Disclaimer: The aim of these rapid reviews is to retrieve, appraise, summarize and update the available evidence on COVID-related health technology. The reviews have not been externally peer- reviewed; they should not replace individual clinical judgement and the sources cited should be checked. The views expressed represent the views of the authors and not necessarily those of their host institutions. The views are not a substitute for professional medical advice.

Copyright Claims: This review is an intellectual property of the authors and of the Institute of Clinical Epidemiology, National Institutes of Health-UP Manila and Asia-Pacific Center for Evidence Based Healthcare Inc.

BACKGROUND

Vitamin C is a water-soluble compound that can be administered by oral, enteral, and parenteral routes. It is a known antioxidant and maintains endothelial barriers. It has been shown in animal studies to prevent cytokine surges which lead to alveolar capillary damage, prevent neutrophil accumulation in alveolar spaces, support phagocytosis of bacteria, and support lymphocyte function. Vitamin C is also involved in non-oxidant processes like biosynthesis of collagen, carnitine, tyrosine and peptide hormones as well as of myelin.

The drug is widely used as a nutritional supplement. A Cochrane meta-analysis on oral Vitamin C > 200 mg/day vs. placebo for the treatment and prevention of the common cold was done in 2013. Regular ingestion of vitamin C

Should Vitamin C be used in the treatment of COVID-19?

did not affect incidence of common colds in the ordinary population (n=11306, 29 trials), but had a modest, consistent effect in reducing duration (31 study comparisons, 9745 common cold episodes). In 5 trials with 598 participants exposed to short periods of extreme physical stress (including marathon runners and skiers), vitamin C reduced by half the risk for common colds.1

The use of oral Vitamin C is associated mostly with gastrointestinal adverse effects such as such as nausea, vomiting, and diarrhea. Formation of formation of calcium- oxalate stones has been reported with long term use. Intravenous administration is not associated with side effects due to the short-term administration. Patients with G6PD deficiency are at risk for hemolysis. The dose of Vitamin C should be adjusted among patients with renal insufficiency. The complete list of known adverse effects can be found in product labels.

METHODS

See General Methods Section.

Articles were selected based on the following inclusion criteria:

•Population: suspected or confirmed COVID-19 patients of any age, with any co-morbidities, any severity

•Intervention: Vitamin C infusion any dose, any duration

•Comparator: placebo, any active control, no intervention

•Outcomes: Mortality, recovery, duration of disease

•Study designs: randomized controlled trials (RCTs), non-randomized studies, systemic reviews/meta- analysis, case report

Exclusion Criteria

•Oral Vitamin C alone

•Non-human studies

•Literary articles (e.g. blogs)

•Studies before 2000

•Academic reviews

•Full text publication not available

•Non-English articles

Characteristics of Included Studies

•Summary of Included Studies

Number of ongoing clinical trials found: 4

Number of included studies in the review: 10

Types of studies included and sample size

•RCT: 2 studies; n=383

•Retrospective cohort: 1; n = 99

•Meta-analysis: 6 studies; n = overlapping total of 11,205; mean of 1867; range of

109 to 6,455

•Case report: 1

Countries where studies were done: most did not specify. Australia, Brazil, Korea, New Zealand, USA

Refer to Appendix 2 Table (Characteristics of Included Studies)

There are no completed clinical trials or systematic reviews/meta-analyses studying the efficacy of intravenous vitamin C in COVID-19. Currently, there are 5 trials registered in clinicaltrials.gov studying intravenous (3 trials) or oral (2 trials) vitamin C in COVID-19. See Appendix 2. No other ongoing or planned trials were registered in the other trial registries.2

In lieu of the absence of completed trials on COVID-19, we describe below the literature on i.v. Vitamin C used in patients who may be suspected of having the disease. For purposes of rapid review, we have limited this to patients who have viral pneumonia, sepsis with or without ARDS, and critically ill patients due to other disease conditions.

1.There was only 1 published study, a case report, on the use of intravenous Vit C in a virus-induced case of ARDS. The effect of Vitamin C in this case report cannot be accepted as conclusive and may only be coincidental.

•In 2017, the primary author of the CITRIS-ALI

RCT and his team published a case report on the use of intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus-induced acute respiratory distress syndrome.3 The patient received standard intensive care management, including antibiotics, mechanical ventilation, bronchoscopy for microbiological sampling, and extracorporeal membrane oxygenation (ECMO). Vitamin C infusion at 200 mg/kg/24hrs was given on the 2nd ECMO day. Patient was eventually discharged on the 12th hospital day.

2.Two randomized clinical trials and 2 meta-analyses studied the effect of vitamin C infusion among septic patients. Of these, 1 RCT and 1 meta-analysis showed significant benefit in mortality but only in the secondary or subset analyses which were underpowered. There was no difference in mortality up to 90 days in the 2nd RCT trial. These are summarized below:

•The CITRIS-ALI trial4 was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis-induced lung injury present for less than 24 hours. The inclusion criteria included conditions such as presence of systemic inflammatory response, arterial hypoxemia, and ARDS that are found in severe COVID-19 cases. Patients were randomly assigned to receive intravenous infusion of vitamin C 200mg/kg/day divided every 6 hours for 96 hours x 4 doses or placebo D5W infusion. Vitamin C did not improve the primary outcome of organ dysfunction scores or alter markers of inflammation (CRP) and vascular injury (thrombomodulin). However, statistically significant benefits with regards to 3

of the 46 pre-specified secondary endpoints were observed with Vit C vs. placebo: a) mortality to day

28: 29.8% vs. 46.3%, respectively, p=0.03 and with KM curves statistically significant as well at p=0.01. b) number of ICU-free days to day 28: 10.7 vs. 7.7, respectively, and c) number of hospital free days to day 60: 22.6 vs. 15.5, respectively. The level of significance was not adjusted for the 46 secondary endpoints and potential for Type 1 error is inherent in the multiple comparisons. These findings were considered exploratory. The supposed benefit on mortality (one of many secondary outcomes) in the CITRIS-ALI trial may not be clinically robust and not representative of the true effect of vitamin C. It may not statistically persist in a larger setting. No drug-related adverse events occurred during the trial.

•The VITAMINS trial5 was a multicenter, open- label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil that recruited 216 patients fulfilling the Sepsis-3 definition of septic shock. Patients were randomized to control of hydrocortisone alone, versus hydrocortisone + thiamine + intravenous vitamin C. Treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. There were also no benefits on the secondary endpoints

(in-hospital, day 28 and day 90 mortality; number of free days from mechanical ventilation, renal replacement therapy, ICU; and length of hospital stay). Adverse events were reported for 2 patients (2 events, fluid overload and hyperglycemia) in the intervention group and 1 patient (1 event, gastrointestinal bleeding) in the control group. No SAEs or SUSARs reported.

•Lin et al6 performed a random effects meta- analysis on 6 trials (4 RCTs and 2 retrospective trials) published up to November 2018 focusing on in-hospital or 28-day mortality as the outcome among patients with sepsis (n=109). There was no difference in mortality in the over-all population. Among 40 patients with severe sepsis given high dose vitamin C (66 mg/kg/hour), there was a statistically significant reduction in mortality (OR 0.39, 95% CI 0.16 - 0.94, P < 0.05).

•The meta-analysis by Li in 2018 was excluded because the trials analyzed were already included in other meta-analyses.7

3.One retrospective study and several meta-analyses evaluated the use of vitamin C in critically ill patients due to conditions other than or in combination with sepsis. All showed no significant differences observed in mortality vs. control group. Most of included trials

Should Vitamin C be used in the treatment of COVID-19?

are overlapping in these meta-analyses which are summarized below:

•A 2018 retrospective study on the effect of intravenous Vit C on in-hospital mortality among ICU patients with severe pneumonia was conducted on 53 patients vs. control group of 46 patients.8 This hospital follows a routine administration of Vit C protocol (vitamin C 1.5 g every 6 h for 4 days + hydrocortisone 50 mg every 6 h for 7 days then tapered over 3 days + i.v. thiamine 200mg every 12 h for 4 days) for severe pneumonia. The treatment group should have received the Vit C protocol within 48 hours of ICU admission. Results in the unmatched cohort showed a tendency towards lower in-hospital mortality in the treatment group. Results in the propensity-matched cohort (n=36 per group) showed a significantly lower mortality in the treatment group. The results were correlated with a significant improvement in radiologic findings starting on 7th day of hospitalization. There were no differences in other secondary outcomes such as event-free days for use of vasopressors and mechanical ventilation, organ function scores, and incidence of AKI. The limitations of this study that preclude its relevance to COVID-19 pneumonia include the following: small sample size, use of corticosteroids, and unreported etiology of pneumonia (viral vs. bacterial). In addition, the authors did not report if their institution has since then discontinued the routine use of their Vit C protocol.

•A Cochrane meta-analysis9 on i.v. and oral vitamin C and length of stay in the ICU based on a search that extended to January 2019 included 17 studies (n=1967). Thirteen of these studies involved cardiac patients, 2 involved septic patients, and the rest, lung contusion and burns. No analysis on mortality was done. Benefits on surrogate endpoints such as length of ICU stay and duration of ventilation were found. Length of ICU stay was significantly lower by 7.7% among those given intravenous Vitamin C (6 trials on i.v. Vit C; n=839). Among patients on mechanical ventilation > 24 hours (2 trials on i.v. Vit C with n=65, 1 on oral Vit C with n= 185), the duration of ventilation was significantly shorter by 18.2 %. This was largely driven by the trial on oral Vit. C. There was no effect on patients who were on ventilation

≤ 24 hours on 3 trials (2 oral n=238; 1 i.v. n=40).

•Meta-analysis by Putz et al10 was done on randomized trials of vitamin C and mixed ICU patients using online search up to October 2018. Both oral and intravenous Vitamin C were used in 44 randomized trials involving 6,455 patients. Among ICU patients (16 trials, n=2,857), vitamin C administration was not associated with a difference in mortality in any of the disease conditions analyzed

(sepsis, acute pancreatitis, burns, and other mixed conditions) as well as no difference in acute kidney injury, ICU or hospital length of stay compared with control. Among patients who underwent cardiac surgery (28 trials, n=3598) there was also no difference in mortality, AKI, stroke, and ventricular arrhythmias. There were significant reductions in supraventricular arrhythmias (mainly with atrial fibrillation) and length of ICU stay.

•A meta-analysis by Wang et al in 201911 using trials identified after search of databases up to 2018. They analyzed the impact of different doses of Vitamin C infusion in 12 randomized trials comparing Vit C (n=624) with placebo or other antioxidants (n=586) for patients with sepsis, burns, critical injury, and postoperative conditions. Four trials, including 1 on patients with sepsis, were new or have not been included in the other meta-analyses described in this report.There was no impact on mortality among patients who given low (< 3g/day) and high (≥ 10 g/day). A significant absolute mortality reduction of 8.5% was found among those who received moderate dose (3-10 gm/day) which included small number of patients with sepsis (69/405 patients in the treatment arm vs. 69/395 patients in the placebo arm). For all dosing groups, there were no differences found in the duration of vasopressor and ventilatory support, occurrence of AKI, and hospital/ICU stay.

•A small meta-analysis in 2018 by Zhang and Jativa12 was conducted on studies up to September 2017 dealing with intravenous vitamin C in critically ill patients (trauma, burns, post-surgery). Five studies (4 RCTs and 1 retrospective review) involving 142 patients were included, with follow-up ranging from 6 to 28 days. Three of the trials were also included in the 2019 Cochrane meta-analysis. However, in contrast to the Cochrane study, mortality was the primary outcome analyzed, of which the results were not significantly different. Intravenous vitamin C use was associated with a statistically significant decrease in need for pressor support and decrease in duration of mechanical ventilation.

•Langlois et al13 performed a meta-analysis on 11 RCTs identified after a database search of up to December 2017 with mortality as the primary outcome. Four of these were conducted using Vit C infusion and the rest were administered via oral or enteral routes. All 4 infusion trials (n=1024) were previously included in other meta-analyses. There were no differences in mortality rates in the overall population (9 trials, n=1322) and in the different subset analyses infusion trials which were conducted on patients with sepsis (n=54), mixed conditions (n=200), or surgical/trauma

cases (n=770); combination therapy; monotherapy; high vs low dose; and high vs. low methodological quality. In addition, there were also no effects seen in other endpoints such as other infections, ICU/hospital stay, and duration of ventilation.

Effectiveness Outcomes

There are currently no completed clinical trials on Vitamin C in COVID-19 with effectiveness outcomes on recovery from the illness, duration of illness, reduction of mortality, reduction in hospitalization.

Safety Outcomes

There are currently no completed clinical trials on Vitamin C in COVID-19 with safety outcomes such as drug-related adverse events.

Recommendations from Other Guidelines

There are no guidelines mentioning the use of vitamin C in the management of COVID-1914,15 or ARDS.16

The TGA (Therapeutic Goods Administration) of the Australian Government Department of Health had issued guidance stating, “there is no robust scientific evidence to support the usage of this vitamin in the management of COVID-19”.17

CONCLUSION

There is no direct evidence available as of this point for efficacy of intravenous vitamin C in preventing mortality or shortening disease course among adults with COVID-19 illness. Three trials on intravenous Vit C and 1 trial on prophylactic oral intake are currently ongoing

Indirect evidence from use of intravenous vitamin C in sepsis showed conflicting benefits on mortality. The studies are small and further studies may be attempted to elucidate the effects of vitamin C, especially on hard outcomes like mortality and length of disease course. The supposed benefit on mortality (one of many secondary outcomes) in the CITRIS-ALI trial [5] may not be clinically robust and not representative of the true effect of vitamin C. It may not statistically persist in a larger setting. The reduction in length of ICU stay may be statistically significant but modest (7.7%) in 1 meta-analysis. This may or may not translate to a clinically significant effect (e.g.

1day shortened in a 13-day ICU stay). The same meta- analysis showed modest, statistically-significant benefits demonstrated in other outcomes such as decreased need for vasopressors, reduced duration of mechanical ventilation), but may not be clinically robust.

The findings from the retrospective study and 5 meta- analyses on critically-ill patients with conditions other than or in combination with sepsis cannot directly be applied to COVID-19 or other viral illness, especially moderate to severe ones, since the pathophysiology of the

diseases are different, and interaction with other factors like comorbidities may further modify the effect of the intervention. Indirect evidence from all these articles showed no effect on mortality. All other meta-analyses that evaluated the use Vitamin C infusion given alone or in combination with other agents when compared to placebo or other treatments did not show benefit with other clinical outcomes (AKI, arrhythmias) and surrogate outcomes (hospital/ICU LOS, duration of vasopressor use, duration of ventilation).

The trials have reported no or minimal adverse events, and the decision to use intravenous vitamin C should also take this into account.

In summary, there is currently no direct evidence showing benefit on mortality and other softer endpoints with the administration of intravenous Vit C to patients with COVID -19. There may be a benefit on mortality, length of ICU stay and duration of mechanical ventilation among patients with sepsis and ARDs who may be considered COVID-19 suspects but larger studies are needed.

The use of	Vit C in other critical conditions did not lead to
a benefit in	mortality and other key clinical endpoints.

Acknowledgments

The authors would like to acknowledge the contribution of Dr. Anna M. Gaborro, Sr. Medical Advisor, Abbott Vascular, Santa Clara, CA, USA.

Declaration of Conflict of Interest

No conflict of interest.

REFERENCES

1.Hemilä H, Chalker E. Vitamin C for preventing and treating the common cold. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No.: CD000980. DOI: 10.1002/14651858.CD000980.pub4

2.https://clinicaltrials.gov/ct2/results?cond=covid-19&term= &type=&rslt=&age_v=&gndr=&intr=Vitamin+C&titles=&outc=&sp ons=&lead=&id=&cntry=&state=&city=&dist=&locn=&rsub=&strd_ s=&strd_e=&prcd_s=&prcd_e=&sfpd_s=&sfpd_e=&rfpd_s=&rfpd_ e=&lupd_s=&lupd_e=&sort=

3.Fowler Iii AA, Kim C, Lepler L, Malhotra R, Debesa O, Natarajan R, et al. 2017. Intravenous vitamin C as adjunctive therapy for enterovirus/rhinovirus induced acute respiratory distress syndrome.

World J Crit Care Med. 2017; 6(1):85-90

Should Vitamin C be used in the treatment of COVID-19?

4.Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, 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. doi:10.1001/jama.2019.11825

5.Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. 2020. 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 Jan 17. doi: 10.1001/jama.2019.22176.

6.Lin J, Li H, Wen Y, Zhang M. Adjuvant administration of vitamin C improves mortality of patients with sepsis and septic shock: A systems review and meta-analysis. Open J Intern Med. 2018; 8(2):146–59.

7.Li J. Evidence is stronger than you think: a meta-analysis of vitamin

C use in patients with sepsis. Crit Care. 2018; 22(1):258.

8.Kim WY, Jo EJ, Eom JS, Mok J, Kim MH, Kim KU, 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. doi:10.1016/j.jcrc.2018.07.004.

9.Hemilä H, Chalker E. Vitamin C can shorten the length of stay in the ICU: A Meta-Analysis. Nutrients. 2019;11(4):708; doi:10.3390/ nu11040708

10.Putzu A, Daems AM, Lopez-Delgado JC, Giordano VF, Landoni G. The effect of Vitamin C on clinical outcome in critically ill patients. Crit

Care Med. 2019; 47(6):774-783. doi:10.1097/ccm.0000000000003700

11.Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann

Intensive Care. 2019; 9(1):58.

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

2018; 6:1–12.

13.Langlois PL, Manzanares W, Adhikari NKJ, Lamontagne F, Stoppe C, Hill A, et al. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. J Parenter Enter Nutr. 2019.

14.Jin YH,Cai L, et al for the Zhongnan Hospital of Wuhan University Novel Coronavirus Management and Research Team, Evidence-Based Medicine Chapter of China International Exchange and Promotive Association for Medical Health Care. A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019- nCoV) infected pneumonia. Military Medical Research. 2020; 7:4 https://doi.org/10.1186/s40779-020-0233-6

15.Alhazzani W, Møller MH, Arabi YM, Loeb M, Gong MN, Fan E, et al. Surviving Sepsis Campaign: guidelines on the management of critically ill adults with Coronavirus Disease 2019 (COVID-19). Intensive Care Med. 2020. https://doi.org/10.1007/s00134-020-06022-5

16.Griffiths MJD, McAuley DF, Perkins GD, Barett N, Blackwood B, Boyle A, et al. Guidelines on the management of acute respiratory distress syndrome. BMJ Open Resp Res. 2019; 6:e000420. doi:10.1136/ bmjresp-2019-000420

17.https://www.tga.gov.au/alert/no-evidence-support-intravenous-high- dose-vitamin-c-management-covid-19

	Author	Journal/Year	Study design	Country	Disease
					condition
	Fowler et al	JAMA. 2019	RCT	USA	Sepsis
	(CITRIS-ALI)				ARDS

Population size Intervention Group(s)

170Vit C 200mg/kg/day divided over 4 doses.

Administered every 6 hours for 96 hours

Comparison Group(s)

5% Dextrose

in-hospital mortality	overall : not associated
28-day mortality	with a reduction in mortality as
	compared placebo (OR 0.46, 95% CI
	0.17 - 1.24, P > 0.05)
	40 patients with severe sepsis given
	high dose vitamin C (66 mg/kg/hour):
	statistically significant reduction in
	mortality (OR 0.39, 95% CI 0.16 -
	0.94, P < 0.05).

significant heterogeneity (P = 0.04 < 0.05, I 2 = 58%). Small sample size

Mortality	duration of vasopressor
	and ventilatory support,
	occurrence of AKI, and
	hospital/ICU stay.

mortality reduction of 8.5% was	Mortality study not
found among those who received	sufficiently powered
moderate dose (3-10 gm/day);
no differences found in low and
high dose
benefit in duration of vasopressor
and MV use; no benefit in AKI, LOS
ICU or hospital

Database	Search strategy / search terms
Medline	(("ascorbic acid"[MeSH Terms] OR ("ascorbic"[All Fields] AND "acid"[All
	Fields]) OR "ascorbic acid"[All Fields] OR "vitamin c"[All Fields])
	AND ("virus diseases"[MeSH Terms] OR ("virus"[All Fields] AND
	"diseases"[All Fields]) OR "virus diseases"[All Fields] OR ("viral"[All
	Fields] AND "disease"[All Fields]) OR "viral disease"[All Fields])) AND
	("2010/04/06"[PDat] : "2020/04/02"[PDat])

Date and time	Results
of search	Yield	Eligible
02 April 2020	8	0