Sepsis
Corey Diamond, PharmD
Results from a new randomized controlled trial published in the New England Journal of Medicine from June 2022 demonstrate that septic patients treated with I.V. vitamin C may have higher mortality and persistent organ dysfunction versus those who received placebo. This study—now the largest investigation to date on I.V. vitamin C treatment in sepsis—has seemingly put this popular practice on hiatus overnight.
An antioxidant that may do more harm than good
The landmark trial from Lamontagne and colleagues investigated the efficacy of I.V. vitamin C as a supplemental treatment for critically ill patients with sepsis. The study, named the Lessening Organ Dysfunction with Vitamin C, or LOVIT, trial is now the largest ever randomized controlled trial investigating the effects of I.V. vitamin C therapy in septic ICU patients. The LOVIT trial researchers pooled data from 35 adult medical–surgical ICUs across Canada, France, and New Zealand, and enrolled over 800 patients.
ICU patients in the trial had less than 24 hours in the ICU with proven or suspected infection, and were receiving vasopressor support, to either receive I.V. vitamin C 50 mg/kg or placebo every 6 hours for up to 96 hours. The primary safety outcome was a composite of death or persistent organ dysfunction at day 28.
In their intention to treat analysis, the researchers found that at day 28, there was a statistically significant 21% relative increase in the primary composite outcome of death and persistent organ dysfunction in the vitamin C group relative to placebo. Curiously, however, no other significant differences were observed in any of the other secondary safety outcomes or subgroup analyses.
An effect without explanation
Severe infections that occur in critically ill patients often manifest with high levels of inflammation and oxidative damage. In a 2018 review article published in Critical Care, Moskowitz and colleagues presented some evidence and mechanistic theory that suggested vitamin C supplementation had the potential to reduce tissue injury via free radical scavenging of reactive oxygen species generated by sepsis, thus improving patient survival.
Much smaller randomized controlled trials, which attempted to put the theory to the test, have had varying results with the use of I.V. vitamin C for severe infections. However, until the LOVIT trial was published, the literature had shown no conclusive negative drawbacks.
There have been two notable randomized controlled trials, one published in 2014 in the Journal of Translational Medicine, which showed a reduction in the Sequential Organ Failure Assessment score in patients receiving high dose vitamin C versus placebo.
The other study, published in 2019 in JAMA, the Vitamin C Infusion for Treatment in Sepsis Induced Acute Lung Injury (CITRIS-ALI) trial, demonstrated a decrease in 28-day mortality compared to the placebo group with the same dosage of I.V. vitamin C.
Until now, both of these trials seemed to confirm the safety and efficacy of I.V. vitamin C in septic patients, leading to its continued use as an adjunctive treatment.
“This was an unexpected finding,” stated the authors of the LOVIT trial in their discussion section. “And the secondary analyses—which included the evaluation of 5 biomarkers of tissue dysoxia, inflammation, and endothelial injury measured up to day 7—did not determine a putative mechanism for harm.”
Further insight
The lack of a clear mechanism behind the negative outcomes of the LOVIT trial has sparked debate within the critical care sphere, however. A recent commentary published by Stoppe and colleagues in Critical Care on July 30, 2022, titled “Intravenous vitamin C in adults with sepsis in the intensive care unit: still LOV’IT?” offered additional insight.
Stoppe and colleagues cite confounds in the LOVIT trial that may have biased the results toward a negative outcome. For instance, 13.3% of the patients in treatment group already may have had a greater than 24-hour onset of sepsis and were not properly excluded from the trial. If the release of reactive oxygen species in sepsis is time dependent, then this may have biased the results in the treatment group toward the negative.
Additionally, given that sepsis is often secondary to several different disease states that have different mortality risks (i.e., sepsis from pneumonia vs. sepsis from a wound infection), the lack of discrete categorization of sepsis phenotypes in the LOVIT trial may have contributed to significant heterogeneity in the patient’s response to vitamin C, which was not accounted for in the analysis.
Regardless, the surfacing of the potential harm from I.V. vitamin C warrants caution moving forward, as the justification of “it couldn’t hurt” is no longer valid.
At this time, clinical pharmacists should push to halt the routine use of I.V. vitamin C in sepsis until further evidence on its safety is revealed. ■