High-Dose Intravenous Vitamin C Fails To Improve Burn Outcomes

Key Takeaways

• High-dose intravenous vitamin C was not associated with improvement in the prespecified primary composite outcome, and 28-day mortality was higher in the vitamin C group.
• Time to discharge alive from hospital within 90 days was not improved, and persistent organ dysfunction-free days favored placebo.
• Acute kidney injury, kidney replacement therapy initiation, and hypoglycemia were reported, while no new oxalate kidney stones, severe hemolysis, severe acid-base or electrolyte imbalances, or refractory hypoglycemia were reported in either group.

In the VICTORY randomized clinical trial, the primary composite outcome of death or persistent organ dysfunction at day 28 occurred more often with adjunctive intravenous vitamin C than placebo, 40.8% versus 29.7%. The adjusted risk ratio was 1.28, with a 95% CI of 0.99 to 1.65 and P=.06. The regimen was given during early burn resuscitation, and the trial stopped early after crossing its prespecified futility and harm boundary. Overall, the main outcomes did not favor vitamin C.

VICTORY was an international, multicenter, randomized, double-blind, placebo-controlled phase 3 trial across 24 burn centers in the Americas, Europe, and Asia. Eligible adults were aged 18 years or older, had deep second- and or third-degree burns involving at least 20% total body surface area, and required skin grafting. Investigators randomized 238 patients, 120 to vitamin C and 118 to placebo, using intravenous vitamin C 50 mg per kg every 6 hours for 96 hours or matched placebo. The primary outcome combined 28-day mortality with persistent organ dysfunction, defined as dependence on mechanical ventilation, kidney replacement therapy, or vasopressor or inotrope support at day 28.

Time to discharge alive from hospital within 90 days was not improved, with an adjusted subdistribution hazard ratio of 0.85 and a 95% CI of 0.62 to 1.16. At 28 days, mortality was 15.0% with vitamin C and 7.6% with placebo, with an adjusted risk ratio of 1.96 and P=.001. Hospital mortality was 23.3% versus 16.1%, with an adjusted risk ratio of 1.44 and a 95% CI of 1.03 to 2.00. ICU mortality was 22.5% versus 15.3%, while 6-month mortality was 25.9% versus 20.2%, with the latter hazard ratio 1.57 and P=.12. Overall, the discharge and mortality findings did not favor vitamin C.

Persistent organ dysfunction-free days favored placebo, with medians of 12.5 days in the vitamin C group and 19.5 days in the placebo group. The difference in medians was minus 7.0 days, with a 95% CI from minus 17.0 to 4.0, and the win ratio was 0.75. With high-dose intravenous vitamin C, acute kidney injury occurred in 15.0% versus 11.0%, kidney replacement therapy initiation in 10.8% versus 5.9%, and hypoglycemia in 6 versus 3 patients. Twelve serious adverse events were reported overall, including 9 with vitamin C and 3 with placebo. No new oxalate kidney stones, severe hemolysis, severe acid-base or electrolyte imbalances, or refractory hypoglycemia were reported in either group.

The investigators concluded that high-dose intravenous vitamin C did not reduce the primary composite outcome of 28-day mortality and persistent organ dysfunction in severe burn injury and was possibly harmful. They also noted that early stopping reduced the precision of the effect estimates. The trial was not powered to detect rare safety events such as oxalate nephropathy, leaving the authors' bottom line unchanged.