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Meta-Analysis
. 2025 Jun 5;6(6):CD002243.
doi: 10.1002/14651858.CD002243.pub5.

Corticosteroids for treating sepsis in children and adults

Djillali Annane  1 , Josef Briegel  2 , David Granton  3 , Eric Bellissant  4 , Pierre Edouard Bollaert  5 , Didier Keh  6 , Yizhak Kupfer  7 , Romain Pirracchio  8 , Bram Rochwerg  9   10
Affiliations
Meta-Analysis

Corticosteroids for treating sepsis in children and adults

Djillali Annane et al. Cochrane Database Syst Rev. .

Abstract

Background: Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. This is an update of a review originally published in 2004 and previously updated in 2010, 2015 and 2019.

Objectives: To examine the benefits and harms of corticosteroids in children and adults with sepsis.

Search methods: We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN and the WHO Clinical Trials Search Portal on 31 December 2023. In addition, we conducted reference checking and citation research, and contacted study authors, to identify additional studies as needed. We updated this search in December 2024, but these results have not yet been incorporated.

Selection criteria: We included randomised controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids.

Data collection and analysis: We used the same methods in comparisons of corticosteroids versus placebo or usual care, and of continuous infusion versus intermittent bolus administration of corticosteroids. The primary outcome was all-cause mortality at 28 days. The most critical secondary outcomes were (i) all-cause mortality in the long term (last follow-up from 90 days to one year) and in the hospital; (ii) length of stay in the intensive care unit and in hospital; (iii) adverse effects, i.e. superinfection and muscle weakness (within 28 days). All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. For this update, we used Covidence software for screening and selection of studies and abstraction of data by paired review authors, with discrepancies resolved by a third review author. We obtained unpublished data from the authors of some trials. We assessed the risk of bias in trials using the Cochrane risk of bias tool (RoB 1) and applied GRADE to assess the certainty of evidence. The review authors did not contribute to the assessment of eligibility or risk of bias, nor to data extraction, for the trials they had participated in.

Main results: We included 87 trials (24,336 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Seventeen additional trials are ongoing and will be considered in future versions of this review. We judged 25 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably reduce 28-day mortality (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.84 to 0.95; 72 trials, 22,915 participants; moderate-certainty evidence). We downgraded the certainty of evidence for this outcome from high to moderate for inconsistency (significant heterogeneity across trial results). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 12 trials, 8468 participants; low-certainty evidence) and probably reduce in-hospital mortality (RR 0.90, 95% CI 0.84 to 0.97; 40 trials, 17,459 participants; moderate-certainty evidence). Corticosteroids may reduce length of intensive care unit (ICU) stay for all participants (mean difference (MD) -0.86 days, 95% CI -1.67 to -0.05; 25 trials, 8069 participants; low-certainty evidence) and may reduce length of hospital stay for all participants (MD -1.09 days, 95% CI -1.85 to -0.34; 31 trials, 16,954 participants; low-certainty evidence). The evidence is uncertain about the effect of corticosteroids on the risk of muscle weakness (RR 1.09, 95% CI 0.78 to 1.53; 7 trials, 6729 participants; very low-certainty evidence). Corticosteroids may result in little to no difference in the risk of superinfection (RR 0.96, 95% CI 0.86 to 1.07; 36 trials, 7961 participants; low-certainty evidence). Continuous infusion of corticosteroids versus intermittent bolus Four trials reported data for this comparison, and the certainty of evidence for all outcomes was very low. We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration on 28-day mortality (RR 1.03, 95% CI 0.81 to 1.32; 3 trials, 310 participants). We downgraded the certainty of evidence to very low due to high risk of bias in all except one trial and due to imprecision. Compared to bolus administration, we are uncertain of the effects of continuous infusion of corticosteroids on long-term mortality (RR 1.36, 95% CI 1.02 to 1.81; 1 trial, 70 participants; very low-certainty evidence), in-hospital mortality (RR 0.92, 95% CI 0.71 to 1.19; 3 trials, 352 participants; very low-certainty evidence), ICU length of stay amongst all participants (MD -0.56 days, 95% CI -3.44 to 2.32; 4 trials, 422 participants; very low-certainty evidence), hospital length of stay amongst all participants (MD -0.21 days, 95% CI -4.72 to 4.30; 4 trials, 422 participants; very low-certainty evidence), risk of muscle weakness (RR 0.89, 95% CI 0.13 to 5.98; 1 trial, 70 participants; very low-certainty evidence) and risk of superinfection (RR 1.12, 95% CI 0.37 to 3.33; 2 trials, 193 participants; very low-certainty evidence).

Authors' conclusions: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day, 90-day and hospital mortality amongst patients with sepsis. Corticosteroids may shorten ICU and hospital length of stay (low-certainty evidence). There may be little or no difference in the risk of superinfection. The risk of muscle weakness is uncertain. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.

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Conflict of interest statement

Djillali Annane is the author of the following studies included in this review: Aboab 2008; Annane 2002; Annane 2010; Annane 2018; Sprung 2008. He obtained funds from the French Ministry of Health to conduct the following trials: Annane 2002; Annane 2010; Annane 2018. He has been the chair of the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency. He is a member of the Cochrane Neuromuscular review group editorial board, but had no role in the editorial processing of this review.

Eric Bellissant is the author of the following studies included in this review: Annane 2002; Annane 2018.

Pierre Edouard Bollaert (author deceased) is the author of the following studies included in this review: Annane 2002; Bollaert 1998. He obtained public funds from the University of Nancy to conduct the trial Bollaert 1998. No declaration of interest form available.

Josef Briegel is the author of the following studies included in this review: Briegel 1999; Keh 2016; Sprung 2008. He obtained public funds to conduct the trial Briegel 1999. He contributed to the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency. He has participated in the European Society of Intensive Care Medicine, the Deutsche Interdisziplinäre Vereinigung Intensivmedizin, and the Deutsche Gesellschaft für Anästhesie und Intensivmedizin, and he has given lectures and talks on hydrocortisone treatment for septic shock.

David Granton reports no conflicts of interest.

Didier Keh is the author of the following studies included in this review: Keh 2003; Keh 2016; Sprung 2008. He obtained public funds from Charité‐Universitätsmedizin Berlin and from the German Federal Ministry of Education and Research to conduct the following trials: Keh 2003; Keh 2016.

Yizhak Kupfer is the author of the following study included in this review: Chawla 1999. He is a member of the Pfizer/BMS speakers' bureau for epixaban. This product has no relationship to steroids in sepsis. He obtained funds from his institution to conduct the trial Chawla 1999.

Romain Pirracchio received funding for International Mobility from the Fulbright Foundation and from the Assistance Publique – Hôpitaux de Paris (APHP). He contributed to the following study: Pirracchio 2023.

Bram Rochwerg is supported by McMaster University Department of Medicine early career research awards. He has contributed to the international task force for elaborating 2017 guidelines for the diagnosis and treatment of critical illness‐related corticosteroid insufficiency. He is a methodologist for the American Thoracic Society, European Society of Intensive Care Medicine and the American Society of Haematology.

Update of

References

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Ngaosuwan 2018 {published data only}
    1. Ngaosuwan K, Ounchokdee K, Chalermchai T. Clinical outcomes of minimized hydrocortisone dosage of 100mg/day on lower occurrence of hyperglycaemia in septic shock. Shock 2018;50(3):280-5. [PMID: ] - PubMed
Oppert 2005 {published and unpublished data}
    1. Oppert M, Schindler R, Husung C, Offerman K, Graef KJ, Boenisch O, et al. Low-dose hydrocortisone improves shock reversal and reduces cytokine levels in early hyperdynamic septic shock. Critical Care Medicine 2005;33(11):2457-64. [PMID: ] - PubMed
Pierre de Oliveira 2023 {published data only}
    1. Methylpredniprednisolone on ICU patients with COVID-19 on mechanical ventilation. Brazilian Registry of Clinical Trials 2023. [BRCT: RBR-58q5y2m]
    1. Pierre de Oliveira E, Marconi de Sousa J, Jaoude CVG, Malacize VQ, Lobato LC et al. Methylprednisolone on ICU patients with COVID-19 on mechanical ventilation. Journal of Community Medicine and Public Health 2023;7:369. [DOI: 10.29011/2577-2228.100369] - DOI
Ram 2022 {published data only}
    1. Ram GK, Shekhar S, Singh RB, Anand R, De RR, Kumar N. Hyperglycemia risk evaluation of hydrocortisone intermittent boluses versus continuous infusion in septic shock: a prospective randomized trial. Anesthesia Essays and Researchers 2022;16(3):321‐5. [DOI: 10.4103/aer.aer_115_22] - DOI - PMC - PubMed
Rezk 2013 {published data only}
    1. Rezk NA, Ibrahim AM. Effects of methylprednisolone in early ARDS. Egyptian Journal of Chest Diseases and Tuberculosis 2013;62(1):167-72. [DOI: 10.1016/j.ejcdt.2013.02.013] - DOI
Rinaldi 2006 {published data only}
    1. Rinaldi S, Adembri C, Grechi S, DeGaudio R. Low-dose hydrocortisone during severe sepsis: effects on microalbuminemia. Critical Care Medicine 2006;34(9):2334-9. [PMID: ] - PubMed
Sabry 2011 {published data only}
    1. Sabry NA, El-Din Omar E. Corticosteroids and ICU course of community acquired pneumonia in Egyptian settings. Pharmacology and Pharmacy 2011;2:73-81.
Sai 2021 {published data only}
    1. Sai TA, Satyanarayana PVS, Gollapudi S. Effect of treatment with low-dose corticosteroids on mortality in patients with severe sepsis and septic shock. JP Journals 2021;25(Suppl 1):S104‐5. [DOI: 10.5005/jp-journals-10071-23711.183] - DOI
Schumer 1976 {published data only}
    1. Schumer W. Steroids in the treatment of clinical septic shock. Annals of Surgery 1976;184(3):333-41. [PMID: ] - PMC - PubMed
Sevransky 2021 {published data only}
    1. NCT03509350. Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) [A multi-center, randomized, placebo-controlled, double-blind, adaptive clinical trial of vitamin C, thiamine and steroids as combination therapy in patients with sepsis]. https://clinicaltrials.gov/ct2/show/NCT03509350 (first received 26 April 2018).
    1. Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, 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. [DOI: 10.1001/jama.2020.24505] - DOI - PMC - PubMed
    1. Williams Roberson S, Nwosu S, Collar EM, Kiehl AL, Harrison FE, Bastarache J, et al. Association of vitamin C, thiamine, and hydrocortisone infusion with long-term cognitive, psychological, and functional outcomes in sepsis survivors: a secondary analysis of the vitamin C, thiamine, and steroids in sepsis randomized clinical trial. Journal of the American Medical Association Network Open 2023;6:e2312173. [DOI: 10.1001/jamanetworkopen] - DOI - PMC - PubMed
Slusher 1996 {published data only}
    1. Slusher T, Gbadero D, Howard C, Lewinson L, Giroir B, Toro L, et al. Randomized, placebo-controlled, double blinded trial of dexamethasone in African children with sepsis. Pediatric Infectious Diseases Journal 1996;15(7):579-83. [PMID: ] - PubMed
Snijders 2010 {published data only}
    1. Snijders D, Daniels JMA, Graaff CS, Werf TS, Boersma WG. Efficacy of corticosteroids in community-acquired pneumonia – a randomized double blinded clinical trial. American Journal of Respiratory and Critical Care Medicine 2010;181(9):975-82. [PMID: ] - PubMed
Sprung 1984 {published and unpublished data}
    1. Sprung CL, Caralis PV, Marcial EH, Pierce M, Gelbard MA, Long WM, et al. The effects of high-dose corticosteroids in patients with septic shock. A prospective, controlled study. New England Journal of Medicine 1984;311(18):1137-43. [PMID: ] - PubMed
Sprung 2008 {published and unpublished data}
    1. Sprung C, Annane D, Keh D, Moreno R, Singer M, Freivogel K, et al. Hydrocortisone therapy for patients with septic shock. New England Journal of Medicine 2008;358(2):111-24. [PMID: ] - PubMed
Sui 2013 {published data only}
    1. Sui DJ, Zhang W, Li WS, Zhao HX, Wang ZY. Clinical efficacy in the treatment of severe community acquired pneumonia and its impact on CRP. Chinese Journal of Integrative Medicine 2013;18:1171-3.
Tagaro 2017 {published data only}
    1. Tagaro A, Otheo E, Baquero-Artigao F, Navarro ML, Velasco R, Ruiz M, et al. Dexamethasone for parapneumonic pleural effusion: a randomized, double-blind, clinical trial. Journal of Pediatrics 2017;185:117-23. [PMID: ] - PubMed
Tandan 2005 {unpublished data only}
    1. Tandan SM, Guleria R, Gupta N. Low dose steroids and adrenocortical insufficiency in septic shock: a double-blind randomised controlled trial from India. In: Proceedings of the American Thoracic Society Meeting. 2005:A24.
Tilouche 2019 {published and unpublished data}
    1. Tilouche N, Jaoued O, Ben Sik Ali H, Gharbi R, Fekih Hassen M, Elatrous S. Comparison between continuous and intermittent administration of hydrocortisone during septic shock: a randomized controlled clinical trial. Shock 2019;52:481-6. [DOI: 10.1097/SHK.0000000000001316] [PMID: ] - DOI - PubMed
Tomazini 2020 {published data only}
    1. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al. Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial. JAMA 2020;324(13):1307‐16. [DOI: 10.1001/jama.2020.17021] - DOI - PMC - PubMed
Tongyoo 2016 {published and unpublished data}
    1. Tongyoo S, Permpikul C, Mongkolpun W, Vattanavanit V, Udompanturak S, Kocak M, et al. Hydrocortisone treatment in early sepsis associated acute respiratory distress syndrome: results of a randomized controlled trial. Critical Care 2016;20(1):329. [PMID: ] - PMC - PubMed
Torres 2015 {published and unpublished data}
    1. Torres A, Sibila O, Ferrer M, Polverino E, Menendez R, Mensa J, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015;313(7):677-86. [PMID: ] - PubMed
Valoor 2009 {published data only}
    1. Valoor HT, Singhi S, Jayashree M. Low-dose hydrocortisone in paediatric septic shock: an exploratory study in a third world setting. Pediatric Critical Care Medicine 2009;10(1):121-5. [PMID: ] - PubMed
VASSCSG 1987 {published data only}
    1. Veterans Administration Systemic Sepsis Cooperative Study Group. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. New England Journal of Medicine 1987;317(11):659-65. [PMID: ] - PubMed
Venkatesh 2018 {published data only (unpublished sought but not used)}
    1. Venkatesh B, Finfer S, Cohen J, Rajbhandari D, Arabi Y, Bellomo R, et al. Adjunctive glucocorticoid therapy in patients with septic shock. New England Journal of Medicine 2018;378:797-808. [DOI: 10.1056/NEJMoa1705835] [PMID: ] - DOI - PubMed
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Villar 2020 {published and unpublished data}
    1. Villar J, Ferrando C, Martínez D, Ambrós A, Muñoz T, Soler JA, et al. Dexamethasone treatment for the acute respiratory distress syndrome: a multicentre, randomised controlled trial. Lancet Respiratory Medicine 2020;8(3):267‐76. [DOI: 10.1016/S2213-2600(19)30417-5] - DOI - PubMed
Wani 2020 {published data only}
    1. Wani SJ, Mufti SA, Jan RA, Shah SU, Qadri SM, Khan UH, et al. Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomised controlled clinical trial and a review of the literature. Infectious Diseases 2020;52(4):271‐78. [DOI: 10.1080/23744235.2020.1718200] - DOI - PubMed
Wittermans 2021 {published data only}
    1. Wittermans E, Vestjens S, Spoorenberg S, Blok W, Grutters J, Janssen R, et al. Late breaking abstract - adjunctive treatment with oral dexamethasone in adults hospitalised with community-acquired pneumonia: a randomised clinical trial. European Respiratory Journal 2020;56:4132. [DOI: 10.1183/13993003.congress-2020] - DOI - PubMed
    1. Wittermans E, Vestjens SMT, Spoorenberg SMC, Blok WL, Grutters JC, Janssen R, et al. Adjunctive treatment with oral dexamethasone in non-ICU patients hospitalised with community-acquired pneumonia: a randomised clinical trial. European Respiratory Journal 2021;58(2):2002535. [DOI: 10.1183/13993003.02535-2020] - DOI - PubMed
Yildiz 2002 {published data only}
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Yildiz 2011 {published data only}
    1. Yildiz O, Tanriverdi F, Simsek S, Aygen B, Kelestimur F. The effects of moderate-dose steroid therapy in sepsis: a placebo-controlled, randomized study. Journal of Research in Medical Sciences 2011;16(11):1410-21. [PMID: ] - PMC - PubMed
Zhou 2015 {published data only}
    1. Zhou M. Application value of glucocorticoid for comprehensive treatment of acute respiratory distress syndrome induced by serious community acquired pneumonia. Clinical Medicine and Engineering 2015;22:57-8. [DOI: 10.3969/j.issn.1674-4659.2015.01.0057] - DOI

References to studies excluded from this review

ACTRN12621000247875 2021 {published data only}
    1. Assessing the efficacy of treatment with vitamin C, vitamin B1 and hydrocortisone in children admitted in intensive care unit with septic shock. Australian New Zealand Clinical Trials Registry 2021. [ANZCTR: ACTRN12621000247875]
Asehnoune 2014 {published data only}
    1. Asehnoune K, Seguin P, Allary J, Feuillet F, Lasocki S, Cook F, et al. Hydrocortisone and fludrocortisone for prevention of hospital-acquired pneumonia in patients with severe traumatic brain injury (Corti-TC): a double-blind, multicentre phase 3, randomised placebo-controlled trial. Lancet. Respiratory Medicine 2014;2:706-16. [PMID: ] - PubMed
Bernard 1987 {published data only}
    1. Bernard GR, Luce JM, Sprung CL, Rinaldo JE, Tate RM, Sibbald WJ, et al. High-dose corticosteroids in patients with the adult respiratory distress syndrome. New England Journal of Medicine 1987;317:1565-70. [PMID: ] - PubMed
Cicarelli 2006 {published data only}
    1. Cicarelli DD, Bensenor FEM, Vieira JE. Effects of single dose of dexamethasone on patients with systemic inflammatory response. São Paulo Medical Journal 2006;124(2):90-5. [PMID: ] - PMC - PubMed
CTRI/2021/11/038268 2021 {published data only}
    1. To compare the results of two treatment protocol (standard treatment plus vitamin C, thiamine and hydrocortisone versus standard treatment plus hydrocortisone) used in surgical patients with septic shock (A/K/A Infection in the body presenting with low blood pressure. Chinese Clinical Trials Registry 2021. [CHICTR: CTRI/2021/11/038268]
Fan 2019 {published data only}
    1. Fan K, Ronaghi R, Rees J, Baghdasaryan P, Tang J, Lee M, et al. The effect of using vitamin C, hydrocortisone, and thiamine triple therapy in the treatment of septic shock. Chest 2019;156(4):A944. [DOI: 10.1016/j.chest.2019.08.874] - DOI
Fujii 2020 {published data only}
    1. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA 2020;323(5):423‐31. [DOI: 10.1001/jama.2019.22176] - DOI - PMC - PubMed
    1. NCT03333278. The vitamin C, hydrocortisone and thiamine in patients with septic shock trial (VITAMINS) [The vitamin C, hydrocortisone and thiamine in patients with septic shock trial (VITAMINS Trial) - a prospective, feasibility, pilot, multi-centre, randomised, open-label controlled trial]. https://clinicaltrials.gov/ct2/show/NCT03333278 (first received 6 November 2017).
Hahn 1951 {published data only}
    1. Hahn EO, Houser HB, Rammelkamp CH, Denny FW, Wannamaker LW. Effect of cortisone on acute streptococcal infections and post-streptococcal complications. Journal of Clinical Investigation 1951;30:274-81. - PMC - PubMed
Huang 2014a {published data only}
    1. Huang L, Gao X, Chen M. Early treatment with corticosteroids in patients with mycoplasma pneumoniae pneumonia: a randomized clinical trial. Journal of Tropical Pediatrics 2014;64:338-42. [PMID: ] - PubMed
Huang 2015 {published data only}
    1. Huang G, Liang B, Liu G, Liu K, Ding Z. Low dose of glucocorticoid decreases the incidence of complications in severely burned patients by attenuating systemic inflammation. Journal of Critical Care 2015;436:436.e7-11. - PubMed
Hughes 1984 {published data only}
    1. Hughes GS Jr. Naloxone and methylprednisolone sodium succinate enhance sympathomedullary discharge in patients with septic shock. Life Sciences 1984;35(23):2319-26. [PMID: ] - PubMed
Hussein 2021 {published data only}
    1. Hussein AA, Sabry NA, Abdalla MS, Farid SF. A prospective, randomised clinical study comparing triple therapy regimen to hydrocortisone monotherapy in reducing mortality in septic shock patients. International Journal of Clinical Practice 2021;75(9):e14376. [DOI: 10.1111/ijcp.14376] - DOI - PubMed
Kaufman 2008 {published and unpublished data}
    1. Kaufmann I, Briegel J, Schliephake F, Hoelzl A, Chouker A, Hummel T, et al. Stress doses of hydrocortisone in septic shock: beneficial effects on opsonization-dependent neutrophil functions. Intensive Care Medicine 2008;34(2):344-9. [PMID: ] - PubMed
Khan 2021 {published data only}
    1. Khan Z, Khan MH, Hussain S, Badshah J, Uddin R, Kashif M. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. Pakistan Journal of Medical and Health Sciences 2021;15(8):2522‐4. [DOI: 10.53350/pjmhs211582522] - DOI
Klastersky 1971 {published data only}
    1. Klastersky J, Cappel R, Debusscher L. Effectiveness of betamethasone in management of severe infections. A double-blind study. New England Journal of Medicine 1971;284(22):1248-50. [PMID: ] - PubMed
Lan 2015 {published data only}
    1. Lan Y, Yang D, Chen Z, Tang L, Xu Y, Cheng Y. Effectiveness of methylprednisolone in treatment of children with refractory mycoplasma pneumoniae pneumonia and its relationship with bronchoalveolar lavage cytokine levels. Zhonghua Er Ke Za Zhi 2015;53:779-83. - PubMed
Lloyd 2019 {published data only}
    1. Lloyd M, Karahalios A, Janus E, Skinner EH, Haines T, De Silva A, et al. Effectiveness of a bundled intervention including adjunctive corticosteroids on outcomes of hospitalized patients with community-acquired pneumonia: a stepped-wedge randomized clinical trial. Journal of the American Medical Association Internal Medicine 2019;179(8):1052‐60. [DOI: 10.1001/jamainternmed.2019.1438] - DOI - PMC - PubMed
Lucas 1984 {published data only}
    1. Lucas C, Ledgerwood A. The cardiopulmonary response to massive doses of steroids in patients with septic shock. Archives of Surgery 1984;119(5):537-41. [PMID: ] - PubMed
Luo 2014 {published data only}
    1. Luo Z, Luo J, Liu E, Xu X, Liu Y, Zeng F, et al. Effects of prednisolone on refractory mycoplasma pneumoniae pneumonia in children. Pediatric Pulmonology 2014;49:377-80. [PMID: ] - PubMed
Malaska 2022 {published data only}
    1. Malaska J, Stasek J, Duska F, Maca J, Hruda J, Klementova O, et al. Effect of dexamethasone in patients with ARDS and COVID-19 (REMED Trial) - prospective, multi-centre, open-label, parallel-group, randomized controlled trial. Trials 2022;10:35. [DOI: 10.1186/s40635-022-00468-1] - DOI - PMC - PubMed
Marik 1993 {published data only}
    1. Marik P, Kraus P, Sribante J, Havlik I, Lipman J, Johnson DW. Hydrocortisone and tumour necrosis factor in severe community-acquired pneumonia. A randomized controlled study. Chest 1993;104:389-92. [PMID: ] - PubMed
McKee 1983 {published data only}
    1. McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1983;1(8322):484. [PMID: ] - PubMed
Meduri 1998b {published and unpublished data}
    1. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, et al. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA 1998;280(2):159-65. [PMID: ] - PubMed
Mikami 2007 {published data only}
    1. Mikami K, Suzuki M, Kitagawa H, Kawakami M, Hirota N, Yamaguchi H, et al. Efficacy of corticosteroids in the treatment of community-acquired pneumonia requiring hospitalization. Lung 2007;185(5):249-55. [PMID: ] - PubMed
Munch 2021 {published data only}
    1. Munch MW, Meyhoff TS, Helleberg M, Kjaer MN, Granholm A, Hjortsø CJS, et al. Low-dose hydrocortisone in patients with COVID-19 and severe hypoxia: the COVID STEROID randomised, placebo-controlled trial. Acta Anaesthesiology Scandinavia 2021;65:1421-30. [DOI: 10.1111/aas.13941] - DOI - PMC - PubMed
NCT02602210 2015 {published data only}
    1. NCT02602210. Supplemental corticosteroids in cirrhotic hypotensive patients with suspicion of sepsis (SCOTCH). https://clinicaltrials.gov/ct2/show/NCT02602210 (first received 11 November 2015).
NCT03335124 2017 {published data only}
    1. NCT03335124. The effect of vitamin C, thiamine and hydrocortisone on clinical course and outcome in patients with severe sepsis and septic shock [A randomized, double blind, placebo-controlled study to investigate the effects of vitamin C, hydrocortisone and thiamine on the outcome of patients with severe sepsis and septic shock]. https://clinicaltrials.gov/ct2/show/NCT03335124 (first received 7 November 2017).
NCT03828929 2019 {published data only}
    1. Effect of IV vitamin C, thiamine, and steroids on mortality of septic shock. ClinicalTrials.gov 2019. [NCT: NCT03828929]
NCT04134403 2019 {published data only}
    1. Steroids, thiamine and ascorbic acid in septic shock. ClinicalTrials.gov 2019. [NCT: NCT04134403]
Newberry 2017 {published data only}
    1. Newberry L, O'Hare B, Kennedy N, Selman A, Omar S, Dawson P, et al. Early use of corticosteroids in infants with a clinical diagnosis of pneumocystis Jiroveci pneumonia in Malawi: a double-blind, randomised clinical trial. Paediatric International Child Health 2017;37:121-8. - PubMed
Peeters 2018 {published data only}
    1. Peeters B, Meersseman P, Vander Perre S, Wouters PJ, Debaveye Y, Langouche L, et al. ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study. Intensive Care Medicine 2018;44:2048-58. - PMC - PubMed
Raghu 2021 {published data only}
    1. Raghu K, Ramalingam K. Safety and efficacy of vitamin C, vitamin B1, and hydrocortisone in clinical outcome of septic shock receiving standard care: a quasi experimental randomized open label two arm parallel group study. European Journal of Molecular and Clinical Medicine 2021;8(2):873‐91.
Rogers 1970 {published data only}
    1. Rogers J. Large doses of steroids in septicaemic shock. British Journal of Urology 1970;42(6):742. [PMID: ] - PubMed
Roquilly 2011 {published data only}
    1. Roquilly A, Mahe PJ, Seguin P, Guitton C, Floch H, Tellier AC, et al. Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study. JAMA 2011;305:1201-9. [PMID: ] - PubMed
Schwingshackl 2016 {published data only}
    1. Schwingshackl A, Kimura D, Rovnaghi CR, Saravia JS, Cormier SA, Teng B, et al. Regulation of inflammatory biomarkers by intravenous methylprednisolone in pediatric ARDS patients: results from a double-blind, placebo-controlled randomized pilot trial. Cytokine 2016;77:63-71. [PMID: ] - PMC - PubMed
Steinberg 2006 {published data only}
    1. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, Hyzy R, et al. Efficacy and safety of corticosteroids for persistent acute respiratory distress syndrome. New England Journal of Medicine 2006;354:1671-84. [PMID: ] - PubMed
Tam 2012 {published data only}
    1. Tam DT, Ngoc TV, Tien NT, Kieu NT, Thuy TT, Thanh LT, et al. Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: a randomized, placebo-controlled trial. Clinical Infectious Disease 2012;55(9):1216-24. [PMID: ] - PMC - PubMed
Thompson 1976 {published data only}
    1. Thompson WL, Gurley HT, Lutz BA, Jackson DL, Kvols LK, Morris IA. Inefficacy of glucocorticoids in shock (double-blind study). Clinical Research 1976;24:258A.
van Woensel 2003 {published data only}
    1. Woensel JB, Aalderen WM, Weerd W, Jansen NJ, Gestel JP, Markhorst DG, et al. Dexamethasone for treatment of patients mechanically ventilated for lower respiratory tract infection caused by respiratory syncytial virus. Thorax 2003;58(5):383-7. [PMID: ] - PMC - PubMed
Venet 2015 {published data only}
    1. Venet F, Plassais J, Textoris J, Cazalis MA, Pachot A, Bertin-Maghit M, et al. Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial. Critical Care 2015;19:21. [PMID: ] - PMC - PubMed
Wagner 1955 {published data only}
    1. Wagner HN, Bennett IL, Lasagna L, Cluff LE, Rosenthal MB, Mirick GS. The effect of hydrocortisone upon the course of pneumococcal pneumonia treated with penicillin. Bulletin of Johns Hopkins Hospital 1955;98(3):197-215. [PMID: ] - PubMed
Weigelt 1985 {published data only}
    1. Weigelt JA, Norcross JF, Borman KR, Snyder WH 3rd. Early steroid therapy for respiratory failure. Archives of Surgery 1985;120(5):536-40. [PMID: ] - PubMed
Xi 2021 {published data only}
    1. Xi P, Zhou Y, Li X-F, Chen Y-J, Peng Y-H, Liu Y. Methylprednisolone prevents urosepsis in high-risk patients undergoing percutaneous nephrolithotomy: a randomized controlled trial. Academic Journal of Second Military Medical University 2021;42(1):21‐7. [DOI: 10.16781/j.0258-879x.2021.01.0021] - DOI

References to studies awaiting assessment

Corral Gudino 2023 {published data only}
    1. Corral‐Gudino L, Cusacovich I, Martín‐González JI, Muela‐Molinero A, Abadía‐Otero J, González‐Fuentes R, et al. Effect of intravenous pulses of methylprednisolone 250 mg versus dexamethasone 6 mg in hospitalised adults with severe COVID-19 pneumonia: an open- label randomized trial. European Journal of Clinical Investigation 2023;53:e13881. [DOI: 10.1111/eci.13881] - DOI - PMC - PubMed
Franco‐Moreno 2024 {published data only}
    1. Franco‐Moreno A, Acedo‐Gutierrez MS, Casado‐Suela MA, Labrador‐San Martin N, Carranza‐Lopez M, Ibanez‐Estellez F, et al. Effect of early administration of dexamethasone in patients with COVID-19 pneumonia without acute hypoxemic respiratory failure and risk of development of acute respiratory distress syndrome: EARLY-DEX COVID-19 trial. Frontiers in Medicine 2024;11:1385833. [DOI: 10.3389/fmed.2024.1385833] - DOI - PMC - PubMed
Laikitmongkhon 2024 {published data only}
    1. Laikitmongkhon J, Tassaneyasin T, Sutherasan Y, Phuphuakrat A, Srichatrapimuk S, Petnak T, et al. A comparative study between methylprednisolone versus dexamethasone as an initial anti-inflammatory treatment of moderate COVID-19 pneumonia: an open-label randomized controlled trial. BMC Pulmonary Medicine 2024;24:562. [DOI: 10.1186/s12890-024-03364-4] - DOI - PMC - PubMed
Mohanty 2024 {published data only}
    1. Mohanty R, Das DK, Sahu SK, Mallik B, Sahu RK. Effect of corticosteroid supplementation on adrenal suppression and survival in patients with sepsis. Journal of Cardiovascular Disease Research 2024;15(5):310‐8. [DOI: 10.48047/jcdr.2024.15.05.36] - DOI
Sahraei 2023 {published data only}
    1. Sahraei Z, Panahi P, Solhjoukhah K, Mesbah M, Afaghi S, Amirdosara M, et al. The efficacy of high-dose pulse therapy vs. low-dose intravenous methylprednisolone on severe to critical COVID-19 clinical outcomes: a randomized clinical trial. Iranian Journal of Pharmaceutical Research 2023;22:e137838. [DOI: 10.5812/ijpr-137838] - DOI - PMC - PubMed
Salhotra 2024 {published data only}
    1. Salhotra R, Sharahudeen A, Tyagi A, Rautela RS, Kemprai R. Effect of continuous infusion vs bolus dose of hydrocortisone in septic shock: a prospective randomized study. Indian Journal of Critical Care Medicine 2024;28:837-41. [DOI: ] - PMC - PubMed
Salton 2023 {published data only}
    1. Salton F, Confalonieri P, Centanni S, Mondoni M, Petrosillo N, Bonfanti P, et al. Prolonged higher dose methylprednisolone versus conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS). European Respiratory Journal 2023;61:2201514. [DOI: 10.1183/13993003.01514-2022] - DOI - PMC - PubMed
Schlapbach 2024 {published data only}
    1. Schlapbach LJ, Raman S, Buckley D, George S, King M, Ridolfi R, et al. Resuscitation with vitamin C, hydrocortisone, and thiamin in children with septic shock: a multicenter randomized pilot study. Paediatric Critical Care Medicine 2024;25:159-70. [DOI: 10.1097/PCC.0000000000003346] - DOI - PMC - PubMed
Sharma 2024 {published data only}
    1. Sharma S, Paneru HR, Shrestha GS, Shrestha PS, Acharya SP. Evaluation of the effects of a combination of vitamin C, thiamine and hydrocortisone vs hydrocortisone alone on ICU outcome in patients with septic shock: a randomized controlled trial. Indian Journal of Critical Care Medicine 2024;28(12):1147‐52. - PMC - PubMed
Taher 2023 {published data only}
    1. Taher A, Lashkari M, Keramat F, Hashemi SH, Sedighi L, Poorolajal J, et al. Comparison of the efficacy of equivalent doses of dexamethasone, methylprednisolone, and hydrocortisone for treatment of COVID-19-related acute respiratory distress syndrome: a prospective three-arm randomized clinical trial. Wiener Medizinische Wochenschrift 2023;173:140-51. [DOI: 10.1007/s10354-022-00993-4] - DOI - PMC - PubMed
Walsham 2024 {published data only}
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