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
Open accessAbstract
Importance: It is unclear whether vitamin C, hydrocortisone, and thiamine are more effective than hydrocortisone alone in expediting resolution of septic shock. Objective: To determine whether the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock. Design, Setting, and Participants: Multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. The first patient was enrolled on May 8, 2018, and the last on July 9, 2019. The final date of follow-up was October 6, 2019. Interventions: Patients were randomized to the intervention group (n = 109), consisting of intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours), or to the control group (n = 107), consisting of intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. Main Outcomes and Measures: The primary trial outcome was duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality. Results: Among 216 patients who were randomized, 211 provided consent and completed the primary outcome measurement (mean age, 61.7 years [SD, 15.0]; 133 men [63%]). Time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was -0.6 hours (95% CI, -8.3 to 7.2 hours; P = .83). Of 10 prespecified secondary outcomes, 9 showed no statistically significant difference. Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported. Conclusions and Relevance: In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. Trial Registration: ClinicalTrials.gov Identifier: NCT03333278.
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There are limited available data on undesirable effects of vitamin C; the point estimate of the HR for 90-day mortality in the largest RCT was 1.18 (95% CI 0.69-2.00), favouring the control group.
“There are limited available data of any undesirable effects: it was noted that the point estimate of the HR for 90-day mortality in the largest RCT [524] was 1.18 (95% CI 0.69–2.00) i.e. favouring the control group.”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [524]
In the Fujii et al. study, no difference was reported for the primary outcome of time alive and free of vasopressors up to 168 h between the intervention and control group (median 122.1 h vs 124.6 h; p = 0.83).
“The authors reported no difference for the primary outcome of time alive and free of vasopressors up to 168 h between the intervention and control group (median 122.1 h [IQR 76.3–145.4 h] vs 124.6 h [IQR 82.1–147 h]; p = 0.83).”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [524]
In the Fujii et al. study, ninety-day mortality was 28.6% (30/105) in the vitamin C group and 24.5% (25/102) in the control group (HR 1.18; 95% CI 0.69-2.0).
“Ninety-day mortality was 28.6% (30/105) in the vitamin C group, and 24.5% (25/102) in the control group (HR 1.18; 95% CI 0.69–2.0).”
From Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021 (2021) · cites this paper as [524]
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- Authors
- Fujii, T., Luethi, N., Young, P. J., Frei, D. R., Eastwood, G. M., French, C. J., Deane, A. M., Shehabi, Y., Hajjar, L. A., Oliveira, G., Udy, A. A., Orford, N., Edney, S. J., Hunt, A. L., Judd, H. L., Bitker, L., Cioccari, L., Naorungroj, T., Yanase, F., Bates, S., McGain, F., Hudson, E. P., Al-Bassam, W., Dwivedi, D. B., Peppin, C., McCracken, P., Orosz, J., Bailey, M., Bellomo, R., & for the VITAMINS Trial Investigators
- Affiliations
- Kyoto University (JP)
- University of Bern (CH)
- Wellington Hospital (NZ)
- Austin Hospital (AU)
- The University of Melbourne (AU)
- The Royal Melbourne Hospital (AU)
- UNSW Sydney (AU)
- Instituto do Câncer do Estado de São Paulo (BR)
- The Alfred Hospital (AU)
- Barwon Health (AU)
- Siriraj Hospital (TH)
- Footscray Hospital (AU)
- Critical Care and Perioperative Services, School of Clinical Sciences, Monash University and Monash Health, Melbourne, Victoria, Australia
- Monash Health (AU)
- Corresponding author
- Bellomo, Rinaldo
- ORCID
- Fujii, Tomoko
- Luethi, Nora
- Young, Paul J.
- Frei, Daniel R.
- Eastwood, Glenn M.
- French, Craig J.
- Deane, Adam M.
- Shehabi, Yahya
- Hajjar, Ludhmila A.
- Udy, Andrew A.
- Orford, Neil
- Bitker, Laurent
- Cioccari, Luca
- Naorungroj, Thummaporn
- Yanase, Fumitaka
- Bates, Samantha
- McGain, Forbes
- Hudson, Elizabeth P.
- Dwivedi, Dhiraj Bhatia
- Orosz, Judit
- Bailey, Michael
- Bellomo, Rinaldo
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2020-02-04
- Volume
- 323
- Issue
- 5
- Pages
- 423
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC7029761
- OpenAlex
- W3000652395
- Semantic Scholar
- fa35352dd05c32230dcf209595f4c3f915001f7d
- Cited by
- 466
- References
- 32
- Citations by year
- 2026: 31 · 2025: 35 · 2024: 39 · 2023: 63 · 2022: 82 · 2021: 138 · 2020: 78
- FWCI
- 64.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- Own your potential (DEAKIN) (submittedVersion)
- Figshare (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Open Access CRIS of the University of Bern
- Funders
- Intensive Care Foundation
- Medical Research Council
- National Health and Medical Research Council (1124532)
- Health Research Council of New Zealand
- Japan Society for the Promotion of Science
- Topics
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Keywords
- septic shock, vitamin C, cortisol, thiamine, sepsis treatment, 90-day mortality, COVID-19 pandemic, intensive care unit patients, corticosteroid therapy, Sepsis-3 criteria, mortality risk stratification, prognostic factors
- MeSH terms
- Aged, Anti-Inflammatory Agents, Ascorbic Acid, Drug Therapy, Combination, Female, Humans, Hydrocortisone, Male, Middle Aged, Shock, Septic, Thiamine, Vasoconstrictor Agents, Vitamins, Hospital Mortality, Administration, Intravenous
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