Reviewed by Dr. Neil Keshvani
Marik et al. CHEST. 2017 Jun;151(6):1229-1238

SUMMARY
This retrospective before-after study compared outcomes of standard therapy (n=47) versus treatment with high dose vitamin C, corticosteroids, and thiamine (n=47) in patients with severe sepsis or septic shock and a procalcitonin score ≥2 ng/mL. The treatment group received IV vitamin C 1.5 g every 6 hours for 4 days or until ICU discharge, IV hydrocortisone 50 mg every 6 hours for 7 days or until ICU discharge, and IV thiamine 200 mg every 12 hours for 4 days or until ICU discharge, all of which were started within 24 hours of ICU admission. None of the control patients received vitamin C or thiamine, and only a subset (n=28, 59.6%) received hydrocortisone (50mg every 6 hours) at the discretion of the attending physician. The primary outcome was in-hospital mortality. Secondary outcomes included duration of vasopressor therapy, requirement for renal replacement therapy, ICU length of stay, and change in SOFA score over the first 72 hours.

Baseline characteristics were similar in treatment and control groups. In-hospital mortality was 8.5% (4/47 patients) in the treatment group compared to 40.4% (19/47 patients) in the control group (p< .001). The mean duration of vasopressors was 18.3 ± 9.8 hours in the treatment group, compared to 54.9 ± 28.4 hours in the control group (p< .001). Renal replacement therapy was needed in 10% (3/47 patients) in the treatment group and 37% (11/47 patients) in the control group (p=.02). ICU length of stay was not significantly different in either group. Finally, the change in 72-hour SOFA score was 4.8 ± 2.4 in the treatment group compared to 0.9 ± 2.7 in the control group (p< .001).

COMMENTARY
In this study, Marik et al report mortality reduction and prevention of progressive organ dysfunction in patients with severe sepsis or septic shock treated with vitamin C, thiamine and hydrocortisone. The authors postulate a mechanistic basis for this cocktail: the antioxidant effects of vitamin C and its inhibition of proinflammatory mediators may help preserve endothelial function and microcirculatory flow, and increase vasopressor sensitivity. Hydrocortisone is proposed to act synergistically by increasing the transport of vitamin C into cells. Finally, the addition of thiamine may reduce conversion of vitamin C to oxalate that could otherwise crystalize in kidneys, therefore exerting a renal protective benefit to guard against toxicity associated with high doses of intravenous vitamin C.

This trial is notable for the controversy that has surrounded it. In this analysis, it is useful to focus on three core issues: 1) What is the strength of the evidence, 2) How does this trial compare to previous literature, and 3) What is the threshold for early adoption of the ICU cocktail?

Limitations of this trial are obvious: the sample size is small, and the trial utilizes a single-center design. Additionally, the before/after non-blinded design introduces the potential for bias. The Hawthorne effect, where individuals modify aspects of their behavior in response to their awareness of being observed, may have had a profound effect on outcomes in the treatment group. Of note, only 59.6% patients in the control group received hydrocortisone, an intervention that may decrease vasopressor requirements and reduce sepsis-associated mortality independent of vitamin C use (Annane et al.). Finally, the control group in this study has an APACHE IV predicted mortality of 40%. However, multiple studies have shown that in developed countries, septic shock patients have an average mortality of 25% at 90 days. This study may not be as generalizable because of this difference.

This trial follows up on recent phase 1 trials regarding the safety of IV vitamin C in severe sepsis (Fowler et al.) and the effect of high-dose vitamin C on vasopressor requirements (Zabet et al.), both of which reported that IV vitamin C is safe and effective in sepsis but are again complicated by extremely small sample sizes. The authors also point to the 50+ years of evidence pertaining to the safety of vitamin C and thiamine as proof that there is low risk of adverse effects. However, much of the literature on vitamin C pertains to oral repletion, not high-dose IV repletion. It is still possible that high-dose vitamin C may have adverse effects or unintended consequences that have yet to be described in safety studies.

Will this trial lead to early adoption of the ICU cocktail? Despite the limitations stated above, these preliminary results are promising. However, in order to truly understand if this protocol has a clear benefit to patients, further evidence is needed. This trial should be viewed as a stepping stone to a larger, multicenter randomized control trial; one that produces more generalizable results and thereby leads to a change in practice.

REFERENCES
1. Annane, D., et al. “Effect of Treatment with Low Doses of Hydrocortisone and Fludrocortisone on Mortality in Patients with Septic Shock.” JAMA 288.7 (2002): 862-71.
2. Fowler, A. A., 3rd, et al. “Phase I Safety Trial of Intravenous Ascorbic Acid in Patients with Severe Sepsis.” J Transl Med 12 (2014): 32.
3. Zabet, M. H., et al. “Effect of High-Dose Ascorbic Acid on Vasopressor’s Requirement in Septic Shock.” J Res Pharm Pract 5.2 (2016): 94-100.

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