Last Updated: April 21, 2021
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 SARS-CoV-2 infection 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 is insufficient evidence 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.
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.
Clinical Data on Vitamin C in Outpatients With COVID-19
Oral Ascorbic Acid Versus Zinc Gluconate Versus Both Agents Versus Standard of Care
In an open-label clinical trial that was conducted at two sites in the United States, outpatients with laboratory-confirmed SARS-CoV-2 infection were randomized to receive either 10 days of oral ascorbic acid 8,000 mg, zinc gluconate 50 mg, both agents, or standard of care.3 The primary end point was the number of days required to reach a 50% reduction in the patient’s symptom severity score. The study was stopped early by an operational and safety monitoring board due to futility after 40% of the planned 520 participants were enrolled (n = 214).
Patients who received standard of care achieved a 50% reduction in their symptom severity scores at a mean of 6.7 days (SD 4.4 days) compared with 5.5 days (SD 3.7 days) for the ascorbic acid arm, 5.9 days (SD 4.9 days) for the zinc gluconate arm, and 5.5 days (SD 3.4 days) for the arm that received both agents (overall P = 0.45). Nonserious adverse effects occurred more frequently in patients who received supplements than in those who did not; 39.5% of patients in the ascorbic acid arm, 18.5% in the zinc gluconate arm, and 32.1% in the arm that received both agents experienced nonserious adverse effects compared with 0% of patients in the standard of care arm (overall P < 0.001). The most common nonserious adverse effects in this study were gastrointestinal events.
The limitations of this study include the small sample size and the lack of a placebo control. In outpatients with COVID-19, treatment with high-dose zinc gluconate, ascorbic acid, or a combination of the two supplements did not significantly decrease the number of days required to reach a 50% reduction in a symptom severity score compared with standard of care.
Recommendation for Critically Ill Patients With COVID-19
- There is insufficient evidence for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in critically ill patients.
There are no controlled trials that have definitively demonstrated a clinical benefit for vitamin C in critically ill patients with COVID-19, and the available observational data are inconclusive. Studies of vitamin C regimens in sepsis patients and ARDS patients have reported variable efficacy and few safety concerns.
Clinical Data on Vitamin C in Critically Ill Patients
Intravenous Vitamin C Alone in Patients With COVID-19
A pilot clinical trial in China randomized 56 adults with COVID-19 in the intensive care unit to receive intravenous (IV) vitamin C 24 g per day or placebo for 7 days. The study was terminated early due to a reduction in the number of cases of COVID-19 in China. Overall, the study found no differences between the arms in mortality, the duration of mechanical ventilation, or the change in median sequential organ failure assessment (SOFA) scores. The study reported improvements in oxygenation (as measured by the ratio of arterial partial pressure of oxygen to fraction of inspired oxygen [PaO2/FiO2]) from baseline to Day 7 in the treatment arm that were statistically greater than those observed in the placebo arm (+20.0 vs. -51.9; P = 0.04).4
Intravenous Vitamin C Alone in Patients Without COVID-19
A small, three-arm pilot study compared two regimens of 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 SOFA scores and lower levels of proinflammatory markers than patients who received placebo.5
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.6 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.7
Intravenous Vitamin C Plus Thiamine With or Without Hydrocortisone in Critically Ill Patients Without COVID-19
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.8,9 Subsequently, several 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 change in SOFA score on Day 3)10,11 or the duration of shock12 without an effect on clinical outcomes. Three other trials, including a large trial of 501 sepsis patients, found no differences in any physiologic or outcome measures between the treatment and placebo groups.13-15
See ClinicalTrials.gov for a list of clinical trials that are evaluating the use of vitamin C in patients with COVID-19.
It is important to note that high circulating concentrations of vitamin C may affect the accuracy of point-of-care glucometers.16,17
- 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.
- 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.
- Thomas S, Patel D, Bittel B, et al. Effect of high-dose zinc and ascorbic acid supplementation vs usual care on symptom length and reduction among ambulatory patients with SARS-CoV-2 infection: the COVID A to Z randomized clinical trial. JAMA Netw Open. 2021;4(2):e210369. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33576820.
- Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann Intensive Care. 2021;11(1):5. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33420963.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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;46(11):2015-2025. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32780166.
- 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.
- Sevransky JE, Rothman RE, Hager DN, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA. 2021;325(8):742-750. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33620405.
- 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.
- Food and Drug Administration. Blood glucose monitoring devices. 2019. Available at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/blood-glucose-monitoring-devices. Accessed March 26, 2021.