Reanalysis of the Effect of Vitamin C on Mortality in the CITRIS-ALI Trial: Important Findings Dismissed in the Trial Report

The CITRIS-ALI trial was a randomized clinical trial assessing the effect of vitamin C on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure (1). Patients with sepsis and acute respiratory distress syndrome were administered 50 mg/kg vitamin C intravenously for four days. The trial report states that, “The Kaplan-Meier survival curves for the 2 groups were significantly different by the Wilcoxon test (χ2 [1df ] = 6.5; P = 0.01)” (1). However, this finding was not mentioned in the abstract and it was downplayed in the discussion section. Previously, we conducted a meta-analysis of 12 controlled trials assessing the effect of vitamin C on intensive care unit (ICU) length of stay. The meta-analysis included 1,766 patients and found that vitamin C shortened ICU stay on average by 8% (95% CI: 4-11%) (2). One of the included trials found that vitamin C reduced mortality in sepsis patients by 78% (P = 0.01) (3). Both our meta-analysis and this trial are relevant when considering the effect of vitamin C on ICU patients, but neither was cited in the CITRIS-ALI trial report (1). The CITRIS-ALI trial report suggested that the effect of vitamin C on mortality might be explained by multiple comparisons (1). The purpose of this reanalysis is to argue that the multiple comparisons issue is an unlikely explanation for the published survival findings.