The RAMER Reviews: LOVIT Trial: IV Vitamin C for Sepsis in the ICU
Written by: Megan Varghese, MD; Edited by: Timothy Khowong, MD, MSEd
Background:
Sepsis contributes to between one third to half of deaths in hospitals worldwide annually. Septic shock is defined as end-organ dysfunction secondary to infection, usually treated with antibiotics and organ support. Vitamin C is usually critically low in septic patients, and is thought to decrease tissue injury caused by oxidative stress. The use of Vitamin C has been evaluated in a few studies, but recent meta-analyses suggested that the evidence supporting use of IV vitamin C was of low benefit.
The Study:
The LOVIT trial (Lessening organ Dysfunction with Vitamin C trial) tested the hypothesis that a high dose of vitamin C would reduce persistent organ dysfunction or the risk of death as a composite at 28 days stay of ICU admission, in adults with sepsis who were receiving vasopressor therapy. It was an international trial, with patients enrolled from 35 medical and surgical ICUs, and the design was a randomized, placebo-controlled trial. Intervention group received an infusion of either vitamin C (at a dose of 50 mg per kilogram of body weight) or matched placebo administered every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction (defined by the use of vasopressors, invasive mechanical ventilation, or new renal-replacement therapy) on day 28.
A total of 872 patients underwent randomization (435 to the vitamin C group and 437 to the control group). Control group received D5 with water or normal saline. The patients were adults who had been in the ICU for no longer than 24 hours, who had proven or suspected infection as the main diagnosis, and who were receiving vasopressors. Exclusion criteria included contraindications to vitamin C therapy, receipt of open-label vitamin C, or expected death or withdrawal of life-sustaining therapy within 48 hours. Pharmacists were not directly involved in patient care and prepared the infusions unblinded. The power of the study is 80%, acceptable to safely reject the null hypothesis. In the primary analysis, baseline characteristics were not adjusted for, but in the secondary analysis of the primary outcome, age, sex, glucocorticoid use, and time from ICU admission were factored into results. Primary analysis was performed in the intention-to-treat population through linear mixed-effects models, analyzed with log link function.
At day 28, 191 of 429 patients (44.5%) in the vitamin C group had died or had persistent organ dysfunction, as compared with 167 of 434 patients (38.5%) in the placebo group (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P=0.01) In the secondary analyses, (with adjustment for baseline characteristics) the risk ratio for the primary comparison was 1.15 (95% CI, 0.90 to 1.47). This was an unexpected finding from the primary analyses, but secondary analyses did not determine a mechanism for harm. The trial did have limitations, with 9 patients who had undergone randomization not contributing data to primary analysis. It is also not known which patients had ARDS at baseline, and thus unsure if there was a different response to vitamin C in this subset. Additionally, the patient population was representative of high-income countries, whereas none of the low to middle income population where the incidence of sepsis is actually higher. Internal validity was strong though, with blinding, high protocol adherence, and assessment of baseline vitamin C and biomarker levels.
Discussion:
In adults with sepsis who were receiving vasopressor therapy in the ICU, receiving intravenous vitamin C resulted in a higher risk of death or persistent organ dysfunction at 28 days versus placebo. In our current practice in the ICU setting, IV vitamin C is not commonly administered to patients, and now thoughts to do so will most likely be unfavored.
References:
Lamontagne, F., Masse, M. H., Menard, J., Sprague, S. A., Pinto, R. L., Heyland, D. K., Cook, D. J., Battista, M. C., Day, A. G., Guyatt, G. H. M., Kanji, S., Parke, R. L., Mcguinness, S., Vijayaraghavan, B. K. T., Annane, D., Cohen, D. N., Arabi, Y. M., Bolduc, B., Marinoff, N., . . . Adhikari, N. (2022). Intravenous Vitamin C in Adults with Sepsis in the Intensive Care Unit. New England Journal of Medicine, 386(25), 2387–2398. https://doi.org/10.1056/nejmoa2200644