Lit Matters #2: Poor Outcomes Associated with Vitamin C in Sepsis

High-dose IV vitamin C in septic shock is not benign. In adults with sepsis on vasopressors in the ICU, a large blinded randomized trial found worse 28-day outcomes with vitamin C, directly challenging the long-running “what could it hurt?” mindset.

Vitamin C in Septic Shock

• Practice-changing trial signal: In vasopressor-dependent sepsis, IV vitamin C was associated with a higher rate of death or persistent organ dysfunction at 28 days, a rare finding for a therapy often framed as harmless.
• Large blinded ICU trial: This was an international double-blind RCT across 35 ICUs with 863 patients, giving the negative signal more weight than the earlier small single-center enthusiasm.
• Composite outcome details: The primary endpoint combined death with ongoing vasopressors, mechanical ventilation, or renal replacement therapy on day 28, anchoring the result in patient-centered organ support.
• Mortality trend without benefit: Mortality alone was numerically higher with vitamin C, and none of the secondary outcomes showed a compensating advantage in organ recovery, quality of life, or biomarkers.
• Why earlier excitement faded: Prior positive studies often bundled vitamin C with hydrocortisone and thiamine, while seven randomized trials overall have been mixed and methodologically uneven. We get into why that early signal was so persuasive in the episode.
• Therapeutic humility lesson: Sepsis care is full of biologically plausible treatments that fail when tested, and vitamin C is a sharp reminder that antioxidant theory does not equal bedside benefit.