Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial

Abstract

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.

Trial registration: ClinicalTrials.gov Identifier: NCT02106975.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fowler reports receiving an honorarium from Virginia Tech School of Medicine; grants from the National Heart, Lung, and Blood Institute (NHLBI); and study materials from McGuff Pharmaceuticals during the conduct of the study. Dr Truwit reports receiving grants from the National Institutes of Health (NIH) during the conduct of the study. Dr Hite reports receiving grants from NHLBI during the conduct of the study, grants from the Marcus Foundation, and grants from NHLBI outside the submitted work. Dr Morris reports receiving grants from NIH during the conduct of the study. Dr Thacker reports receiving grants from NIH during the conduct of the study. Dr Brophy reports receiving grants from NIH during the conduct of the study. Dr Sturgill reports receiving grants from NIH during the conduct of the study. Dr Martin reports receiving grants from NHLBI during the conduct of the study. Dr Sevransky reports receiving grants from NIH during the conduct of the study and grants from the Marcus Foundation outside the submitted work. Ms Egan reports receiving grants from Emory University during the conduct of the study. Dr Duggal reports receiving grants from NIH during the conduct of the study. Ms Graf reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Zellner reports receiving grants from Virginia Commonwealth University during the conduct of the study. Ms Yanny reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms McPolin reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Ms Hollrith reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Dr Damm reports receiving grants from the Medical College of Wisconsin during the conduct of the study. Mr Cassity reports receiving grants from NIH during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients Through the CITRIS-ALI Trial in Sepsis and Acute Respiratory Distress Syndrome

Exclusions could occur for 1 or more reasons. None of the patients excluded after randomization received vitamin C. CPAP indicates continuous positive airway pressure; BiPAP, bilevel positive airway pressure.

Figure 2.. Plasma Ascorbate Concentrations, Modified Sequential Organ Failure Assessment Score, and Plasma Biomarkers

Median values are shown by the horizontal line inside the box, interquartile range (IQR) by the top and bottom of the boxes, 95% CI by the whiskers, and values were outside the 5th and 95th percentiles by circles. Box plots have been offset to avoid superimposition. A, Plasma ascorbate levels at enrollment were marginally deficient (dotted line, P = .68). At 48 hours, median was 166 μM [IQR, 88-376] for vitamin C vs 23 μM for placebo [9-37], P < .001). At 96 hours, median was 169 μM [IQR, 87-412] for vitamin C vs 26 μM for placebo [9-41], P < .001). At 168 hours, median was 46 μM [IQR, 19-66] for vitamin C vs 29 μM for placebo [12-39], P < .002). After cessation of vitamin C infusion, plasma levels in the vitamin C cohort decreased below 100 μM but remained significantly higher than plasma ascorbate levels in placebo patients. B, There was no difference in the initial modified Sequential Organ Failure Assessment (mSOFA) scores of the 2 groups at baseline (vitamin C vs placebo, median, 10 [IQR, 7-12] vs 10 μM [8-12]). During the next 96 hours, mSOFA scores decreased but were not different between the 2 groups. C and D, Plasma levels of C-reactive protein and thrombomodulin were measured at baseline and at 48, 96, and 168 hours. At no time were the levels of these significantly different between the 2 groups.

Figure 3.. All-Cause Mortality From Randomization (Day 0) to Day 28 Among Patients With Sepsis-Associated Acute Respiratory Distress Syndrome

Vitamin C–infused patients exhibited a significant reduction in 28-day all-cause mortality, although the P value was not adjusted for multiple comparisons. The median observation time was 28 days (interquartile range, 15-28 days) for the vitamin C group and 28 days (interquartile range, 5-28 days) for the placebo group.