Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study

Abstract

Background Previous randomized trials of vitamin C, hydrocortisone, and thiamine on sepsis were limited by short-term vitamin C administration, heterogeneous populations, and the failure to evaluate each component’s effect. The purpose of this study was to determine whether vitamin C alone for ≥ 5 days or in combination with corticosteroids and/or thiamine was associated with decreased mortality across the sepsis population and subpopulation. Methods Nationwide population-based study conducted using the Korean National Health Insurance Service database. A total of 384,282 adult patients with sepsis who were admitted to the intensive care unit were enrolled from January 2017 to December 2019. The primary outcome was hospital mortality, while the key secondary outcome was 90-day mortality. Results The mean [standard deviation] age was 69.0 [15.4] years; 57% were male; and 36,327 (9%) and 347,955 did and did not receive vitamin C, respectively. After propensity score matching, each group involved 36,327 patients. The hospital mortality was lower by − 0.9% in the treatment group (17.1% vs 18.0%; 95% confidence interval, − 1.3 to − 0.5%; p < 0.001), a significant but extremely small difference. However, mortality decreased greater in patients who received vitamin C for ≥ 5 days (vs 1–2 or 3–4 days) (15.8% vs 18.8% vs 18.3%; p < 0.001). Further, vitamin C was associated with a lower hospital mortality in patients with older age, multiple comorbidities, pneumonia, genitourinary infection, septic shock, and mechanical ventilation. Consistent findings were found for 90-day mortality. Moreover, vitamin C alone or in combination with thiamine was significantly associated with decreased hospital mortality. Conclusions Intravenous vitamin C of ≥ 5 days was significantly associated with decreased hospital and 90-day mortality in sepsis patients. Vitamin C combined with corticosteroids and/or thiamine in specific sepsis subgroups warrants further study.

Vitamin C for septic shock in previous randomized trials: implications of erroneous dosing, timing, and duration

“…1 d). These findings are consistent with those in our previous nationwide cohort study that found significantly lower in-hospital mortality in sepsis patients treated with IV vitamin C for ≥ 5 days [ 4 ]. In this study, the survival curves of patients who received vitamin C for 1–2 or 3–4 days tended to diverge earlier during the course of sepsis than did those of patients treated for ≥ 5 days.…”

“…In Rosengrave’s study [ 1 ], the median age of the participants was 69 years, and only 15% had comorbidities. However, our data demonstrated that these patients had lower mortality rates when vitamin C was administered [ 4 ]. Interestingly, there was no survival benefit in younger patients (< 70 years) and those with fewer comorbidities.…”

Intravenous vitamin C administration to patients with septic shock: a pilot randomised controlled trial

“…A retrospective study of time sensitive mortality difference with vitamin C combination therapy indicated a significant decrease in mortality in participants who received the intervention within six hours of sepsis presentation relative to those who received it after more than six hours [ 47 ]. Furthermore, the duration of vitamin C administration is an important consideration for long-term clinical outcomes [ 48 ], with intervention for five or more days showing greater benefit [ 49 ]. Half of the intervention group in our trial did not receive the entire four days of intravenous vitamin C. Previous research has indicated that cessation of vitamin C infusions after 2–4 days can result in some patients reverting to hypovitaminosis C concentrations [ 11 , 21 ].…”

The effect of intravenous vitamin C on clinical outcomes in patients with sepsis or septic shock: A meta-analysis of randomized controlled trials

“…A prespecified subgroup analysis stratified by the types of disease (sepsis vs. septic shock), dose [high dose was set to a daily dose of ≥100 mg/kg or 10000 mg/day, according to the review of Patel et al ( 25 )], and duration [<5 days vs. ≥5 days, according to the study by Jung et al ( 26 )] of IV vitamin C treatment. Finally, a sensitivity analysis was conducted to explore the effect of individual study by consecutive exclusion of each study at one time.…”

“…≥5 days, according to the study by Jung et al (26)] of IV vitamin C treatment. Finally, a sensitivity analysis was conducted to explore the effect of individual study by consecutive exclusion of each study at one time.…”