Vitamin C infusion did not affect organ function or biomarkers in sepsis and ARDS

Patients with sepsis and acute respiratory distress syndrome (ARDS) who received vitamin C did have a lower rate of 28-day mortality, one of very few secondary outcomes to show a difference compared to placebo.


A 96-hour vitamin C infusion was not associated with any difference in organ failure scores or plasma biomarkers of inflammation among sepsis patients, a recent randomized trial found.

The trial was conducted in seven medical ICUs in the U.S. from September 2014 to November 2017 and included 167 patients with sepsis and acute respiratory distress syndrome (ARDS) present for less than 24 hours (mean age, 54.8 years; 54% men). They were randomly assigned to receive an IV infusion of vitamin C (50 mg/kg in dextrose 5% in water, n=84) or placebo (dextrose 5% in water only, n=83) every 6 hours for 96 hours. Results were published in the Oct. 1 JAMA.

A total of 103 patients completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the study's primary outcomes. The mean modified Sequential Organ Failure Assessment score went from 9.8 at baseline to 6.8 at 96 hours in the vitamin C group and from 10.3 to 6.8 in the placebo group (difference between groups, −0.10 [95% CI, −1.23 to 1.03]; P=0.86). Similar results were also seen in C-reactive protein levels (54.1 vs. 46.1 μg/mL; difference, 7.94 μg/mL [95% CI, −8.2 to 24.11 μg/mL]; P=0.33) and thrombomodulin levels (14.5 vs. 13.8 ng/mL; difference, 0.69 ng/mL [95% CI, −2.8 to 4.2 ng/mL]; P=0.70) at 168 hours.

The trial also looked at 46 secondary outcomes, 43 of which showed no significant differences. However, vitamin C was associated with a significant reduction in 28-day all-cause mortality and a significant increase in ICU-free days in the first 28 days and hospital-free days in the first 60 days. “However, these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory. It is possible that these observations represent the effects of vitamin C on underlying sepsis-induced biological abnormalities that are not reflected in the biomarker analysis, a hypothesis supported by 3 findings: early deaths in the placebo group, the proportion of patients in the vitamin C–infused cohort who left the ICU before 168 hours, and the survival curve parallel to that of placebo after cessation of vitamin C infusion,” the authors said.

The study had several limitations, including that it only enrolled patients once they had ARDS, although it was a follow-up to a phase 1 trial that had administered vitamin C to patients in the very early stages of severe sepsis. It may also have been underpowered to show a difference in the primary outcomes, and the dose of vitamin C may have been insufficient, the authors said. They called for further research to evaluate the effect of vitamin C on other outcomes in sepsis and ARDS.

“The difference in mortality is tantalizing and likely to spur much debate,” said an accompanying editorial. However, the finding was without adjustment and could be due to chance, the editorialists said. In addition, vitamin C could work by different mechanisms than those that were studied. “For all these reasons, further evaluation in a larger trial seems warranted,” the editorial said.