Evaluating Vitamin C in Septic Shock

A Randomized Controlled Trial of Vitamin C Monotherapy

David A. Wacker, MD, PhD; Susan L. Burton, MD; John P. Berger, DO; A. J. Hegg, MD; Jamie Heisdorffer, MPH, RN; Qi Wang, MS; Emily J. Medcraft, PharmD; Ronald A. Reilkoff, MD


Crit Care Med. 2022;50(5):e458-e467. 

In This Article

Abstract and Introduction


Objectives: To determine whether IV vitamin C therapy reduces 28-day mortality in patients with septic shock.

Design: Multicenter, double-blinded, randomized controlled trial.

Setting: One academic medical ICU and four community ICUs.

Patients: Of 167 adult patients within 24 hours of vasopressor initiation for septic shock, 126 consented to participation, and 124 received study drug and were included in analysis.

Interventions: IV vitamin C (10 mg/mL in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr for 96 hours or placebo of equal volumes of normal saline.

Measurements And Main Results: Of 124 subjects receiving study drug and included in analysis, 60 received vitamin C and 64 placebo. The primary outcome of all-cause 28-day mortality (vitamin C, 26.7%; placebo, 40.6%; p = 0.10) was lower in the vitamin C arm but did not reach statistical significance. Initiation of renal replacement therapy was higher in the vitamin C arm (vitamin C, 16.7%; placebo, 3.3%; p = 0.015), as was volume of fluid administration within 6 hours of study drug initiation (vitamin C, 1.07 L; placebo, 0.76 L; p = 0.03). There were no statistically significant differences in other secondary outcomes. In post hoc subgroup analysis, there was a decrease in 28-day mortality in the vitamin C arm among patients requiring positive-pressure ventilation at the time of enrollment (vitamin C, 36.3%; placebo, 60.0%; p = 0.05). This trial is registered at clinicaltrials.gov under identifier NCT03338569.

Conclusions: Vitamin C monotherapy failed to significantly reduce mortality in septic shock patients as hypothesized. Our findings do not support its routine clinical use for this purpose.


Sepsis and septic shock are common reasons for admission to the ICU with 49 million cases and 11 million sepsis-associated deaths each year worldwide.[1] A therapeutic role for vitamin C (ascorbic acid) supplementation in the treatment of sepsis and septic shock has been suggested for its anti-inflammatory and antioxidant properties,[2–4] and in 2017, an observational before-and-after study reported a remarkable survival benefit with the use of a combination of hydrocortisone, vitamin C (ascorbic acid), and thiamine (HAT therapy).[5] Following this, several randomized controlled trials of HAT therapy[6–11] or vitamin C and thiamine in combination[12] for sepsis and septic shock have been conducted, but these studies did not show the same dramatic effects. Although modest improvements in time to reversal of shock and organ dysfunction were occasionally noted, no study demonstrated a statistically significant survival benefit.[14–16] One study of vitamin C alone for treatment of patients with sepsis-induced acute respiratory distress syndrome (ARDS) did show a reduction in all-cause 28-day mortality in the vitamin C arm with a p value of 0.03; however, this was one of numerous secondary outcomes that obfuscates the statistical significance of the result.[13]

Despite the existing trials of HAT therapy, questions about vitamin C as adjuvant monotherapy remain. First, prior investigations into vitamin C alone have been limited to small pilot studies and unblinded trials,[2–4] and although the interactions between constituents in HAT therapy have been assumed to be synergistically positive,[5] this has never been proven. Unexpected interactions may cancel out or otherwise convolute effects, thus limiting the ability to judge the performance of individual components from trials of a combined regimen. Second, randomized controlled trials of adjuvant corticosteroids[14–16] for septic shock have recently demonstrated clinical benefit with a consistent signal of decreased duration of vasopressor therapy, which has the potential to confound any positive results from prospective investigations of HAT therapy.

In designing our trial, we noted pharmacokinetic studies of vitamin C, which have shown that trough levels of the drug occurring with bolus dosing may result in periodic hypovitaminosis, whereas continuous vitamin C delivery resulted in more stable serum levels.[17] We, therefore, designed the Evaluating Vitamin C in SepTic Shock trial to assess the effect of continuously infused vitamin C monotherapy on all-cause ICU and 28-day mortality in patients with septic shock.