Role of high dose vitamin C in management of hospitalised COVID-19 patients: A minireview

Table 1 Different studies evaluating the role of high dose intravenous Vitamin C in COVID-19

S. No.	Title	Year of publication	Country of origin	Study design	Sample size in the control arm	Sample size in the intervention arm	Intervention summary	Results in brief
1	Effect of high-dose intravenous vitamin C on prognosis in patients with SARS-CoV-2 pneumonia[14]	2022	Turkey	Retrospective study	170 patients	153 patients	2 g/d IV	No difference in mortality
2	High-dose intravenous vitamin C decreases rates of mechanical ventilation and cardiac arrest in severe COVID-19[33]	2022	USA	Retrospective cohort study	75 patients	25 patients	3 gm 6 hrly for 7 d IV	HDIVC group had a prolonged hospital stay, prolonged ICU stay, and prolonged time to deathCRP levels were lower in the HDIVC group while other inflammatory markers (d-dimer and ferritin) were similar in both groups.HDIVC patients had significantly lower rates of IMV and cardiac arrest
3	Efficacy of High Dose Vitamin C, Melatonin and Zinc in Iranian Patients with Acute Respiratory Syndrome due to Coronavirus Infection: A Pilot Randomized Trial[43]	2021	Iran	RCT	11	10	IV vitamin C (2 g, q6hr), oral; melatonin (6 mg, 6 hourly), and oral zinc sulfate (50 mg, 6 hourly) for 10 d	No differences in PaO2/FiO2, CRP, ESR or LDH levels and ICU LOS
4	Pilot trial of high-dose vitamin C in critically ill COVID-19 patients[12]	2021	China	Multi center RCT	29 in control	27 treatment group	12 g of vitamin C/50 ml every 12 h for 7 d at a rate of 12 mL/h IV	No difference in IMV free days at D28; no difference in 28-d mortality. Steady rise in the PaO2/FiO2 in vitamin C group
5	No significant benefit of moderate-dose vitamin C on severe COVID-19 cases[34]	2021	China	Retrospective cohort study	327	70	2-4 gm/d	No significant difference in clinical improvement or mortality rate
6	Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: a retrospective case series study[35]	2021	China	Retrospective case series		12 patients	71 to 350 mg/kg/d for 3 d IV	Reduction in CRPImproved PaO2/FiO2 and SOFA score
7	High Dose Intravenous Vitamin C for Preventing The Disease Aggravation of Moderate COVID-19 Pneumonia. A Retrospective Propensity Matched Before-After Study[36]	2021	China	Retrospective before-after study	55 patients	55 patients	100 mg/kg/d IV for 7 d	Significant reduction in progression to severe disease.Reduced levels of CRP, D-dimer and APTT
8	Safety and effectiveness of high-dose vitamin C in patients with COVID-19: A randomized open-label clinical trial[44]	2021	Iran	Randomised open-label study	30 patients	30 patients	6 g/d IV	Reduced temperature and improved SaO2 in HDIVC group. No difference in ICU or hospital mortalityLonger hospital LOS in HDIVC group
9	Use of Intravenous Vitamin C in Critically Ill Patients With COVID-19 Infection[37]	2021	USA	Retrospective cohort study	24 patients	8 patients	1.5 grams IV vitamin C every 6 h for up to 4 d	HDIVC group had higher rates of hospital mortality and mean SOFA scores post-treatment. No difference in daily vasopressor requirement or ICU LOS
10	High-dose intravenous vitamin C attenuates hyperinflammation in severe coronavirus disease 2019[38]	2021	China	Retrospective cohort study	151	85	100 mg/kg every 6 h for day 1 followed by 100 mg/kg evry 12 h for the next 5 d	Significantly reduced inflammatory markers (hs-CRP, IL-6, TNF-alpha)
11	The efficiency and safety of high-dose vitamin C in patients with COVID-19: A retrospective cohort study[39]	2021	China	Retrospective cohort study	30	46	6 g twice a day on day 1 followed by 6 gm once a day for 4 d IV	Reduced 28 d mortality. No change in oxygen support
12	High-dose vitamin C ameliorates cardiac injury in COVID-19 pandemic: A retrospective cohort study[40]	2021	China	Retrospective cohort study	62	51	100 mg/kg every 6 h for day 1 followed by 100 mg/kg evry 12 h for the next 5 d	HDIVC can ameliorate cardiac injury through alleviating hyperinflammation
13	The Role of Vitamin C as Adjuvant Therapy in COVID-19[13]	2020	Pakistan	RCT	75 patients	75 patients	50 mg/kg/day of intravenous (IV)	Earlier resolution of symptoms and reduced hospital LOS. No significant difference in the need for IMV and mortality
14	Activities of serum ferritin and treatment outcomes among COVID-19 patients treated with vitamin c and dexamethasone:An uncontrolled single-center observational study[41]	2020	India	Prospective, observational study		50 patients	NA	Mortality 6%
15	The use of IV vitamin C for patients with COVID-19: A case series[11]	2020	USA	Case series		17 patients	1 g every 8 h for 3 d IV	Significant decrease in inflammatory markers. Mortality 12%
16	Application of methylene blue -vitamin C -N-acetyl cysteine for treatment of critically ill COVID-19 patients, report of a phase-I clinical trial[42]	2020	Iran	Phase I clinical trial	25 ICU COVID-19 patients. 5 received MCN as last resort	25 healthy individuals	Methylene blue (1 mg/kg) along with vitamin C (1500 mg/kg) and N-acetyl Cysteine (1500 mg/kg) orally or intravenously	Reduced methhemoglobin levels, survival of 4/5 patients

IV: Intravenously; HDIVC: High dose intravenous vitamin C; ICU: Intensive care unit; CRP: C-reactive protein; RCT: Randomised control trial; ESR: Erythrocyte sedimentation rate; LDH: Lactate dehydrogenase; LOS: Length of stay; IMV: Invasive mechanical ventilation; SOFA: Sequential organ failure assessment; APTT: Activated prothrombin time; IL: Interleukin; TNF: Tumour necrosis factor; MCN: Methylene blue; USA: United states; COVID-19: Coronavirus disease 2019; RCT: Randomised control trial; NA: Not available.

Table 2 Meta-analyses evaluating the role of Vitamin C in COVID-19

S. No.	Title	Year of publication	Country of origin	Included studies	Included sample size	Results in brief
1	Intravenous vitamin C use and risk of severity and mortality in COVID-19: A systematic review and meta-analysis[45]	2022	China	7 studies (3 RCTs, 4 observational studies)	807 patients	IV vitamin C treatment did not affect disease severity or mortality
2	The effectiveness of high-dose intravenous vitamin C for patients withcoronavirus disease 2019: A systematic review and meta-analysis[46]	2022	Korea	5 studies (3 RCTs, 2 retrospective trials)	374 patients (186 HDIVC and 184 control group)	No difference in hospital LOS or mortality
3	Vitamin C and COVID-19 treatment: A systematic review and metaanalysis of randomized controlled trials[47]	2021	India	6 RCTs	572 patients	Vitamin C treatment didn’t reducemortality, ICU LOS, hospital LOS or need for invasive mechanical ventilation

RCT: Randomised control trial; IV: Intravenously; HDIVC: High dose intravenous vitamin C; LOS: Length of stay; ICU: Intensive care unit.

Table 3 Adverse effects reported with vitamin C

Item	Description
General	Interference with laboratory tests, phlebitis, nausea, vomiting
Neuro-muscular	Lethargy, fatigue, muscle cramps, headache, altered mental status
Metabolic	Hyperglycemia, hypernatremia
Haematological	Haemolysis, disseminated intravascular coagulation, methemoglobinemia
Renal	Oxalosis, renal stones, acute kidney injury