Vitamin C may not provide benefit in sepsis with acute respiratory failure

1. In this randomized clinical trial, intravenous infusion of high-dose vitamin C vs placebo for 96 hours resulted in no significant differences in the modified Sequential Organ Failure Assessment score at 96 hours or in levels of C-reactive protein and thrombomodulin at 168 hours.

2. There were three secondary outcomes which were significantly different between groups but lacked adjustment of multiple comparisons.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Acute respiratory distress syndrome (ARDS) is a common complication in sepsis which contributes to multi-organ dysfunction and mortality. Currently, research has shown the possibility that vitamin C can reduce inflammation and reverse sepsis-induced coagulopathy. In this randomized trial, CITRIS-ALI, patients with sepsis and ARDS in the intensive care unit who received high-dose vitamin C did not have lower rates of organ failure and biomarkers of inflammation and vascular injury.

There needs to be more research on vitamin C’s use in sepsis and ARDS. The study has several limitations. First, CITRIS-ALI was based on a previously performed vitamin C safety trial of vitamin C administered to patients in the very early stages of severe sepsis and not ARDS. This trial’s ARDS patients underwent intubation, which could have delayed vitamin C administration. Second, this trial may have been underpowered to detect a difference in modified Sequential Organ Failure Assessment (mSOFA) scores and biomarker levels. The dosage of vitamin C used in this trial (50mg/kg every 6 hours for 96 hours) may also be insufficient for optimal care of sepsis associated ARDS. Higher vitamin C dosages or longer administration times may have produced different results. Lastly, because death and ICU graduation rates between the 2 groups were not similar, there could be internal selection bias.

Click to read the study in JAMA

Click to read an accompanying editorial in JAMA

Relevant Reading: Vitamin C and Thiamine for Sepsis and Septic Shock

In-Depth [randomized controlled trial]: 167 patients from 7 medical intensive care units were randomly assigned to receive intravenous infusion of vitamin C (50mg/kg in dextrose 5% in water, n = 84) or placebo (dextrose 5% in water only, n = 83) every 6 hours for 96 hours. Patients were randomized 1:1 to receive vitamin C or placebo. The primary outcomes were organ failure or change in mSOFA score (range, 0-20, with higher scores indicating more dysfunction) from baseline to 96 hours, and plasma biomarkers of inflammation (C-reactive protein levels) and vascular injury (thrombomodulin levels) measured at 0, 48, 96, and 168 hours. There was no statistically significant difference in mSOFA scores between placebo and the vitamin C–infused patients; mean mSOFA score from baseline to 96 hours decreased from 9.8 to 6.8 in the vitamin C group and from 10.3 to 6.8 in the placebo group (difference, –0.10; CI₉₅, −1.23 to 1.03; p = .86). There were no significant differences between the vitamin C group and placebo group in the C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94; CI₉₅, −8.23 to 24.1; p = .33) or thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69; CI₉₅, −2.8 to 4.2; p = .70) assessed at 168 hours. Though exploratory analysis did not adjust for multiple comparisons, 3 secondary outcomes were significantly different between groups: day 28 mortality was 46.3% in the placebo group vs 29.8% in the vitamin C group (χ2 = 4.84; p = .03); the number of ICU-free days to day 28 was 10.7 in the vitamin C group vs 7.7 in the placebo group (mean difference, 3.2; CI₉₅, 0.3 to 5.9; p = .03); and the number of hospital-free days in the vitamin C group vs the placebo group was 22.6 vs 15.5, respectively (mean difference, 6.69; CI₉₅,0.3 to 13.8; p = .04).

Image: PD

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