Summary
Dr. Sergio Zanotti interviews Dr. Emily Brandt, an intensivist at the University of Pittsburgh Medical Center, about the clinical evidence for high-dose vitamin C in sepsis treatment. They discuss the recently published Citrus ALI clinical trial alongside the earlier Marik protocol and the scientific rationale for why vitamin C might help septic patients. The episode provides a thorough evidence-based analysis of the Citrus ALI trial, which enrolled 167 ICU patients and tested 50 mg/kg of IV vitamin C every 6 hours for 96 hours. While the primary endpoints showed no significant differences in organ failure scores or biomarkers, a secondary outcome revealed a striking 28-day mortality reduction from 46.3% to 29.8% in the vitamin C group. Dr. Brandt discusses the trial's strengths and limitations, including potential issues with timing of vitamin C administration and selection of biomarkers, while urging caution about changing clinical practice based on secondary outcomes alone.
Key Points
- Sepsis affects over 2 million people annually and represents about 6% of US healthcare spending
- Critically ill septic patients have significantly depleted vitamin C levels, sometimes approaching scurvy-level concentrations
- The Citrus ALI trial tested 50 mg/kg IV vitamin C every 6 hours for 96 hours in 167 ICU patients with sepsis and ARDS
- Primary endpoints (modified SOFA score, CRP, thrombomodulin) showed no significant differences between vitamin C and placebo
- A secondary outcome showed 28-day mortality of 29.8% vs 46.3% favoring vitamin C (hazard ratio 0.55, p=0.01)
- The Marik protocol (hydrocortisone, ascorbic acid, thiamine) is mechanistically different from vitamin C alone
- Vitamin C binds adrenergic receptors, improves catecholamine response, reduces endothelial dysfunction, and may be bacteriostatic
- Multiple larger randomized trials were underway at the time of recording to provide more definitive answers
Key Moments
Why vitamin C is promising for sepsis treatment
Dr. Brandt explains the molecular rationale for vitamin C in sepsis, including its antioxidant properties, effects on adrenergic receptors to limit hypotension, reduction of capillary leak, and potential bacteriostatic activity.
"it's an antioxidant. So number one, it binds to the adrenergic receptors and sort of improves the catecholamine response, therefore limiting the hypotension that's seen in sepsis."
Septic patients have near-scurvy vitamin C levels
Dr. Brandt explains that critically ill septic patients have dramatically depleted vitamin C levels due to increased metabolic turnover, with levels approaching those seen in scurvy.
"In septic patients, we have seen that levels can be as low as the low to mid teens, albeit not at scurvy levels. But in one observation of cohort patients with septic shock had levels as low as about 15 micromoles per liter."
Citrus ALI trial shows mortality signal but negative primary endpoints
The Citrus ALI trial's primary endpoints were negative, but a striking secondary outcome showed 28-day mortality of 29.8% in the vitamin C group versus 46.3% in placebo, with a hazard ratio of 0.55.
"Among those patients who received vitamin C, it was 29.8%, and among the placebo group, it was 46.3%. This is a hazard ratio of 0.55 in favor of the treatment group, with a p-value of 0.01."
Clinician versus scientist perspective on vitamin C use
Dr. Brandt admits she would personally try vitamin C in a profoundly septic patient as a bedside clinician, but as a scientist she believes more data is needed before making sweeping changes to standard of care.
"if I had a patient who was in profound septic shock on multiple vasopressors, was on glucocorticoids and was simply not doing well, would I try vitamin C in that patient? If I'm honest with you as a bedside clinician, I probably would."
