Optimization of High-Dose Sodium Ascorbate for Reversing Organ Dysfunction in Gram-Negative Sepsis

Overview

This preclinical randomized controlled trial evaluated the efficacy of varying doses of intravenous sodium ascorbate in reversing cardiovascular, neurological, and renal dysfunction induced by Gram-negative sepsis in sheep. The study identified dose-dependent improvements in organ function and reductions in vasopressor requirements, supporting the potential of high-dose sodium ascorbate as a multi-organ protective therapy in sepsis.

Background

Sepsis is a leading cause of mortality worldwide, with no current treatments that reverse multiple organ dysfunction. Plasma ascorbate levels are often depleted in sepsis and correlate with illness severity, prompting investigation of intravenous vitamin C as a therapeutic agent. Previous clinical trials using low-to-moderate doses of ascorbic acid have yielded inconsistent results. This study explores the use of sodium ascorbate at doses exceeding those previously tested, hypothesizing that very high plasma concentrations are necessary for optimal organ protection.

Data Highlights

Key Findings

• High-dose sodium ascorbate (3.75 g/kg) rapidly reversed cardiovascular, neurological, and renal dysfunction in a sheep model of Gram-negative sepsis.
• Lower doses (1.0, 2.0, 3.0 g/kg) produced dose-dependent improvements but did not fully replicate the megadose benefits.
• Sodium ascorbate reduced norepinephrine requirements to maintain target mean arterial pressure, indicating improved hemodynamic stability.
• Renal medullary tissue oxygenation and urine output increased with higher doses, reflecting improved renal function.
• Markers of inflammation (NF-κB) decreased and endothelial nitric oxide synthase phosphorylation increased, suggesting reduced inflammation and enhanced nitric oxide bioavailability.

Clinical Implications

These findings suggest that achieving very high plasma concentrations of sodium ascorbate is critical for reversing multi-organ dysfunction in sepsis. The use of sodium ascorbate, rather than ascorbic acid, may mitigate metabolic acidosis risks in septic patients. This preclinical evidence supports further clinical trials to optimize dosing strategies for intravenous sodium ascorbate in septic shock management.

Conclusion

Megadose intravenous sodium ascorbate effectively reverses multiple organ dysfunction induced by Gram-negative sepsis in a large animal model, with dose-dependent benefits observed at lower doses. These results provide a strong rationale for clinical evaluation of high-dose sodium ascorbate in sepsis treatment.

References

1. Rudd et al. 2020 -- Global, regional, and national sepsis incidence and mortality
2. Marik et al. 2017 -- Vitamin C as a treatment for sepsis
3. Fowler et al. 2019 -- Intravenous vitamin C in sepsis
4. Carr and Rosengrave 2020 -- Vitamin C in critical illness
5. Lykkesfeldt and Michels 2012 -- Vitamin C pharmacokinetics
6. Kellum et al. 2018 -- Metabolic acidosis in septic shock
7. Carr et al. 2021 -- Preclinical studies of sodium ascorbate in sepsis
8. Fowler et al. 2019 -- Pilot RCT of sodium ascorbate in septic shock