of evidence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Evidence primarily from RCTs indicates that HC\u202f+\u202fFC is associated with improved survival compared to placebo in septic shock. However, large-scale observational data suggest no significant incremental benefit over hydrocortisone alone. While the combination appears safe regarding gastrointestinal bleeding, the increased reinfection risk compared to placebo warrants caution. Given the non-causal nature of observational findings, these results are suggestive rather than definitive. Future head-to-head trials are essential to confirm the marginal efficacy of fludrocortisone supplementation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Systematic review registration<\/jats:title>\n                    <jats:p>\n                      <jats:uri>https:\/\/www.crd.york.ac.uk\/PROSPERO\/view\/CRD420251001999<\/jats:uri>\n                      , Identifier: CRD420251001999\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1755626","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T07:36:58Z","timestamp":1770795418000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Hydrocortisone combined with fludrocortisone for treatment of adults with septic shock: an updated meta-analysis and systematic review"],"prefix":"10.3389","volume":"13","author":[{"given":"Alin","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Weifang People\u2019s Hospital","place":["Weifang, Shandong, China"]},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Weifang People\u2019s Hospital","place":["Weifang, Shandong, China"]},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhipeng","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Weifang People\u2019s Hospital","place":["Weifang, Shandong, China"]},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghai","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Weifang People\u2019s Hospital","place":["Weifang, Shandong, China"]},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenzheng","family":"He","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Weifang People\u2019s Hospital","place":["Weifang, Shandong, China"]},{"name":"Department of Critical Care Medicine, The First Affiliated Hospital of Shandong Second Medical University","place":["Weifang, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1164\/rccm.201504-0781OC","article-title":"Assessment of global incidence and mortality of hospital-treated sepsis. Current estimates and limitations","volume":"193","author":"Fleischmann","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"129","DOI":"10.2478\/rjim-2020-0012","article-title":"Sepsis, a 2020 review for the internist","volume":"58","author":"Purcarea","year":"2020","journal-title":"Rom J Intern Med"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1001\/jama.2016.0289","article-title":"Developing a new definition and assessing new clinical criteria for septic shock: for the third international consensus definitions for sepsis and septic shock (sepsis-3)","volume":"315","author":"Shankar-Hari","year":"2016","journal-title":"JAMA"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1097\/ccm.0000000000000861","article-title":"Predictors of patients who present to the emergency department with sepsis and progress to septic shock between 4 and 48 hours of emergency department 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An updated systematic review with Bayesian network meta-analysis of randomized controlled trials and an observational study with target trial emulation","volume":"52","author":"Lai","year":"2024","journal-title":"Crit Care Med"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"e563","DOI":"10.1002\/ams2.563","article-title":"Hydrocortisone with fludrocortisone for septic shock: a systematic review and meta-analysis","volume":"7","author":"Yamamoto","year":"2020","journal-title":"Acute Med Surg"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/1471-2288-14-135","article-title":"Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range.","volume":"14","author":"Wan","year":"2014","journal-title":"BMC Med Res Methodol"}],"updated-by":[{"DOI":"10.3389\/fmed.2026.1811616","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000}}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1755626\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T14:45:08Z","timestamp":1772462708000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1755626\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":44,"alternative-id":["10.3389\/fmed.2026.1755626"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1755626","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]},"article-number":"1755626"}}