In this retrospective cohort study of critically ill patients with COVID-19, patients who received enteral ascorbic acid in a dose of 1000 mg daily (supplemental dose) have similar mortality rate with patients who did not receive it.
We observed that both the in-hospital and 30-days ICU mortality were similar in both groups after matching patients based on the severity of illness (i.e., APACHE II, SOFA score, NUTRIC scores), study center, and steroid use. More patients in the ascorbic acid group received a systemic steroid in our study than in the non-ascorbic acid group 92.9 vs. 86.5 (P-value 0.0312), respectively. This could justify ascorbic acid's survival benefit before controlling for the effect of steroid use in the overall cohort. However, the ascorbic acid group showed no mortality benefits after controlling for steroid use's potential impact.
In critically ill patients, the ascorbic acid deficiency is commonly observed despite receiving proper ascorbic acid intake (16). Furthermore, in critically ill patients, the 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 vital pathophysiological mechanisms of sepsis, ascorbic acid may have a beneficial effect against sepsis (19). Moreover, patients with severe COVID-19 are known to have higher inflammatory markers and cytokine storm 31.
Large randomized controlled studies using ascorbic acid for COVID-19 in ICU patients are lacking. One study that evaluated the use of ascorbic acid in COVID-19 patients was conducted by Jing et al. They randomized patients admitted to the ICU with COVID-19 to receive high dose ascorbic acid 12g every 12 hours for seven days versus placebo. 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). A recent RCT was stopped after interim analysis due to futility, high-dose zinc and vitamin C (ascorbic acid) had no impact on the course of symptoms in patients with mild COVID-19 but did not evaluate the benefits in critically ill COVID 19. In addition, there was no difference in secondary endpoints, including days to symptom resolution, severity of symptoms, hospitalizations, or deaths 34.
Our study shows that low supplemental dose of enteral ascorbic acid had a significant reduction in thrombosis risk during ICU stay. The underlying benefit of ascorbic acid on thrombosis could be due to its anti-inflammatory properties. Of interest, deep vein thrombosis (DVT) prophylaxis considered as a standard of care in our patients, and using DVT prophylaxis was similar between the two groups (p-value: >0.999). Several published studies showed that the incidence of thrombosis was high in critically ill patients with COVID-19 (31,33). 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). None of the previously investigated pharmacological modalities for COVID-19 have shown a reduction in the risk of thrombosis.
Our findings showed a statistically insignificant higher rate of AKI, liver Injury and respiratory failure requiring MV in ascorbic acid group. Even though multiple trials showed positive outcomes with ascorbic acid (8,20,21, 24,25), other trials did not show an improvement in the clinical outcomes (26,27). In a phase I trial, 16 patients with severe sepsis received a high IV ascorbic acid dose (50-200mg/kg/day) for four days. Ascorbic acid use showed a 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). The lack of significant improvement in the clinical outcomes in our study could be related to the use of supplemental dose which is lower dose in comparison to previous published studies.
Ascorbic acid in non-COVID-19 patients has been studied extensively in several randomized controlled trials and observational studies with mixed results due to the lack of consistency in terms of the ascorbic acid dose, route, timing, frequency of administration in these studies, and primary outcome measures. Studies addressing ascorbic acid in COVID 19 critically ill patients are lacking. Our study provides a hypothesis-generating idea of the potential benefit of using ascorbic acid in critically ill patients with COVID-19 in reducing the risk of thrombosis. We believe that this hypothesis needs to be further investigated at a larger scale using more robust, validated modalities and study designs 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; that was minimized via using the propensity score. Also, baseline ascorbic acid levels were not measured before initiating the supplemental regimen, given our study's retrospective nature. Moreover, there was 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.