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Myths in Emergency Medicine

Myths in Emergency Medicine

Vitamin C Trial Lacks Answers for Sepsis

Spiegel, Rory MD

doi: 10.1097/01.EEM.0000650944.44357.15
    sepsis, vitamin C

    The validity of a vitamin C sepsis cocktail has been hotly debated since the first observational study was published two years ago, and an empiric attempt to validate these results has been lacking—until now.

    Marik, et al., noted in 2017 that ICU mortality dropped by an extraordinary 31.9 percent (8.5%-40.4%) after introducing a cocktail that included IV vitamin C, thiamine, and hydrocortisone. (Chest. 2017;151[6]:1229.)

    The publication of CITRIS-ALI now gives us new evidence examining the benefits of vitamin C in sepsis. (JAMA. 2019;322[13]:1261.) Fowler, et al., randomized 167 patients with sepsis and ARDS admitted to one of seven medical ICUs in the United States to high-dose IV vitamin C (50 mg/kg) every six hours for 96 hours or placebo. All patients were managed using lung-protective ventilation and a restricted fluid strategy.

    Overall, the authors reported no difference in their primary outcome, the difference in the modified SOFA (mSOFA) scores between placebo and the vitamin C arms at 96 hours. The mean mSOFA score from baseline to 96 hours decreased from 9.8 to 6.8 in the vitamin C group (3 points), and from 10.3 to 6.8 in the placebo group (3.5 points) (p=0.86). The authors also reported no significant difference between the vitamin C group and placebo group in the C-reactive protein levels or thrombomodulin levels assessed at 168 hours.

    Of the 46 secondary outcomes assessed, the authors reported on three that were statistically significant. Most notably, the 28-day mortality was 46.3 percent in the placebo group v. 29.8 percent in the vitamin C group (p=0.03). This amounts to an absolute between-group difference of 16.6 percent. They also reported a statistical difference in the number of ICU-free days, the number of patients transferred out of the ICU by hour 168, and the number of hospital-free days, all in favor of the vitamin C group. No adverse events were noted in either group.

    Primary Outcomes

    One should always question a surrogate outcome that contradicts the patient-centered outcome it is meant to predict. CITRIS-ALI failed to identify a difference in primary outcomes in the face of a statistically significant difference in 28-day mortality. The trial has a number of limitations. It examined only the use of vitamin C without the use of thiamine or hydrocortisone, so it is unclear what effect the remainder of the cocktail has on patient outcomes. Fowler, et al., also selected the subset of patients with sepsis who also had ARDS while the original Marik cohort examined septic patients with and without lung injury.

    In comparison with the data published by Marik, et al., CITRIS-ALI is a randomized controlled trial, limiting the influences of nonrandom error or bias, but the small sample size makes it extremely vulnerable to random error, exemplified by a fragility index of 1. The likelihood of a type I error is further potentiated by the sheer quantity of secondary endpoints examined by the authors. In fact, with 46 secondary endpoints, the potential of at least one outcome demonstrating statistical significance, simply by chance alone, nears certainty.

    The results of CITRIS-ALI will only serve to harden the dogged resolve of the two opposing camps that have formed surrounding this issue. Those who believe in the efficacy of the sepsis cocktail will view the difference in mortality as endorsement of their beliefs. Those who have resisted while awaiting more definitive evidence will likely view CITRIS-ALI as insufficient to meet the threshold to accept vitamin C alone or in concert with thiamine and hydrocortisone as a proven therapy.

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    Dr. Spiegel is an assistant professor of emergency medicine and critical care at Washington Hospital Center in Washington, D.C. Visit his blog at, follow him on Twitter@emnerd_, and read his past articles at

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