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Randomized Controlled Trial
. 2022 Oct 21;14(20):4415.
doi: 10.3390/nu14204415.

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS

Xian Qiao  1 , Markos G Kashiouris  1 , Michael L'Heureux  1 , Bernard J Fisher  1 , Stefan W Leichtle  2 , Jonathon D Truwit  3 , Rahul Nanchal  3 , Robert Duncan Hite  4 , Peter E Morris  5 , Greg S Martin  6 , Jonathan Sevransky  6 , Alpha A Fowler  1
Affiliations
Randomized Controlled Trial

Biological Effects of Intravenous Vitamin C on Neutrophil Extracellular Traps and the Endothelial Glycocalyx in Patients with Sepsis-Induced ARDS

Xian Qiao et al. Nutrients. .

Abstract

(1) Background: The disease-modifying mechanisms of high-dose intravenous vitamin C (HDIVC) in sepsis induced acute respiratory distress syndrome (ARDS) is unclear. (2) Methods: We performed a post hoc study of plasma biomarkers from subjects enrolled in the randomized placebo-controlled trial CITRIS-ALI. We explored the effects of HDIVC on cell-free DNA (cfDNA) and syndecan-1, surrogates for neutrophil extracellular trap (NET) formation and degradation of the endothelial glycocalyx, respectively. (3) Results: In 167 study subjects, baseline cfDNA levels in HDIVC (84 subjects) and placebo (83 subjects) were 2.18 ng/µL (SD 4.20 ng/µL) and 2.65 ng/µL (SD 3.87 ng/µL), respectively, p = 0.45. At 48-h, the cfDNA reduction was 1.02 ng/µL greater in HDIVC than placebo, p = 0.05. Mean baseline syndecan-1 levels in HDIVC and placebo were 9.49 ng/mL (SD 5.57 ng/mL) and 10.83 ng/mL (SD 5.95 ng/mL), respectively, p = 0.14. At 48 h, placebo subjects exhibited a 1.53 ng/mL (95% CI, 0.96 to 2.11) increase in syndecan-1 vs. 0.75 ng/mL (95% CI, 0.21 to 1.29, p = 0.05), in HDIVC subjects. (4) Conclusions: HDIVC infusion attenuated cell-free DNA and syndecan-1, biomarkers associated with sepsis-induced ARDS. Improvement of these biomarkers suggests amelioration of NETosis and shedding of the vascular endothelial glycocalyx, respectively.

Keywords: acute respiratory distress syndrome; cell-free DNA; glycocalyx; sepsis; syndecan-1; vitamin C.

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Conflict of interest statement

M.G.K. received funding from Xellia Pharmaceuticals for serving in the advisory board. J.D.T. received industry-academic funding from Olympus Spiration for serving on a DSMB. G.S.M. received industry-academic funding from The Marcus Foundation, Bristol-Myers Squibb, Cheetah Medical, and Grifols research advisory board funds. J.E.S. received industry-academic funding from The Marcus Foundation, and BARDA. All other authors declare no competing interest.

Figures

Figure 1
Figure 1
Forty-eight-hour change in cell-free DNA (cfDNA) in the two groups, Placebo and HDIVC. Median values, the top and bottom of the boxes show the interquartile range (IQR), whiskers show 95% CI. Outliers outside the 95% confidence intervals were graphically omitted.
Figure 2
Figure 2
Forty-eight-hour increase in syndecan-1 in the two groups, Placebo and HDIVC. Median values, the top and bottom of the boxes show the interquartile range (IQR), whiskers show 95% confidence interval (CI). The extreme outliers outside the 95% confidence intervals have been omitted.
Figure 3
Figure 3
Scatterplot of (a) baseline levels and (b) 48 h levels and (c) 48 h change from baseline, of plasma cfDNA and syndecan-1. The fitted line corresponds to the regression line. Survivors at 7 days are represented with hollow circles, and expired subjects are represented with red crosses (+). Baseline (0 h): Beta = 0.37 p < 0.001 R-Squared = 0.18/48-h: Beta = 0.29, p < 0.001, R-Squared = 0.12/48 h change: Beta = 0.29 p < 0.001 R-Squared = 0.26. Abbreviations: cfDNA, cell-free deoxyribonucleic acid.
Figure 4
Figure 4
Scatterplots of the 48 h change in the PaO2/FiO2 ratio and the change in the plasma syndecan-1 during the same time-period. The figure illustrates the change of the PaO2/FiO2 ratio, a marker of oxygenation and lung injury which corresponds to the change in the plasma biomarker syndecan-1 among the two groups, Placebo and HDIVC. The linear fitted line corresponds to the regression line for each group: Placebo and HDIVC, respectively. The subjects of the placebo group are represented with red x symbols, and the subjects of the HDIVC group are represented with blue triangles. Abbreviations: FiO2, fraction of inspired oxygen; HDIVC, high-dose intravenous vitamin C; PaO2, arterial oxygen pressure.
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