EM Nerd-The Case of the Sour Remedy

In 2017 Marik et al (1) published an observational before and after study examining the initiation of the sepsis cocktail for ICU patients admitted with sepsis. The authors noted, following the introduction of this cocktail, which included IV vitamin C, thiamine and hydrocortisone, ICU mortality dropped by an extraordinary 31.9% (40.4% to 8.5%). Since this publication the validity of Marik’s findings have been hotly debated, but an empiric attempt to validate these results has been lacking. With the publication of CITRIS-ALI in JAMA (2), we now have evidence examining the benefits of vitamin C in sepsis.

Published in JAMA, Fowler et al randomized 167 patients admitted to one of seven medical ICUs in the US with sepsis and ARDS to high-dose IV vitamin C (50 mg/kg) every 6 hours for 96 hours, or placebo. Otherwise all patients were managed using lung protective ventilatory and a restricted fluid strategy in both groups.

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 = .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 3 which were observed to be statistically significant. Most notably, the 28-day mortality was 46.3% in the placebo group vs 29.8% in the vitamin C group (p = .03). This amounts to an absolute between-group difference of 16.6%. 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.

Much has been written discussing the validity of the authors’ primary outcome (here and here). One should always question a surrogate outcome that contradicts the patient centered outcome it is meant to predict. In this case, CITRIS-ALI failed to identify a difference in their primary outcomes, in the face of a statistically significant difference in 28-day mortality. The trial has a number of limitations. First, CITRIS-ALI examined only the use of vitamin C without the use of thiamine or hydrocortisone, and so it is unclear what effect the remainder of the cocktail has on patient outcomes. In addition, Fowler et al 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 to the data published by Marik et al, CITRIS-ALI is an RCT, limiting the influences of non-random 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-1 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 that believe in the efficacy of the sepsis cocktail will view the difference in mortality as endorsement of their strongly held beliefs. Those that have resisted, 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.

Sources Cited:

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):1229-1238.
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. JAMA. 2019;322(13):1261-1270.