The Emerging Role of Vitamin C as a Treatment for Sepsis

Markos G Kashiouris, Michael L'Heureux, Casey A Cable, Bernard J Fisher, Stefan W Leichtle, Alpha A Fowler, Markos G Kashiouris, Michael L'Heureux, Casey A Cable, Bernard J Fisher, Stefan W Leichtle, Alpha A Fowler

Abstract

Sepsis, a life-threatening organ dysfunction due to a dysregulated host response to infection, is a leading cause of morbidity and mortality worldwide. Decades of research have failed to identify any specific therapeutic targets outside of antibiotics, infectious source elimination, and supportive care. More recently, vitamin C has emerged as a potential therapeutic agent to treat sepsis. Vitamin C has been shown to be deficient in septic patients and the administration of high dose intravenous as opposed to oral vitamin C leads to markedly improved and elevated serum levels. Its physiologic role in sepsis includes attenuating oxidative stress and inflammation, improving vasopressor synthesis, enhancing immune cell function, improving endovascular function, and epigenetic immunologic modifications. Multiple clinical trials have demonstrated the safety of vitamin C and two recent studies have shown promising data on mortality improvement. Currently, larger randomized controlled studies are underway to validate these findings. With further study, vitamin C may become standard of care for the treatment of sepsis, but given its safety profile, current treatment can be justified with compassionate use.

Keywords: HDIVC; high-dose intravenous vitamin C; sepsis; septic shock; vitamin C.

Conflict of interest statement

The primary authors (M.G.K., B.J.F., A.A.F.III) were investigators on the CITRUS-ALI study.

Figures

Figure 1
Figure 1
The last step in vitamin C (C6H8O6, or l-Ascorbic acid) biosynthesis. Humans have lost the ability to synthesize the GLO enzyme, and thus are dependent on exogenous vitamin C intake through their diet. Modified from: U.S. National Library of Medicine, PubChem.
Figure 2
Figure 2
Ascorbic Acid (AA) and dehydroascorbic Acid (DHA) transporters (left). Concentration of AA and DHA in human organs and cells in uM (right). Inspired by Padayatty and Levine [25].
Figure 3
Figure 3
Infographic of differential vitamin C peak plasma concentrations based on alternative routes of administration and dosage.
Figure 4
Figure 4
Pleiotropic effects of high-dose intravenous vitamin C (HDIVC) in sepsis-induced acute respiratory distress syndrome (ARDS). The orange star [✯] points to possible therapeutic targets of HDIVC. The figure illustrates a human alveolus with the capillary membrane, and the blood-gas barrier during sepsis.
Figure 5
Figure 5
Kaplan–Meier mortality curves in patients with sepsis induced acute respiratory distress syndrome (ARDS) who were randomized to receive a 4-day course of high-dose intravenous vitamin C (HDIVC) versus placebo, upon ARDS onset-recognition.

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