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Vitamin C in Sepsis

Posted on March 15, 2020 in: Professional Practice

Jamie George, Pharm.D.; Carly Burns, Pharm.D.; Christopher DeBiase, Pharm.D.; Nicole Elkhoury, Pharm.D., pharmacy residents, Ascension St. John Hospital, Detroit

Sepsis is a life-threatening illness induced by infection. It affects 1.7 million adults in the United States each year and is responsible for over 250,000 deaths.1 Septic shock is a subset of sepsis in which metabolic and circulatory abnormalities are present.2 Given the mortality associated with sepsis, new treatment options are being explored.

Vitamin C, or ascorbic acid, has recently been evaluated as adjunctive therapy in sepsis but its role remains unclear. There are several hypotheses regarding the role of Vitamin C. First, Vitamin C acts as a cofactor in endogenous norepinephrine production and provides antioxidant properties. Oxidative stress is known to occur in sepsis.3 In addition, patients with sepsis often have low Vitamin C concentrations (<15 μM/L) secondary to inflammation.4,5 Thiamine and hydrocortisone are also utilized in combination with Vitamin C in sepsis. Similar to Vitamin C, thiamine is a micronutrient found to be below normal range in patients with sepsis. Thiamine modifies Vitamin C metabolism to reduce oxalate production, therefore decreasing the rate of Vitamin C oxalate-induced nephropathy. Hydrocortisone has consistently shown to improve patient outcomes in sepsis. It has been suggested hydrocortisone works synergistically with Vitamin C to decrease inflammatory mediators and increase vasopressor sensitivity.6 

Prior to 2017, there was limited evidence regarding high-dose Vitamin C, monotherapy or in combination with thiamine and hydrocortisone, as a therapeutic option for sepsis. Table 1 provides a summary of the four major trials. 

The role of Vitamin C in sepsis remains unknown; however, the answer may soon be within our reach. Hager et al (2019) are currently enrolling patients into the VICTAS trial to test the efficacy of combined Vitamin C, thiamine, and hydrocortisone in patients with respiratory or circulatory dysfunction resulting from sepsis. VICTAS is anticipated to be a large scale, randomized-controlled trial conducted across 40 sites within the United States. All eyes will be directed towards the results of this highly anticipated trial come late 2021 to confirm Vitamin C’s place in therapy. 

References

  1. Rhee C, Dantes R, Epstein L, et al; CDC Prevention Epicenter Program. Incidence and trends of sepsis in US hospitals using clinical vs claims data, 2009-2014. JAMA. 2017;318(13):1241-1249
  2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810.
  3. Rudyk O, Phinikaridou A, Prysyazhna O, Burgoyne JR, Botnar RM, Eaton P. Protein kinase G oxidation is a major cause of injury during sepsis. Proc Natl Acad Sci U S A. 2013;110:9909–9913.
  4. Prauchner CA. Oxidative stress in sepsis: pathophysiological implications justifying antioxidant co-therapy. Burns. 2017;43:471–485.
  5. Padh H, Aleo JJ. Activation of serum complement leads to inhibition of ascorbic acid transport. Proc Soc Exp Biol Med. 1987;185:153–157.
  6. Hager D, Hooper M Bernard G, et al. The Vitamin C, Thiamine and Steroids in Sepsis (VICTAS) Protocol: a prospective, multi-center, double-blind, adaptive sample size, randomized, placebo-controlled, clinical trial. Trials, 2019;20(1):1-16.
  7. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. Journal of Translational Medicine, 2014;12:32:1-10.
  8. Marik PE, Khangoora V, Rivera R, 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):1229-1238.
  9. 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. JAMA, 2019;322(13):1261-1270.
  10. Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA, 2020;323(5):423-431.

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