By Fowler AA, Truwit JD, Hite RD, et al. Effect of vitamin C infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure. JAMA 2019; 322(13):1261-1270.
Reviewed by: Kyle Hobbs, MD
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Acute respiratory distress syndrome (ARDS) often accompanies sepsis and contributes to significant morbidity and mortality. This randomized, double-blind, placebo-controlled, multicenter trial investigated whether high-dose vitamin C infusion would reduce organ failure, biomarkers of inflammation and vascular injury in septic patients with ARDS.
Patients were included if they were mechanically ventilated, met ARDS criteria (PaO2/FiO2 ratio < 300mm Hg, bilateral opacities on CXR within 1 week of insult, new or worsening respiratory symptoms without evidence of left atrial hypertension), had suspected or proven infection, and met 2/4 SIRS criteria. Exclusion criteria included vitamin C allergy, < 18 years old, > 48 hours from meeting ARDS criteria, chronically mechanically ventilated or on > 2 L home O2, interstitial lung disease, DKA, or active nephrolithiasis.
Patients were randomized 1:1 to 96 hours of vitamin C infusion or placebo. Mechanical ventilation was performed according to ARDS network tidal volume settings and a standardized conservative fluid administration protocol was followed. Primary outcomes were modified Sequential Organ Failure Assessment (mSOFA) scores at 96 hours and plasma levels of C-reactive protein (CRP) and thrombomodulin. Secondary outcomes included 28-day all-cause mortality, ventilator- and ICU-free days to day 28 (days requiring intubation/ICU admission were subtracted from 28), and hospital-free days at day 60, as well as numerous respiratory and hemodynamic parameters. Modified SOFA scores with bilirubin eliminated from SOFA score were measured at hours 0, 48 and 96.
One hundred sixty seven patients were randomized (83 placebo, 84 vitamin C). The most common presumed etiology of sepsis was pneumonia. Mean mSOFA scores at baseline were 9.8 (vitamin C group) and 10.3 (placebo), and both decreased to 6.8 at 96 hours (p = 0.86). There were no significant differences between vitamin C and placebo groups in CRP levels (p = 0.33) or thrombomodulin levels (p = 0.70) at 168 hours. There were no significant differences between groups in 43/46 prespecified secondary outcomes. Twenty-eight-day mortality was significantly lower in the vitamin C group (29.8% vs 46.3%, p = 0.03), and the Kaplan Meier survival curves were significantly different by the Wilcoxon test (p = 0.01). The number of ventilator-free days were not significantly different (13.1 vitamin C vs 10.6 placebo, p = 0.15), but the vitamin C group did have significantly more ICU-free days (10.7 vs 7.7, p = 0.03) and hospital-free days (22.6 vs 15.5, p = 0.04). There were no unexpected study-related adverse events in either group.
Vitamin C infusion was not associated with improved organ dysfunction, decreased inflammation or decreased vascular injury in septic patients with ARDS. The authors suggest that the lack of effect of vitamin C infusion on mSOFA scores, CRP and thrombomodulin levels was the result of advanced sepsis prior to the development of ARDS; a prior phase 1 safety trial of vitamin C administered to patients in early severe sepsis demonstrated a decrease in SOFA scores and reduced CRP and procalcitonin. The delay in vitamin C infusion until patients were intubated with ARDS could account for the discrepancy in results between these studies.
While vitamin C was associated with significant reductions in 28-day all-cause mortality as well as increased ICU-free days to day 28 and hospital-free days to day 60, these findings did not account for multiple comparisons, and thus merit further exploration. This study was limited by small sample size and may have been underpowered to detect differences between vitamin C and placebo groups. It is also unclear if the dose used was the optimal dose for patients with sepsis associated ARDS.