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Meta-Analysis
. 2019 Dec 6;12(12):CD002243.
doi: 10.1002/14651858.CD002243.pub4.

Corticosteroids for treating sepsis in children and adults

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

Corticosteroids for treating sepsis in children and adults

Djillali Annane et al. Cochrane Database Syst Rev. .

Update in

  • Corticosteroids for treating sepsis in children and adults.
    Annane D, Briegel J, Granton D, Bellissant E, Bollaert PE, Keh D, Kupfer Y, Pirracchio R, Rochwerg B. Annane D, et al. Cochrane Database Syst Rev. 2025 Jun 5;6(6):CD002243. doi: 10.1002/14651858.CD002243.pub5. Cochrane Database Syst Rev. 2025. PMID: 40470636

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. The original review was published in 2004 and was updated in 2010 and 2015 prior to this update.

Objectives: To examine the effects of corticosteroids on death 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 25 July 2019. In addition, we conducted reference checking and citation searching, and contacted study authors, to identify additional studies as needed.

Selection criteria: We included randomized 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: 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. We obtained unpublished data from the authors of some trials. We assessed the methodological quality of trials and applied GRADE to assess the certainty of evidence. Review authors did not contribute to assessment of eligibility and risk of bias, nor to data extraction, for trials they had participated in.

Main results: We included 61 trials (12,192 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Nine studies are ongoing and will be considered in future versions of this review. We judged 19 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably slightly reduce 28-day mortality (risk ratio (RR) 0.91, 95% confidence interval (CI) 0.84 to 0.99; 11,233 participants; 50 studies; moderate-certainty evidence). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 6236 participants; 7 studies; low-certainty evidence) and probably slightly reduce hospital mortality (RR 0.90, 95% CI 0.82 to 0.99; 8183 participants; 26 trials; moderate-certainty evidence). Corticosteroids reduced length of intensive care unit (ICU) stay for all participants (mean difference (MD) -1.07 days, 95% CI -1.95 to -0.19; 7612 participants; 21 studies; high-certainty evidence) and resulted in a large reduction in length of hospital stay for all participants (MD -1.63 days, 95% CI -2.93 to -0.33; 8795 participants; 22 studies; high-certainty evidence). Corticosteroids increase the risk of muscle weakness (RR 1.21, 95% CI 1.01 to 1.44; 6145 participants; 6 studies; high-certainty evidence). Corticosteroids probably do not increase the risk of superinfection (RR 1.06, 95% CI 0.95 to 1.19; 5356 participants; 25 studies; moderate-certainty evidence). Corticosteroids increase the risk of hypernatraemia (high-certainty evidence) and probably increase the risk of hyperglycaemia (moderate-certainty evidence). Moderate-certainty evidence shows that there is probably little or no difference in gastroduodenal bleeding, stroke, or cardiac events, and low-certainty evidence suggests that corticosteroids may result in little to no difference in neuropsychiatric events. Continuous infusion of corticosteroids versus intermittent bolus We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration. Three studies reported data for this comparison, and the certainty of evidence for all outcomes was very low.

Authors' conclusions: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day and hospital mortality among patients with sepsis. Corticosteroids result in large reductions in ICU and hospital length of stay (high-certainty evidence). There may be little or no difference in the risk of major complications; however, corticosteroids increase the risk of muscle weakness and hypernatraemia, and probably increase the risk of hyperglycaemia. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.

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Conflict of interest statement

Djillali Annane is an 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 Minisitry of Health to conduct the following trials: Annane 2002; Annane 2010; and 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.

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

Pierre Edouard Bollaert is an 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).

Josef Briegel is an 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 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.

Didier Keh is an 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 an author of the following studies 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).

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 American Thoracic Society, European Society of Intensive Care Medicine, and American Society of Haematology.

Figures

1
1
Study flow diagram.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Figure represents the results from meta‐regression of log of risk ratio of dying and the dose of corticosteroids given at day 1 and expressed as equivalent milligrams of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model. Meta‐regression included 53 trials. REML estimate of between‐study variance: tau² = .008551.
 % residual variation due to heterogeneity: I² res = 28.86%.
 Proportion of between‐study variance explained: Adj R² = 43.76%.
4
4
Figure represents results from meta‐regression of log of risk ratio of dying and log of cumulated dose of corticosteroids expressed as equivalent milligrams of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model. Meta‐regression included 53 trials. REML estimate of between‐study variance: tau² = .008628.
 % residual variation due to heterogeneity: I² res = 28.68%.
 Proportion of between‐study variance explained: Adj R² = 43.25%.
5
5
Meta‐regression of the log of the risk ratio for 28‐day mortality against actual mortality at 28 days in the control arm.
6
6
Funnel plot of comparison: 1 Steroids vs control, outcome: 1.1 28‐Day all‐cause mortality.
7
7
Contour‐enhanced funnel plot. Log of risk ratio for 28‐day mortality is plotted against its standard error.
1.1
1.1. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 1 28‐Day all‐cause mortality.
1.2
1.2. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 2 28‐Day all‐cause mortality ‐ sensitivity analysis based on methodological quality.
1.3
1.3. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 3 28‐Day all‐cause mortality by subgroups based on study drug.
1.4
1.4. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 4 28‐Day all‐cause mortality by subgroups based on treatment dose/duration.
1.5
1.5. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 5 28‐Day all‐cause mortality based on mode of drug administration.
1.6
1.6. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 6 28‐Day all‐cause mortality based on mode of drug termination.
1.7
1.7. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 7 28‐Day all‐cause mortality by subgroups based on age.
1.8
1.8. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 8 28‐Day all‐cause mortality by subgroups based on targeted population.
1.9
1.9. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 9 28‐Day mortality in participants with critical illness‐related corticosteroid insufficiency.
1.10
1.10. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 10 90‐Day all‐cause mortality.
1.11
1.11. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 11 Long‐term mortality.
1.12
1.12. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 12 Intensive care unit mortality.
1.13
1.13. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 13 Hospital mortality.
1.14
1.14. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 14 Number of participants with shock reversal at day 7.
1.15
1.15. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 15 Number of participants with shock reversal at 28 days.
1.16
1.16. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 16 SOFA score at day 7.
1.17
1.17. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 17 Length of intensive care unit stay for all participants.
1.18
1.18. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 18 Length of intensive care unit stay for survivors.
1.19
1.19. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 19 Length of hospital stay for all participants.
1.20
1.20. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 20 Length of hospital stay for survivors.
1.21
1.21. Analysis
Comparison 1 Corticosteroids versus placebo or usual care, Outcome 21 Number of participants with adverse events.
2.1
2.1. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 1 28‐Day all‐cause mortality.
2.2
2.2. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 2 90‐Day all‐cause mortality.
2.3
2.3. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 3 Long‐term mortality.
2.4
2.4. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 4 Intensive care unit mortality.
2.5
2.5. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 5 Hospital mortality.
2.6
2.6. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 6 Number of participants with shock reversal at day 7.
2.7
2.7. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 7 Number of participants with shock reversal at day 28.
2.8
2.8. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 8 SOFA score at day 7.
2.9
2.9. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 9 Length of intensive care unit stay for all participants.
2.10
2.10. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 10 Length of hospital stay for all participants.
2.11
2.11. Analysis
Comparison 2 Continuous infusion versus bolus administration of corticosteroids, Outcome 11 Number of participants with adverse events.
See this image and copyright information in PMC

Update of

Comment in

References

References to studies included in this review

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Tilouche 2019 {published data only}
    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.; PUBMED: 30628950] - DOI - 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. [PUBMED: 27741949] - PMC - PubMed
Torres 2015 {published data only}
    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; Vol. 313, issue 7:677‐86. [PUBMED: 25688779] - 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. [PUBMED: 19057445] - 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. [PUBMED: 2888017] - 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; PUBMED: 29347874] - DOI - PubMed
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Yildiz 2002 {published data only}
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Yildiz 2011 {published data only}
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Zhou 2015 {published data only}
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References to studies excluded from this review

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. The Lancet. Respiratory Medicine 2014;2:706‐16. [PUBMED: 25066331] - 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. [PUBMED: 3317054] - 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. Sao Paulo Medical Journal 2006;124(2):90‐5. [PUBMED: 16878192 ] - PMC - PubMed
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. [PUBMED: 24710342] - 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. J Crit 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. [PUBMED: 6390057] - 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. [PUBMED: 17906853 ] - PubMed
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. [PUBMED: 4929896] - 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
Lucas 1984 {published data only}
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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. [PUBMED: 23401275] - 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. [PUBMED: 8339624] - PubMed
McKee 1983 {published data only}
    1. McKee JI, Finlay WE. Cortisol replacement in severely stressed patients. Lancet 1983;1(8322):484. [PUBMED: 6131207 ] - 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. [PUBMED: 9669790] - 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. [PUBMED: 17710485] - PubMed
Newberry 2017 {published data only}
    1. Newberry L, O'Hare B, Kennedy N, Selman A, Omar S, Dawson P, Stevenson K, Nishihara Y, Lissauer S, Molyneux E. Early use of corticosteroids in infants with a clinical diagnosis of Pneumocystis jiroveci pneumonia in Malawi: a double‐blind, randomised clinical trial. Paediatr Int Child Health. 2017;37:121‐128.. - PubMed
Peeters 2018 {published data only}
    1. Peeters B, Meersseman P, Vander Perre S, Wouters PJ, Debaveye Y, Langouche L, Berghe G. 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
Rogers 1970 {published data only}
    1. Rogers J. Large doses of steroids in septicaemic shock. British Journal of Urology 1970;42(6):742. [PUBMED: 4923652] - 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. [PUBMED: 21427372] - 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. [PUBMED: 26545141] - 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. [PUBMED: 16625008] - 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. [PUBMED: 22865871] - 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. [PUBMED: 12728156] - 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. [PUBMED: 25619170] - 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. [PUBMED: 13304518] - PubMed
Weigelt 1985 {published data only}
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References to ongoing studies

NCT02517489 {published data only}
    1. NCT02517489. Community‐acquired pneumonia: evaluation of corticosteroids (CAPE COD) [Effects of low‐dose corticosteroids on survival of severe community‐acquired pneumonia]. https://clinicaltrials.gov/ct2/show/NCT02517489. First received 7 August 2015.
NCT02602210 {published data only}
    1. NCT02602210. Supplemental corticosteroids in cirrhotic hypotensive patients with suspicion of sepsis (SCOTCH) [Supplemental corticosteroids in cirrhotic hypotensive patients with suspicion of sepsis]. https://clinicaltrials.gov/ct2/show/NCT02602210. First received 11 November 2015.
NCT03258684 {published data only}
    1. NCT03258684. Hydrocortisone, vitamin C, and thiamine for the treatment of sepsis and septic shock (HYVCTTSSS) [Hydrocortisone, vitamin C, and thiamine for the treatment of sepsis and septic shock: a prospective study]. https://clinicaltrials.gov/ct2/show/NCT03258684. First received 23 August 2017.
NCT03333278 {published data only}
    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.
NCT03335124 {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.
NCT03389555 {published data only}
    1. NCT03389555. Ascorbic acid, corticosteroids, and thiamine in sepsis (ACTS) trial [Ascorbic acid, hydrocortisone, and thiamine in sepsis and septic shock ‐ a randomized, double‐blind, placebo‐controlled trial]. https://clinicaltrials.gov/ct2/show/NCT03389555. First received 3 January 2018.
NCT03422159 {published data only}
    1. NCT03422159. Metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in sepsis (ORANGES) [Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis]. https://clinicaltrials.gov/ct2/show/NCT03422159. First received 5 February 2018.
NCT03509350 {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.
NCT03592693 {published data only}
    1. NCT03592693. Vitamin C, hydrocortisone and thiamine for septic shock (CORVICTES) [A randomized, double blind, placebo‐controlled trial to investigate the effect of vitamin C, hydrocortisone and thiamine on the outcome of patients with septic shock]. https://clinicaltrials.gov/ct2/show/NCT03592693. First received 19 July 2018.

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