Providers in recent years have turned to vitamin C to treat sepsis based on limited evidence, but a new, largest-of-its-kind study published in JAMA found vitamin C didn't improve sepsis patients' outcomes by a statistically significant margin, Richard Harris reports for NPR's "Shots."

Despite those new findings, however, some experts say there may still be hope for vitamin C as a sepsis treatment.

Evidence on vitamin C, sepsis has long been unclear

According to Harris, the evidence on whether vitamin C could improve sepsis outcomes has long been confusing.

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.

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. And soon after, other doctors started using the so-called "Marik protocol" for treating their sepsis patients.

Marik's claims garnered a lot of attention, as providers have long looked for ways to improve sepsis outcomes. "Sepsis is one of the most common causes (of death) in the hospital, so finding a good treatment is extraordinarily important," Jonathan Sevransky, a researcher and critical care physician at Emory University, told Harris.

However, subsequent studies have generated mixed results.

For instance, after hearing that more doctors were turning to the "Marik protocol," Fowler decided to re-examine vitamin C's effects. 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 and were placed on a mechanical ventilator.

Fowler and his colleagues found the vitamin C infusion "did not significantly improve organ dysfunction scores or alter markers of inflammation and vascular injury," they wrote in their study.

However, 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, they found.

In addition, the researchers 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.

But, ultimately, Fowler and other experts said the study left many questions unanswered. Emily Brant and Derek Angus from the University of Pittsburgh in an editorial accompanying Fowler's study noted the researchers "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," they noted.

New study raises doubts that vitamin C significantly improves sepsis outcomes

Given the remaining unknowns, Sevransky set out to do his own research—and his findings cast doubt on the treatment's efficacy.

For the study, Sevransky and colleagues conducted a large clinical trial involving 501 patients who received treatment at 43 ICUs across the United States. According to Harris, the study "was the largest" so far to evaluate vitamin C as a potential treatment for sepsis.

The researchers administered intravenous infusions of vitamin C, thiamine, and hydrocortisone to one group of patients and a placebo to another group, which served as the study's control group. They administered the treatment or placebo to patients every six hours for 96 hours or until the patients were discharged from the ICU or died.

The researchers found that the number of ventilator- and vasopressor-free days was a median of 25 among patients in the treatment group, compared with a median of 26 days among the control group. They also found that 30-day mortality was 22% among the treatment group, compared with 24% among the control group. The differences were not statistically significant.

According to the researchers, those results showed that "[a]mong critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone ... did not significantly improve ventilator- and vasopressor-free days." However, the researchers also noted that their "trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference."

Still, Sevransky told Harris, "We can say with some confidence that if there were such a large effect, we would have seen that in our patients."

Is there still hope for vitamin C as a sepsis treatment?

Sevransky said that although vitamin C may not have as dramatic effect on sepsis patients' outcomes as previous studies suggested, even if the vitamin had a modest effect, it could help to save people's lives. He told Harris that there is an ongoing, large study in Canada evaluating vitamin C that could have different results.

Similarly, Marik told Harris that although "[s]ome people think the matter is dead" after this latest study, "[w]e would disagree."

Marik told Harris that his more recent experiences treating sepsis patients have indicated that vitamin C is effective only when administered early in the disease's course. As a result, Marik now provides vitamin C infusions when sepsis patients first present in an ED—instead of waiting until they end up in an ICU, where researchers largely have studied the treatment.

"This should really be an [ED] study, not [an] ICU study," Marik said. "Once you've waited until they get to the ICU you've missed the boat."

Marik told Harris that researchers in Belgium currently are trying to study the use of vitamin C as a treatment for sepsis in EDs (Harris, "Shots," NPR, 2/24; Sevansky et al., JAMA, 2/23).