Sodium ascorbate versus ascorbic acid in sepsis: a narrative review of emerging cardiovascular and neurological benefits

Sepsis remains the leading cause of death in intensive care units globally, with catecholamine-resistant shock posing a persistent therapeutic challenge. Norepinephrine is the primary vasopressor used to treat hypotension in sepsis, but its efficacy is often limited by multifactorial loss of pressor responsiveness, including adrenergic receptor desensitisation, excess nitric oxide, systemic inflammation, and endothelial injury. Ascorbate (vitamin C) has emerged as a potential adjunct therapy because it supports endothelial function, reduces oxidative stress, activates the immune system and enhances endogenous vasopressor synthesis. Despite restoration of systemic hemodynamics with fluids and vasopressors, the frontal cortex remains particularly vulnerable to microcirculatory ischemia and hypoxia, contributing to sepsis-associated encephalopathy through hypoperfusion, hypoxia, hyperthermia, oxidative stress, neuroinflammation, and mitochondrial dysfunction, ultimately leading to neuronal injury and delirium. Plasma levels of ascorbate are profoundly depleted in sepsis and correlate with disease severity. Cerebral cortical neurons actively concentrate ascorbate at levels up to 250-fold higher than plasma, underscoring its importance in maintaining redox homeostasis and metabolism in the brain. While the conventional intravenous vitamin C formulation, ascorbic acid, has been associated with harm in clinical trials, emerging preclinical and early clinical data suggest that intravenous sodium ascorbate, a pH–neutral formulation of vitamin C, may restore noradrenaline sensitivity and re-establish frontal cortical microvascular perfusion and oxygenation. This review discusses the mechanistic rationale and therapeutic potential of sodium ascorbate in sepsis, including its ability to cross the blood-brain barrier. By stabilising cardiovascular and cerebrovascular function, sodium ascorbate may represent a promising adjunctive therapy to improve the management of sepsis.