Vitamin C as a Therapeutic Agent in Sepsis

The largest meta-analysis conducted by S. Sattar and colleagues provides strong evidence of Vitamin C as a therapeutic agent in sepsis. The researchers reported that vitamin C, either in enteral or IV form, in monotherapy as well as combined therapy, continues to demonstrate a promising reduction in hospital length of stay, mortality, duration of mechanical ventilation, ICU length of stay, and vasopressor requirement compared to control.

"We strongly encourage conducting further large pivotal studies to establish vitamin C as a standard of care in sepsis to reduce mortality given its low cost and fewer adverse effects," Sattar et al. wrote in their study.

The study findings were presented at the American Thoracic Society (ATS) 2022 International Conference held from May 13-18, 2022, in San Francisco, CA.

Background

The mortality rate of sepsis remains very high with an overall very poor prognosis despite all the advancements in critical care. From a pathophysiology point of view, it is known that endotoxins of bacterial cell walls stimulate macrophages to produce pro-inflammatory cytokines. Activated macrophages also release high mobility group box 1 (HMGB1), which is an essential mediator of sepsis. Extracellular HMGB1 is the culprit for triggering a lethal cascade of cytokines and inflammatory proteins. Ascorbic acid (AscA) induces heme oxygenase (HO)-1 which inhibits the release of HMGB1 in lipopolysaccharide (LPS)-stimulated cells and increases survival in sepsis. As HO-1 is one of the rate-limiting enzymes in heme catabolism.

Pharmacological Studies

Pharmacological studies have shown that parenteral high-dose vitamin C inhibits endotoxin-induced endothelial dysfunction and vasohyporeactivity in humans, normalized physiological functions that attenuated the development of multiple organ dysfunction syndrome in sepsis, and significantly reduced pro-inflammatory biomarkers in severe sepsis patients. AscA induces the expression of HO-1 protein via Nrf-2/Keap-1 pathways. Indeed, Nrf-2 is a ubiquitous master transcription factor regulating a complex cellular stress response network that functions to lessen stress signaling.

Study Methodology

For the study, a systemic review search was conducted on PubMed, Embase, and Central Cochrane Registry. For analysis, the selection of 21 prospective randomized clinical trials with Vitamin C as an intervention in the septic adult patient population was done.

Standardized mean difference (SMD) was used for continuous variables and the odds ratio (OR) was used for discrete variables.

Results

RCTs showed that in the patient population with a sample size of 2548 (n=2548), treated with vitamin C there was a statistically significant reduction in:

• Mortality, OR=0.788
• SOFA score, -0.333
• Days on mechanical ventilation, SMD=-0.732
• Days on pressors, SMD=-0.637
• ICU length of stay, SMD= -0.351

Reference

Sattar S, Jahangir A, Kassem A, et al. Efficacy of vitamin C in septic patient population: A Systematic Review and Metanalysis: Presented at: the American Thoracic Society (ATS) 2022 International Conference; May 13-18, 2022; San Francisco, CA. Abstract P530.