Vitamin C and Sepsis: Data Turn Sour, Suggesting Harm

Vitamin C turned out to be associated with significant harm when used in patients with sepsis in the intensive care unit (ICU), the LOVIT trial found.

For patients receiving vasopressor therapy in the ICU, the endpoint of death or persistent organ dysfunction at day 28 was more common in those who had been randomized to IV vitamin C therapy instead of placebo (44.5% vs 38.5%, risk ratio [RR] 1.21, 95% CI 1.04-1.40), according to Francois Lamontagne, MD, of Université de Sherbrooke in Quebec, and colleagues, writing in the New England Journal of Medicine.

The individual outcomes of mortality (35.4% vs 31.6%, respectively) and persistent organ dysfunction (9.1% vs 6.9%) both trended unfavorably for the vitamin C group but were not significantly different:

• Mortality: RR 1.17 (95% CI 0.98-1.40)
• Persistent organ dysfunction: RR 1.30 (95% CI 0.83-2.05)

And a secondary analysis of the primary outcome that adjusted for prespecified baseline characteristics was also not significant (RR 1.15, 95% CI 0.90-1.47).

Furthermore, vitamin C recipients were not at greater risk of tissue dysoxia, inflammation, or endothelial injury, leaving the investigators unable to determine the mechanism for vitamin C's potential harm, the group reported.

The study findings were also presented at the 2022 Critical Care Reviews meeting.

The researchers acknowledged that there may have been confounding in the study, given the lack of information on specific pathogens, antimicrobial therapy, and presence of acute respiratory distress syndrome in trial participants.

More data are anticipated from ongoing trials of vitamin C. Those include REMAP-CAP in the setting of pneumonia, LOVIT-COVID in hospitalized COVID patients, and a European study in sepsis complicated by acute respiratory distress syndrome.

Interest in IV vitamin C as a potential treatment for sepsis is rooted in the belief that its antioxidant properties might reduce tissue injury caused by oxidative stress.

The evidence for vitamin C's effectiveness in sepsis has not been strong, however, as shown by a recent meta-analysis. The 2017 paper that sparked interest in vitamin C in this setting has been criticized as potentially "too good to be true," and the underlying data have been called into question as well.

Meanwhile, sepsis remains a common cause of death even if treated early. It is responsible for over a third of all hospital deaths and kills up 11 million people worldwide each year, Lamontagne's group noted.

The phase III LOVIT trial was conducted in France, Canada, and New Zealand. Eligible patients were adults with sepsis who were receiving vasopressor therapy and had been in the ICU for no longer than 24 hours. All had proven or suspected infections as their main diagnosis. Excluded were patients with contraindications to vitamin C therapy, those receiving open-label vitamin C, and those with withdrawals or deaths expected within 48 hours.

From November 2018 to July 2021, investigators had 872 patients randomized 1:1 to vitamin C or placebo. The experimental group received a vitamin C bolus, whereas controls got matching dextrose or saline. Assigned treatments were administered over 30 to 60 minutes every 6 hours for up to 96 hours. All other treatments were performed at the discretion of the treatment team.

Mean age was 65 years and under 40% of patients were women. Baseline characteristics were similar between vitamin C and placebo groups, as was the use of cointerventions and life-sustaining therapies during the course of their ICU stays.

Lamontagne and colleagues cautioned that their study was conducted in high-income countries, and thus may not be generalizable to lower-income countries where the rate of sepsis can be much higher.

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