European Journal of Pharmacology 868 (2020) 172889

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European Journal of Pharmacology

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Efficacy of vitamin C in patients with sepsis: An updated meta-analysis T

1 1 ∗
Xue-biao Wei , Zhong-hua Wang , Xiao-long Liao, Wei-xin Guo, Jian-Yi Wen, Tie-he Qin ,
Shou-hong Wang∗∗
Department of Critical Care Medicine, Guangdong Provincial Geriatrics Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences,
Guangzhou, 510080, China

A R T I C LE I N FO A B S T R A C T

Keywords: Previous studies have suggested the beneficial effects of vitamin C in patients with sepsis. However, the results
Meta-analysis could not be reproduced in the subsequent studies. This meta-analysis aimed to reevaluate the value of vitamin C
Sepsis treatment in patients with sepsis. Electronic databases were searched from inception to August 2019 for the
Vitamin C studies comparing the effect of vitamin C versus non-vitamin C infusion in patients with sepsis. Data from 10
studies (4 randomized controlled trials [RCTs] and 6 retrospective studies) involving 1671 patients (495 in the
vitamin C treatment group and 1176 in the control group) were included. The use of vitamin C did not reduce the
risk of 28-day (OR = 0.84, P = 0.611, I2 = 56.3%), intensive care unit (ICU; OR = 0.79, P = 0.319,
I2 = 46.2%), or in-hospital mortality (OR = 0.76, P = 0.251, I2 = 51.0%). No difference in the duration of
vasopressor usage and the length of ICU or hospital stay was present. The subgroup analysis for two RCTs
suggested that vitamin C treatment showed reduced 28-day mortality (OR = 0.22, P = 0.014, I2 = 35.7%),
whereas this beneficial effect did not occur in subgroup analysis for three retrospective studies (OR = 1.11,
P = 0.527, I2 = 0%). Retrospective meta-analysis could not reveal the beneficial effect of vitamin C on patients
with sepsis. Therefore, in order to clarify the role of vitamin C in sepsis the high-quality RCTs will be required in
the future study.

1. Introduction Supplementation of exogenous vitamin C might be a potential treat-

Sepsis is a life-threatening critical disease triggered by a dysregu-
lated immuno-inflammatory response to an infection (Hotchkiss et al.,
2016; Singer et al., 2016). It is a major health care problem affecting
31.5 million people globally each year, including 19.4 million people
with severe sepsis (Fleischmann et al., 2016). In spite of earlier diag-
nosis and improvement in management, sepsis was still associated with
high mortality. Data from high-income countries indicated that the
number of sepsis-related deaths was 2.8 million per year (Cecconi et al.,
2018). In addition, patients with sepsis suffer from numerous other
complications, reducing their quality of life (Yende et al., 2016; Ou
et al., 2016). Given the great danger of sepsis, more effective ther-
apeutic approaches were required.
A significant low vitamin C level was common in patients with
sepsis (Belsky et al., 2018). Vitamin C, also known as ascorbic acid, is
an important antioxidant that participates in several kinds of biosyn-
thetic and metabolic processes in the human body (Marik, 2018a,b).
ment for sepsis. In animal studies, the infusion of vitamin C reduced
organ injury and prevented the deleterious consequences in a septic
condition (Gao et al., 2017; Fisher et al., 2014). Therefore, a large
number of clinical studies were performed to investigate the ther-
apeutic effect of vitamin C in patients with sepsis. A meta-analysis
conducted by Li (2018) demonstrated that the use of vitamin C could
significantly reduce the mortality caused by sepsis. However, these
results could not be reproduced in the subsequent studies (Mitchell
et al., 2019; Ahn et al., 2019; Litwak et al., 2019; Shin et al., 2019).
Thus, the role of vitamin C in patients with sepsis remains controversial.
Due to the contrasting results, this updated meta-analysis, including
newly published studies, was performed to further assess the value of
vitamin C in patients with sepsis.

∗
Corresponding author.
∗∗
Corresponding author.
E-mail addresses: qintiehe@163.com (T.-h. Qin), gdwangshouhong@163.com (S.-h. Wang).
1
These authors are considered co-first authors.

https://doi.org/10.1016/j.ejphar.2019.172889
Received 21 October 2019; Received in revised form 30 November 2019; Accepted 19 December 2019
Available online 21 December 2019
0014-2999/ © 2019 Elsevier B.V. All rights reserved.
X.-b. Wei, et al. European Journal of Pharmacology 868 (2020) 172889

2. Materials and methods

2.1. Search strategy and study selection

The PubMed, Web of Science, ClinicalTrials.gov, and Cochrane

Library databases were searched from inception to August 2019 for
relevant studies. The following search terms were used: (vitamin C or
ascorbic acid) and (sepsis or septic). Also, the reference lists in the in-
cluded studies and previous relevant meta-analyses were reviewed. The
language was restricted to English.
The studies comparing the effect of vitamin C versus non-vitamin C
infusion in patients with sepsis were included. The exclusion criteria
were as follows: (1) duplicate publications; (2) pediatric studies; (3)
non-sepsis; (4) studies involving oral or enteral vitamin C treatment;
and (5) lacking the data of predefined endpoints. After excluding the
duplicate publications, two reviewers (Wx G and Xl L) independently
reviewed the titles and abstracts of all identified studies. Following the
assessment of titles and abstracts, all identified studies were acquired as
full-text. A third reviewer (Sh W) resolved any disagreements by dis-
cussion and consensus.

2.2. Data abstraction and study endpoints

The key information from individual eligible studies was extracted:

first author's name, publication year, study design and population,
number of participants, and patients' characteristics; medicine in the
intervention group; vitamin C regimen; and outcomes. The study end-
points included 28-day, intensive care unit (ICU), and in-hospital
mortality; duration of vasopressor usage; length of ICU or hospital stay,
acute kidney injury (AKI); and new use of renal replacement therapy for
AKI.

2.3. Quality evaluation for the included studies Fig. 1. Flow chart of study selection.

Two authors (Xb W and Zh W) independently assessed the study-

duplicate studies and 657 were excluded because they did not associate
level risk of bias. Disagreements in ratings were resolved by the third with the research topic, after reviewing their titles and abstracts. The
reviewer (Sh W). Randomized controlled trials and retrospective studies
remaining 102 studies were considered to be of relevance, and full
were apraised, respectively.. The quality of randomized controlled trials papers were carefully screened. Five meta-analyses, 24 review studies,
was assessed using the Cochrane Risk-of-Bias Tool (Higgins et al.,
1 case report, 18 comments, 2 studies in Chinese language, and 42
2011). The Newcastle-Ottawa scale was used to assess the risk of bias
having no available data were discarded. Finally, 10 studies (four
for retrospective studies (Stang, 2010).
randomized controlled trials and six retrospective studies) met the se-
lection criteria (Sadaka et al., 2019; Marik et al., 2017; Zabet et al.,
2.4. Statistical analysis
2016; Fowler et al., 2014; Ferron-Celma et al., 2009; Galley et al., 1997;
Ahn et al., 2019; Litwak et al., 2019; Mitchell et al., 2019; Shin et al.,
Data were analyzed using Stata version 12.0 (StataCorp, College
2019). The main characteristics of the studies are shown in Table 1. The
Station, TX, USA). The Q statistic was calculated, and heterogeneity was
sample sizes ranged from 20 to 1144. A total of 1671 patients with
quantified using the I2 statistic. Random-effect models were used when
sepsis were included in the analysis (495 in the treatment group and
I2 was > 50%; otherwise, a fixed-effects model was used. The pub-
1176 in the control group). The severity level of sepsis was not exactly
lication bias was evaluated using the Egger's linear regression test. The
the same. Two studies did not focus on septic shock or severe sepsis
results of categorical variables were reported as forest plots with odds
(Mitchell et al., 2019; Ferron-Celma et al., 2009). One study focus on
ratio (OR) and 95% confidence interval (CI). Forest plots with stan-
septic shock or severe sepsis and a procalcitonin (PCT) level > 2 ng/mL
dardized mean difference (SMD) and 95% CI were used for continuous
(Marik et al., 2017). Vitamin C was administered with other medicines
variables. The dose-dependent actions of vitamin C was also analyzed.
in six studies with the length of treatment ranging from 1 to 4 days
Doses < 2.5 g/day were defined as low, ≥10 g/day as high, and
(Mitchell et al., 2019; Litwak et al., 2019; Shin et al., 2019; Sadaka
2.5–10 g/day as medium. A P value < 0.05 was considered to indicate
et al., 2019; Marik et al., 2017; Galley et al., 1997). The dose of vitamin
statistical significance.
C was 6.0 g/day in six retrospective studies (Mitchell et al., 2019; Ahn
et al., 2019; Litwak et al., 2019; Shin et al., 2019; Sadaka et al., 2019;
3. Results
Marik et al., 2017). The risk-of-bias assessment is listed in Tables 2 and
3.
3.1. Study characteristics

The flow diagram of screening strategy for inclusion in the meta-
analysis is displayed in Fig. 1. A total of 946 references were identified
according to the search strategy: PubMed (n = 281), Web of Science
(n = 531), ClinicalTrials.gov (n = 20), and Cochrane Library
(n = 114). Among these, 188 were excluded because they were
3.2. Vitamin C and mortality
The 28-day mortality was reported in five studies (two randomized
controlled trials and three retrospective studies) (Mitchell et al., 2019;
Ahn et al., 2019; Shin et al., 2019; Zabet et al., 2016; Fowler et al.,

2
 Table 1
Study characteristics.
Study Design Population Number of participants (intervention/ Intervention Vitamin C regimen
X.-b. Wei, et al.

control)

Shin et al., 2019 Retrospective Septic shock 229/915 Vitamin C and thiamine 3g bid or 1.5 g IV qid for 1 d
Mitchell et al., 2019 Retrospective Sepsis or septic shock 38/38 Vitamin C, thiamine, and hydrocortisone 1.5 g IV qid for 4 days
Litwak et al., 2019 Retrospective Septic shock 47/47 Vitamin C, thiamine, and hydrocortisone 1.5 g IV qid at least one dose
Ahn et al., 2019 Retrospective Severe sepsis or septic shock requiring mechanical 35/40 Vitamin C 2g IV tid until ICU discharge
ventilation
Sadaka et al., 2019 Retrospective Septic shock 31/31 Ascorbic acid, thiamine, and steroids 1.5 g IV qid for 4 days
Marik et al., 2017 Retrospective Severe sepsis or septic shock and a PCT > 2 ng/mL 47/47 Vitamin C, hydrocortisone, and thiamine 1.5 g IV qid for 4 days or until ICU
discharge
Zabet et al., 2016 RCT Septic shock 14/14 Vitamin C 25 mg/kg IV qid for 3 days
Fowler et al., 2014 RCT Severe sepsis 16/8 Vitamin C 12.5 or 50 mg/kg IV qid for 4 days
Ferron-Celma et al., 2009 RCT Postoperative sepsis 10/10 Vitamin C 450 mg IV qd for 6 d
Galley et al., 1997 RCT Septic shock 16/14 Vitamin C, vitamin E, NAC 1g IV qd for 1 d

ICU, Intensive care unit; IV, intravenous; RCT, randomized controlled trial.

3
Table 2
Risk-of-bias assessment about RCT.
Study Random sequence generation Allocation concealment Blinding of participants and Blinding of outcome Incomplete outcome Selective reporting Anything else, ideally
personnel assessment data prespecified

Zabet et al., 2016 Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Low risk of bias Unclear risk of bias
Using a randomization scheme Centralized Blinding of all participants Blinding of evaluators Outcome data complete None
generated
Fowler et al., 2014 Low risk of bias Low risk of bias Low risk of bias Unclear risk of bias Low risk of bias Low risk of bias Unclear risk of bias
Using a randomization scheme Centralized Blinding of all participants Outcome data complete None
generated
Ferron-Celma et al., 2009 Low risk of bias Low risk of bias Low risk of bias Unclear risk of bias Low risk of bias Low risk of bias Unclear risk of bias
Using a randomization scheme Centralized Blinding of all participants Outcome data complete None
generated
Galley et al., 1997 Unclear risk of bias Low risk of bias Unclear risk of bias Unclear risk of bias Low risk of bias Low risk of bias Unclear risk of bias
Centralized Outcome data complete None
European Journal of Pharmacology 868 (2020) 172889
X.-b. Wei, et al. European Journal of Pharmacology 868 (2020) 172889

2014). The incidence of 28-day mortality was 25.8% (85/332) and

Age and gender matched

20.2% (205/1015) in the treatment and control groups, respectively.
Truly representative

Complete follow up
The Egger's test showed no significant differences in publication bias

Independent blind
Same hospital among these studies (P = 0.373). The heterogeneity was statistically
Secure record significant (I2 = 56.3%, P = 0.058). The pooled data based on the
Marik,2017

assessment

In-hospital
random-effects model indicated that the use of vitamin C did not reduce
the 28-day mortality (OR = 0.84, 95% CI: 0.43–1.65, P = 0.611,
Yes

No
Fig. 2). The subgroup analysis for two randomized controlled trials
(Zabet et al., 2016; Fowler et al., 2014) suggested that vitamin C
Age and gender matched

treatment showed reduced 28-day mortality (OR = 0.22, 95% CI:

Truly representative

Complete follow up
0.06–0.73, P = 0.014, I2 = 35.7%), whereas this beneficial effect did
Independent blind

not occur in subgroup analysis for three retrospective studies

Same hospital
Secure record
Sadaka,2019

(OR = 1.11, 95% CI: 0.80–1.54, P = 0.527, I2 = 0%) (Mitchell et al.,

assessment

In-hospital

2019; Ahn et al., 2019; Shin et al., 2019). No statistical difference was
also found in four studies (Ahn et al., 2019; Shin et al., 2019; Zabet
Yes

No

et al., 2016; Fowler et al., 2014) on severe sepsis or septic shock

(OR = 0.74, 95% CI: 0.28–1.95, P = 0.549, I2 = 67.0%). The medium
Age and gender matched

doses (2.5–10g/day) of vitamin C was not associated with decreased 28-

Truly representative

Complete follow up
Independent blind

day mortality (OR = 0.98, 95% CI: 0.71–1.35, P = 0.902, I2 = 57.4%).

Same hospital

Five studies compared the incidence of ICU death between the vi-
Secure record

assessment

tamin C treatment and control groups (Mitchell et al., 2019; Ahn et al.,
Ahn,2019

90 days

2019; Litwak et al., 2019; Sadaka et al., 2019; Galley et al., 1997). The
Yes

No

dose of vitamin C was 2.5–10g/day in four studies and < 2.5g/day in

one study. No significant difference in publication bias was found
Age and gender matched

(Egger's test P = 0.562). The pooled estimate showed that vitamin C

Truly representative

administration was not associated with a significant difference in ICU

Complete follow up
Independent blind

mortality (OR = 0.79, 95% CI: 0.51–1.25, P = 0.319, I2 = 46.2%,

Same hospital
Secure record

Fig. 3). No beneficial effect was also found in four studies (Ahn et al.,
Litwak,2019

assessment

In-hospital

2019; Litwak et al., 2019; Sadaka et al., 2019; Galley et al., 1997) on
severe sepsis or septic shock (OR = 0.76, 95% CI: 0.31–1.85,
Yes

No

P = 0.543, I2 = 59.6%). The medium doses of vitamin C did not de-

crease ICU mortality (OR = 0.71, 95% CI: 0.33–1.49, P = 0.361,
Age and gender matched

I2 = 54.2%).
Truly representative

Complete follow up

The in-hospital mortality was explored in seven studies (Mitchell

Independent blind

et al., 2019; Ahn et al., 2019; Litwak et al., 2019; Shin et al., 2019;
Same hospital
Mitchell,2019

Secure record

Sadaka et al., 2019; Marik et al., 2017; Ferron-Celma et al., 2009). The
assessment

publication bias was not significantly different (P = 0.638). A high

60 days

degree of nonsignificant heterogeneity was present (I2 = 51.0%). The

Yes

No

meta-regression results with the random-effects analysis suggested no

difference in the in-hospital mortality in the treatment and control
Age and gender matched

groups (OR = 0.76, 95% CI: 0.47–1.22, P = 0.251, Fig. 4). No statis-
Truly representative

Complete follow up

tical difference was found in five studies (Ahn et al., 2019; Litwak et al.,
Independent blind

2019; Shin et al., 2019; Sadaka et al., 2019; Marik et al., 2017) on
Same hospital
Secure record

assessment

severe sepsis or septic shock (OR = 0.67, 95% CI: 0.37–1.23,

Newcastle-Ottawa Quality Assessment Scale for the retrospective studies.
Shin,2019

28 days

P = 0.196, I2 = 63.5%). The medium doses of vitamin C did not de-

Yes

crease in-hospital mortality (OR = 0.71, 95% CI: 0.43–1.16, P = 0.167,

No

I2 = 54.4%).
Was follow-up long enough for outcomes to occur
Demonstration that outcome of interest was not

3.3. Vitamin C and duration of vasopressor use

Comparability of cohorts on the basis of the
Representativeness of the exposed cohort

Data on the duration of vasopressor use were available in three

Selection of the non exposed cohort

studies (Litwak et al., 2019; Marik et al., 2017; Zabet et al., 2016). The
Adequacy of follow up of cohorts

pooled results showed that vitamin C infusion did not impact the
duration of vasopressor use (SMD = −0.873, 95% CI: 2.269 to 0.523,
Ascertainment of exposure

present at start of study

Assessment of outcome

P = 0.220, I2 = 95.2%, Fig. 5).

design or analysis

3.4. Vitamin C and the length of ICU or hospital stay

Seven studies reported the data on the length of ICU stay (Ahn et al.,
2019; Litwak et al., 2019; Shin et al., 2019; Sadaka et al., 2019; Marik
et al., 2017; Zabet et al., 2016; Fowler et al., 2014). The meta-regres-
Comparability

sion analysis did not reveal any significant correlation between vitamin
C use and the length of ICU stay (SMD = 0.028, 95% CI: 0.090 to 0.146,
Selection

Outcome

P = 0.641, I2 = 0%, Fig. 6). The pooled analysis for four studies (Ahn
Table 3

et al., 2019; Litwak et al., 2019; Shin et al., 2019; Sadaka et al., 2019)
indicated that the use of vitamin C did not have any influence on the

4
X.-b. Wei, et al. European Journal of Pharmacology 868 (2020) 172889

Fig. 2. Forest plot of OR and 95% CI for 28-day

mortality from five studies including 1347 patients
(332 in vitamin C treatment group and 1015 in
control group). The incidence of 28-day mortality
was 25.8% and 20.2% in the treatment and control
groups, respectively. The pooled data based on the
random-effects model indicated that the use of vi-
tamin C did not reduce the 28-day mortality
(OR = 0.84, 95% CI: 0.43–1.65, P = 0.611,
I2 = 56.3%).

Fig. 3. Forest plot of OR and 95% CI for ICU mor-

tality from five studies including 337 patients (167 in
vitamin C treatment group and 170 in control
group). The incidence of ICU mortality was 32.9%
and 37.6% in the treatment and control groups, re-
spectively. The pooled estimate showed that vitamin
C administration was not associated with a sig-
nificant difference in ICU mortality (OR = 0.79, 95%
CI: 0.51–1.25, P = 0.319, I2 = 46.2%).

Fig. 4. Forest plot of OR and 95% CI for in-hospital

mortality from seven studies including 1565 patients
(437 in vitamin C treatment group and 1128 in
control group). The incidence of in-hospital mor-
tality was 25.2% and 23.0% in the treatment and
control groups, respectively. The meta-regression
results with the random-effects analysis suggested no
difference in the in-hospital mortality in the treat-
ment and control groups (OR = 0.76, 95% CI:
0.47–1.22, P = 0.251, I2 = 51.0%).

5
X.-b. Wei, et al.
Fig. 5. Forest plot for the duration of vasopressor usage from three studies including 216 patients (108 in vitamin C treatment group and 108 in control group). The
pooled results showed that vitamin C infusion did not impact the duration of vasopressor use (SMD = −0.873, 95% CI: 2.269 to 0.523, P = 0.220, I2 = 95.2%).
length of hospital stay (SMD = 0.104, 95% CI: 0.300 to 0.507,
P = 0.615, I2 = 80.2%, Fig. 7).
3.5. Vitamin C and AKI
The incidence of AKI was reported in three studies (Ahn et al., 2019;
Litwak et al., 2019; Marik et al., 2017) and the use of renal replacement
therapy for AKI in six studies (Mitchell et al., 2019; Ahn et al., 2019;
Litwak et al., 2019; Shin et al., 2019; Sadaka et al., 2019; Marik et al.,
2017). The meta-regression analysis did not identify any possible re-
lationships between vitamin C use and the incidence of AKI
(OR = 1.12, 95% CI: 0.67–1.89, P = 0.665, I2 = 25.2%, Fig. 8) or the
new use of renal replacement therapy for AKI (OR = 0.87, 95% CI:
0.63–1.20, P = 0.394, I2 = 0%, Fig. 9).
4. Discussion
The present systematic review and meta-analysis of the currently
available published data reassessed the impact of vitamin C on patients
with sepsis. The infusion of vitamin C did not have any beneficial effect
on mortality in patients with sepsis. In addition, the use of vitamin C
6
European Journal of Pharmacology 868 (2020) 172889
did not reduce the length of ICU or hospital stay and the duration of
vasopressor administration. The incidence of AKI and renal replace-
ment therapy for AKI did not increase in patients treated with vitamin
C.
Sepsis is characterized as a systemic inflammatory response to in-
fection (Kaukonen et al., 2015). It is known that oxidative stress is in-
volved in the pathogenesis of organ damage in a septic condition
(Mantzarlis et al., 2017). The increased metabolism in patients with
intense inflammatory response and oxidative stress can deplete serum
and intracellular vitamin C levels (de Grooth et al., 2018; Rodemeister
et al., 2014). A previous study showed that 90% patients with septic
shock had hypovitaminosis C and 40% had vitamin C deficiency (Carr
et al., 2017). A low vitamin C level could reflect excessive oxidative
stress and portend a poor prognosis (Spoelstra-de et al., 2018). Vitamin
C has an antioxidant property and hence its supplementation is a pos-
sible adjunctive therapy for patients with sepsis. In preclinical studies,
parenteral vitamin C infusion could relieve the inflammatory reaction
and oxidative stress, improve immune function, regulate micro-
circulation, and prevent thrombosis (Marik, 2018b). Through these
beneficial effects, vitamin C played a role in attenuating the sepsis-in-
duced organ injury and improve outcomes (Fisher et al., 2012).
Fig. 6. Forest plot for the length of ICU stay from
seven studies including 1513 patients (411 in vi-
tamin C treatment group and 1102 in control group).
The meta-regression analysis did not reveal any sig-
nificant correlation between vitamin C use and the
length of ICU stay (SMD = 0.028, 95% CI: 0.090 to
0.146, P = 0.641, I2 = 0%).
X.-b. Wei, et al.
Fig. 7. Forest plot for the length of hospital stay from four studies including 1375 patients (342 in vitamin C treatment group and 1033 in control group). The pooled
analysis indicated that the use of vitamin C did not have any influence on the length of hospital stay (SMD = 0.104, 95% CI: 0.300 to 0.507, P = 0.615, I2 = 80.2%).
A large number of clinical studies explored the therapeutic effects of
vitamin C in sepsis. The first study was a randomized clinical trial
conducted on 30 patients with septic shock. The results revealed that
the use of vitamin C, together with N-acetylcysteine and vitamin E, had
beneficial effects on hemodynamics, improving the cardiac function
and microcirculation. However, no statistically significant difference
was found in the mortality rate (Galley et al., 1997). The subsequent
studies were confined to a small sample size. A meta-analysis with three
studies (two randomized controlled trials and one retrospective study;
n = 146) was performed, and the pooled analysis indicated a marked
reduction in mortality in patients treated with vitamin C (Li, 2018). A
recent retrospective cohort study with 1144 patients with septic shock
demonstrated that early vitamin C did not improve survival (Shin et al.,
2019). The present meta-analysis did not show any beneficial effect of
vitamin C in patients with sepsis, even severe sepsis/septic shock. The
following aspects could account for the difference from previous meta-
analyses. First, a majority of studies included in the present meta-
analysis were retrospective studies. Although well-balanced baseline
characteristics was found in treatment and control groups, the residual
confounding factors might affect the outcomes in retrospective studies.
Second, the duration of vitamin C infusion varied from each study.
Vitamin C was used from day one to until ICU discharge. We suspected
7
European Journal of Pharmacology 868 (2020) 172889
the different duration of vitamin C use might lead to the inconsistency
between our meta-analysis and previous one. However, this relation-
ship could not be clarified due to data deficiencies. Third, the severity
of illness might play a role. In the subgroup analysis conducted by Shin
et al. (2019), patients with more severe condition (hypoproteinemia or
Sequential Organ Failure Assessment score > 10) could benefit from
vitamin C administration. In addition, results from the Marik et al.
(2017) study seem to differ considerably from those in other retro-
spective studies. This was the only one study which conducted in pa-
tients with severe sepsis or septic shock and a PCT level > 2 ng/mL.
Hence, it is uncertain whether PCT might be useful for identifying pa-
tients who benefited from vitamin C. Finally, the intervention was not
the same in the included studies. Vitamin C was prescribed along with
thiamine and steroids in most retrospective studies, while the treatment
group received only vitamin C infusion in the two randomized con-
trolled trials.
Previous study indicated that 2 g/day dose of vitamin C led to only
normal plasma concentrations, and 10 g/day dose tiggered supra-
normal plasma concentrations, increased oxalate excretion and meta-
bolic alkalosis (de Grooth et al., 2018). A meta-analysis conducted in
critically ill patients showed that the medium dose (3–10 g/day) re-
sulted in lower overall mortality rates (Wang et al., 2019). However, we
Fig. 8. Forest plot of OR and 95% CI for the in-
cidence of AKI from three studies including 263 pa-
tients (129 in vitamin C treatment group and 134 in
control group). The meta-regression analysis did not
identify any possible relationships between vitamin
C use and the incidence of AKI (OR = 1.12, 95% CI:
0.67–1.89, P = 0.665, I2 = 25.2%).
X.-b. Wei, et al.
did not find that the medium dose has beneficial effect on mortality.
The different population played a role in this discordance. In addition,
the recently published negative studies were not included in that meta-
analysis. The dose-dependent effect of vitamin C on sepsis needs further
investigation.
AKI is a frequent complication in patients with sepsis, which was
attributed to increased oxidative damage (Peerapornratana et al., 2019;
Dennis and Witting, 2017). Marik et al. (2017) found that the infusion
of vitamin C, together with corticosteroids and thiamine, reduced the
incidence of AKI. On the contrary, the oxalate as a breakdown product
from vitamin C accumulates in the kidneys, triggering AKI (Colliou
et al., 2017). This inconsistency in findings led to explore the value of
vitamin C in sepsis-associated AKI. The results showed that vitamin C
administration had no effect on AKI. In addition, it did not decrease the
rate of renal replacement therapy for AKI.
Vitamin C is a co-factor in the synthesis of catecholamines. In a
previous meta-analysis conducted by Li (2018), vitamin C infusion
could reduce the duration of vasopressor administration. However, this
result derived from the pooled analysis of only two studies (Marik et al.,
2017; Zabet et al., 2016). Our analysis additionally included one study
and did not find positive results (Litwak et al., 2019). The effect of
vitamin C on the duration of vasopressor use remained unclear because
of limited evidence.
Several limitations should be considered while discussing the find-
ings of this meta-analysis. First, most included studies were retro-
spective studies. The evidence level of retrospective studies was not
high enough. However, the subgroup analysis for randomized con-
trolled trials was also performed in this meta-analysis. Second, the ef-
fect of vitamin C duration on patients with sepsis was not evaluated in
our study because of data deficiencies. Third, the severity of illness and
intervention were not precisely the same in the included studies. This
was the inherent weakness of this meta-analysis. Finally, it is uncertain
whether vitamin C is beneficial for patients with more severe condition
or higher PCT.
In conclusion, including the recently published retrospective studies
in our meta-analysis could not reveal the beneficial effect of vitamin C
on patients with sepsis. It did not reduce the 28-day, ICU, or in-hospital
mortality. Also, it did not shorten the ICU or hospital stay and duration
of vasopressor administration. Vitamin C administration did not in-
crease the risk of AKI. The value of vitamin C in sepsis needs to be
clarified through more high-quality randomized controlled trials in the
future.
8
European Journal of Pharmacology 868 (2020) 172889
Fig. 9. Forest plot of OR and 95% CI for the in-
cidence of renal replacement therapy for AKI from
six studies including 1545 patients (427 in vitamin C
treatment group and 1118 in control group). The
meta-regression analysis did not identify any pos-
sible relationships between vitamin C use and the
new use of renal replacement therapy for AKI
(OR = 0.87, 95% CI: 0.63–1.20, P = 0.394,
I2 = 0%).
Funding
This study was supported by Medical science and Technology
Research Funding of Guangdong (grant no. A2019409), the
Fundamental Research Funds for the Central Universities (grant no.
2019MS136) and National Clinical Key Specialty Construction Project
of China (2012-649, 2013-544). The funders had no role in the study
design, data collection and analysis, decision to publish, or preparation
of the manuscript.
Authors' contributions
Tie-he Qin and Shou-hong Wang conceived and designed the study.
Xiao-long Liao, Wei-xin Guo and Jian-Yi Wen performed abstract
screening and data extraction. Xue-biao Wei and Zhong-hua Wang
analyzed the data and drafted the manuscript. All authors revised and
approved the final manuscript.
Declaration of competing interest
There were no competing interests among authors.
Acknowledgements
None.
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