Abstract
Objective: Severe sepsis is a leading cause of mortality and morbidity in the critically ill with no reliably effective treatments. The goal of this study was to determine whether intravenous ascorbic acid impacted novel biomarkers in sepsis. Methods: This is a retrospective study of a phase I, randomized, double-blinded, placebo controlled safety trial of intravenous ascorbic acid in severe sepsis. In the safety trial, 24 patients were randomized to receive full ICU standard of care support plus intravenous ascorbic acid (50 or 200 mg/kg/24h) for 4 days or placebo. Novel biomarkers of sepsis such as circulating cell free DNA (cf-DNA), mitochondrial DNA (mtDNA), endogenous antimicrobial proteins (alpha-4-defensin [α4D] and bactericidal permeability interacting protein [BPI]) and the red cell distribution width (RDW) were measured. Results: Cf-DNA values were higher in non-survivors at baseline and remained elevated for 96 hours. MtDNA levels increased in the placebo group, but declined in the treatment groups without reaching statistical significance. RDW increased significantly only in the placebo group, while expression of the antimicrobial proteins increased significantly only in the treatment groups. Conclusion: Ascorbic acid infusion may improve sepsis outcomes by reducing cf- and mtDNA levels while augmenting endogenous antimicrobial proteins and preserving RDW.
Highlights
Severe sepsis is a leading cause of death in the critically ill with more than 700,000 new cases diagnosed in the United States annually [1]
Temporal changes in serum cell free DNA (cf-DNA) in severe sepsis patients Serial serum samples and mortality data were available from the 24 patients enrolled in the study
Over the course of the study there was a trend toward a marginal increase in the mitochondrial DNA (mtDNA)-74 levels in the placebo group (p=0.7) (Figure 3)
Summary
Severe sepsis is a leading cause of death in the critically ill with more than 700,000 new cases diagnosed in the United States annually [1]. Numerous advances continue to be made in both the identification and treatment of sepsis, the incidence of sepsis and its associated multiple organ failure continues to rise worldwide This new reality has made sepsis a leading cause of morbidity and mortality in critically ill patients [1]. In our pre-clinical studies, we showed that parenteral infusion of ascorbic acid (200 mg/kg) could attenuate sepsis induced organ injury in wild type mice [2,3] and in vitamin C knockout mice (lacking L-gulono-γ-lactone oxidase, Gulo) [4]. In these studies parenteral ascorbic acid was effective at reducing mortality and sepsis-induced organ injury through pleiotropic mechanisms including down-regulation of pro-inflammatory mediator secretion, normalization of coagulopathy, improved alveolar fluid clearance and enhanced alveolar epithelial barrier function
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