The results of a pilot trial investigating the effect of high-dose intravenous vitamin C (HDIVC) for severe COVID-19 have been published in Annals of Intensive Care.1 The study findings are limited by a reduced sample size, however the data obtained suggests that vitamin C may help to improve oxygenation in critically ill COVID-19 patients. A greater improvement in PaO2/FiO2 – the ratio of arterial oxygen partial pressure to fractional inspired oxygen – was observed in patients that received vitamin C when compared to the placebo group.
A year after the initial outbreak of SARS-CoV-2, the search for safe and effective therapeutics to treat COVID-19 patients continues. The exact role that vitamins may have in our susceptibility and immune response to infectious diseases such as COVID-19 is just one avenue of research being undertaken. The latest addition to this body of work has focused specifically on vitamin C.
What is vitamin C?
Vitamin C is a water-soluble vitamin that is also known as L-ascorbic acid. It is synthesized by most species of animals except for humans, who are therefore required to obtain it via food sources. It's known roles include protecting the health of cells, skin, blood vessels, cartilage and bone, as well as aiding wound healing.
Vitamin C and inflammation: What's the story so far?
Previous research has explored the anti-inflammatory properties of vitamin C. One study examined the effect of vitamin C supplementation on plasma cytokine concentration in a group of 29 ultramarathon runners. A higher dose of vitamin C supplementation for one week prior to the race and on race day was found to attenuate increases in plasma cytokines IL-6, IL-10, IL-1RA and IL-8.2
A 2019 study investigated whether IV vitamin C would attenuate inflammation and vascular injury associated with both sepsis and acute respiratory distress syndrome (ARDS). The results did not demonstrate a statistically significant improvement in organ dysfunction scores or other markers of inflammation and vascular injury and the scientists concluded that further research was required that focused on other measurable outcomes in sepsis and ARDS.3
Last year, Chiscano-Camón and colleagues measured vitamin C levels in 18 adult intensive care unit (ICU) patients that met the criteria for a diagnosis of ARDS. Seventeen of these patients were found to have undetectable levels of vitamin C, whilst one patient had low levels. The size of the sample was noted as a limitation to the study, but the authors shared that they "think these findings might stimulate clinicians to measure vitamin C levels in COVID-19 patients".4
Thus, the exact role that vitamin C could have in patients diagnosed with ARDS required further elaboration.
Vitamin C and COVID-19
Zhiyong Peng, professor and chair of Critical Care Medicine from the Zhongnan Hospital in Wuhan and colleagues decided to conduct a randomized, controlled and blinded clinical trial to find out more. Peng said: “We undertook this study because we had learnt that a high dose of vitamin C was effective against ARDS and other types of acute lung injury."
The scientists hypothesized that HDIVC – in addition to standard care – would improve the outcomes of patients admitted to ICUs by preventing cytokine storms and ameliorating lung and other organ injuries.
The trial took place across three hospitals in the Hubei province of China. Patients that received a SARS-CoV-2 diagnosis in the ICU were assigned at random to receive either HDIVC at a dose of 24 g vitamin C per day, or a placebo, over a seven-day treatment period. In the paper, the authors attribute the decision to dose at 24 g as a reflection of what is deemed safe by the National Institutes of Health, and what would likely demonstrate efficacy; the metabolism of vitamin C in the blood is fast, and the authors write "only large dose and long course of VC supplement can maintain an adequate concentration in blood."
The primary outcome of the study was the number of invasive mechanical ventilation free days in 28 days (IMVFD28). Secondary outcomes included 28-day mortality, inflammation progression (measuring interleukin-6) and organ failure as measured by the sequential organ failure assessment, or SOFA, score.
Decreasing COVID-19 cases: An unfortunate irony for the trial
Ironically, the hospitals involved in the clinical trial saw a reduction in the number of critically ill patients admitted to ICU after the trial commenced. “Unfortunately, our trial is underpowered because we ran out of critical COVID-19 patients. In fact, we have had none since May," said Peng.
As such, the total number of participants was 56, rather than the original target of 140 patients, ultimately reducing the power of the trial. Of the total number of recruits, 29 were assigned to the HDIVC group and 29 received a placebo.
What is power in a clinical trial?
Power in the context of a clinical trial relates to the probability that a difference between study groups (when a true difference does exist) will be detected. The power of the trial increases as the sample size increases. The higher the power of the trial, the less likely that you are to miss detecting a true difference.
Study findings suggest a potential signal of benefit, but data is limited
The scientists did not find a significant difference in IMVFD28 between the vitamin C supplemented group (median = 26 days) and the placebo group (median = 22 days), which they attribute to the smaller than expected sample size. They do suggest that HDIVC "may provide a potential signal of benefit in oxygenation and IL-6" based on their data. During the treatment period of seven days, patients allocated to the HDIVC group showed an increase in PaO2/FiO2 – the ratio of arterial oxygen partial pressure to fractional inspired oxygen – which was not observed in the control group.
In the results of the paper, the authors outline that on day one of treatment, median IL-6 levels of the HDIVC group were 22.6, which declined to 19.4 by day seven. In the control group, median IL-6 levels at day one are reported as 54.7, with an increase to 158 by day seven.
In the paper the authors share their suspicions that the patients presenting with severe organ dysfunction may have had a more severe vitamin C deficiency, and thus the HDIVC may have improved the deficiency and consequently their organ function.
Limitations to the study include the reduced sample size, the time period between a patient's first COVID-19 symptom and treatment time, a lack of measurement of anti-oxidative variables and gender distribution.
Further research, addressing such limitations, is evidently still required to further examine vitamin C deficiency and the effects of vitamin C treatment in COVID-19 patients.
Dr Marcela Vizcaychipi, head of research at the Chelsea and Westminster Foundation, said “We have started testing vitamin C levels in some of our patients using a urine dipstick and many are deficient. We are now giving three to six grams to these deficient patients because this seems to be the amount needed to correct this deficiency.”
1. Zhang J, Rao X, Li Y, et al. Pilot trial of high-dose vitamin C in critically ill COVID-19 patients. Annals of Intensive Care. 2021;11(1):5. doi:10.1186/s13613-020-00792-3.
2. Nieman DC, Peters EM, Henson DA, Nevines EI, Thompson MM. Influence of vitamin C supplementation on cytokine changes following an ultramarathon. J Interferon Cytokine Res. 2000;20(11):1029-1035. doi:10.1089/10799900050198480.
3. Fowler AA 3rd, Truwit JD, Hite RD, 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.
4. Chiscano-Camón L, Ruiz-Rodriguez JC, Ruiz-Sanmartin A, Roca O, Ferrer R. Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome. Critical Care. 2020;24(1):522. doi:10.1186/s13054-020-03249-y.