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

Materials and Methods

Study Design and Setting

This was an investigator-initiated, randomized, placebo-controlled, double-blinded study examining the effect of IV vitamin C on outcomes in patients with septic shock. The study was performed in five hospitals, including one tertiary academic medical center and four nonteaching community hospitals (Table S1, https://links.lww.com/CCM/G946) between January 2018 and June 2020.

Study Population

Adult patients within 24 hours of onset of septic shock were eligible for enrollment. Main exclusion criteria were inability to obtain written consent and initiate study drug within 24 hours of eligibility, known history of nephrolithiasis, and shock occurring immediately following cardiac arrest. See Figure 1 and the Supplemental Methods section (https://links.lww.com/CCM/G946) for complete inclusion and exclusion criteria and definitions.

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 All subjects who withdrew prior to completing the protocol were withdrawn due to transition to comfort measures only (CMO), except one in the vitamin C group who was withdrawn due to transfer to a hospital not actively participating in the study.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.


After giving written informed consent, subjects were randomized to two parallel groups receiving either vitamin C (10-mg/mL solution in normal saline) administered as a 1,000-mg bolus over 30 minutes followed by continuous infusion of 250 mg/hr or placebo of normal saline. The study infusion ended after 96 hours or the subject remaining vasopressor-free for 24 consecutive hours, whichever occurred sooner.


The primary outcome for this study was all-cause 28-day mortality. Secondary outcomes included all-cause ICU mortality, time to lactate clearance, need for renal replacement therapy (RRT), changes in severity-of-disease index scores, and durations of ICU and hospital stay following study drug initiation. The Supplemental Methods section (https://links.lww.com/CCM/G946) provides a full list of secondary outcomes.

Sample Size

Based on a prior retrospective study[5] showing a greater than 30% mortality reduction (risk difference) with vitamin C therapy, we anticipated at least a 20% reduction in absolute mortality between the groups at 28 days. Institutional data from participating centers suggested historical mortality rates for septic shock of approximately 30%. Using this baseline mortality rate and employing a two-tailed alpha of 0.05, we calculated that 124 subjects (an average of 62 per group) would be needed to detect a 20% decrease in absolute mortality with 80% power.

Randomization and Blinding

Participants, their families, study staff, and treatment teams were all blinded to group allocation. Site stratified randomization strategy and criteria for unblinding are given in the Supplemental Methods section (https://links.lww.com/CCM/G946).

Data Collection and Statistical Analysis

Analysis was performed based on intention to treat. For categorical values, statistical significance was assessed using a chi-square test or Fisher exact test. For continuous variables, the median test was used. Full details of data collection, statistical analysis, and subgroup analyses are provided in the Supplemental Methods section (https://links.lww.com/CCM/G946).

Oversight and Data Availability

This study was approved by the institutional review board of the University of Minnesota, as well as the institutional review boards pertaining to each individual study site (Table S1, https://links.lww.com/CCM/G946). An independent data and safety monitoring board consisting of two intensive care physicians and one statistician who were not otherwise involved with the study met at least every 6 months and oversaw study activities. This trial is registered at clinicaltrials.gov under identifier NCT03338569. Full details of plans for data sharing can be found in the Supplemental Methods section (https://links.lww.com/CCM/G946).