Background: Sepsis results from the inability of the host to resolve an infection, leading to systemic infection, multi-organ dysfunction and death. Despite available treatments, sepsis remains the primary cause of death in intensive care units, accounting for ~11 million global deaths annually. Effective treatments are urgently needed. Our data from human and sheep studies show that sodium ascorbate improves clinical outcomes in sepsis, but the mechanisms are still unknown.
Aim: To assess the ability of intravenous mega-dose sodium ascorbate to accelerate resolution of systemic bacterial sepsis in rodents.
Methods: Sprague-Dawley male rats were intravenously administered a live Escherichia coli (E. coli) bolus (4 x 109 CFUmL-1), and treated with either intravenous mega-dose sodium ascorbate (1-3g/kg; N=7) or fluid-matched vehicle-saline (N=7) for 3-h. Blood samples were collected prior to sepsis-induction and at 1.5-h and 3-h following treatment. We determined blood bacterial counts by using a colony-forming assay. Blood was stimulated in vitro to assess phagocytosis with S. aureus- or E. coli-coated beads, and reactive oxygen species production in myeloid cells using spectral cytometry.
Results: 3-h after receiving the E. coli bolus, bacterial counts in rats treated with sodium ascorbate (3.76 ± 0.11 log10[CFUmL-1]) were significantly lower than the animals that received vehicle-treatment (4.27 ± 0.12 log10[CFUmL-1]) (PGroup = 0.01). At these concentrations sodium ascorbate did not have any bacteriostatic or bactericidal effects. Rats treated with ascorbate had a 5-fold increase in the granulocytes (RP-1+) that were phagocytic and producing reactive oxygen species compared to vehicle-treated animals (26.5 ± 6.63 vs 5.55 ± 2.38%).
Conclusion: IV-administered mega-dose sodium ascorbate rapidly enhanced bacterial clearance in a rodent model of sepsis. This was not due to direct bacterial killing or inhibiting bacterial growth, indicating immune-mediated effects. Our data indicates a key mechanism of ascorbate action is stimulating reactive oxygen species production by granulocytes.