Patients with severe COVID-19 are known to have higher inflammatory markers and cytokine storm. In this retrospective and multi-center observational study for critically ill patients with COVID-19, patients received enteral ascorbic acid in a dose of 1000 mg daily for a median of 11 days (IQR 7–18 days).
Ascorbic acid with its proposed anti-inflammatory activity through its antioxidant effect associated with lower 30-days and in-hospital mortality in our overall cohort. However, after matching patients based on the severity of illness (i.e., APACHE II, SOFA score, NUTRIC scores), center, and steroid use, both 30-days and in-hospital mortality were similar in both groups. However, patients who received ascorbic acid had longer ICU LOS, mechanical ventilation duration and hospital LOS in both matched and unmatched groups. This might be secondary to the survival benefits of ascorbic acid which was asscoitaed longer hospitalization and using invasive MV modalities. Interstingly, we also observed a significant reduction in the risk of thrombosis during ICU stay in the ascorbic acid group. This could be as result of its anti-inflammatory properties. Moreover, DVT prophylaxis was used as a standard of care in our cohort
Several pharmacological regimens have been proposed to impact the outcomes for patients with COVID-19 positively. Out of these regimens, only dexamethasone has been shown to improve survival (15). In our study, more patients in the ascorbic acid group received a systemic steroid than in the non-ascorbic acid group 92.9 vs. 86.5 (P-value 0.0312), respectively. This could justify the survival benefit of ascorbic acid prior to controlling for the effect of steroid use. However, the ascorbic acid group showed no mortality benefits after controlling for the potential impact of steroid use.
In critically ill patients, ascorbic acid deficiency is commonly observed despite receiving proper vitamin C intake (16). Furthermore, in critically ill patients, ascorbic acid deficiency is associated with multi-organ failure and increased mortality (17,18). A bioinformatic study highlighted the potential role of ascorbic acid in sepsis. By suppressing inflammatory response and oxidative stress, which are key pathophysiological mechanisms of sepsis, ascorbic acid may have a beneficial effect against sepsis (19).
Large randomized controlled studies using ascorbic acid for COVID-19 in ICU patients are lacking. However, ascorbic acid in non-COVID-19 patients has been studied extensively, and the results have been mixed. One explanation for these mixed results is the differences in the baseline characteristics of the enrolled patients. Moreover, there was a lack of consistency in terms of the ascorbic acid dose, route, timing, and frequency of administration in these studies.
Multiple studies reported positive results for ascorbic acid therapy in respiratory infections including upper respiratory tract infection (URTI) and pneumonia (20,21). Ascorbic acid has been widely used in the literature for critically ill and septic patients. In a phase I trial, 16 patients with severe sepsis received IV ascorbic acid (50-200mg/kg/day) for 4 days. Ascorbic acid use showed reduction in sequential organ failure assessment (SOFA) score, and proinflammatory biomarkers while being well tolerated (7). Nathens et al. used IV ascorbic acid 1 g every eight hours for 28 days in 594 critically ill surgical patients and found a significantly lower incidence of multi-organ failure, shorter mechanical ventilation duration and ICU length of stay (22). A retrospective study reported the use of IV ascorbic acid 1.5g every 6 hours for 4 days with thiamine and hydrocortisone in 47 septic ICU patients. This study showed a significant reduction in mortality rate and vasopressor requirement in the group treated with IV ascorbic acid (23). Multiple other trials showed positive outcomes with ascorbic acid in critically ill septic patients (8,24,25). However, several other trials did not show improvement in clinical outcomes using ascorbic acid in septic patients with ARDS (26,27). Compared to these trials, our study used a consistant and lower dose (1000 mg entrally once daily).
A pilot study randomized patients in the ICU with COVID-19 to receive high dose ascorbic acid 12g every 12 hours for 7 days or placebo. Only 56 patients were included in the study in which 26 patients recevied ascorbic acid. This study showed no benefit of using ascorbic acid in the 28-days mortality or duration of mechanical ventilation. However, oxygenation was significantly improved in the ascorbic acid patients(28).
Our study is the first study to describe the association of ascorbic acid with clinical outcomes in a matched-controlled ICU COVID-19 patients. This research is providing a hypothesis-generating idea of the potential benefit of using ascorbic acid in critically ill patients with COVID-19. This study is suggesting that using ascorbic acid could potentially reduce the risk of ICU thrombosis. We believe that this hypothesis needs to be further investigated at a larger scale using stronger and more validated modalities and study designs in order to eliminate the risk of bias.
Our study has several limitations in terms of the retrospective design and the heterogeneity in the comorbid conditions and disease severity. This was eliminated via using the propensity score. Moreover, there were a dynamic change in the clinical practice of managing patients with COVID-19 as evidence continued to emerge over time. Furthermore there was no consensus on when to start ascorbic acid, and it was mainly at the discretion of the treating team. In the future, there is a plan to investigate the difference in clinical outcomes in the early versus late ascorbic acid initiation.