Vitamin C and Sepsis – Miracle, Madness or Still Murky?

Experimental and emerging data suggest intravenous ascorbic acid may be a potential therapy in patients presenting with septic shock, but more evidence is needed to confirm or refute the clinical utility of ascorbic acid (vitamin C). Proposed mechanisms of this essential water-soluble vitamin include anti-inflammatory effects, reduction in oxidative damage, and preservation of endothelial function and microcirculatory flow.¹ Additionally, ascorbic acid is a cofactor in the enzymes required for synthesizing endogenous norepinephrine and vasopressin.² Intravenous administration may be required to achieve normal serum levels in these patients due to saturable intestinal absorption.³ Findings indicate serum levels of ascorbic acid are lower in critically ill patients due to the increased metabolic turnover in this acute inflammatory response and are associated with severity of illness.^4,5 Low plasma levels of ascorbic acid have been shown to be inversely correlated with multiple organ failure incidence and directly correlated with survival.⁶

A randomized controlled trial of intravenous ascorbic acid in patients with severe sepsis in a medical ICU in the United States showed no study-related adverse events (i.e., tachycardia, hypotension, hypernatremia, nausea/vomiting), a faster reduction in Sequential Organ Failure Assessment (SOFA) scores, and improved inflammatory markers.⁷ A total of 24 patients were assigned to placebo, low dose ascorbic acid (50 mg/kg/day), or high dose ascorbic acid (200 mg/kg/day) for 96 hours.⁷

Further, Zabet et al. conducted a randomized double blind trial in Iran and evaluated the effect of ascorbic acid 25 mg/kg IV q6h on 28 critically ill surgical patients with septic shock requiring vasopressor support.⁸ Mean norepinephrine dose (7.44 ± 3.65 vs. 13.79 ± 6.48 mcg/min, p=0.004) and duration of use (49.64 ± 25.67 vs. 71.57 ± 1.60 h, p=0.007) were significantly lower in patients treated with ascorbic acid than placebo. There were no differences in length of ICU stay; however, patients in the treatment group had a significantly lower 28-day mortality (14.28% vs. 64.28%, p=0.009) and no adverse effects were found during the study.⁸

The most recently published study was a retrospective review comparing the clinical course of 47 septic patients with a procalcitonin > 2 ng/ml treated with thiamine 200 mg IV q12hr, ascorbic acid 1.5 g IV q6hr, and hydrocortisone 50 mg IV q6hr.⁹ Hospital mortality was significantly reduced in the treatment group (8.5% vs. 40.4%, 95% CI 0.04-0.48). A reduction in SOFA scores, requirement for RRT, and duration of vasopressor use were also shown. The authors believe ascorbic acid and hydrocortisone act synergistically by restoring glucocorticoid function, improving transport of ascorbic acid into the cell, and preserving endothelial integrity.  A concern with high doses of ascorbic acid is the metabolic conversion to oxalate. Although oxalate is excreted through the kidneys, patients with renal impairment may have increased serum levels resulting in crystallization in the kidney. However, within the small sample size, Marik et al. reported improvement in renal function.⁹  There were many scientific limitations in Marik et al study which are highlighted within a letter to the editor of CHEST written by Drs. Kalil, Johnson and Cawcutt. Click here to read the letter.

The optimal dose and time of administration are still to be determined. The safety concerns of oxalate accumulation and pro-oxidant effects should also be considered with high-dose ascorbic acid. Although recent and very limited evidence suggests potential benefits with intravenous ascorbic acid, further studies are needed to confirm these preliminary findings. A large double-blind placebo-controlled randomized clinical trial is necessary to confirm or refute the efficacy and safety of ascorbic acid in patients with septic shock.

References

1. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Crit Care. 2014;18(4):460.
2. Carr AC, Shaw GM, Fowler AA, et al. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 2015;19:418.
3. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-7.
4. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res. 2003 Feb;109(2):144-8.
5. Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. Am J Clin Nutr. 1996;63(5):760-5.
6. Borrelli E, Roux-Lombard P, Grau GE, et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk.Crit Care Med. 1996;24(3):392–397.
7. Fowler AA, Syed AA, Knowlson S, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12:32.
8. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor’s requirement in septic shock. J Res Pharm Pract. 2016;5(2):94-100.
9. 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. 2016.S0012-3692(16)62564-3.

Content courtesy of Stephanie Willis, Scott Bergman and Dr. Andre Kalil. Commentary and opinions reflect those of the authors and may not reflect the opinions of the Division or UNMC as a whole.