Vitamin C (ascorbic acid) monotherapy does not reduce all-cause mortality significantly in patients with septic shock, according to results of a study reported in January in Critical Care Medicine.

The double-blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT03338569), named the Evaluating Vitamin C in SepTic Shock Trial, was conducted at the medical center intensive care unit (ICU) of the University of Minnesota in Minneapolis and at 4 community hospital ICUs. For the study, researchers hypothesized that vitamin C alone would reduce absolute 28-day mortality by 20%, based on an earlier retrospective study that found a more than 30% mortality reduction (risk difference) after vitamin C therapy.

Vitamin C showed promise in the treatment of septic shock after a 2017 observational before-and-after study described a dramatic survival benefit using a combination of hydrocortisone, vitamin C, and thiamine (HAT therapy). Several subsequent RCTs of HAT therapy or vitamin C-thiamine combinations in treating sepsis and septic shock failed to show the same impressive effects, however.


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Adult patients available within 24 hours of the onset of septic shock met the inclusion criteria for enrollment. The principal exclusion criteria included the inability to get written consent to initiate the study drug within 24 hours of eligibility, history of nephrolithiasis, and shock occurring directly after cardiac arrest. Using an historical mortality rate for septic shock of about 30% and a 2-tailed alpha of 0.05, the researchers calculated that 124 subjects (an average of 62 per group) would be needed to spot a 20% reduction in absolute mortality with 80% power.

Of 124 participants included in the analysis, 60 received vitamin C (10-mg/mL solution in normal saline) given as a 1000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hour, and 64 participants got a placebo (normal saline). The study infusion stopped after 96 hours or after the subject stayed vasopressor-free for 24 consecutive hours, whichever came first. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; P = .10) was lower in the vitamin C group but did not attain statistical significance. Volume of fluid administration within 6 hours of study drug initiation also was higher in the vitamin C group (vitamin C, 1.07 L; placebo, 0.76 L; P = .03). A reduction in 28-day mortality was observed in the vitamin C group among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; P = .05) during post hoc subgroup analysis.

As part of routine clinical care, corticosteroids were administered to 72 subjects, but no statistically significant differences in 28-day or ICU mortality between the vitamin C and placebo groups in the steroid or nonsteroid subgroups was seen. A higher incidence in the need for renal replacement therapy (RRT) was noted in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; P = .015) in both the steroid (23.3% vs 4.8%; P = .02) and nonsteroid (10.0% vs 0%; P = .27) subgroups, underscoring the increased incidence of needed RRT in the vitamin C group overall.

Limitations of the study included having all centers in 1 geographic area, underrepresentation of non-White participants, being underpowered to find smaller differences between groups, lack of assessment of the degree of preexisting hypovitaminosis, immeasurable variations in the time between shock onset and drug initiation, and a statistically significant difference in RRT use between groups.

Although this study failed to support using vitamin C in septic shock patients, further studies might shed more light on the vitamin’s importance. “Additional trials of vitamin C for patients with septic shock and sepsis-induced respiratory dysfunction employing short-term mortality as a primary outcome could further inform whether vitamin C carries an enhanced therapeutic effect for this population,” said the authors.

Disclosures: Multiple authors declare affiliations with various university programs and and foundations. Please refer to the original article for a full list of disclosures.

Reference

Wacker DA, Burton SL, Berger JP, et al. Evaluating vitamin C in septic shock: a randomized controlled trial of vitamin C monotherapy. Crit Care Med. Published online January 5, 2022. doi:10.1097/CCM.0000000000005427