Table 3. Clinical Studies Involving IVAA in COVID-19.
| Study type | Intervention | Outcome IVAA vs. control | Comments/level of evidence |
|---|---|---|---|
| RCT of 56 COVID-19 pneumonia and multiple organ injury ICU patients. Age: 67 ± 13 years. Severe COVID-19 PaO2/FIO2 < 300 [81] | IVAA: 24 g/day (n = 27) or placebo (n = 29) for 7 days (*corticosteroid allowed) (time to treatment 11 - 25 days to onset of symptoms) | IVAA: lower ICU and hospital mortality in patients with SOFA scores ≥ 3 (3 - 10 days, P = 0.03). No difference in ventilation-free days (26.5 vs. 10.5 days, P = 0.56) | IVAA group had higher PaO2/FIO2 and lower IL-6 levels on admission. Level of evidence 2 |
| Open label RCT of 150 patients with severe COVID-19. Age: 52 - 53 years [82] | IVAA: 50 mg/kg/day + standard therapy or standard therapy (75 per group) | IVAA: sooner to symptom-free status (7.1 ± 1.8 vs. 9.6 ± 2.1) (P < 0.0001). No difference in mortality or need for mechanical ventilation | Corticosteroids allowed. Level of evidence 2 |
| Open label RCT of 60 patients with severe COVID-19. Age: 57 - 61 years [83] | IVC 6 g/day + standard therapy or standard therapy (n = 30 per group) for 5 days | Lower body temperature on third day of hospitalization (P = 0.001) Improvement in oxygen saturation on third day of hospitalization (P = 0.014). No difference in mortality | Both groups received dexamethasone. Level of evidence 2 |
| Retrospective cohort study of 76 patients with moderate to severe COVID-19. Age: 52 - 71 years [84] | IVAA: 6 g/12 h on first day, 6 g/day for following 4 days + standard therapy (n = 30) or standard therapy (n = 46) for 5 days | Improved oxygenation in treatment group. Decrease in pro-inflammatory biomarkers. Reduced risk of 28-day mortality (HR: 0.14, 95% CI: 0.03 - 0.72, P = 0.037) | Level of evidence 3 |
| Propensity matched before and after retrospective analysis of 110 patients with moderate COVID-19 pneumonia. Age: 31 - 47 years [85] | IVAA: 100 mg/kg/day + standard therapy or standard therapy (55 per group) for 7 days | Fewer patients progressing to severe type of COVID-19 (P = 0.03). Reduction in incidence and progression of SIRS (P = 0.008) | Level of evidence 3 |
| Retrospective analysis of 232 patients with COVID-19 pneumonia. Age: 46 - 74 years [86] | IVAA: 2 g/day + standard therapy (n = 153) or standard therapy (n = 170) | Shorter length of hospital stay (7 vs. 8 days, P = 0.05). No difference in re-admission rate (P = 0.94), admission to ICU, need for advanced oxygen support (P = 0.49), and mortality (P = 0.52). Need for advanced medical treatment (P < 0.001) | Level of evidence 3 |
| Retrospective study of 34 critically ill patients with COVID-19. Age: 53 - 77 years [87] | IVAA: 1.5 g/6 h + standard therapy (n = 8) or standard therapy (n = 24) for 4 days | Higher rate of hospital mortality in treatment group (19 (79%) vs. 7 (88%), P = 0.049) and SOFA score. No difference in daily vasopressor requirement or ICU length of stay | Higher baseline SOFA score in IVAA group. Level of evidence 3 |
| Retrospective study of 236 patients with severe COVID-19. Age: 57 - 73 years [88] | IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 85) or standard therapy (n = 151 | Reduction in inflammatory markers (CRP, P = 0.032; IL-6, P = 0.005; TNF-α, P = 0.015) | Level of evidence 3 |
| Retrospective study of 113 patients with severe COVID-19 and cardiac injury. Age: 59 - 77 years [89] | IVAA: 100 mg/kg/6 h on day 1 then 100 mg/kg/12 h for the next 5 days + standard therapy (n = 51) or standard therapy (n = 62) | IVAA was associated with ameliorated cardiac injury (P = 0.04). Reduced levels of inflammatory markers (CRP, IL-6, IL-8, and TNF-α) at 21 days of hospitalization | Level of evidence 3 |
Based on level 5 evidence (cited in text) and current studies, we recommend the use of IVAA as adjunctive therapy in patients with COVID-19. IVAA: intravenous ascorbic acid; SOFA: sequential organ failure assessment; RCT: randomized controlled trial; HR: hazard ratio; CI: confidence interval; TNF-α: tumor necrosis factor alpha; IL-6: interleukin-6; IL-8: interleukin-8; CRP: C-reactive protein; SIRS: systemic inflammatory response syndrome; IVC: intravenous vitamin C.