High-dose vitamin C does not improve outcomes in burn patients, and in fact, may even accelerate their mortality risk, writes David Greenhalgh in an editorial published in JAMA Network last week, concurring with findings of an international study published in the same issue.
Greenhalgh writes:
In this issue of JAMA, Stoppe and colleagues present the results of an international randomised clinical trial that provides evidence that high-dose intravenous vitamin C does not improve outcomes in patients with large burns, with the data from the VICTORY trial even suggesting using vitamin C in patients with large burns might increase mortality.
This well-designed study had strict criteria for stopping based on futility or harm.
It is clear that the possibility of vitamin C improving outcomes in major burns is extremely low.
The idea that high-dose vitamin C has the potential to improve outcomes was championed by Linus Pauling, who was awarded two unshared Nobel Prizes (Chemistry [1954] and Peace [1962]).
His 1970 book Vitamin C and the Common Cold2 was followed by an article that cited four randomised clinical trials justifying his hypothesis. While the scientific community questioned the validity of using high-dose vitamin C to prevent upper respiratory tract infections, the idea that an otherwise safe vitamin could improve outcomes has persisted.
The primary hypothesised mechanism is that as an antioxidant, ascorbic acid has the potential to reduce the reactive oxygen species that are the drivers of the inflammatory response. Antioxidants are produced by stressed cells and are used as agents to fight microbes. The antioxidants may also be considered friendly fire that damages nearby normal tissues.
Over the past 50-plus years, several trials have addressed the question of whether vitamin C improves outcomes in sepsis. Since sepsis is considered an out-of-control systemic inflammatory response, the antioxidant effects of ascorbic acid should reduce its damaging effects.
The results from randomised trials are variable. In 2022, Agarwal et al published a review of 41 randomised clinical trials and found that vitamin C might reduce mortality in patients with severe infections, but the evidence was of low certainty. When the authors adjusted for low risk of bias, however, the significance was attenuated.
More recent studies have revealed that using vitamin C in combination with hydrocortisone and thiamine did not improve outcomes in sepsis. Results of trials of high-dose intravenous vitamin C alone (without steroids or thiamine) are negative.
The LOVIT trial also suggested that high-dose vitamin C may increase mortality risk in patients with sepsis. These data ended the routine administration of high-dose vitamin C in sepsis.
High-dose vitamin C is administered to patients with burn injury to reduce fluid requirements during initial burn shock. All injuries lead to localised oedema, but burns larger than 20% of total body surface area have a profound systemic capillary leak that leads to massive fluid resuscitation requirements for the first 24 to 48 hours.
In my experience, 24-hour fluid requirements in a burn covering more than 80% of total body surface area can exceed 50 L. Clinicians may also unnecessarily provide too much fluid (called fluid creep), and careful management is required to optimise fluid resuscitation.
One strategy to reduce fluid requirements was developed in Japan based on several preclinical studies suggesting that high-dose vitamin C decreased resuscitative volumes. Tanaka et al subsequently performed a clinical trial that demonstrated that fluid requirements could be reduced by providing vitamin C at an intravenous dose of 66 mg/kg/h.
Other investigators found that vitamin C reduced initial fluid requirements. Eventually, doubts developed about the efficacy of high-dose vitamin C in burn resuscitation, and there was a suggestion that within 48 to 72 hours, patients treated with vitamin C had 48-hour fluid volumes equal to those of patients treated without vitamin C. Another study suggested that high-dose vitamin C provided no benefit and increased risk of kidney failure.
Vitamin C appears to act as a diuretic, so patients treated with vitamin C often needed fluid boluses toward the end of the first 24 to 48 hours.
In response to those multiple studies, the use of vitamin C for the initial burn resuscitation has essentially stopped.
However, the role of high-dose vitamin C to reduce sepsis in patients with burn injury has remained a question. Sepsis and its associated multiple organ dysfunction are the primary causes of death in patients with major burns. Sepsis in burns is different from other forms of sepsis, since skin loss removes the primary barrier to microbial invasion.
Chronic exposure leads to persistent inflammation and a prolonged hypermetabolic state. Slowing this response by reducing reactive oxidative species would, in theory, reduce this response.
The VICTORY trial tested the use of vitamin C with the goal of reducing sepsis in patients with burn injury, to subsequently improve survival and reduce the need for organ support.
The authors followed the design of the LOVIT trial by providing intravenous vitamin C at a dosage of 50 mg/kg every six hours for 96 hours. Treatment started within 24 hours, and the burn was more than 20% of total body surface area with expectation for the need for skin grafting.
The experience of high-dose vitamin C for treatment after sepsis onset in the non-burn population provided sufficient equipoise to test it in patients with large burns to prevent sepsis and multiple organ dysfunction.
However, there are some nuances to the burn population that are worth considering. First, sepsis is very rare during the first few days after a burn, occurring weeks to even months after a major burn. The reason for the prolonged exposure in large burns is the lack of donor skin, so after the initial skin harvest, the donor sites must heal.
Patients with burns of more than 60% of total body surface area often need multiple grafting procedures, so they are exposed for prolonged periods.
In addition, there is a tendency for burn wound colonisation to change throughout the prolonged treatment of burns. Gram-positive bacteria appear initially, followed by gram-negative bacteria, then fungi and, gradually, multidrug-resistant organisms. Targeting sepsis prevention in the first 96 hours is unlikely to have an effect on sepsis that occurs weeks later.
Future trials may consider, although with low pre-test probability, whether vitamin C has a treatment effect if administered more proximate to sepsis onset.
Overall, the VICTORY trial was well-conceived and had several strengths. First, the authors demonstrated that high-dose vitamin C did not have an adverse diuretic effect. Second, they performed the trial in both high- and low-middle–income countries, extending generalisability of these findings. Third, the authors enrolled patients at high risk for skin grafting; as reported, autografting was performed in 54.2% in the vitamin C group and 67.8% in the placebo group.
Spray-on epithelial cells or cultured epithelial autograft were used in 18.3% and 28.8%, respectively.
Fourth, the authors measured long-term outcomes and thus demonstrated no prolonged adverse effects of either treatment.
In the end, the VICTORY trial leaves a clear message. High-dose intravenous vitamin C administered early after injury did not reduce organ dysfunction or death and should not be a treatment in severe burns.
David G. Greenhalgh, MD – Department of Burns, Shriners Children’s Northern California, Sacramento, Department of Surgery, University of California-Davis, Sacramento.
Study details
High-Dose Intravenous Vitamin C and Mortality and Organ Dysfunction in Severe Burn Injury: The VICTORY Randomised Clinical Trial
Christian Stoppe, Aileen Hill, Leopoldo Cancio et al.
Published in JAMA Network on 10 June 2026
Importance
Severe burn injury triggers systemic inflammation that can lead to multiple organ dysfunctions and death. High-dose intravenous vitamin C has been proposed to mitigate these effects, but strong evidence in patients with burn injury is lacking.
Objective
To evaluate the efficacy of high-dose intravenous vitamin C in patients with severe burn injury.
Design, Setting, and Participants
Randomised, double-blind, placebo-controlled phase 3 trial conducted across 24 burn centres in North, Central, and South America; Europe; and Asia. Adults (≥18 years) with deep second- and/or third-degree burns covering 20% or more of total body surface area and requiring skin grafting were enrolled between August 18, 2020, and September 12, 2025. Final follow-up was completed in March 2026. The trial was stopped early after the first pre-specified interim analysis for futility/harm.
Interventions
Patients were randomly assigned (1:1) to receive intravenous vitamin C (50 mg/kg every 6 hours for 96 hours) or matched placebo.
Main Outcomes and Measures
The primary outcome was a composite of 28-day mortality and persistent organ dysfunction (defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor/inotrope support at day 28). The main secondary outcome was time to discharge alive from hospital within 90 days.
Results
Among 238 patients enrolled (mean age, 48.9 [SD, 19.1] years; 79% male; mean total body surface area, 37.0% [SD, 14.6%]), 120 were assigned to vitamin C and 118 to placebo. The primary composite outcome occurred in 49 patients (40.8%) in the vitamin C group and 35 patients (29.7%) in the placebo group (adjusted risk ratio [RR], 1.28 [95% CI, 0.99-1.65]; P = .06), crossing the pre-specified futility/harm threshold and prompting early trial termination. Time to discharge alive from hospital within 90 days was not improved (adjusted subdistribution hazard ratio, 0.85 [95% CI, 0.62-1.16]; P = .31). Twenty-eight–day mortality was 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).
Conclusions and Relevance
Among patients with severe burn injury, high-dose intravenous vitamin C did not reduce 28-day mortality and persistent organ dysfunction and is possibly harmful.
JAMA article – High-Dose Vitamin C in Burns: Time to Stop (Open access)
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