Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis
Two recent publications by Sheikh and Horner and Teng et al. reviewed studies on incorporating vitamin C to treat septic patients; however, a meta-analysis was not offered in either report. This commentary extends both reviews by integrating a meta-analysis and sharing aggregated results. Pooled analyses demonstrated a marked reduction in mortality and duration of vasopressor administration in the group with the use of vitamin C.
KeywordsSepsis Severe sepsis Sepsis management Vitamin C Ascorbic acid Meta-analysis
Intensive care unit length of stay
Standardized mean difference
Sepsis is a severe condition with high mortality rates. Sheikh and Horner  and Teng et al.  recently published review articles regarding the incorporation of vitamin C in the treatment of sepsis. While the reviews offered insightful appraisals regarding the original studies and reported them in perspective, a meta-analysis was not produced and therefore aggregated quantitative results were not available for review. Considering both reviews were recent publications, this commentary extends their work by performing a meta-analysis and demonstrating the pooled results.
Sheikh and Horner  conducted a literature search of EMBASE, Medline, and PubMed through January 2018 surrounding sepsis and intravenous vitamin C; Teng et al.  completed a review of the literature using PubMed in terms of sepsis and vitamin C. Teng et al. summarized five pertinent papers in their review; however, two of the original articles described in their review, one written by Fowler et al.  and the other by Natarajan et al. , were derived from the same clinical trial. In addition, the study reported by Tanaka et al. concerned patients with burns . Although the authors reasoned that most deaths in modern burn centers are from septic shock , this paper was deemed irrelevant for the review and meta-analysis on sepsis and vitamin C. After removing one of the duplicate studies—the Natarajan et al. paper—and the Tanaka et al. paper, the three studies summarized by Teng et al. matched those of Sheikh and Horner. A search of EMBASE and PubMed similar to that of Sheikh and Horner was performed on 8 June 2018, but no further full-text articles were found; therefore, the three papers reviewed by Sheikh and Horner were included in the meta-analysis.
Characteristics of included studies
Dose of vitamin C
Marik et al. 
Retrospective before-after study
Primary diagnosis of severe sepsis or septic shock and a procalcitonin level ≥ 2 ng/mL
< 18 years, pregnant, or with limitations of care
Mean age for treated group 58.3 years, 57% male; mean age for control group 62.2 years, 49% male
1.5 g IV every 6 h
Hospital mortality, ICU-LOS, duration of vasopressors, RRT for AKI, reduction in serum procalcitonin and SOFA over the first 72 h
Neither randomized nor blinded, although propensity-adjusted; protocol included intravenous hydrocortisone and thiamine, in addition to vitamin C
Fowler et al. 
Prospective phase I trial
Diagnosis of severe sepsis
< 18 years, pregnant, prisoners, cognitively impaired and unable to provide consent, or non-English speakers
Age for treated group: 30–92 years, 56% male; age for control group: 54–68 years, 50% male
50 mg/kg/day, or 200 mg/kg/day
Vitamin C safety and tolerability, days on vasopressor, ventilator-free days, ICU-LOS, 28-day mortality
Randomized, double-blind, placebo-controlled, but underpowered
Zabet et al. 
Prospective clinical trial
Adult (18–65 years) with diagnosis of septic shock and required vasopressor drug to maintain MAP > 65 mmHg
Mean age for treated group 64.14 years, 71% male; mean age for control group 63.71 years, 79% male
25 mg/kg IV every 6 h
Vasopressor dose and duration, ICU-LOS, 28-day mortality
Randomized, double-blind, placebo-controlled, but small sample size
A meta-analysis was performed on these three outcomes using Comprehensive Meta-Analysis (version 3.3.070). Considering diversity in the study populations and differences in the treatments including varying doses of vitamin C, a random-effects model was used in all analyses. Mortality was considered the primary outcome for this meta-analysis, and a fail-safe N test was carried out to assess publication bias. Fowler et al. randomized patients into three groups: low-dose ascorbic acid, high-dose ascorbic acid, and placebo . The low-dose and high-dose groups were combined into the vitamin C group for meta-analysis. If the original study did not incorporate a power analysis or mention a one-sided or two-sided test, a two-sided test was assumed.
All three studies reported ICU-LOS. Results from Marik et al.  and Zabet et al.  were incorporated in the meta-analysis; however, the study by Fowler et al.  was excluded as it did not provide either standard deviation (SD) for direct synthesis or the median for estimating SD . Although Marik et al. reported median and interquartile range for ICU-LOS in their publication, the mean and SD were supplied by Dr. Marik via an email inquiry . Pooled analysis favored the use of vitamin C, but statistical significance was not reached (standardized mean difference (SMD) = −0.30, 95% CI −0.83 to 0.23; p = 0.27; Fig. 1b). Heterogeneity between these two studies was not significant (I2 = 42.3%; p = 0.19 for Cochran’s Q).
All three studies reported the duration of vasopressor use. Results from Marik et al.  and Zabet et al.  were incorporated in the meta-analysis; however, the study by Fowler et al.  was excluded as it did not provide either SD for direct synthesis or the median for estimating SD, and the duration was summarized in days while the other two studies reported hours . Pooled analysis showed a significant reduction in duration of vasopressor administration in the group with vitamin C (SMD = −1.57, 95% CI −2.03 to −1.11; p < 0.001; Fig. 1c). Heterogeneity between these two studies was not significant (I2 = 15.0%; p = 0.28 for Cochran’s Q).
Despite varying degrees of statistical significance between the original studies, this meta-analysis reveals a positive correlation between incorporating vitamin C in the treatment of sepsis and favorable patient outcomes, including better survival and shorter duration of vasopressor use; I2 was shown to be insignificant, and therefore corroborates the consistency of evidence. Since this is a quantitative synthesis of a small number of studies, further randomized clinical trials are required to prove a causal relationship. If this relationship is confirmed, vitamin C has enormous potential to improve patient care and reduce mortality rates due to its low cost and wide availability.
The author would like to thank Isabella Zikakis for her assistance with editing the manuscript.
Publication costs for this article were funded by the author’s organization.
Availability of data and materials
All data can be found in the referenced articles or in the table and figure included in this article.
JL conceived the commentary, performed the meta-analysis, drafted, revised, and approved the manuscript.
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