From the Journals

Vitamin C infusion falls short for sepsis and ARDS patients

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Promising mortality findings warrant larger study

Although none of the primary outcomes was significant, “the difference in mortality is tantalizing and likely to spur much debate,” wrote Emily B. Brant, MD, and Derek C. Angus, MD, in an accompanying editorial.

“However, this outcome was one of many secondary outcomes, and although reported as statistically significant, that finding was without adjustment for multiple comparisons,” they said.

The study was well-designed, and resulted in the collection of considerable patient data, they said. Previous studies have suggested that approximately 40% of sepsis patients are vitamin C deficient, and vitamin C is considered safe and inexpensive, which may be reason to pursue research in this area, they added.

Study design for addition research should keep in mind the timing and dosage that were limitations in the current study; the lack of effect on organ dysfunction may have occurred because vitamin C was given too late, they said.

Researchers planning further evaluation might “reconsider optimal dosing and timing, as well as the likelihood that any potential benefits may only accrue to subsets of patients, given the underlying heterogeneity of sepsis,” they concluded (JAMA. 2019 Oct 1; 322:1257-8).

Dr. Brant and Dr. Angus are affiliated with the department of critical care medicine, University of Pittsburgh. Dr. Angus serves as a associate editor for JAMA and disclosed receiving consulting fees from Ferring, Bristol-Myers Squibb, and Beckman Coulter; holding stock in Alung Technologies; and holding pending patents for selepressin and for proteomic biomarkers of sepsis in elderly patients. Dr. Brant had no financial conflicts to disclose.



Vitamin C infusion did not improve outcomes related to organ failure, inflammation, or vascular injury for patients with sepsis and acute respiratory distress syndrome, based on data from 167 adults.

3D illustration showing Sepsis bacteria in blood with red blood cells and leukocytes. Dr_Microbe/Getty Images

“Previous research found that vitamin C attenuates systemic inflammation, corrects sepsis-induced coagulopathy, and attenuates vascular injury,” wrote Alpha A. Fowler III, MD, of Virginia Commonwealth University, Richmond, and colleagues.

To examine the impact of vitamin C infusion on patients with sepsis and acute respiratory distress syndrome (ARDS), the researchers designed the CITRIS-ALI trial, a randomized, double-blind, placebo-controlled study conducted at 7 medical intensive care units in the United States.

In the study, published in JAMA, the researchers randomized 167 adults with sepsis and ARDS to receive high-dose intravenous vitamin C (50 mg/kg in 5% dextrose in water) or placebo (5% dextrose in water only) every 6 hours for 96 hours. The primary outcomes were measures of organ failure based on changes in the modified Sequential Organ Failure Assessment score (mSOFA), inflammation (based on changes in C-reactive protein), and vascular injury based on thrombomodulin.

Overall, no significant differences appeared between the vitamin C and placebo groups, respectively in the three primary outcome measures: change in average SOFA score (3-point change vs. a 3.5-point change) at 96 hours; change in C-reactive protein levels (change of 54.1 mcg/mL vs. 46.1 mcg/mL) at 168 hours; and change in thrombomodulin levels (14.5 ng/mL vs. 13.8 ng/mL) at 168 hours.

The average age of the patients was 55 years, and 54% were men.

The researchers also assessed 46 secondary outcomes. Most of these showed no significant differences between the groups, but 28-day all-cause mortality was significantly lower in the vitamin C group, compared with the placebo group (46.3% vs. 29.8%), the researchers said. Vitamin C also was significantly associated with increased ICU-free days to day 28 and hospital-free days to day 60, compared with placebo.

No significant differences were seen between the groups on 43 other secondary outcomes including ventilator-free days and vasopressor use. However, “these findings were based on analyses that did not account for multiple comparisons and therefore must be considered exploratory,” they said.

“The inability of vitamin C to affect C-reactive protein and thrombomodulin levels in this trial possibly resulted from the advanced stages of sepsis that were present before the development of ARDS,” the researchers noted.

The findings were limited by several factors including the variability in the timing of vitamin C administration and the use of a single high dose of vitamin C, they emphasized. However, the results suggest that further research may be needed to determine the potential of vitamin C for improving outcomes in patients with sepsis and ARDS, they said.

The study was supported by the National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, VCU Wright Center for Translational Science Award, VCU Investigational Drug Services, and McGuff Pharmaceuticals, who supplied the vitamin C free of charge. Dr. Fowler disclosed funding from Virginia Polytechnic Institute and State University, Richmond; the NHLBI; and study materials from McGuff Pharmaceuticals.

SOURCE: Fowler AA et al. JAMA. 2019 Oct 1;322:1261-70. doi:10.1001/jama.2019.11825.

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