Written by Seth Walsh-Blackmore
A double-blind, international, multi-center RCT of septic adult ICU patients found an increased risk of death or persistent organ dysfunction at 28 days with a high dose IV vitamin C (HDIVVC) regimen.
Why does this matter?
There is a clinical rationale for why vitamin C should benefit critically ill patients with sepsis. However, subsequent trials have been equivocal at best. A recent meta-analysis suggested acceptable safety and possible mortality benefit of HDIVVC, with the caveat that more robust RCTs were needed. Well, here we have one!
Not C-ing a reason to LOVIT
This was a randomized, placebo-controlled, double-blinded study of 863 septic adult ICU patients recruited from 35 centers across Canada, New Zealand, and France. Additional criteria were <24 hours in the ICU, a vasopressor requirement, and no contraindication to or prior receipt of vitamin C. The intervention was 50 mg/kg IV boluses of vitamin C (in D5W or NS) every six hours for 96 hours. The authors exceeded the enrollment goal of their power analysis, and 96.7% of the patients enrolled received at least 90% of the scheduled doses.
The primary outcome was a composite of death, continued vasopressor requirement, mechanical ventilation, or renal-replacement therapy on trial day 28. This occurred in 44.5% of the vitamin C group and 38.5% of the placebo group (Risk Ratio 1.21 (95%CI 1.04-1.40). An after-adjustment analysis of the primary outcome for baseline characteristics found a RR of 1.15 (95%CI 0.90-1.47). Secondary outcomes, including death at 6 months and days without signs of organ dysfunction, lacked a significant difference.
We can confidently say HDIVVC does not improve meaningful clinical outcomes in septic ICU patients. The risk of harm is less clear but is likely moot, as there is no other indication for vitamin C in sepsis. This was a vitamin C-only regimen, a successor to the CITRIS-ALI trial. LOVIT is not direct evidence against “metabolic resuscitation” (aka HAT therapy – hydrocortisone, ascorbic acid, and thiamine). Still, RCTs using this regimen failed to produce the benefit observed in earlier retrospective studies. I would argue it’s time to move on, perhaps examining early vs. late escalation strategies with established sepsis interventions, which may be why metabolic resuscitation has been found effective in some studies.
For a review of the rationale and earlier studies that have driven more recent trials, see our friends at PulmCrit.
Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. N Engl J Med. 2022 Jun 23;386(25):2387-2398. doi: 10.1056/NEJMoa2200644. Epub 2022 Jun 15.