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Original Investigation
Caring for the Critically Ill Patient
February 23, 2021

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial

Author Affiliations
  • 1Division of Pulmonary, Allergy, Critical Care, and Sleep, Emory University School of Medicine, Atlanta, Georgia
  • 2Emory Critical Care Center, Emory Healthcare, Atlanta, Georgia
  • 3Department of Emergency Medicine, Johns Hopkins University, Baltimore, Maryland
  • 4Division of Pulmonary Critical Care, Johns Hopkins University, Baltimore, Maryland
  • 5Division of Pulmonary Critical Care, Vanderbilt University Medical Center, Nashville, Tennessee
  • 6Division of Pulmonary Critical Care, Intermountain Medical Center and University of Utah, Salt Lake City
  • 7Department of Surgery, Emory University School of Medicine, Atlanta, Georgia
  • 8Division of Pulmonary Critical Care, Virginia Commonwealth University, Richmond
  • 9Johns Hopkins Critical Illness, Brain Dysfunction, and Survivorship (CIBS) Center, Baltimore, Maryland
  • 10Veteran’s Affairs Tennessee Valley Geriatric Research Education Clinical Center (GRECC), Nashville
  • 11Division of Brain Injury Outcomes, Johns Hopkins University, Baltimore, Maryland
  • 12Department of Emergency Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania
  • 13Department of Critical Care, Montefiore Medical Center, Bronx, New York
  • 14Department of Emergency Medicine, Emory University, Atlanta, Georgia
  • 15Division of Pulmonary Critical Care, Sentara Healthcare, Norfolk, Virginia
  • 16Division of Pulmonary Critical Care, Oregon Health & Science University, Portland
  • 17Molecular and Clinical Nutrition Section, National Institutes of Health, Bethesda, Maryland
  • 18Department of Emergency Medicine, Harbor-UCLA Medical Center, Torrance, California
  • 19Berry Consultants LLC, Austin, Texas
  • 20Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
  • 21Lundquist Institute for Biomedical Innovation, Torrance, California
  • 22Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
  • 23Vanderbilt Coordinating Center, Vanderbilt University Medical Center, Nashville, Tennessee
  • 24Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia
  • 25Department of Biostatistics, University of Kentucky, Lexington
JAMA. 2021;325(8):742-750. doi:10.1001/jama.2020.24505
Visual Abstract. Vitamin C, Thiamine, and Hydrocortisone and Ventilator- and Vasopressor-Free Days in Sepsis
Vitamin C, Thiamine, and Hydrocortisone and Ventilator- and Vasopressor-Free Days in Sepsis
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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