The lung is an important target of inflammatory mediators in severe sepsis and increased pulmonary NF-kappa-B drives inflammatory mediators in severe sepsis. Reactive oxygen species (ROS) oxidize vital proteins and activate redox-sensitive pathological signaling pathways, and this exuberant ROS synthesis also damages cells and host tissues and contribute to the pathogenesis of ARDS. A growing body of evidence supports the notion that vitamin C alters the pathogenesis of sepsis and sepsis-induced organ dysfunction. For example, low ascorbate concentrations are common features of patients with sepsis and correlate inversely with multiple organ failure and mortality. Further, prior data obtained from a phase I human safety study suggests that high doses of vitamin C can be administered intravenously with little or no adverse events. At Emory and Grady Memorial Hospital, Greg Martin, MD and Jon Sevransky, MD, MHS were co-investigators in an NHLBI-sponsored study with colleagues at Virginia Commonwealth University, the Cleveland Clinic and the University of Wisconsin to conduct a phase II multi-center study of high dose intravenous vitamin C in patients with sepsis-induced ARDS (NCT02106975). This study, published in JAMA in 2019, enrolled 167 patients and found no difference in biomarkers or organ dysfunction but a significant reduction in mortality and more days free of the ICU for patients treated with high-dose vitamin C.
High dose vitamin C has been considered as a potential therapy for patients with sepsis due to its pleiotropic effects, including being both antioxidant and anti-inflammatory, its effects on endothelial integrity and immune function, and its critical role in the synthesis and function of catecholamines. The addition of thiamine and hydrocortisone to vitamin C have been suggested to be beneficial in preclinical and observational studies. These observations led Sevransky, David Wright, MD, chair of Emergency Medicine, and Richard Rothman, MD, professor in the Department of Emergency Medicine at Johns Hopkins, to conduct the Vitamin C, Thiamine, and Steroids (VICTAS) in patients with sepsis. This multi-center study completed enrollment of over 500 patients ahead of schedule and is now completing analysis and reporting. This study was registered in ClinicalTrials.gov with identifier NCT03509350.