by DU Li-ping (1) , MEI Dan (1)* ,LI Da-kui (1) ,CHEN Qi (2) ,WANG Zi-hou (3)
(OMNS August 6, 2020) High-dose intravenous infusion of vitamin C (IVC) is used as part of supportive treatment for patients with severe respiratory virus infection, but the dose regimen and clinical efficacy are still controversial. This review article introduces the physiological functions and in vivo characteristics of vitamin C, and the mechanism of it antiviral actions in vitro and in vivo. This review also summarizes and analyzes the theoretical basis and existing clinical evidence of the application of IVC in patients with severe respiratory virus infection, including severely ill patients, as well as summarizing the effectiveness and safety of different dose regimens, in order to provide references for rational clinical application.
Severe respiratory virus infection is a life-threatening disease, especially when specific medications and vaccines are absent. Supportive treatment is of particular importance under this circumstance. Many hospitals in China and worldwide have used high-dose intravenous infusion of vitamin C (IVC) to treat critically ill patients and have achieved positive outcomes . However, there are still controversies in the field about the dose regimen and treatment efficacy of vitamin C. This article aims to analyze the mechanism and clinical evidence of high-dose vitamin C treatment in severe respiratory viral infections, in order to provide reference for rational clinical applications.
1. DU Li-ping, MEI Dan, LI Da-kui , Department of Pharmacy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China；
2. CHEN Qi, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, KS Kansas City 66160, USA；
3. WANG Zi-hou , Center for Drug Evaluation, National Medical Products Administration, Beijing 100022, China
Corresponding author: Mei, Dan firstname.lastname@example.org
Funding: The Capital Health Development Research Project of China (Shoufa 2018-3-4017) and Chinese Academy of Medical Sciences Medicine and Health Technology Innovation Project (2017-12M-1-011). Chen, Qi received no funding from any of these resources.
Manuscript received 2020-04-16 by the Clinical Medication Journal. Published in Clinical Medication Journal Vol 18, No. 7. July 2020. Doi：10. 3969/j. issn. 1672-3384. 2020. 07. 015 Translated into English 2020-08-01. Reprinted with permission.
1. Physiological functions and characteristics of vitamin C
Vitamin C (L-ascorbic acid) is an essential water-soluble vitamin and participates in various physiological functions as an antioxidant and as a cofactor for many enzymes . Because of loss of function in the L-gulono-γ-lactone oxidase (GLO) gene, the gene encoding for the critical enzyme in vitamin C biosynthesis, humans must rely on exogenous intake of this vitamin to maintain normal physiological functions . In normal adults, daily intake of vitamin C of 0. 1 g (male 0. 09 g, female 0. 075 g) can meet the daily needs . The plasma concentration in a healthy adult is about 50-80 μmol/L, while the tissue concentrations largely exceed the plasma concentration and can reach millimolar levels . Human body usually stores about 1.5 g vitamin C in all tissues. A single small oral dose (e.g. 0.2 g) of Vitamin C can be absorbed 100%, but when taking a single large dose (e.g. 1. 25 g) the intestinal absorption is saturated, and the bioavailability drops to 33% . Continuous large doses of oral vitamin C (e.g. 3 g every 4 hours, total daily dose 18 g) gives a maximum peak concentration about 220 μmol/L. But high-dose intravenous infusion of Vitamin C bypasses the limitation of intestinal absorption, and the peak blood concentration can reach about 15 000 μmol/L or even higher [7-8].
2. The antiviral mechanisms of vitamin C in vivo and in vitro
In vitro studies have shown that vitamin C can inactivate various types of circulating DNA and RNA viruses at a concentration level equivalent to human oral supplementation. The antiviral mechanism is believed to be that vitamin C produces free radicals in the process of self-oxidation and inactivates viruses by degrading viral nucleic acids . In vivo, vitamin C is reported to stimulate immune activities in addition to direct inactivation of the viral nucleic acids [9-10]. The antiviral mechanism of vitamin C under pharmacological concentrations seems to be different from that of a physiological concentration. Cellular and animal studies have found that when reaching the pharmacological concentrations (2.5～20 mmol/L), vitamin C produces hydrogen peroxide under catalysis of trans-metal ions and inactivates viruses without harming the host cells, inhibiting virus replication in the cell and reducing viral infectivity [11-13]. The optimum effects of viral inactivation were achieved in the early stage of virus infection (8-12 hours after infection) . However, these positive outcomes in cells and animal studies did not reach clear and consistent results when translated into clinical applications. In 2013, a meta-analysis including 29 clinical trials (n=11 306) showed that the oral preventive doses of vitamin C (≥0.2 g/d) did not reduce the incidence of colds in the general population . However, in subgroups under intensive physical exertion (n=598) such as extreme athletes and soldiers in winter training, supplementation of oral vitamin C reduced the incidence of colds by 50% (RR = 0.48, 95% CI: 0.35～0.64) , suggesting oral vitamin C is beneficial in preventing colds to certain population (such as people in high-intensity physical activity). The same analysis also found that oral preventive doses of Vitamin C (≥0.2 g/d) could improve the duration and severity of cold symptoms when taken before these symptoms appeared, but if taken after symptoms appeared, no significant improvements were found by even ≥1 g/d of oral vitamin C .
3. Theoretical basis of applications of high-dose intravenous infusion of vitamin C in acute and severe illnesses
Many disease states change the homeostasis of vitamin C in human body, some examples are myocardial infarction, acute pancreatitis, sepsis, and other acute and critical illnesses. Under these circumstances, the concentration of vitamin C usually decreases significantly [15-17]. Studies have shown that the drop of vitamin C concentration in blood (to about 18 μmol/L on average) is a predictable sign in patients with severe sepsis . Low blood levels of vitamin C are associated with multiple organ failure and poor prognosis in patients with sepsis . The drop of vitamin C levels may be due to at least two mechanisms. On one hand, the release of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) affects the cellular regulation of vitamin C absorption, resulting in decreased intracellular vitamin C levels . On the other hand, as in acute and severe illnesses oxidative stress and the production of reactive oxygen species (ROS) increase, the utilization for antioxidants such as vitamin C also increases sharply. Increased demand and utilization for vitamin C also originate in the need to produce more white blood cells and for their differentiation . In sepsis-induced acute respiratory distress syndrome (ARDS), vitamin C can strengthen the lung epithelial barrier, and accelerate the clearance of lung effusion by enhancing epigenetic and transcriptional regulation of multiple proteins and pathways including aquaporin-5, cystic fibrosis transmembrane regulator nodal protein (CFTR), epithelial sodium channel and Na+/K+ ATPase . Studies also showed that intravenous infusion of large doses of vitamin C (IVC) significantly decreased the levels of circulating DNA and circulating syndecan-1 in ARDS patients, both of which are associated with increased risk of multiple organ failure and ARDS mortality . In addition, lymphopenia is a common clinical feature in ARDS. Vitamin C is an essential factor to promote lymphocyte production and activity, and is important for lymphocyte functioning . Therefore, it is considered reasonable to use IVC in early stages of severe sepsis .
4. Clinical evidences for IVC application in acute and severely ill patients
4. 1. The effectiveness and safety of IVC in acute and severely ill patients
As early as in 1989, there were reports of efficacious application of IVC in patients with acute severe diseases, mainly in ARDS patients with IVC 1 g q6 h combined with other antioxidants (N acetylcysteine, selenium and vitamin E) . Results showed that mortality in the treatment group (n=16) was significantly lower than that of the control group (n=16) (37% vs. 71%, P<0.01). A paper published in 2014 reporting a phase I clinical trial of IVC in septic patients  showed that there was a dose dependency on IVC in the prevention of multiple organ failure. The sequential organ failure score (SOFA score) after IVC treatment was significantly lower than that of the placebo control group, and in both the high-dose group (50 mg/kg q6 h, 4 days in total) and low-dose group (12.5 mg/kg q6 h, 4 d), there was a decrease in C-reactive protein (CRP), procalcitonin (PCT) and other inflammation indicators compared to the placebo group . The study found no adverse events related to IVC, indicating that IVC is safe in septic patients . Another retrospective study published in 2017 using IVC (1.5g q6 h, 4 days or until ICU dismission) combined with hydrocortisone and vitamin B1 in severe sepsis and septic shock (n=47) showed that compared with the historical control group (n=47), the hospital mortality rate was reduced by 31.9%, and the duration of use of hypertensives was also significantly reduced (18.3 h vs. 54.9 h, P<0. 001) . Another single-center randomized double-blind controlled trial (n=28) showed that IVC at 25 mg/kg q 6 h for a total of 3 days significantly reduced the 28 day-mortality rate compared to placebo control group (14.3% vs. 64.3%, P<0. 01) .
However, the therapeutic effect of vitamin C is under question as a number of other clinical studies showed conflicting results. In 2019, a meta-analysis including 44 studies of a total of 6455 critically ill patients showed that Vitamin C in general did not improve the mortality, length of hospital stay or ICU stay . However the meta-analysis did not distinguish between oral and intravenous infusion, and did not distinguish between high and low doses. Several studies in China also systematically reviewed and evaluated the impact of vitamin C in the prognosis of severely ill or sepsis patients [29-30], and also found no reduction in mortality rate, and controversies in the ICU hospitalization time and total hospitalization time. Again, these studies also did not distinguish between the dosages of vitamin C and routes of administration.
The CITRIS-ALI research published in 2019  is a multi-center, randomized, double-blind, placebo-controlled large-scale clinical trial for patients with sepsis and ARDS. The IVC group (n= 84) received vitamin C 50 mg/kg q6 h intravenously for 4 days, and the control group received a placebo (n=83). It was found that the 2 groups had no significant difference in several primary end-point indices, i.e. day-4 SOFA score, day-7 CRP and thrombomodulin levels (P>0.05), but in the secondary end-point, the 28-day mortality, the IVC group was significantly lower than the control group (29.8% vs. 46.3%, P<0.05). No study-related adverse events were found during the trial.
The VITAMINS research published in February 2020  is the largest clinical trial on IVC so far . This open-label multicenter randomized controlled trial recruited 211 patients with septic shock. The intervention group (n=107) was given intravenous infusion of Vitamin C 1.5 g q6 h, hydrocortisone 50 mg q6 h, and Vitamin B1, the control group (n=104) was given intravenous hydrocortisone alone 50 mg q6 h; both groups were administered until the shock was relieved or the longest 10 days. The results showed no statistical difference in the primary endpoint – the 7-day no hypertensives survival time (122.1 h vs. 124. 6 h, P>0.05), as well as no statistical differences in most of the secondary endpoints, such as 28-d mortality, 28-day cumulative non-hypertensive time, length of hospital stay, etc. The intervention group only performed better in the decrease of SOFA score on day 3 (-2 points vs. -1 points, P<0.05). This study suggested no improvement in therapeutic effects by using the triple-combination regimen of vitamin C (1.5 g q6h) + hydrocortisone + vitamin B1 compared to Hydrocortisone alone.
4.2. Research on different dose regimens of IVC
The controversy and conflicting results from different studies may be related to the different doses and timing of administration of vitamin C. However, an optimum dosage plan has not yet been determined. A pharmacokinetic study was reported in 20 critically ill patients using different dosages and infusion methods of IVC . The participants were randomly divided into 4 groups: 2 g/d (1 g q12 h 15 min rapid IV infusion), 2 g/d (continuous IV infusion), 10 g/d (5 g q12 h 15 min rapid IV infusion) and 10 g/d (continuous IV infusion), with each group given IVC for 48 hours. The results showed a linear relationship between the vitamin C doses and blood concentrations. The dose of 2 g/d only brought the blood concentration to normal physiological level, and 10 g/d achieved exceedingly high concentrations. With rapid infusions, there were concentration peaks at ~1 h of infusion with Cmax in the range of 1060～1391 μmol/L, while with continuous infusion, no plasma peak value was detected, and the steady-state blood concentration fluctuated between 228 and 1681 μmol/L. The maximum concentration achieved by continuous infusion was lower than rapid pulse infusion of the same dose in fractions. The authors also suggested that the high concentration produced by 10 g/d IVC could provide an favorable method for cells to quickly take up vitamin C, but may also increase the urine excretion of oxalate and the risk of mild metabolic alkalosis. The study was not conclusive on whether rapid pulse infusion could provide better therapeutic effects than continuous infusion. At 48 hours after stop of the infusion, the blood vitamin C levels of the 2 g/d group and 10 g/d group were no longer statistically significant (P>0.05), and 15% of patients had Vitamin C levels fallen below the low limit of normal physiological level, suggesting the course of treatment may need to be prolonged to prevent vitamin C deficiency in severely ill patients.
5. Evidence of clinical application of IVC in severe respiratory viral infection
As early as in 2003 in the outbreak of severe acute respiratory syndrome (SARS), some scholars outside China suggested the use of vitamin C for severe respiratory viral infections . In 2017, the first successful use of IVC in the US for the treatment of ARDS caused by enterovirus/rhinovirus infection. The patient received a daily dose of 0.2 g/kg, divided into 4 IV infusions . In addition, there are scattered reports on vitamin C effectively controlling influenza (including A H5N1 avian influenza) . However, there has not been a randomized controlled clinical study published on the treatment of severe respiratory viral infections with IVC. Since the outbreak of the COVID-19 caused by SARS-CoV-2 at the end of 2019, many hospitals in clinics in China have used IVC in the treatment of COVID-19 and have gained experience and positive results in individual cases . In the “Expert Consensus on Comprehensive Treatment of 2019 Coronavirus Disease in Shanghai City” , IVC is recommended when mild to moderate cases are at risk of progressing to more severe conditions. IVC is also recommended in “The Expert Consensus on the Clinical Rational Use of Medications of the New Coronavirus Pneumonia in Guangdong Province (Third Edition)” in preventing and reducing the “cytokine storm” . Based on treatment experience gained in Shanghai, hospitals in New York, USA also have utilized IVC in patients with severe COVID-19, with specific doses determined by the attending physician. In February 2020, Wuhan University Zhongnan Hospital took the lead in officially launching a phase II prospective randomized controlled clinical trial using IVC in severe cases of COVID-19 (NCT04264533) . The study uses 12 g vitamin C with continuous IV pump q12 h for 7 days in the intervention group, and the control group is infused with sterile water in parallel. The primary end point is 28-day ventilator-free survival time. The study is expected to recruit 140 patients and is expected to be concluded in September 2020. A phase III multi-center randomized and controlled clinical trial launched in November 2018 in Canada (the LOVIT research, NCT03680274)  plans to include COVID-19 patients who meet the set trial inclusion criteria for severe infections. The intervention group receives IVC 50 mg/kg in 30-60 min q6 h for 96 hours, the control group receives 5% glucose or saline in parallel. The primary endpoint is 28-day mortality or 28-day persistent organ failure rate. The LOVIT study plans to enroll 800 patients and is expected to conclude at the end of 2022. High-quality clinical data are expected to more clearly define the role of IVC in the treatment of severe respiratory viral infections.
Although vitamin C has been artificially synthesized for nearly a hundred years, there still lacks scientific consensus for its role in the treatment of infections, tumors, sepsis, ARDS and other diseases. Many controversies still exist in the clinical efficacy of IVC supportive treatment in critically ill patients. Given that preclinical in vitro and in vivo studies have shown IVC’s broad spectrum of antiviral effects and its anti-oxidative stress and immunomodulatory effect, high-dose intravenous infusion of vitamin C has been empirically applied to severe COVID-19 patients, as an option when there is no effective specific treatment, but its effectiveness and safety are still pending verification by large-scale clinical trials.
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