Critical Care, Critical Care Alert, Sepsis

Critical Care Alert: Effect of Vitamin C, Thiamine and Hydrocortisone on Ventilator- and Vasopressor-Free Days in patients with sepsis - The VICTAS Randomized Clinical Trial

Critical Care Alert

ARTICLE
Sevransky JE, Rothman RE, Hager DN, 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):742–750.

OBJECTIVE
To determine if treatment with vitamin C, thiamine, and hydrocortisone resulted in an increase in the number of days alive and free of mechanical ventilation and vasopressor use.

BACKGROUND
(adapted from previous CCA)

In June 2017, Chest published a before-after retrospective study investigating the effect of ascorbic acid, steroids, and thiamine administration in patients with sepsis. Their data showed that the mortality rate was 8.5.% in the treatment group and 40.4% in the control group. Post-publication editorial criticized the paper for publishing "spurious findings, biased results, and overstated conclusions," noting that a >30% absolute risk reduction is "biologically implausible."1,2

In October 2019, the CITRIS-ALI RCT was published in JAMA and investigated whether IV vitamin C reduced organ failure scores or biomarkers of inflammation and vascular injury in patients with sepsis +  acute respiratory distress syndrome (ARDS). Primary outcomes demonstrated no significant drop in SOFA scores or other organ dysfunction markers; however, secondary outcome of reduction in mortality was seen. Critics note that this finding may be misleading, as there is a large confidence interval and the study was not powered to detect this outcome. Additionally, there were a large number of secondary outcomes which makes finding one significant by chance more likely.3,4

In January 2020 the VITAMIN trial was published in JAMA and investigated the difference in resolution of sepsis in patients receiving ascorbic acid, hydrocortisone, and thiamine vs hydrocortisone alone. Primary outcomes were time alive and time free of vasopressors. Between the experimental and control group, there was no significant difference. One secondary outcome, change in SOFA score, was seen to be significantly lower in the experimental group. Overall, the authors determined there was no faster resolution of septic shock in patients receiving the experimental cocktail.5

In July 2020, the ORANGES trial was published in Chest, which evaluated yet again whether ascorbic acid, hydrocortisone, and thiamine improved clinical outcomes in sepsis and septic shock. In this trial, the primary outcome was resolution of shock as measured by discontinuation of vasopressor support as well as change in SOFA score. They found a statistically significant reduction in the time to shock resolution in the experimental group vs control without associated significant change in SOFA score. It is important to note that the primary outcome of this study was originally 28-day mortality, but was changed after full data collection was gathered which makes the overall interpretation of the study more suspect.3

More recently in August 2020, the ACTS trial aimed to determine if the combination of ascorbic acid, corticosteroids, and thiamine attenuates organ injury in patients with septic shock. The study group found no statistically significant difference between the intervention group and the control group for the primary outcome of change in SOFA score. Additionally, there was no significant difference in rates of  kidney failure, 30-day mortality, ventilator-free days or days free from the ICU.6

Enter the VICTAS Trial where the study authors sought to further evaluate the effect of vitamin c, thiamine, and hydrocortisone on days alive and days free of mechanical ventilation. Of note, this study was stopped early due to a lack of funding.

DESIGN
Multicenter, randomized, double-blind, adaptive-sample-size placebo-controlled trial

Inclusion Criteria

  • Suspected infection
  • Acute respiratory or cardiovascular dysfunction Clinically with acute hypoxic respiratory failure
    • Vasopressor agents >1 hour to maintain MAP 65 mmHg
  • Planned admit to the ICU

Exclusion Criteria (long list in study protocol)

  • <18 years of age
  • Weight <40kg
  • Cardiovascular/Respiratory failure secondary to illness other than sepsis
  • DNR/DNI status
  • Long hospitalization (>30) days prior to randomization
  • Chronic hypoxemia requiring supplemental non-invasive oxygen or home mechanical ventilation
  • *Many others*

INTERVENTION & Control
501 patients screened from 43 hospitals were randomized to receive intravenous vitamin C, thiamine, and hydrocortisone every 6 hours or matching placebo for 4 days, or until discharge from the ICU or death.

OUTCOMES
Primary

  • Number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization

Secondary

  • 30-day mortality

KEY RESULTS

  • No significant difference in the number of ventilator- and vasopressor-free days between the experimental and control group
  • No significant difference in 30-day mortality between the experimental and control group
  • Long-term outcome: no significant 180-day mortality difference between the experimental and control group

STRENGTHS

  • Large sample size
  • Randomized control trial
  • High adherence to protocols and well-matched placebo and experimental group

LIMITATIONS

  • Terminated early for lack of funding
  • Fixed dose of vitamin C used
  • Corticosteroids used at clinician discretion
  • Only sepsis-induced cardiovascular or respiratory failure

EM TAKE-AWAYS
Sepsis-inspired vitamin + steroid trial highlighting the lack of significant difference when compared to placebo in two patient-centered outcomes: ventilator-free days and 30-day mortality. The answer remains the same - there is no current evidence supporting the use of a combination of vitamin C, thiamine, and steroids in sepsis patients with cardiovascular and respiratory complications.


References

  1. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-38.
  2. Møller MH, Laake JH, Myburgh JA, Alhazzani W, Perner A. The Magic Bullet in Sepsis or the Inflation of Chance Findings?. Chest. 2017;152(1):222-3.
  3. Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. 2019;322(13):1261–1270.
  4. Rezaie SR. CITRIS-ALI: Vitamin C in Patients with Sepsis and Severe Acute Respiratory Failure. REBEL EM. Nov. 25, 2019.
  5. Fujii T, Luethi N, Young PJ, 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):423–431.
  6. Sumner B, Hickey S. Critical Care Alert: Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock - The ACTS Randomized Clinical Trial. EM Resident. 2020;47(4).

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