Our meta-analysis systematically evaluate whether vitamin C improves the prognosis of adult patients with sepsis in randomized controlled trials. Through an analysis of 1823 patients from the 14 included studies, we found that when vitamin C is used as an adjunct method in patients with sepsis, it may not significantly reduce mortality, but when vitamin C is administered monotherapy instead of combination therapy, it may be beneficial for reducing mortality. In addition, we found a statistically significant reduction in SOFA score during the first 72 hours after enrollment.
Two recent meta-analyses showed that vitamin C does not have a positive therapeutic role in critically ill patients [39, 40], but these meta-analyses included various patients, not sepsis patients only; thus, there may have greater heterogeneity. Last year and this year, two meta-analyses showed that the use of vitamin C did not reduce mortality in sepsis patients[41, 42], but they included many retrospective studies, which may have led to lower evidence quality, and several recently published high-level large RCTs was not included, especially the largest study to date including 501 patients (the VICTAS Randomized Clinical Trial) was not included[25].
In animals, studies have shown that when animals are stressed, the synthesis of endogenous vitamin C increases [43, 44], as it does in mice exposed to tumors [45]. Other studies have shown that the synthesis of vitamin C is eight times greater than it is in animals exposed to drugs [46, 47]. It can be seen that when animals are affected by diseases and drugs, the demand for vitamin C increases significantly. This is especially obvious for humans who cannot synthesize vitamin C themselves. Long et al confirmed that the levels of vitamin C are very low in plasma after trauma and infection [48]. In patients with sepsis, as the disease worsens, an excessive inflammatory response increases the metabolism of vitamin C, and vitamin C levels gradually decline [12, 49]. Carr et al found that 88% of septic shock patients had hypovitaminosis C, and 38% were deficient in vitamin C [50]. Therefore, vitamin C supplementation is particularly important for patients with sepsis.
The amount of vitamin C that sepsis patients need to be supplemented with is still inconclusive, ranging from 0.45 g/d to 12 g/d. Under normal physiological conditions, 100–300 mg of vitamin C per day can meet daily needs [51]. However, critically ill patients may need more, and studies have shown that critically ill patients need more than 3 g daily doses to restore normal vitamin C levels [48]. We tried to explore whether the dose of vitamin C affects mortality, but we found that there was no significant difference between the high-dose vitamin C subgroup (≥ 5 g/d) and the low-dose vitamin C subgroup (< 5 g/d). In recent years, Wang et al found that medium doses (3–10 g/d) of vitamin C were associated with decreased mortality in critically ill patients, with neither low doses (< 3 g/d) nor high doses (≥ 10 g/d) having a significant impact [39]. According to the grouping method of Wang et al, we found that high doses can significantly reduce mortality in patients with sepsis, while medium or low doses cannot (Figure S16). However, what is worth to notice is that both studies in the high-dose group used vitamin C monotherapy, this may be a confounding factor.
Recently, cocktail therapy combining vitamin C, thiamine, and corticosteroids has become a hot topic among new therapies for sepsis. Since vitamin C, thiamine, and corticosteroids have the same cellular signaling pathways and metabolic cascades [52], this cocktail therapy is theoretically justified. Since the treatment was proposed by Marik et al in 2016, the combination therapy of vitamin C, thiamine, and corticosteroids in patients with sepsis has received increasing attention. They found that the early use of intravenous vitamin C, together with corticosteroids and thiamine, is effective in preventing progressive organ dysfunction and in reducing the mortality of patients with severe sepsis and septic shock [14]. However, a recent retrospective observational cohort study suggests that incorporating vitamin C, hydrocortisone, and thiamine into standard practice may not improve patient outcomes [53], what is worth to notice is that non-sequential patients were included in the vitamin C group in this study resulting in a severe selection bias which may limit the interpretation. Since these two studies are observational studies, we did not include them in our meta-analysis. Excitingly, several large RCT studies on this cocktail therapy have been published recently, providing new evidence for our meta-analysis. Fujii et al found that the combination of vitamin C, thiamine, and hydrocortisone did not reduce mortality or vasopressor time in a study of 216 sepsis patients [19]. Recent years, Iglesias et al [21], Chang et al [18], Moskowitz et al[23] and Sevransky et al[25] used similar methods and found no significant change in mortality or SOFA score.
Through subgroup analysis, we found that the combined results of six studies using vitamin C monotherapy showed a significant reduction in mortality in patients with sepsis, while the combined results of the other eight studies using vitamin C combined with other drugs, including thiamine and hydrocortisone, mainly showed no significant effect on mortality. We speculate that patients with sepsis using vitamin C monotherapy instead of combination therapy may play a more active role.
It should be noted that our research still has many limitations. First, the included study included a 25-year time span during which significant changes in the recognition and management of sepsis may have had different effects on the trial populations. Second, many studies mentioned that the initial time of vitamin C application in patients with sepsis may have a significant impact on the results, such as mortality. We tried to perform subgroup analysis according to the initial time of medication; unfortunately, it was difficult for us to extract this part of the data. Third, since the vitamin C regimen and control regimen in each study are not the same, it will lead to greater clinical heterogeneity. Fourth, some of the included studies were co-intervention (vitamin E, NAC, etc), it will weaken the relative contribution of vitamin C. Fifth, some secondary results (duration of vasopressor use and 72-h ΔSOFA score) were not reported in the protocol, they were exploratory outcomes and may led to several bias. Sixth, although we performed a comprehensive database search and a manual search and made a funnel plot, which had symmetry, we did not search the gray literature or contact authors to confirm whether there were any unpublished studies. Therefore, we still cannot rule out the existence of publication bias. Additionally, TSA shows that the sample size did not reach the RIS, so the sample size was not enough to draw firm conclusions about the clinical efficacy of vitamin C, and more large multicenter RCTs are needed.