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Fowler AA 3rd. "Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure". JAMA. 2019. 322(13):1261-1270.
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Clinical Question

In adult patients admitted to the ICU with sepsis and acute respiratory distress syndrome (ARDS), does intravenous administration of high-dose vitamin C reduce organ failure scores and biomarkers of inflammation and vascular injury?

Bottom Line

Intravenous high dose vitamin C does not make a significant difference in SOFA and organ dysfunction markers but made a difference in mortality as a secondary outcome, however, the secondary outcome analysis may have been flawed. More, larger studies are needed.

Major Points

Following the trail by Marik et al.[1] in 2017, many clinical trials have been registered testing the use of high dose vitamin C—with various protocols—for patients in sepsis. This trial is one of the first prospective trials to be published in response. Sepsis is life threatening organ dysfunction caused by a dysregulated host response to infection leading to an imbalance in oxygen demand and supply, and is a leading cause of infectious death.[2]Sepsis was originally defined in 1992 via a consensus based definition from SCCM and ACCP, defined as a systemic inflammatory response (SIRS) with a suspected source of infection. These patients were then stratified into one of three categories: sepsis, severe sepsis (with lactic acidosis or hypotension), or septic shock (severe sepsis with persistent hypotension despite fluid resuscitation).[3] In 2016, these definitions were modified with the Sepsis-3 update, the SIRS criteria were eliminated and the SOFA and q-SOFA criteria have now been adopted.[2][4] Sepsis research has been marred with multiple negative findings, initially showing positive outcomes like the Rivers Trial or Annane Trial, further research does not pan out into solid outcomes.

This is the first large randomized controlled trial on the use of vitamin C in ARDS. This study of 167 patients randomized to high-dose vitamin C (50mg/kg every 6 hours for 96 hours) vs placebo, did not show any difference in the primary outcomes: mSOFA (modified Sequential Organ Failure Assessment) score at 96 hours or levels of C-reactive protein or thrombomodulin at 168 hours. Out of the 46 evaluated secondary outcomes, only 3 showed a significant difference: high-dose vitamin C was associated with improved 28-day all-cause mortality (29.8% vs. 43.6%, P = 0.03), increased ICU-free days (10.7 vs. 7.7, P = 0.03), and increased hospital-free days to day 60 (22.6 vs. 15.5, P = 0.04).

There are several limitations with this trial. The population included in this trial was mostly non-Hispanic white. Two thirds of the population was exposed to corticosteroids which may have altered outcomes. Waiting for patients to develop ARDS may have blunted the positive effects of Vitamin C. Finally, the secondary outcomes were completed as an exploratory analysis that was not adjusted for multiple comparisons. This may have led to these outcomes being found significant by chance. The authors report that no unexpected trial related adverse events were observed, however, nothing was reported in the paper.

Overall this is an exciting outcome that requires further study to confirm findings.

Guidelines

As of October 2019, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, prospective, double-blind, randomized, controlled trial
  • N=167
    • Vitamin C (n=84)
    • Placebo (n=83)
  • Setting: 7 ICUs in the United States
  • Enrollment: September 2014 to November 2017
  • Follow-up: 60 days
  • Analysis: Intention-to-treat
  • Primary outcome: Change in mSOFA score at 96 hours and inflammatory biomarkers (C-reactive protein and thrombomodulin) at 0, 48, 96, and 168 hours.

Population

Inclusion Criteria

  • Met the following criteria within a 24 hour period:
    • Admitted to ICU
    • invasive mechanical ventilation
    • PaO2 : FiO2 ratio <300 mm Hg
    • bilateral opacities by chest radiography within 1 week of known clinical insult
    • new or worsening respiratory symptoms without evidence of left atrial hypertension
    • suspected or proven infection
    • met at least 2 of 4 systemic inflammatory response (SIRS) criteria

Exclusion Criteria

  • known allergy to vitamin C
  • no ability to obtain informed consent (younger than 18 years, non-English speaking, ward of the state)
  • > 48 hours had elapsed since patient met ARDS criteria
  • pregnant or breastfeeding
  • moribund
  • not expected to survive 24 hours
  • they required home mechanical ventilation
  • receiving home oxygen > 2 L/min
  • history of interstitial lung disease, diffuse alveolar hemorrhage, diabetic ketoacidosis, or an active kidney stone.

Baseline Characteristics

Vitamin C Group displayed

  • Demographics: median age 54 years, 46% female, 81% white, 15% black, 4% Hispanic/Asian/Pacific Islander
  • Sepsis etiology: 82% Thorax, 7% abdomen, 4% Urinary tract, 1% Central nervous system, 6% unkown
  • Admission portal: 46% emergency, 31% outlying hospital transfer, 20% inpatient ward transfer, 1% operating room transfer, 1% direct admission
  • Physiologic parameters: 25% acute kidney insufficiency, 8% chronic kidney failure/dialysis, 68% baseline shock (vasopressor use), mean oxygenation index 10.7, 67% corticosteroid use

Interventions

  • Vitamin C 50mg/kg total body weight every 6 hours for 96 hours
  • Matched placebo (5% dextrose in water)

Outcomes

Comparisons are vitamin C vs. placebo.

Primary Outcomes

Mean change in mSOFA score at 96 hours
3 vs. 3.5 (difference 0.5, 95% CI -1.23 to 1.03; P = 0.86)
C-reactive protein level at 168 hours
54.1 vs 46.1 mcg/mL (difference 7.94; 95% CI −8.23 to 24.1; P = 0.33)
Thrombomodulin level at 168 hours
14.5 vs 13.8 ng/mL (difference 0.69; 95% CI −2.8 to 4.2; P = 0.70)

Secondary Outcomes

Exploratory analysis not adjusted for multiple comparisons

28-day mortality
29.8% vs. 43.6% (Difference 13.8, 95% CI 2-31.1; P = 0.03)
ICU-free days at 28-days
10.7 vs. 7.7 (mean difference 3.2, 95% CI 0.3-5.9; P = 0.03)
Hospital-free days at 60-days
22.6 vs. 15.5 (mean difference 6.69, 95% CI 0.3-13.8; P = 0.04)

Remaining 43 of 46 pre-specified secondary outcomes not significant

Adverse Events

Trial reported no unexpected trial related adverse effects and did not report any further.

Criticisms

  • External validity maybe limited as the majority of the population was non-Hispanic white
  • approximately 2/3 of the population was exposed to corticosteroids which may have affected sepsis outcomes
  • secondary analysis did not adjust for multiple comparisons so statistical differences may be due to chance
  • waiting until development of ARDS may have led to treatment delay and blunted affect of the intervention, but time to enrollment was not reported

Funding

  • National Heart, Lung, and Blood Institute (UM1HL116885)
  • National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award (CTSA) (UL1TR000058, NIH P50 AR072000)
  • VCU Investigational Drug Services and McGuff Pharmaceuticals, supplied vitamin C at no charge

Further Reading

  1. Marik PE et al. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest 2017. 151:1229-1238.
  2. 2.0 2.1 Singer M et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016. 315:801-10.
  3. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit. Care Med. 1992. 20:864-74.
  4. Vincent JL et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996. 22:707-10.