Vitamin C in Sepsis: Evidence-Based Recommendations
Vitamin C should NOT be routinely administered to patients with sepsis or septic shock based on current guideline recommendations, despite some promising mechanistic rationale and mixed research evidence.
Guideline-Based Recommendations
Pediatric Sepsis Guidelines
The Surviving Sepsis Campaign pediatric guidelines (2020) explicitly recommend against the use of ascorbic acid (vitamin C) in the treatment of children with septic shock or other sepsis-associated organ dysfunction (weak recommendation, very low quality of evidence) 1.
Adult Sepsis Guidelines
The Surviving Sepsis Campaign adult guidelines (2016) make no specific recommendation regarding vitamin C for sepsis treatment, notably absent from their comprehensive nutrition and supplementation sections that address selenium, glutamine, arginine, and other micronutrients 1.
ESPEN Micronutrient Guidelines
The ESPEN guidelines (2022) provide context-specific recommendations 1:
- During critical illness: A higher vitamin C repletion dose of 2-3 g per day IV during the acute phase of inflammation (Grade B recommendation, 84% consensus) 1
- Important caveat: This recommendation applies to critical illness in general, not specifically to sepsis, and measurement of plasma vitamin C is not recommended in critical illness or severe inflammation due to difficulty in interpretation 1
Why Guidelines Recommend Against Routine Use
Recent High-Quality Trial Evidence
The C-EASIE 2025 trial used 1.5 g every 6 hours for 4 days (total 6 g/day) and found no significant reduction in the mean SOFA score post-baseline (ratio 0.91,95% CI 0.77-1.08, P=0.30) 2. This represents the most recent high-quality evidence directly addressing vitamin C in sepsis.
Conflicting Research Evidence
While some observational studies suggest benefit:
- One prospective cohort (2024) showed vitamin C as adjuvant therapy decreased mortality risk by 46% in patients with SOFA ≥9 (RR: 0.54,95% CI: 0.31-0.96, p = 0.03) 3
- A meta-analysis (2022) of 23 RCTs showed reduced mortality (OR = 0.778, p = 0.016), SOFA score (MD = −0.749, p < 0.001), and vasopressor duration (MD = −1.034 days, p = 0.001) 4
However, these findings are contradicted by:
- Inconsistency between randomized controlled trials and observational studies 5
- Heterogeneity in vitamin C regimen, initiation timing, and treatment duration 5
- The failure of the most recent rigorous trial to demonstrate benefit 2
Clinical Reasoning Algorithm
When to Consider Vitamin C
Do NOT routinely administer vitamin C for sepsis treatment based on current evidence 1.
If Considering Off-Guideline Use
Only in the context of:
- Documented severe vitamin C deficiency with clinical suspicion of scurvy 1
- Research protocol participation with appropriate informed consent
- Refractory septic shock after exhausting all guideline-recommended therapies, understanding this is not evidence-based
Dosing Protocols (If Used Off-Guideline)
The most commonly studied regimen is 1.5 g IV every 6 hours for 4 days (total 6 g/day), often combined with thiamine and hydrocortisone 5, 2. Alternative protocols include 2-3 g/day IV during acute inflammation 1.
Critical Safety Considerations
Absolute Contraindications
Avoid vitamin C supplementation in 1, 6:
- Hemochromatosis (risk of iron overload)
- G6PD deficiency (risk of hemolysis)
- Renal dysfunction (risk of oxalate stone formation)
- History of oxalate kidney stones
Monitoring Requirements
- Screen for contraindications before administration 6
- Monitor for edema if using doses above 1 g daily 6
- Be aware that plasma vitamin C levels decline rapidly with inflammation (CRP >10 mg/L), making interpretation difficult 1
Common Pitfalls to Avoid
Do not delay standard sepsis care (antibiotics, source control, fluid resuscitation, vasopressors) to administer vitamin C 1
Do not assume observational study benefits translate to clinical practice - the most rigorous RCT showed no benefit 2
Do not use vitamin C as monotherapy - if used off-guideline, it should only be adjunctive to standard care 3
Do not measure plasma vitamin C levels in acute sepsis - inflammation makes interpretation unreliable 1
Mechanistic Rationale (Not Translating to Clinical Benefit)
While vitamin C theoretically prevents microcirculatory flow deterioration, inhibits platelet aggregation, restores vascular response to vasoconstrictors, preserves endothelial barrier, and enhances antibacterial defenses 2, these mechanisms have not translated to significant clinical benefits in rigorous trials 2.
Bottom line: Current best practice is to NOT routinely use vitamin C for sepsis treatment, focusing instead on guideline-recommended therapies with proven mortality benefit.