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Vitamin C

Last Updated: November 3, 2020

Vitamin C (ascorbic acid) is a water-soluble vitamin that is thought to have beneficial effects in patients with severe and critical illnesses. It is an antioxidant and free radical scavenger that has anti-inflammatory properties, influences cellular immunity and vascular integrity, and serves as a cofactor in the generation of endogenous catecholamines.1,2 Because humans may require more vitamin C in states of oxidative stress, vitamin C supplementation has been evaluated in numerous disease states, including serious infections and sepsis. Because serious COVID-19 may cause sepsis and acute respiratory distress syndrome (ARDS), the potential role of high doses of vitamin C in ameliorating inflammation and vascular injury in patients with COVID-19 is being studied.

Recommendation for Non-Critically Ill Patients With COVID-19

  • There are insufficient data for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in non-critically ill patients.

Rationale

Because patients who are not critically ill with COVID-19 are less likely to experience oxidative stress or severe inflammation, the role of vitamin C in this setting is unknown.

Recommendation for Critically Ill Patients With COVID-19

  • There are insufficient data for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in critically ill patients.

Rationale

There are no completed controlled trials of vitamin C in patients with COVID-19, and the available observational data are sparse and inconclusive. Studies of vitamin C in sepsis patients and ARDS patients have reported variable efficacy and few safety concerns.

Clinical Data on Vitamin C in Critically Ill Patients Without COVID-19

Intravenous Vitamin C Alone

A small, three-arm pilot study compared two regimens of intravenous (IV) vitamin C to placebo in 24 critically ill patients with sepsis. Over the 4-day study period, patients who received vitamin C 200 mg/kg per day and those who received vitamin C 50 mg/kg per day had lower sequential organ failure assessment (SOFA) scores and levels of proinflammatory markers than patients who received placebo.3

In a randomized controlled trial in critically ill patients with sepsis-induced ARDS (n = 167), patients who received IV vitamin C 200 mg/kg per day for 4 days had SOFA scores and levels of inflammatory markers that were similar to those observed in patients who received placebo. However, 28-day mortality was lower in the treatment group (29.8% vs. 46.3%; P = 0.03), coinciding with more days alive and free of the hospital and the intensive care unit.4 A post hoc analysis of the study data reported a difference in median SOFA scores between the treatment group and placebo group at 96 hours; however, this difference was not present at baseline or 48 hours.5

Intravenous Vitamin C Plus Thiamine With or Without Hydrocortisone

Two small studies that used historic controls reported favorable clinical outcomes (i.e., reduced mortality, reduced risk of progression to organ failure, and improved radiographic findings) in patients with sepsis or severe pneumonia who received a combination of vitamin C, thiamine, and hydrocortisone.6,7

Three recent randomized trials in which patients received vitamin C and thiamine (with or without hydrocortisone) to treat sepsis and septic shock showed that this combination conferred benefits for certain clinical parameters. However, no survival benefit was reported. Two trials observed reductions in organ dysfunction (as measured by a SOFA score at Day 3)8,9 or the duration of shock10 without an effect on clinical outcomes. Two other trials found no differences in any physiologic or outcome measure between the treatment and placebo groups.11,12

See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of vitamin C in patients with COVID-19.

Other Considerations

It is important to note that high circulating concentrations of vitamin C may affect the accuracy of point-of-care glucometers.13

References

  1. Wei XB, Wang ZH, Liao XL, et al. Efficacy of vitamin C in patients with sepsis: an updated meta-analysis. Eur J Pharmacol. 2020;868:172889. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31870831.
  2. Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit Care Med. 2011;39(6):1454-1460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21358394.
  3. Fowler AA, 3rd, 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24484547.
  4. Fowler AA, 3rd, 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31573637.
  5. Fowler AA, 3rd, Fisher BJ, Kashiouris MG. Vitamin C for sepsis and acute respiratory failure–reply. JAMA. 2020;323(8):792-793. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32096845.
  6. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27940189.
  7. Kim WY, Jo EJ, Eom JS, et al. Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study. J Crit Care. 2018;47:211-218. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30029205.
  8. 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. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31950979.
  9. Chang P, Liao Y, Guan J, et al. Combined treatment with hydrocortisone, vitamin c, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest. 2020;158(1):174-182. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32243943.
  10. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest. 2020;158(1):164-173. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32194058.
  11. Hwang SY, Ryoo SM, Park JE, et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med. 2020; Published online ahead of print. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32780166.
  12. Moskowitz A, Huang DT, Hou PC, et al. Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: the ACTS randomized clinical trial. JAMA. 2020;324(7):642-650. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32809003.
  13. Hager DN, Martin GS, Sevransky JE, Hooper MH. Glucometry when using vitamin C in sepsis: a note of caution. Chest. 2018;154(1):228-229. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30044741.