• Pei-Chun Lai, Chao-Han Lai, Edward Chia-Cheng Lai, and Yen-Ta Huang.
• Education Center, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
• Crit. Care Med. 2024 Apr 1; 52 (4): e193e202e193-e202.

ObjectivesThis systematic review and Bayesian network meta-analysis evaluated the efficacy and safety of hydrocortisone combined with fludrocortisone or hydrocortisone alone, compared with placebo in adult patients with septic shock.Data SourcesBy extending a prior Cochrane review, databases, including PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov , along with other relevant websites, were searched until August 31, 2023.Study SelectionRandomized controlled trials (RCTs) and observational studies using target trial emulation were included.Data ExtractionThe primary outcome was short-term mortality with an emphasis on 28- or 30-day mortality as the main measure and in-hospital or ICU mortality as the nearest surrogate of this measure. Three of the most common adverse events, namely, gastroduodenal bleeding, superinfection, and hyperglycemia, were also considered.Data SynthesisA total of 19 studies involving 95,841 patients were included. Hydrocortisone plus fludrocortisone showed the lowest short-term mortality versus placebo (odds ratio [OR]: 0.79; 95% credible interval [CrI], 0.64-0.99; number needed to treat [NNT]: 21, range: 12-500; low certainty of evidence) in terms of informative priors. The surface under the cumulative ranking curve values for hydrocortisone plus fludrocortisone, hydrocortisone alone, and placebo were 0.9469, 0.4542, and 0.0989, respectively. Consistent results were observed in RCTs alone and those using a daily 200-mg dose of hydrocortisone. Although gastroduodenal bleeding or superinfection showed no clear increase, hyperglycemia risk increased. The ORs were 0.53 for placebo versus hydrocortisone plus fludrocortisone and 0.64 for placebo versus hydrocortisone alone, with very low certainty of evidence.ConclusionsIn adults with septic shock, hydrocortisone plus fludrocortisone improved short-term survival with minimal adverse events compared with hydrocortisone alone or placebo. However, these findings are not definitive due to the limited certainty of evidence and wide NNT range. Additional large-scale, placebo-controlled RCTs are needed to provide conclusive evidence.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.

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