Pro and Con: Vitamin C and Sepsis – Con

Is Vitamin C (ascorbic acid) the new and improved answer to decreasing sepsis-related mortality? It’s unclear. Up until this point, ascorbic acid has been studied in small cohorts of mostly cancer or burn patients.1 Studies in these populations have had variable results, some showing no difference in outcomes and others displaying impressive benefits. One notable study, a small randomized control trial, showed that continuous dosing over 24 hours in burn patients could reduce the need for additional IV fluid resuscitation and vasopressors.2 While impressive, these results were based on novel, continuous dosing, in a very specific population. There is minimal precedent for similarly impressive results in septic patients.

Currently, we lack a clear physiologic mechanism for how ascorbic acid improves immune function. In animal studies, there is evidence that ascorbic acid acts as an antioxidant and anti-inflammatory agent, scavenging free radicals and potentially reducing cell injury.3 We know that septic patients have low vitamin C levels, but we do not know how normalizing levels impacts immune function. Sepsis is a complex, dysregulated inflammatory response marked by multiple abnormal hormone, mineral, and vitamin levels. Without a clear mechanism or understanding of the dose-response, it is very difficult to determine if higher vitamin C levels are responsible for lower sepsis-related mortality.

The 2017 study by Marik and colleagues that has made vitamin C in sepsis a hot topic of discussion should be interpreted with caution. At first glance, the results are astounding. Septic patients treated with to vitamin C, thiamine, and hydrocortisone had a estimated 31.9% decreased odds of mortality from sepsis.4 However, this retrospective before-after cohort study has many limitations. It was conducted at a single center, with a small study group (n=47) that was matched to a control group from 2 years prior. While the investigators made reasonable efforts to minimize variation between groups in their statistical analyses, these measures do not account for confounding due to provider variability, unmeasured exposures, and variation in practice with time. For example, between the control cohort in 2015 and the study cohort in 2017, the Sepsis 3 guidelines were published, potentially impacting the time in which we diagnose, triage, and treat septic patients.5 Time to intervention alone can dramatically impact sepsis related mortality.

Vitamin C, while essential to survival, is not without side effects when administered in greater doses. High levels of Vitamin C can lead to undesirable side effects such as nausea, diarrhea, insomnia, and calcium oxalate stones. The current daily-recommended dose is less than 2g.6 Many studies, including the Eastern Virginia Medical study, used doses much higher than this to normalize levels. There have been few trials to illustrate that higher doses in a clinical setting are tolerable, and no trials exclusively in patients with acute kidney injury.7 Typically, vitamin C metabolites are excreted in the urine but could conceivably accumulate in acute kidney dysfunction.8 Without further investigation, there is no reliable way to determine safe dosing at this time in patients with organ dysfunction.

While potentially an exciting and promising direction for sepsis management, there are still many questions to be answered on how best to use vitamin C in septic patients today. Until further studies help validate the findings, we should emphasize that early recognition and timely resuscitation, vasopressor use, and early antibiotics remain the mainstays for fighting sepsis.

References
  1. Reczek CR, Chandel NS. Revisiting vitamin C and cancer. Science 2015; 350(6266): 1317-8.
  2. Tanaka H et al. Reduction of resuscitation fluid volumes in severely burned patients using ascorbic acid administration: a randomized, prospective study. Arch Surg 2000; 135(3): 326-31.
  3. Fisher BJ et al. Attenuation of sepsis-induced organ injury in mice by vitamin C. J Parenteral Enteral Nutrition 2014; 38(7): 825-39.
  4. 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(6): 1229-38.
  5. Singer M. et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 2016; 315(8): 801-10.
  6. Staff MC. Vitamin C. 2018; Available from: https://www.mayoclinic.org/drugs-supplements-vitamin-c/art-20363932.
  7. Fowler AA et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Translational Medicine 2014; 12(1): 32.
  8. Knight J et al. Ascorbic acid intake and oxalate synthesis. Urolithiasis 2016; 44(4): p. 289-297.

Author

Rhea Ittoop, MD MPH
New York Presbyterian Hospital
New York, New York