Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis | Complementary and Alternative Medicine | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With SepsisThe VICTAS Randomized Clinical Trial

Educational Objective
To learn the effect of combination therapy with vitamin C, thiamine, and hydrocortisone on clinical outcomes in critically ill patients with sepsis.
1 Credit CME
Key Points

Question  In adults with sepsis-induced respiratory or cardiovascular dysfunction, does treatment with vitamin C, thiamine, and hydrocortisone result in an increase in the number of days alive and free of mechanical ventilation and vasopressor use?

Findings  In this randomized clinical trial that included 501 patients, treatment with vitamin C, thiamine, and hydrocortisone compared with placebo resulted in a median of 25 vs 26 ventilator- and vasopressor-free days within the 30 days following randomization, a difference that was not statistically significant.

Meaning  Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone did not significantly improve ventilator- and vasopressor-free days, although, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.

Abstract

Importance  Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis.

Objective  To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis.

Design, Setting, and Participants  Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020.

Interventions  Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone.

Main Outcomes and Measures  The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality.

Results  Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of −1 day (95% CI, −4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group.

Conclusions and Relevance  Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference.

Trial Registration  ClinicalTrials.gov Identifier: NCT03509350

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Article Information

Corresponding Author: Jonathan E. Sevransky, MD, MHS, Emory University Hospital, Room D226, Atlanta, GA 30322 (jsevran@emory.edu).

Accepted for Publication: January 19, 2021.

Author Contributions: Dr Lindsell and Mr Nwosu had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Sevransky, Rothman, Hager, Bernard, Buchman, Busse, Coopersmith, DeWilde, Ely, Fowler, Gaieski, Gong, Hall, Hinson, Hooper, Kelen, Khan, Levine, Lewis, Marlin, McGlothlin, Rice, Rudolph, Sanfilippo, Viele, Martin, Wright.

Acquisition, analysis, or interpretation of data: Sevransky, Rothman, Hager, Bernard, Brown, Busse, Coopersmith, DeWilde, Ely, Eyzaguirre, Fowler, Gaieski, Gong, Hall, Hinson, Hooper, Kelen, Khan, Levine, Lewis, Lindsell, Marlin, McGlothlin, Moore, Nugent, Nwosu, Polito, Rice, Ricketts, Viele, Martin, Wright.

Drafting of the manuscript: Sevransky, Rothman, Hager, Bernard, Busse, DeWilde, Ely, Hall, Hinson, Khan, Rice, Rudolph, Viele, Wright.

Critical revision of the manuscript for important intellectual content: Sevransky, Rothman, Hager, Bernard, Brown, Buchman, Busse, Coopersmith, Ely, Eyzaguirre, Fowler, Gaieski, Gong, Hall, Hinson, Hooper, Kelen, Khan, Levine, Lewis, Lindsell, Marlin, McGlothlin, Moore, Nugent, Nwosu, Polito, Rice, Ricketts, Sanfilippo, Viele, Martin, Wright.

Statistical analysis: Ely, Lewis, Lindsell, McGlothlin, Nwosu, Viele.

Obtained funding: Sevransky, Rothman, Bernard, Buchman, Hall, Kelen, Sanfilippo, Wright.

Administrative, technical, or material support: Sevransky, Rothman, Hager, Bernard, Buchman, DeWilde, Ely, Eyzaguirre, Fowler, Gaieski, Hall, Hinson, Hooper, Kelen, Khan, Levine, Lewis, Marlin, Rice, Ricketts, Rudolph, Sanfilippo, Martin, Wright.

Supervision: Sevransky, Rothman, Hager, Bernard, Brown, DeWilde, Ely, Gaieski, Gong, Hall, Hinson, Hooper, Kelen, Khan, Marlin, Nugent, Sanfilippo, Martin, Wright.

Conflict of Interest Disclosures: Dr Sevransky reported receipt of a stipend from Critical Care Medicine for work as an associate editor and grants from the CDC Foundation. Dr Brown reported receipt of personal fees from Hamilton, Oxford University Press/Brigham Young University, and New York University and grants from Faron, Sedana, Janssen, the National Institutes of Health (NIH), and the Department of Defense. Dr Buchman reported that he is senior advisor and intergovernmental personnel assignment to BARDA DRIVe, detailed to the Solving Sepsis program, that he is editor in chief of Critical Care Medicine and Critical Care Explorations, and that he received grants and salary support as site principal investigator for the Surgical Critical Care Initiative managed by the Uniformed Services University of the Health Sciences. Dr Busse reported receipt of speakers bureau fees from La Jolla Pharmaceutical Company. Dr Ely reported receipt of grants from Bioxcel as a trial principal investigator and honoraria for continuing medical education teaching activities from Pfizer and Orion and serving as an unfunded investigator for Eli Lilly. Dr Fowler reported receipt of grants from the National Heart, Lung, and Blood Institute (NHLBI). Dr Gong reported receipt of grants from the NHLBI and the Agency for Healthcare Research and Quality (AHRQ). Dr Hall reported receipt of grants from the Centers for Disease Control and Prevention (CDC), Johnson and Johnson, the NIH, and Nico Corporation. Dr Hinson reported receipt of grants from the AHRQ and the CDC. Dr Khan reported receipt of grants from United Therapeutics, Janssen, Reata Pharma, and the NIH. Dr Lewis reported that he is the senior medical scientist at Berry Consultants LLC, a statistical consulting firm that specializes in adaptive clinical trial design. Dr Lindsell reported receipt of grants from the NIH, the CDC, and the Department of Defense; receipt of research contracts to his institution from Entegrion Inc, Endpoint Health Research, and bioMérieux; and holding stock options in Bioscape Digital; in addition, Dr Lindsell has a patent for risk stratification in pediatric septic shock issued to Cincinnati Children’s Hospital Medical Center. Dr Rice reported consulting for Cumberland Pharmaceuticals Inc, Avisa Pharma LLC, and Cytovale Inc. Dr Martin reported receipt of research advisory board fees from Beckman Coulter, Regeneron, and Grifols. No other disclosures were reported.

Funding/Support: Funding for the trial was provided by the Marcus Foundation to Emory University, which supervised the distribution of resources to clinical sites. Johns Hopkins served as the clinical coordinating center and Vanderbilt University as the data coordinating center. Nova Biomedical Inc provided support to 6 sites with point-of-care glucometers. Vitamin C, thiamine, and hydrocortisone were purchased from McGuff Pharmaceuticals Inc. SCCM Discovery, a critical care research infrastructure program, facilitated the design and conduct of the study, provided administrative support to conducting the study, and was involved in critical manuscript revision. SCCM Discovery reviewed and critiqued the study, which met criteria for SCCM Discovery endorsement.

Role of the Funder/Sponsor: SCCM Discovery was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation and review of the manuscript. SCCM Discovery was not involved in the approval of the manuscript or the decision to submit the manuscript for publication. The other funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Group Information: For a list of the VICTAS Investigators, see Supplement 5.

Data Sharing Statement: See Supplement 6.

Additional Contributions: We thank Roger J. Lewis, MD, PhD, Harbor-UCLA Medical Center, Jason Connor, PhD, Confluence Stats, R. Phillip Dellinger, MD, Cooper Medical School of Rowan University, Steven Opal, MD, Brown University, and Tiffany M. Osborne, MD, MPH, Washington University, for participation in the trial data and safety monitoring board.

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