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October 9, 2019

A major new study examined vitamin C to fight sepsis. The results are… complicated.

Daily Briefing

    Providers in recent years have turned to vitamin C to treat sepsis based on limited evidence, and a recent JAMA study that sought to demonstrate whether the treatment is effective has left providers with no clear answers.

    The Sepsis CVR Starter Kit: Implementation resources from Emory Healthcare

    How vitamin C became a sepsis treatment

    Each year, more than 1.7 million adults in the United States suffer from sepsis—a dangerous a medical complication resulting from the body's inflammatory response to an infection. The condition plays a role in more than 250,000 U.S. deaths annually.

    Alpha Fowler, a professor of medicine at the VCU School of Medicine, in 2014 published a study that suggested vitamin C could be effective against sepsis. The study, which involved 24 patients, found that patients' mSOFA score, a measure of organ failure, improved more when they received vitamin C.

    However, the study was too small to determine whether vitamin C was truly effective.

    But, after hearing about the study, Paul Marik, a physician from the Eastern Virginia Medical School, started to regularly treat his sepsis patients with an intravenous form of vitamin C, combined with corticosteroids and vitamin B1. In the spring of 2017, Marik claimed the mortality rate for sepsis in his ICU decreased substantially after he started using the treatment. Soon after, other doctors started using the so-called "Marik protocol."

    Researchers re-examine the treatment

    After hearing that more doctors were turning to the "Marik protocol" to treat sepsis, Fowler decided to re-examine vitamin C's effects on sepsis patients.

    Fowler and his colleagues studied 167 patients treated for sepsis across ICUs between 2014 and 2017. All of the patients had complications due to acute respiratory distress syndrome (ARDS) and were placed on a mechanical ventilator.

    Half the patients received an intravenous infusion of high-dose vitamin C and the other half received a placebo. After four days, the researchers used patients' mSOFA scores to measure the treatment's success.

    Key findings

    The researchers found no statistical difference between the mSOFA scores of the patients in the treatment group and patients in the control group. In other words, the vitamin C infusion "did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury," Fowler and his colleagues wrote.

    But the researchers also considered 46 other secondary endpoints, or measures of success, including mortality rate, ventilator-free days, and hospital-free days. The researchers found that patients who received the vitamin C infusion averaged 11 ICU-free days compared with eight days for patients in the control group. The vitamin C patients also spent about seven fewer days in the hospital overall.

    The researchers also found that mortality rates were lower for patients in the vitamin C infusion group: 28 days after treatment, 25 of the 84 patients treated with vitamin C, or 30%, had died compared with 38 of the 83 patients, or 46%, in the control group.


    Ultimately, the findings leave a lot of unknowns.

    Fowler said he regrets using not using mSOFA scores as the primary endpoint over mortality, noting that had he chosen mortality, the findings would have supported the hypothesis that vitamin C is an effective sepsis treatment. However, statistical analysis rules prevent researchers from placing too much emphasis on statistically significant findings derived from multiple comparisons, so the study's design prevented the researchers from pointing to the mortality findings as evidence in favor of vitamin C infusions.

    The findings also do not fully address the effectiveness of the Marik protocol because the Marik protocol uses a combination of vitamins and steroid hormones, and is usually administered in healthier patients than those included in the latest study.

    Emily Brant and Derek Angus from the University of Pittsburgh in an accompanying editorial wrote, "Despite this rigorous clinical trial, the question remains: does administration of vitamin C in patients with organ dysfunction confer benefit."

    According to Brant and Angus, none of the clinical measurements that are usually associated with better health outcomes confirm the lower mortality rate among the vitamin C-treated patients. "They did not see any difference in markers of organ injury or inflammation between groups, something we'd expect to see if the mortality benefit is real" (Harris, "Shots," NPR, 10/1; Mozes, HealthDay/U.S. News & World Report, 10/1).

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