Controversies with high-dose vitamin C therapy in human sepsis
Single-centre controlled randomised clinical trials (RCT) showed that intravenous vitamin C reduced inflammatory biomarkers and reduced sequential organ failure assessment (SOFA) scores (50, 100, 200 mg/kg/day, n=24) (Fowler et al., 2014) and improved vasopressor sensitivity (2 g 4 times/day, n=28) (Zabet, Mohammadi, Ramezani & Khalili, 2016). A widely publicised single-centre before and after study (n=47), using a combination therapy of vitamin C (1.5 g 4 times/day) with hydrocortisone and thiamine, reduced organ failure and mortality from 40.4% to 8.5% (Marik, Khangoora, Rivera, Hooper & Catravas, 2017). However, subsequent multi-centre RCTs, VITAMINS (Fujii et al., 2020), ACTS (Moskowitz et al., 2020) and ATESS (Hwang et al., 2020) that trialled a maximum dose of vitamin C of 6 g/day for up to 10 days with thiamine ± corticosteroid, had no significant benefit above placebo (Fujii et al., 2020) (Moskowitz et al., 2020) (Hwang et al., 2020). The CITRUS-ALI trial, that used 200 mg/kg/day (16 g/day in an 80 kg patient) of vitamin C for 4 days, however, reduced 28-day mortality from 46% to 30% (Fowler et al., 2019).
We hypothesized that the lack of consistent benefit in the clinical trials of vitamin C in sepsis might be due to the use of inadequate doses. In view of these findings, and the fact that very high doses of intravenous vitamin C have been shown to be safe in burns and cancer patients (Yanase et al., 2020), we recently investigated the safety and efficacy of a much larger dose (mega-dose) of vitamin C in experimental sepsis.