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Randomized Controlled Trial
. 2022 May 1;50(5):e458-e467.
doi: 10.1097/CCM.0000000000005427. Epub 2022 Jan 5.

Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy

David A Wacker  1 , Susan L Burton  1 , John P Berger  2   3 , A J Hegg  1 , Jamie Heisdorffer  4   5 , Qi Wang  1 , Emily J Medcraft  1 , Ronald A Reilkoff  1
Affiliations
Randomized Controlled Trial

Evaluating Vitamin C in Septic Shock: A Randomized Controlled Trial of Vitamin C Monotherapy

David A Wacker et al. Crit Care Med. .

Abstract

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.

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Conflict of interest statement

Dr. Wacker’s institution received funding from the University of Minnesota Critical Care Program for an unrelated project, the University of Minnesota Foundation, and the Fairview Foundation. Drs. Wacker, Berger, Medcraft, and Reilkoff disclosed the off-label product use of Vitamin C in septic shock. Dr. Hegg’s institution received funding from the Essentia Health DC Foundation; he disclosed he is employed by Essentia Health. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Figures

Figure 1.
Figure 1.
Subject flow through the trial: flow diagram showing subject screening, recruitment, randomization, and analysis. All subjects who withdrew prior to completing the protocol were withdrawn due to transition to comfort measures only (CMO), except one in the vitamin C group who was withdrawn due to transfer to a hospital not actively participating in the study. In almost all cases when a patient was excluded due to inability to initiate study drug within 24 hr of pressor initiation (39 excluded patients), this stemmed from the patient lacking decisional capability and inability to obtain written informed consent from the patient’s legally authorized representative within the designated timeframe. ESRD = end-stage renal disease.
Figure 2.
Figure 2.
Comparison of survival in the 28-d study follow-up period: Kaplan-Meier survival analysis comparing survival over 28 d following study drug initiation for patients in the vitamin C and placebo groups. Log-rank testing p value is 0.10.
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