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Holford, P. Vitamin C Intervention for Critical COVID-19. Encyclopedia. Available online: https://encyclopedia.pub/entry/16087 (accessed on 16 May 2024).
Holford P. Vitamin C Intervention for Critical COVID-19. Encyclopedia. Available at: https://encyclopedia.pub/entry/16087. Accessed May 16, 2024.
Holford, Patrick. "Vitamin C Intervention for Critical COVID-19" Encyclopedia, https://encyclopedia.pub/entry/16087 (accessed May 16, 2024).
Holford, P. (2021, November 17). Vitamin C Intervention for Critical COVID-19. In Encyclopedia. https://encyclopedia.pub/entry/16087
Holford, Patrick. "Vitamin C Intervention for Critical COVID-19." Encyclopedia. Web. 17 November, 2021.
Vitamin C Intervention for Critical COVID-19
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This entry is adapted from the peer-reviewed paper 10.3390/life11111166

Coronaviruses are single-stranded ribonucleic acid viruses comprising a lipid bilayer containing crown-like spikes (Latin, Corona = Crown) on their outer surface.

vitamin C SARS-CoV2 COVID-19 clinical trials randomised controlled trials

1. Introduction

Coronaviruses are single-stranded ribonucleic acid viruses comprising a lipid bilayer containing crown-like spikes (Latin, Corona = Crown) on their outer surface [1]. Infection with these viruses can affect both the upper and lower respiratory tract and can cause diseases ranging from a mild form, or common cold, to pneumonia [2]. In early December 2019, there were reports of infections with pneumonia-like symptoms of unidentified causes in China [3]. The infections were subsequently identified as being caused by a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the resultant disease being named coronavirus disease (COVID-19) in February 2020 [4]. Globally, as of August 2021, there have been over 200 million confirmed cases of COVID-19, including nearly 4.5 million deaths, reported [5]. Initial data indicated that the majority of patients were aged over 40 years, and that the risk of death increased with age [1]. Since then, numerous other risk factors have been identified, including specific underlying health conditions [6]. Currently, there is a global research effort to try and identify therapies that may help in the treatment of COVID-19.
Vitamin C is an essential nutrient that has important roles in immune function, including antioxidant, anti-inflammatory, antithrombotic, and immuno-modulatory functions [7][8]. Vitamin C deficiency, defined as a plasma concentrations of ≤11 µmol/L, is more common in the elderly, male gender, people with comorbidities, and low socioeconomic status [9]. These are also risk factors for COVID-19 infection [6]. Severe respiratory infections, such as pneumonia, are common clinical conditions that lead to a high requirement for vitamin C, thus providing grounds for active vitamin C replacement in patients who suffer from severe respiratory infections [10]. Although a vitamin C intake of 200 mg daily in healthy volunteers produces a saturating plasma concentration of 70 to 90 µmol/L [11][12], at least ten-fold higher doses (i.e., 2–3 g/day) are required to saturate the plasma of critically ill patients [13][14][15]. Critically ill patients are defined as patients at high risk for actual or potential life-threatening injuries and illnesses, requiring at least organ support and are continuously monitored in the intensive care unit (ICU). Vitamin C is generally administered parenterally to critically ill patients as it provides significantly higher circulating concentrations than enteral vitamin C [16].
Vitamin C administration in patients with pneumonia, sepsis and acute respiratory distress syndrome (ARDS) has shown potential benefits such as reducing duration of hospital and ICU stay and mortality [8]. Pneumonia, sepsis and ARDS are common complications of patients with severe COVID-19 and in March 2020, the World Health Organization highlighted vitamin C as a potential adjunctive therapy with biologic plausibility for patients with critical COVID-19 [17].

2. Vitamin C Status in Patients with COVID-19

Significant evidence indicates that patients with severe respiratory infections have depleted vitamin C status, with the prevalence of deficiency increasing with the severity of the condition [18][19][20]. The vitamin C status of patients with COVID-19 has been reported in several small observational studies (Table 1) [21][22][23][24][25][26]. Plasma concentrations of vitamin C in most of these patients were reported to be very low with 70–80% of the patients having hypovitaminosis C (plasma concentration <23 µmol/L) [22][24]. The low concentrations were despite patients receiving on average 124 mg/day vitamin C in their enteral or parenteral nutrition [26]. Interestingly, markers of oxidative stress were elevated in the COVID-19 patients relative to controls and there was an inverse correlation between oxidative stress markers and vitamin C status in the patients [25]. Thus, vitamin C supplementation appears warranted in these patients to address their hypovitaminosis C and restore adequate plasma vitamin C status [21]. It should be noted that short-term (i.e., 2–4 day) intervention with intravenous vitamin C may not be of sufficient duration to provide lasting benefit as 15–25% of patients can return to hypovitaminosis C status following cessation of intervention [15][27].
Table 1. Vitamin C status in patients with COVID-19.
Population
Location		 Method Findings Reference
18 patients with ARDS 1
Barcelona, Spain.		 Plasma
HPLC-PDA 2		 17 patients had <8 µM vitamin C
1 patient had 14 µM vitamin C		 [23]
21 ICU 3 patients
Thornton, Colorado, USA		 Serum Total cohort (n = 21) had 22 µM vitamin C
(45% were deficient, 70% were hypovitaminosis C)
Survivors (n = 11) had 29 µM vitamin C
Non-Survivors (n = 10) had 15 µM vitamin C		 [22]
31 hospitalised patients
51 healthy controlsShanghai, China		 Plasma
UHPLC-MS 4		 6 patients (no IVC 5) had 11 µM vitamin C
25 patients given 100 mg/kg/day IVC had 76 µM
51 healthy controls had 52 µM vitamin C		 [21]
50 symptomatic patients
21 healthy controls
Jigwa, Nigeria		 Serum
Colourimetric		 Patients had 19 µM vitamin C
Controls had 25 µM vitamin C		 [25]
9 ICU patients with severe pneumonia
Liège, Belgium		   Patients had 22 µM vitamin C
(reference range: 35–86 µM)		 [26]
67 patients with ARDS
Barcelona, Spain		 Plasma
HPLC		 Mean vitamin C concentration was 8 ± 3 µM
55 patients (82%) had values <23 µM
12 patients (18%) had values <6 µM		 [24]

1 ARDS: acute respiratory distress syndrome, 2 PDA: photo diode array, 3 ICU: intensive care unit, 4 UHPLC-MS: ultra-high-performance liquid chromatography-mass spectrometry, 5 IVC: intravenous vitamin C. Note: vitamin C concentrations <11 µM are considered deficient, and <23 µM are considered hypovitaminosis C.

3. Randomised Controlled Trials with Intravenous Vitamin C

The first published randomised placebo-controlled trial was carried out in Wuhan, China, and administered IVC at a dose of 12 g/12 h at a late stage (10–17 days after the onset of the first symptoms) for seven days (Table 2) [28]. This trial reported a 70% reduced ICU and hospital mortality in patients with sequential organ failure assessment (SOFA) scores ≥3 who received IVC relative to those who received placebo (4 vs. 10 days, p = 0.03). There was no difference in invasive ventilation-free days of the intervention vs. placebo group overall (26.5 vs. 10.5 days, p = 0.56), however, this trial was halted early due to diminishing patient numbers. Nevertheless, increased peripheral capillary oxygen saturation/pulmonary function was observed in the IVC group relative to placebo (PaO2/FiO2; 229 vs. 151 mmHg, p = 0.01). Furthermore, the study group also had a lower inflammation marker (interleukin-6, IL-6) than the placebo group (19 vs. 158 pg/mL, p = 0.04). Patients with worse organ dysfunction may have more severe vitamin C deficiency [29], which could contribute to the benefit of intervention being more significant in the more severe COVID-19 patients with higher baseline SOFA scores in this study.
Table 2. Randomised controlled trials investigating the effect of intravenous vitamin C (IVC) in patients with COVID-19.
Population
Mean Age
Location		 Intervention
Duration		 Findings (IVC vs. Control) Reference
54 patients with
COVID-19-pneumonia
and multiple organ injury
Age = 67 ± 13 years
Wuhan, Hubei, China		 IVC 1 24 g/day (n = 27)
or placebo (n= 29)
for 7 days		 Higher PaO2/FiO2 2 (229 vs. 151 mmHg, p = 0.01)
Lower Interleukin-6 (19 vs. 158 pg/mL, p = 0.04)
Lower ICU 3 and hospital mortality in patients with SOFA 4 scores ≥3 (4 vs. 10 days, p = 0.03)
No difference in ventilation-free days (26.5 vs. 10.5 days, p = 0.56)		 [28]
150 patients with severe COVID-19
Age = 52–53 years
Karachi, Pakistan		 IVC 50 mg/kg/day
+ standard therapy
or standard therapy
(75 per group)		 Patients became symptom-free earlier
(7.1 ± 1.8 vs. 9.6 ± 2.1 days, p < 0.0001)
Patients spent fewer days in the hospital
(8.1 ± 1.8 vs. 10.7 ± 2.2 days, p < 0.0001)
No difference in need for mechanical ventilation (16% vs. 20%, p = 0.4)
No difference in mortality (9.3% vs. 14.6%, p = 0.3)		 [30]
60 patients with COVID-19
Age = 57–61 years
Tehran, Iran		 IVC 6 g/day
+ standard therapy
or standard therapy
(30 per group)
for 5 days		 Lower body temperature on 3rd day
of hospitalisation (p = 0.001)
Improvement in oxygen saturation on 3rd day
of hospitalisation (p = 0.014)
No differences in length of ICU stay or mortality		 [31]

1 IVC: intravenous vitamin C, 2 PaO2/FiO2: ratio of partial pressure of oxygen to fraction of inspired oxygen, 3 ICU: intensive care unit, 4 SOFA: sequential organ failure assessment.

An open label RCT of 150 critical COVID-19 patients in Karachi, Pakistan, administered IVC at 50 mg/kg/day (3.5 g for 70 kg person) along with standard care or standard therapy alone and reported that the IVC group became symptom-free earlier (7.1 vs. 9.6 days, p < 0.0001), and spent fewer days in the hospital (8.1 vs. 10.7 days, p < 0.0001; Table 2) [30]. However, there were non-significant reductions in need for mechanical ventilation and mortality. A similar open label RCT in Tehran, Iran, randomised 60 patients with COVID-19 to 6 g/day IVC for five days or standard care [31]. Body temperature was reduced (p = 0.001) and oxygenation (SpO2) increased (p = 0.014) after three days of receiving the treatment. There were, however, no differences in ICU length of stay or mortality.

References

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  3. Zhu, N.; Zhang, D.; Wang, W.; Li, X.; Yang, B.; Song, J.; Zhao, X.; Huang, B.; Shi, W.; Lu, R.; et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N. Engl. J. Med. 2020, 382, 727–733.
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  5. WHO Coronavirus Disease 2019 (COVID-19) Situation Report as of 2 August 2021 (5:19pm CEST). Available online: https://covid19.who.int/ (accessed on 3 August 2021).
  6. Centres for Disease Control and Prevention Assessing Risk Factors for Severe COVID-19 Illness 2020. Available online: https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/assessing-risk-factors.html (accessed on 18 August 2021).
  7. Carr, A.C. Vitamin C in pneumonia and sepsis. In Vitamin C: New Biochemical and Functional Insights; Chen, Q.V.M., Ed.; CRC Press/Taylor & Francis: Boca Raton, FL, USA, 2020; pp. 115–135.
  8. Holford, P.; Carr, A.C.; Jovic, T.H.; Ali, S.R.; Whitaker, I.S.; Marik, P.E.; Smith, A.D. Vitamin C-An Adjunctive Therapy for Respiratory Infection, Sepsis and COVID-19. Nutrients 2020, 12, 3760.
  9. Carr, A.C.; Rowe, S. Factors Affecting Vitamin C Status and Prevalence of Deficiency: A Global Health Perspective. Nutrients 2020, 12, 1963.
  10. Hemilä, H. Vitamin C and Infections. Nutrients 2017, 9, 339.
  11. Levine, M.; Conry-Cantilena, C.; Wang, Y.; Welch, R.W.; Washko, P.W.; Dhariwal, K.R.; Park, J.B.; Lazarev, A.; Graumlich, J.F.; King, J.; et al. Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. USA 1996, 93, 3704–3709.
  12. Levine, M.; Wang, Y.; Padayatty, S.J.; Morrow, J. A new recommended dietary allowance of vitamin C for healthy young women. Proc. Natl. Acad. Sci. USA 2001, 98, 9842–9846.
  13. Carr, A.C.; Rosengrave, P.C.; Bayer, S.; Chambers, S.; Mehrtens, J.; Shaw, G.M. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Critical Care 2017, 21, 300.
  14. Long, C.L.; Maull, K.I.; Krishnan, R.S.; Laws, H.L.; Geiger, J.W.; Borghesi, L.; Franks, W.; Lawson, T.C.; Sauberlich, H.E. Ascorbic acid dynamics in the seriously ill and injured. J. Surg Res. 2003, 109, 144–148.
  15. De Grooth, H.J.; Manubulu-Choo, W.P.; Zandvliet, A.S.; Spoelstra-de Man, A.M.E.; Girbes, A.R.; Swart, E.L.; Oudemans-van Straaten, H.M. Vitamin C Pharmacokinetics in Critically Ill Patients: A Randomized Trial of Four IV Regimens. Chest 2018, 153, 1368–1377.
  16. Padayatty, S.J.; Sun, H.; Wang, Y.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Wesley, R.A.; Levine, M. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann. Intern. Med. 2004, 140, 533–537.
  17. World Health Organization. A Coordinated Global Research Roadmap: 2019 Novel Coronavirus; World Health Organization: Geneva, Switzerland, 2020.
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  21. Xing, Y.; Zhao, B.; Yin, L.; Guo, M.; Shi, H.; Zhu, Z.; Zhang, L.; He, J.; Ling, Y.; Gao, M.; et al. Vitamin C supplementation is necessary for patients with coronavirus disease: An ultra-high-performance liquid chromatography-tandem mass spectrometry finding. J. Pharm. Biomed. Anal. 2021, 196, 113927.
  22. Arvinte, C.; Singh, M.; Marik, P.E. Serum Levels of Vitamin C and Vitamin D in a Cohort of Critically Ill COVID-19 Patients of a North American Community Hospital Intensive Care Unit in May 2020: A Pilot Study. Med. Drug Discov. 2020, 8, 100064.
  23. Chiscano-Camón, L.; Ruiz-Rodriguez, J.C.; Ruiz-Sanmartin, A.; Roca, O.; Ferrer, R. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Crit. Care 2020, 24, 522.
  24. Tomasa-Irriguible, T.M.; Bielsa-Berrocal, L. COVID-19: Up to 82% critically ill patients had low Vitamin C values. Nutr. J. 2021, 20, 66.
  25. Muhammad, Y.; Kani, Y.A.; Iliya, S.; Muhammad, J.B.; Binji, A.; El-Fulaty Ahmad, A.; Kabir, M.B.; Umar Bindawa, K.; Ahmed, A. Deficiency of antioxidants and increased oxidative stress in COVID-19 patients: A cross-sectional comparative study in Jigawa, Northwestern Nigeria. SAGE Open. Med. 2021, 9, 2050312121991246.
  26. Pincemail, J.; Cavalier, E.; Charlier, C.; Cheramy-Bien, J.P.; Brevers, E.; Courtois, A.; Fadeur, M.; Meziane, S.; Goff, C.L.; Misset, B.; et al. Oxidative Stress Status in COVID-19 Patients Hospitalized in Intensive Care Unit for Severe Pneumonia. A Pilot Study. Antioxidants 2021, 10, 257.
  27. Fowler, A.A.; Truwit, J.D.; Hite, R.D.; Morris, P.E.; DeWilde, C.; Priday, A.; Fisher, B.; Thacker, L.R.; Natarajan, R.; Brophy, D.F.; 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, 1261–1270.
  28. Zhang, J.; Rao, X.; Li, Y.; Zhu, Y.; Liu, F.; Guo, G.; Luo, G.; Meng, Z.; De Backer, D.; Xiang, H.; et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Ann. Int. Care 2021, 11, 5.
  29. Borrelli, E.; Roux-Lombard, P.; Grau, G.E.; Girardin, E.; Ricou, B.; Dayer, J.; Suter, P.M. 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, 392–397.
  30. Kumari, P.; Dembra, S.; Dembra, P.; Bhawna, F.; Gul, A.; Ali, B.; Sohail, H.; Kumar, B.; Memon, M.K.; Rizwan, A. The Role of Vitamin C as Adjuvant Therapy in COVID-19. Cureus 2020, 12, e11779.
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