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- Vitamin C Intervention for Critical COVID-19: A Pragmatic Review of the Current Level of Evidence
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Life 2021, 11(11), 1166; https://doi.org/10.3390/life11111166
by Patrick Holford 1,*,Anitra C. Carr 2ORCID,Masuma Zawari 2 andMarcela P. Vizcaychipi 3,4
1 Founder of Institute for Optimum Nutrition, Ambassador House, Richmond TW9 1SQ, UK
2 Nutrition in Medicine Research Group, Department of Pathology & Biomedical Science, University of Otago, Christchurch 8140, New Zealand
3 Faculty of Medicine, Imperial College, London SW7 2AZ, UK
4 Intensive Care Medicine, Chelsea & Westminster Hospital, London SW10 9NH, UK
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Severe respiratory infections are characterized by elevated inflammation and generation of reactive oxygen species (ROS) which may lead to a decrease in antioxidants such as vitamin C and a higher requirement for the vitamin.
Administration of intravenous vitamin C to patients with pneumonia and sepsis appears to decrease the severity of the disease and potentially improve survival rate. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes pneumonia, sepsis and acute respiratory distress syndrome (ARDS) in severe cases, and is referred to as coronavirus disease 2019 (COVID-19). Patients with COVID-19 infection also appear to have depleted vitamin C status and require additional supplementation of vitamin C during the acute phase of the disease.
To date there have been
- 12 vitamin C and COVID-19 trials published, including
- five randomised controlled trials (RCTs) and
- seven retrospective cohort studies.
The current level of evidence from the RCTs suggests that intravenous vitamin C intervention may improve oxygenation parameters, reduce inflammatory markers, decrease days in hospital and reduce mortality, particularly in the more severely ill patients.
High doses of oral vitamin C supplementation may also improve the rate of recovery in less severe cases No adverse events have been reported in published vitamin C clinical trials in COVID-19 patients. Upcoming findings from larger RCTs will provide additional evidence on vitamin supplementation in COVID-19 patients.
Uptake of oral vitamin C is regulated by the kinetics of the intestinal vitamin C transporter (SVCT-1), which limits the amount of vitamin C that can be absorbed at any one time to between 200 and 500 mg [11,45]. Thus, adverse events related to high-dose oral vitamin C are generally related to gastrointestinal disturbance from unabsorbed vitamin C passing through the intestines . In contrast, intravenous vitamin C by-passes the regulated intestinal uptake of oral vitamin C, resulting in significantly higher circulating concentrations . This elevated peak is still relatively transient, however, because vitamin C is water-soluble and is rapidly cleared by the kidneys, with a half-life of approx. 2-4 h depending on the administration regimen [47,48]. Nevertheless, circulating vitamin C concentrations can remain elevated if IVC is administered to people with renal dysfunction due to their attenuated ability to clear the infused doses.
Oxidative degradation of vitamin C can result in elevated oxalate concentrations which can potentially result in oxalate nephropathy, particularly in people predisposed to the condition [49,50]. However, because oxidised vitamin C (dehydroascorbic acid) is readily reduced back to vitamin C by both chemical and enzymatic means in the body, further degradation of dehydroascorbic acid to oxalate would only occur in the absence of other reducing agents. Furthermore, in the ICU setting, patients with renal insufficiency generally receive intermittent or continuous haemodialysis, which decreases circulating vitamin C concentrations . People with glucose-6-phosphatedehydrogenase deficiency can experience haemolytic anaemia with high-dose IVC administration due to an inability to neutralise excess hydrogen peroxide, however, this is less likely to occur at the lower divided doses administered in ICU settings . Spurious point-of-care glucometer readings can occur following IVC administration due to interference of high concentrations of vitamin C with specific glucometer biochemistry . At the doses used in the ICU setting, this generally only occurs in patients with renal impairment .
To date, no adverse events have been reported in the published vitamin C and COVID- 19 clinical trials (Tables 2-4). There have been two cases reported in the literature of oxalate nephropathy in patients with COVID-19 who were administered IVC at a dose of 50 mg/kg 4x daily, although the cause of the acute kidney injury was acknowledged as likely multifactorial . A third case occurred in a kidney transplant recipient with COVID-19 who had apparently consumed oral vitamin C (500 mg 3x daily), however, the connection to vitamin C was extremely tenuous due to no evidence of elevated oxalate concentrations in their blood or urine . Thus, there is no evidence that vitamin C is harmful when the above contraindications are taken into consideration .
There are currently numerous trials up and running around the world investigating vitamin C for the prevention and treatment of COVID-19. A number of these trials comprise combination therapies with other nutrients and/or medications, such as dexamethasone, however it will be difficult to tease out the contribution of vitamin C to any observed effects in these trials. Although pharmacokinetic studies have indicated that doses of vitamin C of 2-3 g/day can saturate the blood of critically ill patients [14,15], it is likely that higher doses will be required to optimise tissue levels due to possible downregulation of cellular vitamin C transporters as a result of elevated inflammation . This premise is supported by trials which have shown dose-dependent effects of vitamin C administration . Thus, future trials should explore optimisation of dosing regimens. Early administration of vitamin C is also likely to have greater benefit [59,60].
Two large monotherapy RCTs are currently underway internationally (LOVIT-COVID NCT04401150 and REMAP-CAP NCT02735707) with IVC dose and duration of 200 mg/kg/day for 4 days. Of note, these trials will be assessing survivor health-related quality of life at 6 months. This is relevant to the long-term complications of COVID-19, or what is being referred to as 'long COVID' [61,62]. However, as has been alluded to above, cessation of IVC after only a few days may result in return to hypovitaminosis C status in some patients, and is thus unlikely to have an impact on long term quality of life outcomes. Therefore, moving forward, trials may want to adopt a more pragmatic design whereby patients receive IVC whilst hospitalised and then move to oral vitamin C following discharge to determine if this has a greater impact on the ongoing complications of long COVID.
Observational studies have indicated that patients with COVID-19 have high rates of hypovitaminosis C and vitamin C deficiency, which are comparable to patients with sepsis and septic shock . Previous studies of high-dose IVC administration in patients with sepsis and ARDS have shown reduced duration of ICU and hospital stay as well as decreased mortality [27,63]. Based on the evidence from preliminary RCTs and retrospective cohort studies, vitamin C appears to also support positive outcomes in COVID-19 in both inpatient and outpatient settings, leading to a beneficial effect in patients with moderate symptoms, as well as patients with pneumonia, sepsis and ARDS. Intervention with IVC resulted in improved oxygenation and pulmonary function, reduced inflammatory markers and temperature, decreased days in ICU and hospital, and decreased mortality, particularly in the more severely ill patients. Oral supplementation in mild to moderate cases also increased the rate of recovery when taken in high-doses.
Overall, the intervention studies to date have a number of limitations such as small sample sizes and early termination of some studies, differences in vitamin C dose and duration and lack of optimisation of these, lack of placebo controls, and no pre-and postintervention plasma vitamin C concentrations. However, living meta-analysis of the studies as they are published is supporting the premise that high-dose IVC can improve the complications associated with COVID-19 and potentially decrease mortality . Notably, there have been no adverse events reported in the published trials to date.
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Vitamin C helps COVID-19 (IV and oral) – review of 12 studies Oct 2021
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