Effect of IV High-Dose Vitamin C on Mortality in Patients With Sepsis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials*

Abstract

OBJECTIVES: The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials to investigate whether IV high-dose vitamin C improves the short-term mortality of patients with sepsis. DESIGN: This study is a systematic review and meta-analysis of randomized controlled trials. We searched EMBASE, the Cochrane Central Register of Controlled Trials, and MEDLINE for randomized controlled trials that met inclusion criteria. The protocol was registered at the University hospital Medical Information Network Clinical Trials Registry (UMIN000040528). All analyses were presented with the use of random-effects models. The primary outcome was short-term mortality defined as 28-day, 30-day, or in-hospital mortality. PATIENTS: Two authors independently evaluated the following eligibility criteria: 1) randomized controlled trial, 2) patients with sepsis aged ≥18 years, and 3) received intravenous high-dose vitamin C in addition to standard of care, or standard of care alone. Then, two authors independently extracted the selected patient and study characteristics and outcomes from studies that met above eligibility criteria. MEASUREMENTS AND MAIN RESULTS: Eleven randomized controlled trials (n = 1,737 patients) were included in this meta-analysis. High-dose IV vitamin C was not associated with a significantly lower short-term mortality (risk ratio, 0.88; 95% CI, 0.73–1.06; p = 0.18; I 2 = 29%) but was associated with a significantly shorter duration of vasopressor use (standardized mean difference, –0.35; 95% CI, –0.63 to –0.07; p < 0.01; I 2 = 80%) and a significantly greater decline in the Sequential Organ Failure Assessment score at 72–96 hours (standardized mean difference, –0.20; 95% CI, –0.32 to –0.08; p < 0.01; I 2 = 16%). One study reported significant association with hypernatremia, but adverse effects were rare, and high-dose vitamin C is deemed relatively safe. CONCLUSIONS: In this meta-analysis, the use of IV high-dose vitamin C in patients with sepsis was not associated with lower short-term mortality although it was associated with significantly shorter duration of vasopressor use and greater decline in the Sequential Organ Failure Assessment score at 72–96 hours.

The outcome of IV vitamin C therapy in patients with sepsis or septic shock: a meta-analysis of randomized controlled trials

“…However, there are only 9 RCTs presenting time to intervention initiation in our meta-analysis, resulting in difficulty in judgement the effect of initiation time. Recent meta-analyses [11,13,[41][42][43]] also failed to find improved mortality among patients with sepsis, no matter combined therapy or monotherapy. Different inclusion criterion, duration, patient populations and timing of administration explain the heterogeneity of different research results to some extent.…”

“…The Surviving Sepsis Campaign of 2021: International Guidelines for Management of Sepsis and Septic Shock suggest IVVC for patients with sepsis or septic shock was not recommended, only as a weak recommendation according to the low quality of evidence [12]. Although systematic reviews and meta-analyses discussing IVVC in patients with sepsis were recently published [11,13,14], these studies did not include the newer randomized controlled trials (RCTs) [15][16][17] with a larger population of patients to provide better evidence.…”

Meta-analysis assessing the effectiveness of intravenous vitamin C in patients with sepsis and septic shock

“…Vitamin C has been suggested as a possible therapy that attenuates the pathophysiology of sepsis [2]. Multiple randomized controlled trials (RCTs) addressing effectiveness and safety of vitamin C have reported varied conclusions [3]. Previously, published meta-analysis were limited by the sample size and highlighted the need of further studies with a larger number of patients to provide further evidence [3].…”

“…Multiple randomized controlled trials (RCTs) addressing effectiveness and safety of vitamin C have reported varied conclusions [3]. Previously, published meta-analysis were limited by the sample size and highlighted the need of further studies with a larger number of patients to provide further evidence [3]. The recent publication of results from LOVIT (Lessening Organ Dysfunction with Vitamin C), the largest trial to date addressing this question, justifies re-examination of the evidence [4].PubMed and Scopus databases were searched for relevant studies by two investigators (MAT, UA) using the following keywords: "ascorbic, " "Vitamin C, " "ascorbic acid, " "sepsis, " "septic shock. "…”

“…Statistical heterogeneity in studies was assessed by I 2 statistics. A P<0.05 was considered significant.The initial literature search identified 854 unique studies, 14 trials with 2,793 patients met the eligibility criteria [3][4][5]. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of the study selection is shown in Supplementary Figure 1.…”