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October - 2019


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Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure

Alpha A. Fowler, Jonathon D. Truwit, R. Duncan Hite, et al. JAMA, 2019, 322(13):1261-1270


There has been a spike of interest in vitamin C, with some evidence it attenuates systemic inflammation , corrects sepsis-induced coagulopathy, and attenuates vascular injury.

The CITRIS-ALI trial examines the effect of intravenous administration of high-dose vitamin C on organ failure scores and biomarkers of inflammation and vascular injury among patients with sepsis and acute respiratory distress syndrome (ARDS)?

What did they do;

  • Enrolled ICU patients receiving mechanical ventilation, PF ratio < 300 mm Hg, bilateral opacities on CXR within 1 week of known clinical insult, had new or worsening respiratory symptoms without evidence of left atrial hypertension, suspected or proven infection, and 2 of 4 systemic inflammatory response criteria. All criteria had to be met within a 24-hour period. 
  • 167 patients were randomized to receive vitamin C or placebo. Vitamin C was IV infused at 50 mg/kg actual body weight every 6 hours for 96 hours.
  • At baseline they were similar, although there was more respiratory and less abdominal sepsis in the vitamin C group
  • Primary outcome: 
    • No differences in the modified mean SOFA score at 96 hours (decrease from 9.8 to 6.8 in the vitamin C group (3 points) vs 10.3 to 6.8 in the placebo group (3.5 points) (difference, –0.10; 95% CI, −1.23 to 1.03; P = .86). 
    • No difference in CRP and thrombomodulin at 168 hours.
  • There were 46 prespecified secondary outcomes
    • There were no difference in 43 of the secondary outcomes
    • Day 28, mortality was 46.3% (placebo group) vs 29.8% (vitamin C) (χ2 = 4.84; P = .03; between-group difference, 16.58% [95% CI, 2% to 31.1%]). The Kaplan-Meier survival curves for the 2 groups were significantly different by the Wilcoxon test (χ21 = 6.5; P = .01)
    • ICU-free days to day 28 was 10.7 (vitamin C) vs 7.7 (placebo) (mean difference, 3.2; 95% CI, 0.3 to 5.9; P = .03)
    • Transfer out of the ICU by hour 168 or less was 25% of patients (vitamin C) vs vs 12.5% (placebo) (χ2 = 4.63; P = .03; difference, 12.95% [95% CI, 1.16% to 24.73%; P = .31]
    • Hospital-free days were 22.6% (vitamin C) vs 15.5% (placebo) (mean difference, 6.69; 95% CI, 0.3 to 13.8; P = .04)
    • Vitamin C levels were low in all patients, and increased in vitamin C group

This was a well designed, and the largest RCT of vitamin C in critical illness. The primary outcomes were not different, so high-dose vitamin C infusion did not improve organ failure scores or biomarkers in patients with sepsis and ARDS. The improvement in secondary outcomes, mortality and length of stay, are encouraging, but with so many secondary outcomes and no evidence of biological benefit, should be considered exploratory only. It appears a larger well designed RCT may be needed to understand this better.



Importance  Experimental data suggest that intravenous vitamin C may attenuate inflammation and vascular injury associated with sepsis and acute respiratory distress syndrome (ARDS).

Objective  To determine the effect of intravenous vitamin C infusion on organ failure scores and biological markers of inflammation and vascular injury in patients with sepsis and ARDS.

Design, Setting, and Participants  The CITRIS-ALI trial was a randomized, double-blind, placebo-controlled, multicenter trial conducted in 7 medical intensive care units in the United States, enrolling patients (N = 167) with sepsis and ARDS present for less than 24 hours. The study was conducted from September 2014 to November 2017, and final follow-up was January 2018.

Interventions  Patients were randomly assigned to receive intravenous 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.

Main Outcomes and Measures  The primary outcomes were change in organ failure as assessed by a modified Sequential Organ Failure Assessment 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.

Results  Among 167 randomized patients (mean [SD] age, 54.8 years [16.7]; 90 men [54%]), 103 (62%) completed the study to day 60. There were no significant differences between the vitamin C and placebo groups in the primary end points of change in mean modified Sequential Organ Failure Assessment score from baseline to 96 hours (from 9.8 to 6.8 in the vitamin C group [3 points] and from 10.3 to 6.8 in the placebo group [3.5 points]; difference, −0.10; 95% CI, −1.23 to 1.03; P = .86) or in C-reactive protein levels (54.1 vs 46.1 μg/mL; difference, 7.94 μg/mL; 95% CI, −8.2 to 24.11; P = .33) and thrombomodulin levels (14.5 vs 13.8 ng/mL; difference, 0.69 ng/mL; 95% CI, −2.8 to 4.2; P = .70) at 168 hours.

Conclusions and Relevance  In this preliminary study of patients with sepsis and ARDS, a 96-hour infusion of vitamin C compared with placebo did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury. Further research is needed to evaluate the potential role of vitamin C for other outcomes in sepsis and ARDS.


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