Vitamin C caused death and organ failure in burn patients
VICTORY is defeat for high-dose supplementation in critical illness
Vitamin C would seem to be an excellent candidate intervention for patients with severe burns. The reactive oxygen species released in massive quantities during burn injuries cause endothelial damage, capillary leakage, edema, shock, and widespread inflammation. Vitamin C scavenges these oxygen-free radicals, potentially mitigating this pathophysiologic cascade.
In a tiny pseudo-randomized trial of 37 patients with severe burns (Tanaka et al, JAMA Surg 2000), those receiving high-dose vitamin C supplementation required much lower volumes of infused fluids to reach resuscitation targets and had shorter durations of mechanical ventilation, without a mortality difference. Patients received the undeniably high dose of 66 mg/kg/hr for 24 hours (about 5 g per hour, or about 120 g per day for a 70 kg patient). The trial was unblinded, and randomization allocation was not concealed.
In the absence of higher-quality evidence, and in a foreshadowing of what was to transpire in medical ICUs fifteen years later, high-dose vitamin C gained popularity in burn units in the wake of the small trial.
A 2017 retrospective review of 40 patients at UW Seattle’s Harborview seemed to support the finding, with authors concluding “vitamin C is associated with a decrease in fluid requirements and an increase in urine output during resuscitation after thermal injury, [and] can be safely used without an increased risk of renal failure.”
A 2022 scoping review analyzed ten published papers: virtually all suggested a benefit of high-dose vitamin C supplementation in burn patients.
Guidelines and reviews mentioned the Tanaka data as plausible, while also highlighting the need for more rigorous study of vitamin C supplementation in severe burns.
Twenty-six years later, that trial was completed and published in JAMA.
The VICTORY Trial
At 24 burn centers in the Americas, Europe, and Asia, 666 patients with severe burns were planned to be randomized to receive either vitamin C (50 mg/kg every 6 hours for 96 hours, i.e., ~200 mg/kg/day or ~14 g/day for a 70 kg patient; i.e., a lower dose for longer than in Tanaka et al) or placebo for four days.
The trial was stopped early at the first prespecified interim analysis after 238 patients had been enrolled, for apparent harm.
Mortality at 28 days was significantly higher in the vitamin C group (15.0% vs 7.6%; adjusted RR, 1.96 [95% CI, 1.32-2.90]; P = .001), as was hospital mortality (23.3% vs 16.1%; adjusted RR, 1.44 [95% CI, 1.03-2.00]; P = .03).
These figures implied at least a 32% relative increased risk for death from receiving vitamin C (and probably significantly higher).
The composite outcome (death or persistent organ dysfunction at 28 days) occurred in 40.8% (49 of 120) patients assigned to vitamin C, compared with 29.7% (35 of 118) assigned to placebo (adjusted relative risk 1.28 with a 95% confidence interval from 0.99 to 1.65). The P value was .06, but the result crossed the trial’s prespecified boundary for futility or harm.
Renal failure occurred numerically more frequently in the vitamin C arm (15% vs. 11%), and numerically almost twice as many vitamin C patients required dialysis (10.8% vs. 5.9%); these did not reach statistical significance.
Discussion
Many more patients with severe burns died while receiving high-dose vitamin C supplementation than placebo. Vitamin C patients experienced more persistent organ dysfunction, with a strong suggestion of an increase in renal failure. Oxalate crystal formation is a known risk from high-dose vitamin C, although this was not a proven mechanism of harm in VICTORY.
The flameout of high-dose vitamin C in VICTORY is a cautionary coda that concludes the inspiring but imaginary story first told in Tanaka et al in 2000.
In an ironic conceptual cross-contamination between specialties, the Tanaka data was cited by authors of various papers touting vitamin C for sepsis as a basis for its putative therapeutic effects. This apparent evidentiary support helped to launch the vitamin C cargo cult that seized the critical care community for a half-decade starting in 2017.
In an interesting parallel to the burn literature, multiple randomized trials in ICUs suggested that vitamin C therapy could save lives in sepsis and critical illness generally—producing a 27% relative risk reduction for mortality, according to a meta-analysis of 16 randomized trials.
The large multicenter randomized LOVIT trial (NEJM 2022, n=872) then reported the counterfactual: a 17% increase in mortality and 30% increase in persistent organ dysfunction (relative) in patients receiving vitamin C monotherapy for sepsis. This followed the ACTS trial, which also showed no benefit for vitamin C in sepsis.
Although it took 26 years after the first kindling of enthusiasm, results from the VICTORY and LOVIT trials seem likely to definitively end any defensible use of high-dose vitamin C for critical illness in either clinical practice or research.
References
High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury. JAMA. 2026 Jun 10:e2610728. doi: 10.1001/jama.2026.10728. Epub ahead of print. PMID: 42267884.
Lee ZY, Ortiz-Reyes L, Lew CCH, et al. Intravenous vitamin C monotherapy in critically ill patients: a systematic review and meta-analysis of randomized controlled trials with trial sequential analysis. Annals of Intensive Care. 2023;13(1):14. doi:https://doi.org/10.1186/s13613-023-01116-x
Soltany A, Al Aissami M. A scoping review of the role of ascorbic acid in modifying fluid requirements in the resuscitation phase in burn patients. Ann Med Surg (Lond). 2022 Mar 2;75:103460. doi: 10.1016/j.amsu.2022.103460. PMID: 35386786; PMCID: PMC8978049.
Tanaka H. Reduction of Resuscitation Fluid Volumes in Severely Burned Patients Using Ascorbic Acid Administration. Archives of Surgery. 2000;135(3):326. doi:https://doi.org/10.1001/archsurg.135.3.326
Kahn, Steven et al . Resuscitation After Severe Burn Injury Using High-Dose Ascorbic Acid: A Retrospective Review. Journal of burn care & research : official publication of the American Burn Association. 2011
I don’t see enough severe burn patients for this to matter in my practice. However, I agree with the reply that indicates this does not disprove previous results of Tanaka.
The method of action of vitamin C in the previous trials was surmised and theorized but not proven, as is the case with many other drugs. So being, the effect of a much higher dose may follow a totally different pathway than the lower dose.
To disprove Tanaka an exact same regimen should have been used.
All I gather from this study is that the lower dose does not work. Does Tanaka’s dose work? I don’t know. Replicate that and we will see.
This conclusion and the whole paper is such a disappointment. The so-called failure study used a 10th of the vitamin C used in the Tanaka trial. This reminds me of the earlier studies in the early 2000s that claims to debunk vitamin C's affectiveness, but instead of replicating the proven method, that is going IV with vitamin C, the debunking studies used PO vitamin C which is a completely different animal. Then as now they use an apples and oranges argument to debunk vitamin C's effectiveness returning everyone back to a baseline of pseudoscience. An utter embarrassment. Isn't it the most basic of science to replicate other studies that have proven success and not creature own study and then try to apply those findings to previous models?