Acute and Critical Care [Epub ahead of print]

https://doi.org/10.4266/acc.2022.01088

| pISSN 2586-6052 | eISSN 2586-6060

Meta-analysis assessing the effectiveness of intravenous

vitamin C in patients with sepsis and septic shock
Muhammad Ali Tariq1, Hamza Amin2, Uzair Ali1
1
Department of Medicine, Dow University Hospital, Dow International Medical College, Karachi; 2Department of Medicine, Dr. Ruth KM Pfau Civil Hospital, Dow
University of Health Sciences, Karachi, Pakistan

Dear Editor:
Sepsis continues to be leading cause of mortality among patients admitted to intensive care Letter to the Editor
unit (ICU), with about 48.9 million cases of sepsis diagnosed and 11 million deaths world-
Received: August 10, 2022
wide in 2017 [1]. Despite significant advances in the understanding of the pathophysiology of Revised: September 1, 2022
sepsis, the mainstay management still relies on active fluid resuscitation for hemodynamic Accepted: September 2, 2022
support, early administration of antibiotics, and identification of source and infection control
[2]. Vitamin C has been suggested as a possible therapy that attenuates the pathophysiology Corresponding author
Muhammad Ali Tariq
of sepsis [2]. Multiple randomized controlled trials (RCTs) addressing effectiveness and safety
Department of Medicine, Dow
of vitamin C have reported varied conclusions [3]. Previously, published meta-analysis were
University Hospital, Dow International
limited by the sample size and highlighted the need of further studies with a larger number of Medical College, Gulzar-e-Hijri
patients to provide further evidence [3]. The recent publication of results from LOVIT (Less- Scheme 33, Suparco Rd, Karachi,
ening Organ Dysfunction with Vitamin C), the largest trial to date addressing this question, Pakistan
justifies re-examination of the evidence [4]. Tel: +92-312-2319607
Fax: +92-342-88454
PubMed and Scopus databases were searched for relevant studies by two investigators
E-mail: m.alitariqpk@gmail.com
(MAT, UA) using the following keywords: “ascorbic,” “Vitamin C,” “ascorbic acid,” “sepsis,”
“septic shock.” Studies were included if they were: (1) RCT (2) comprised of adult patients
with Sepsis or septic shock (3) treatment arm: high-dose intravenous (IV) vitamin C (≥1.5 g
every 6 hours or 25 mg/kg every 6 hours) either as monotherapy or combination therapy with
thiamine and hydrocortisone, (4) control arm: placebo or standard regiment. Outcomes of
interest were ICU mortality, 30-day and 90-day mortality, change in Sequential Organ Failure
Assessment score (delta SOFA) within 72 hours. Subgroup analyses were conducted for vita-
min C as monotherapy versus combination therapy. Review articles, non-randomized stud-
ies, conference abstracts and studies published prior to 2010 were excluded. Odds ratios (ORs)
or weighted mean difference (WMD) with 95% confidence intervals (CI) were calculated
using random effects model. Statistical heterogeneity in studies was assessed by I2 statistics. A
P<0.05 was considered significant.
Copyright © 2022 The Korean Society of
The initial literature search identified 854 unique studies, 14 trials with 2,793 patients met Critical Care Medicine
the eligibility criteria [3-5]. The preferred reporting items for systematic reviews and me- This is an Open Access article distributed
ta-analyses (PRISMA) flowchart of the study selection is shown in Supplementary Figure 1. under the terms of Creative Attributions
Non-Commercial License (https://creativecom-
Baseline study characteristics are shown in Supplementary Table 1. IV vitamin C in combi- mons.org/li-censes/by-nc/4.0/) which permits
unrestricted noncommercial use, distribution,
nation with thiamine and hydrocortisone significantly reduced SOFA score at 72 hours (7 and reproduction in any medium, provided the
RCTs, 1,318 patients; WMD: –0.52, 95% CI: –1.01 to –0.03, P=0.037, I2=53%) (Figure 1D). For original work is properly cited.

https://www.accjournal.org 1
Tariq MA, et al.  High dose IV vitamin C in patients with sepsis

A ICU mortality

B 30-Day mortality

Figure 1. Forest plot showing the effect of intravenous vitamin C compared with control on (A) intensive care unit (ICU) mortality, (B) 30-day
mortality, (C) 90-day mortality, and (D) change in Sequential Organ Failure Assessment (SOFA) score at 72 hours. Vit: vitamin; MH: Mantel-
Haenszel; CI: confidence interval; HAT: hydrocortisone, ascorbic acid, and thiamine. A list of articles indicated in Figure 1 can be found in the
online Supplementary Table 1. (Continued to the next page)

2 https://www.accjournal.org Acute and Critical Care [Epub ahead of print]

Tariq MA, et al.  High dose IV vitamin C in patients with sepsis

C 90-Day mortality

D Change in SOFA score at 72 hours

Figure 1. Forest plot showing the effect of intravenous vitamin C compared with control on (A) intensive care unit (ICU) mortality, (B) 30-day
mortality, (C) 90-day mortality, and (D) change in Sequential Organ Failure Assessment (SOFA) score at 72 hours. Vit: vitamin; MH: Mantel-
Haenszel; CI: confidence interval; HAT: hydrocortisone, ascorbic acid, and thiamine. A list of articles indicated in Figure 1 can be found in the
online Supplementary Table 1.

Acute and Critical Care [Epub ahead of print] https://www.accjournal.org 3

Tariq MA, et al.  High dose IV vitamin C in patients with sepsis
other outcomes, IV vitamin C was not statistically significant
in reducing the ICU mortality (6 RCTs, 1,284 patients; OR:
0.98, 95% CI: 0.74 to 1.30, P=0.91, I2=0.0%) (Figure 1A), 30-day
mortality (14 RCTs, 2,783 patients; OR: 0.87, 95% CI: 0.69 to
1.09, P=0.22, I2=32.0%) (Figure 1B), 90-day mortality (5 RCTs,
1,740 patients; OR: 1.10, 95% CI: 0.91 to 1.34, P=0.33, I2=0.0%)
(Figure 1C). The results were consistent across the subgroups.
In this meta-analysis we analyzed IV vitamin C therapy in
sepsis summarizing the most recent available clinical data.
Overall meta-analysis results indicate use of IV high dose vi-
tamin C in combination with thiamine and hydrocortisone is
associated with significantly improved SOFA score at 72 hours
but has no effect on ICU stay and mortality. However, the
clinical significance of reduction in SOFA score is still unclear
and caution should be exercised when utilizing surrogate
outcomes instead of patient centered outcomes such as mor-
tality. In conclusion, this systematic review and meta-analysis
provide conclusive evidence into the effects of IV vitamin C in
sepsis. With marginal improvement in delta SOFA among sep-
tic patients there no mortality benefit. Little evidence exists to
support the routine use of vitamin C in sepsis patients.
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was re-
ported.
ORCID
Muhammad Ali Tariq https://orcid.org/0000-0003-1108-0731
Hamza Amin https://orcid.org/0000-0001-8564-4195
Uzair Ali https://orcid.org/0000-0003-0993-0901
4 https://www.accjournal.org
AUTHOR CONTRIBUTIONS
Conceptualization: MAT. Formal analysis: all authors. Meth-
odology: all authors. Writing–original draft: HA, UA. Writing–
review & editing: all authors.
SUPPLEMENTARY MATERIALS
Supplementary materials can be found via https://doi.org/
10.4266/acc.2021.01088.
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Acute and Critical Care [Epub ahead of print]