#VisualAbstract: Intravenous vitamin C increases mortality and organ dysfunction in sepsis patients

1. In patients with sepsis receiving a vasopressor in the intensive care unit (ICU), intravenous vitamin C was associated with a higher risk of death and persistent organ dysfunction compared to placebo.

2. The study sample size was significantly larger than in previous trials where Vitamin C had no significant impact on prognosis.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Sepsis is a life-threatening state of organ failure due to an abnormal immune response to infection. This disorder is associated with high mortality and is often managed with antibiotics and supportive therapies. Oxidative stress is a major mechanism of tissue damage in sepsis. Therefore, vitamin C, an antioxidant, was purported to mitigate this damage and could benefit critically ill sepsis patients. Nevertheless, evidence supporting its use has been inconclusive. The present randomized, placebo-controlled trial sought to study the effects of high-dose intravenous vitamin C in adults with sepsis on vasopressor therapy in the ICU. Compared to placebo, vitamin C was associated with a higher composite risk of death or persistent organ dysfunction at 28 days. The study highlighted its large sample size compared to previous trials as a strength and reason for its divergent finding. Despite a small number of patients not contributing data following randomization, the study showed evidence of harm from intravenous vitamin C in sepsis patients in the ICU.

Click here to read the study in NEJM

In-Depth [randomized controlled trial]: This phase three, double-blind randomized controlled trial investigated the effect of intravenous high-dose vitamin C in patients with sepsis admitted to the ICU. Adult patients who had stayed in the ICU for less than 24 hours with proven or suspected sepsis, and who were receiving a vasopressor were included. Exclusion criteria included contraindication to vitamin C and expected death within 48 hours. Overall, 872 patients underwent randomization (435 in the vitamin C group and 437 in the control group). Vitamin C at 50mg per kilogram body weight or matched placebo were given every 6 hours for up to 96 hours. The primary outcome was a composite of death or persistent organ dysfunction by day 28. The primary outcome occurred in 44.5% of vitamin C recipients and 38.5% of the control group (Risk Ratio [RR], 1.21; 95% Confidence Interval [CI], 1.04 to 1.40; p=0.01). At 28 days, 35.4% of the patients in vitamin C and 31.6% of patients in the control group had died (RR, 1.17; 95% CI, 0.98 to 1.40), while persistent organ dysfunction occurred in 9.1% and 6.95% of the patients in each group, respectively (RR, 1.30; 95% CI, 0.83 to 2.05). Both groups also had comparable safety outcomes. The finding of increased risk of death or organ dysfunction was unexpected and the study’s large sample size overcoming large effect estimates was attributable to this result. Overall, the trial demonstrated that for patients with sepsis admitted to the ICU who were on vasopressor therapy, intravenous vitamin C was associated with a higher risk of death or persistent organ dysfunction.

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