The protective role of intravenous ascorbic acid (vitamin C) in critically ill patients with Covid-19

By: DSM Pharma Solutions Editors

Covid-19 poses an unprecedented global health risk to patients and healthcare systems, alike. In severe cases, Covid-19 can precipitate multiple organ failure and death; this may be the result of host immune response dysfunction, which can decompensate into a systematic inflammatory response, or a ‘cytokine storm.’ While data is limited, recent research indicates the potentially beneficial role of intravenous (IV) ascorbic acid administration in critically ill patients. 

“Covid-19 precipitates endothelial dysfunction and systemic inflammation – in critically ill patients, this may precipitate a ‘cytokine storm’ and, in the most severe cases, result in multi-organ failure or death.”   

Covid-19 was initially assumed to be primarily a lung/respiratory disease. But more recent evidence indicates it should be considered a multi-organ disease, a systemic condition affecting the lung, but also e.g. the epithelium in the gut and in blood vessels.1 In severe cases, it may decompensate into multiple organ failure and eventual death.2-6 Upon reaching the lung alveoli, the responsible virus, SARS-CoV-2, rapidly replicates and elicits a robust immune response, often referred to as a ‘cytokine storm,’ which often develops in patients with severe disease.  A ‘cytokine storm’ most often denotes an injurious and hyperactive immune response characterized by the release of interferons, interleukins, tumor-necrosis factors, chemokines, and several other mediators.7 This profound rise in inflammatory mediators often contributes to the deleterious effects of Covid-19 in critically ill patients, resulting in sepsis and septic shock.24 In fact, data from a retrospective cohort study from Wuhan, China demonstrated that nearly 60% of critically ill Covid-19 cases developed sepsis and 20% septic shock, while sepsis and septic shock were present in 100% and 70% of fatal cases, respectively.5

In the absence of an approved prophylactic vaccine, a number of empirical therapeutic approaches have emerged. One particularly promising intervention is IV ascorbic acid administration in critically ill patients with Covid-19. The protective role of ascorbic acid is hypothesized to act via a range of mechanisms including, but not limited to, attenuating oxidative stress/ inflammation, enhancing immune cell function and improving vasopressor synthesis.8 Plasma ascorbic acid levels are particularly low in critically ill patients8-12, particularly in those with sepsis14-16 and are typically associated with higher levels of inflammation8 and poorer outcomes (e.g. multiple organ failure and mortality).17,18

A recent meta-analysis evaluating the effect of IV ascorbic acid in critically ill patients without Covid-19, demonstrated vasopressor-sparing effects, in addition to a reduced need for mechanical ventilation. Compared with controls, the administration of IV ascorbic acid was associated with a decreased need for vasopressor support (standardized mean difference -0.71; 95% confidence interval (-1.16 to -0.26); p = 0.002) and decreased duration of mechanical ventilation (standardized mean difference -0.5; 95% confidence interval (-0.93 to -0.06); p = 0.03), although no difference was detected in mortality.19 A second meta-analysis, which evaluated the impact of ascorbic acid on ICU length of stay and duration of mechanical ventilation found a significant effect of on both parameters.20 In this analysis, ascorbic acid was most beneficial for patients with the longest ventilation, corresponding to the most severely ill patients, for which a dosage of 1–6 g/day shortened ventilation time by 25% (P< 0.0001).21 Regarding dose, the prevailing literature suggests that IV ascorbic acid doses up to 3 to 6 g daily are required in order to restore normal plasma concentrations in critically ill patients.10 No significant adverse effects from high-dose IV ascorbic acid have been reported22 and doses of 200 mg/kg/day were generally well-tolerated in critically ill patients with sepsis.16 Given the heterogeneity of critically ICU patients, minimizing therapeutic variance remains paramount. Regarding dosing and administration, ascorbic acid absorption may be reduced via the oral or enteral route, thus increasing the preference for IV administration in patients presenting with signs and symptoms of endothelial dysfunction and systemic inflammation.23

While robust evidence for the treatment of Covid-19 patients with IV ascorbic acid is not yet available, several clinical trials are underway. Until then, evidence from otherwise critically ill patients suggests IV ascorbic acid may represent a safe, inexpensive and promising adjunct therapy for critically ill Covid-19 patients with sepsis and related complications.

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1. Spuntarelli, V., Luciani, M., Bentivegna, E. et al. COVID-19: is it just a lung disease? A case-based review. SN Compr. Clin. Med. 2, 1401–1406 (2020).

2. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020;382:727-33.

3. Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507-13.

4. Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.

5. Bouadma L, Lescure FX, Lucet JC, Yazdanpanah Y, Timsit JF. Severe SARS-CoV-2 infections: practical considerations and management strategy for intensivists. Intensive Care Med 2020;46:579-82.

6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet 2020;395:1054-62.6. Sinha P, Matthay MA, Calfee CS, et al. Is “cytokine storm” relevant to Covid-19? JAMA Internal Med 2020;180(9):1152-1154.

7. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Critical care (London, England) 2015;19:418-.

8. Schorah CJ, Downing C, Piripitsi A, et al. Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients. The American Journal of Clinical Nutrition 1996;63:760-5.

9. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 2003;109:144-8.

10. Evans-Olders R, Eintracht S, Hoffer LJ. Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition 2010;26:1070-4.

11. Rodemeister S, Duquesne M, Adolph M, Nohr D, Biesalski HK, Unertl K. Massive and long-lasting decrease in vitamin C plasma levels as a consequence of extracorporeal circulation. Nutrition 2014;30:673-8.

12. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Critical Care 2017;21:300.

13. Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors 2009;35:5-13.

14. Galley HF, Davies MJ, Webster NR. Ascorbyl radical formation in patients with sepsis: Effect of ascorbate loading. Free Radical Biology and Medicine 1996;20:139-43.

15. 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.

16. Grooth HJ, Spoelstra-de Man AME, Oudemans-van Straaten HM. Early plasma vitamin C concentration, organ dysfunction and ICU mortality. Intensive Care Med 2014;40:S199.

17. Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care 2018;22:70.

18. Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE Open Medicine 2018;6:2050312118807615.

19. Hemilä H, Chalker E. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients 2019;11:708.

20. Hemila H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care 2020;8:15.

21. Oudemans-van Straaten HM, Spoelstra-de Man AM, de Waard MC. Vitamin C revisited. Critical care 2014;18:460-.

22. Seno T, Inoue N, Matsui K, et al. Functional expression of sodium-dependent vitamin C transporter 2 in human endothelial cells. Journal of vascular research 2004;41:345-51.

23. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. The Lancet 2018;392:75-87.

Published on

29 September 2020


7 min read

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