Application of Intravenous Vitamin C in Adult Patients with Sepsis: A Meta-Analysis of Randomized Controlled Trials

DOI: https://doi.org/10.21203/rs.3.rs-850576/v1

Abstract

Background: The efficacy of intravenous vitamin C among sepsis patients is uncertain according to recent randomized controlled trials (RCTs). We conducted a meta-analysis to evaluate the efficacy of vitamin C application in adults with sepsis.

Methods: We performed a systematic literature search in PubMed, Web of Science, Embase and the Cochrane Library. Eligible studies were RCTs that investigated the application of intravenous vitamin C in adult patients with sepsis. We assessed the risk of bias of the included studies using the Cochrane risk of bias tool and the certainty of evidence according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach, for each outcome.

Results: Fourteen trials involving a total of 1823 patients were included. We found that there was no significant effect of vitamin C on 28-day mortality [risk ratio (RR) 0.87, 95% confidence interval (CI) 0.73 to 1.04, p = 0.12, TSA-adjusted CI 0.70 to 1.08, low quality evidence], but among patients who were treated with vitamin C monotherapy instead of combination therapy, the mortality was reduced (RR 0.66, 95% CI 0.49 to 0.88, p = 0.004). Vitamin C was associated with a significant improvement of 72-h ΔSOFA score (SMD = 0.20, 95% CI 0.07 to 0.32, p = 0.002, I2=11%, moderate quality evidence).

Conclusions: In this meta-analysis of patients with sepsis, the use of vitamin C was not associated with reduction in 28-day mortality, but vitamin C may have a positive effect in improving organ function. As the certainty of evidence was low, Larger RCTs were needed.

Introduction

Sepsis is a life-threatening organ dysfunction resulting from dysregulated host responses to infection [1], and it is still one of the leading causes of hospital deaths in ICU patients [2]. In the United States, sepsis affects approximately 1.7 million adults each year and causes more than 250 000 deaths [3, 4]. Given the high morbidity and mortality of sepsis, new therapeutic approaches are required to improve outcomes and reduce the global burden but it should be effective, inexpensive and safe [5, 6].

Vitamin C, a free radical scavenger, is an antioxidant compound [7, 8]. It can neutralize the reactive oxygen produced by the large number of inflammatory reactions in sepsis [9]. It can regenerate other oxygen radical scavengers by acting as a donor [10]. Vitamin C also plays an important role in the synthesis of catecholamines and vasopressor, which is of great significance in maintaining adequate systemic perfusion [11]. In the initial stage of sepsis, vasopressor levels increase significantly, but as patients progress to hypotension and shock, vasopressor and vitamin C levels in the plasma gradually decrease [12]. Low plasma concentrations of vitamin C are associated with inflammation, the severity of organ failure, and mortality [13], so supplementation with vitamin C in sepsis patients is theoretically necessary.

In 2016, Marik et al [14] pointed out that early use of vitamin C, corticosteroid and thiamine through a vein may effectively prevent progressive organ dysfunction and reduce the mortality of severe sepsis and septic shock. This seems to have provided a new feasible plan for the clinical treatment of sepsis patients. A large multicenter RCT study by Fowler et al [15] also found a significant improvement in Sequential Organ Failure Assessment (SOFA) score and mortality in the vitamin C group. However, as studies on the application of vitamin C in sepsis patients have become increasingly thorough, this plan becomes controversial. Nabil Habib et al [16] and Ferrón-Celma et al [17] found that vitamin C is not beneficial or even harmful in reducing the mortality of patients with sepsis. In 2020 and 2021, A large number of randomized trials of vitamin C alone or in combination with hydrocortisone and thiamine have been published,but they have had varied design and inconsistent results [1825]. Due to the differences in the administration time, dosage and administration method in different studies, revealing the role of vitamin C in patients with sepsis more objectively and concretely has become particularly important. Considering that previous meta-analyses including complex and diverse critically ill patients and studies that were relatively early, we think it is necessary to systematically review relevant evidence for the role of vitamin C in sepsis patients.

Methods

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses: the PRISMA statement [26] (Table S1). The systematic review protocol was registered with the PROSPERO International prospective register of systematic reviews (registration number CRD42020157573).

Eligibility criteria

The studies included in our meta-analysis should meet the following PICOS criteria:

  1. Population: Adult patients with sepsis
  2. Intervention: Intravenous vitamin C
  3. Comparison: Placebo or conventional treatment
  4. Outcomes:
    1. Primary outcome: 28-day mortality
    2. Secondary outcome: ICU LOS (days), ventilator days, duration of vasopressor use (days), change in SOFA score within 72 h after experimental intervention (72-h ΔSOFA score, SOFA score at enrolment–SOFA score after 72 h).
  5. Study design: Randomized controlled trials (RCTs)


Search strategy

We performed a systematic literature search of PubMed, Web of Science, Embase and Cochrane Library databases for potentially eligible studies from inception to April 1, 2020, then updated to March 1, 2021. We searched for studies that referred to adult sepsis patients treated with vitamin C by using MeSH and free-text terms for various forms of the terms ‘vitamin C’ and ‘sepsis’. The search was restricted to publications in English and human studies, and the electronic search strategy was shown in Table S2. In addition, we manually identified other potentially eligible trials by screening the references of included studies and other relevant systematic reviews.

All the studies we included were independently screened and read by two reviewers. By reading the abstracts and topics, we excluded unrelated literatures, and by reading the full texts, we finally included articles that fully met the requirements. When there was a disagreement about a study, the third reviewer arbitrated discussions until a decision was reached.

Data extraction

Data were collected using an author-created information extraction form. The two reviewers (HC and PC) independently extracted the required content by screening the literature. The data extracted from each trial included the following: study characteristics (first author, country, published year, and study design), baseline data (number of participants, age, sex), the risk of bias data, intervention and control details, outcomes.

Risk of bias

Two independent reviewers (HC and PC) assessed the risk of bias using the Cochrane Collaboration’s tool for assessing the risk of bias in RCTs. Risk of bias was rated according to the following domains: (1) random sequence generation; (2) allocation concealment; (3) blinding of the participants and personnel; (4) blinding of the outcome assessment; (5) incomplete outcome data; (6) selective reporting and (7) other biases. We judged the trials as ‘overall low risk of bias’ if all domains were at low risk, ‘overall high risk of bias’ if any domain was at high risk of bias, and ‘unclear’ if at least one domain was unclear, but no domain was at high risk of bias. We qualitatively evaluated the publication bias by funnel plots, and quantitatively analyzed by the Harbord’s test, which is the modification of Egger’s test [27] (p < 0.05 was regarded as significant evidence of publication bias).

Trial sequential analysis (TSA)

To assess the risk of random errors due to sparse data and multiple testing of accumulating data [2830], we conducted a TSA using Trial Sequential Analysis v.0.9.5.10 beta, which could also estimate required information size (RIS) [31], thereby stopping similar research in time and preventing the waste of medical resources. We performed a two-sided TSA to summarize and analyze the data of the included studies for the primary outcome with a statistical significance level of 5%, a power of 80%, and a relative risk reduction (RRR) of 20%. The control group incidence was calculated by all included trials.

Statistical analysis

We used Review Manager 5.3 software to combine aggregate data. Given the possible clinical heterogeneity, a random-effects model was used to combine data. we calculated the pooled RR and 95% CI for dichotomous outcomes, and standardized mean difference (SMD) with 95% CI for continuous outcomes. Continuous variables in two articles were reported with median and interquartile range (IQR): for one article [15], we recalculated the mean and standard deviation (SD) from the original data in the supplementary materials; for the other [32], we did not get the original data, so we estimated the mean and SD in reference to recently established methods [33, 34]. In terms of statistical heterogeneity, a quantitative analysis was performed using the Mantel-Haenszel (MH) χ² test and the I² test; when p was < 0.05 for the MH χ² test or I² was > 50% for the I² test, there was obvious heterogeneity. Besides, we conducted a sensitivity analysis using STATA version 15.1 to determine whether any single study incurred undue weight in the analysis, and a fixed-effects model was only used.

Subgroup analyses

In order to assess the reliability of the results and explore the impact of different clinically meaningful subgroups on the results, we performed a subgroup analysis for primary outcome based on a pre-defined subgroup: (1) Low risk of bias versus high risk of bias; (2) low dose (< 5 g/d) versus high dose (≥ 5 g/d) [35]; (3) vitamin C monotherapy versus combination therapy.

Assessment of quality of evidence

We assessed the quality of evidence by using the GRADE approach [36], the certainty of evidence was classified into high, moderate, low, or very low for each outcome. Well-conducted RCTs were considered as high-quality evidence but can be downgraded based on the following five domains: risk of bias, inconsistency, indirectness, imprecision and reporting bias.

Results

Study selection

We screened a total of 1921 studies through electronic search and manual search, 47 studies were selected for full-text review after removal of duplicates and reading titles and abstracts. Finally, fourteen studies with 1823 participants were included in the systematic review. The search process and the reasons for excluding the ineligible studies are provided in Fig. 1, The major exclusions were showed in Table S3.

Characteristics of the included studies

The characteristics of the included studies were summarized in Table 1. All the studies were published between 1997 and 2021, with samples ranged from 20 to 501 patients. Vitamin C monotherapy was used in 6 trials [1517, 22, 32, 37] and combination therapy in 8 trials [1821, 2325, 38], six of them were combination of vitamin C, thiamine, and hydrocortisone [18, 19, 21, 2325]. One was combination of vitamin C, vitamin E, NAC [38]. One was combination of vitamin C and thiamine [20]. The dose of vitamin C ranged from 0.45 g/d to 12 g/d (we convert mg/kg/d to g/d based on a typical adult's weight of 60 kg). All the studies included mortality, ten studies [15, 16, 18, 2022, 24, 25, 32, 37] reported ICU LOS, six studies [15, 16, 18, 20, 32, 37] reported ventilator days, and seven studies [16, 18, 21, 22, 24, 32, 37] reported duration of vasopressor use, seven studies [18, 2025] reported 72-h ΔSOFA score.

Table 1

Characteristics of included studies

Study

Country

Design

Population

Age

Experimental

Intervention

VC Dose

(original data)

VC Dose

(g/d)

CON

VC

CON

VC

CON

Chang 2020

China

Single

center

40

40

60 ± 15

64 ± 13

vitamin C

hydrocortisone

thiamine

1.5 g qid for 4 d or until ICU

discharge

6

saline

Ferrón

-Celma 2009

Spain

Single

center

10

10

68 ± 5

65 ± 4

vitamin C

450 mg qd

for 6 d

0.45

Placebo

(5%GS)

Fowler 2014

United

States

Single

center

16

8

60 ± 10

61 ± 4

vitamin C

12.5 or

50 mg/kg qid for

4 d

3 or 12*

Placebo

(5%GS)

Fowler 2019

United

States

multicenter

84

82

53 ± 21

57 ± 20

vitamin C

50 mg/kg qid for

4 d

12*

Placebo

(5%GS)

Fujii

2020

Australia

multicenter

107

104

62 ± 16

62 ± 14

vitamin C

hydrocortisone

thiamine

1.5 g qid

6

hydrocortisone

Galley 1997

United

Kingdom

Single

center

16

14

67 ± 14

70 ± 17

vitamin C

vitamin E

NAC

1,000 mg

qd for 1 d

1

Placebo

(5%GS)

Hwang 2020

Korea

multicenter

53

58

70 (62–76)

69 (62–74)

vitamin C

thiamine

daily dose 6 g

6

Placebo

( 0.9% saline)

Iglesias 2020

United

States

multicenter

68

69

70 ± 12

67 ± 14

vitamin C

hydrocortisone

thiamine

1,500 mg

qid

6

Placebo

( 0.9% saline)

Lv 2020

China

Single

center

61

56

58.7 ± 14.3

60.2 ± 14.1

vitamin C

3.0 g, bid

6

5% dextrose

Moskowitz 2020

United

States

multicenter

101

99

68.9 ± 15.0

67.7 ± 13.9

vitamin C

hydrocortisone

thiamine

1500 mg every 6 hours

6

Placebo

( 0.9% saline)

Nabil Habib 2017

Egypt

Single

center

50

50

43 ± 9

42 ± 10

vitamin C

1,500 mg

qid until ICU discharge

6

conventional sepsis

treatment

Sevransky 2021

United

States

multicenter

252

249

62 (51–69)

61 (50–72)

vitamin C

hydrocortisone

thiamine

1.5g every 6 hours

6

placebo

Wani

2020

Indian

Single

center

50

50

51 ± 36

52 ± 36

vitamin C

hydrocortisone

thiamine

1.5 g qid

6

standard care

Zabet 2016

Iran

Single

center

14

14

64 ± 16

64 ± 14

vitamin C

25 mg/kg

qid for 3 d

6*

Placebo

(5%GS)

NAC = N-acetylcysteine, qd = once a day, qid = four times a day, IV = Intravenous, VC = Vitamin C, CON = Control
* We convert mg/kg/d to g/d based on a typical adult's weight of 60 kg

Risk of bias assessment

Figure S1 and Figure S2 present the risk of bias assessment of the included studies, and the reasons for judgment of each item were shown in Table S4. Five studies [15, 21, 23, 25, 32] were adjudicated as overall low risk of bias, four [17, 20, 22, 38] were ‘unclear’, and five [16, 18, 19, 24, 37] were ‘high’.

Quality of the evidence

As was shown in Table 2, the overall quality of evidence was assessed as very low for mortality, ICU LOS, ventilator days and duration of vasopressor use, and moderate for 72-h ΔSOFA score according to GRADE. Mainly because of high heterogeneity, co-interventions and limited sample size.

Table 2

GRADE evidence profile

Certainty assessment

 

No. of patients

 

Effect

Certainty

No. of studies

Design

Risk of bias

Inconsistency

Indirectness

Imprecision

Other considerations

 

Vitamin C

Control

 

Relative

(95% CI)

Absolute

Mortality

             

14a

Randomised trials

Not serious

Not serious

seriousb

Seriousc

None

 

241/921

(26.2%)

270/902

(29.9%)

 

RR 0.87 (0.73 to 1.04)

39 fewer per 1000 (from 81 fewer to 12 more)

⊕⊕OO

VERY LOW

ICU LOS

             

10d

Randomised trials

Seriouse

Not serious

seriousb

Seriousf

None

 

679

666

 

-

SMD 0.09 lower (0.25 lower to 0.06 higher)

⊕OOO

VERY LOW

Ventilator days

             

6g

Randomised trials

Serioush

Very seriousi

seriousb

Seriousj

None

 

227

218

 

-

SMD 0.29 lower (0.79 lower to 0.22 higher)

⊕OOO

VERY LOW

Duration of vasopressor use

             

7k

Randomised trials

Seriousl

Very seriousm

seriousb

Not Serious

None

 

299

287

 

-

SMD 0.83 lower

(1.28 to 0.38 lower)

⊕OOO

VERY LOW

∆SOFA score

             

7n

Randomised trials

Not Serious

Not serious

seriousb

Not Serious

None

 

615

611

 

-

SMD 0.2 higher

(0.07 to 0.32 higher)

⊕⊕⊕O

MODERATE

CI confidence interval; RR risk ratio; SMD standardised mean difference
a Chang et al. [18], Ferrón-Celma et al. [17], Fowler et al. [32], Fowler et al. [15], Fujii et al. [19], Galley et al. [38], Hwang et al. [20], Iglesias et al. [21], Lv et al. [22], Moskowitz et al. [23], Nabil Habib et al. [16], Sevransky et al. [25], Wani et al. [24], Zabet et al. [37].
b Most of the included trails are co-interventions.
c The total sample size is small, and the 95% CI includes significant benefit and harm (0.73, 1.04).
d Chang et al. [18], Fowler et al. [32], Fowler et al. [15], Iglesias et al. [21], Lv et al. [22], Nabil Habib et al. [16], Sevransky et al. [25], Wani et al. [24], Zabet et al. [37].
e 4/10 trials had overall high risk of bias.
f The total sample size is small, and the 95% CI includes significant benefit and harm (-0.25, 0.06).
g Chang et al. [19], Fowler et al. [18], Fowler et al. [28], Hwang et al. [20], Nabil Habib et al. [17], Zabet et al. [37].
h 3/6 trials had overall high risk of bias.
i I2 = 83%, P < 0.0001. Substantial heterogeneity.
j The total sample size is small, and the 95% CI includes significant benefit and harm (-0.79, 0.22).
k Chang et al. [18], Fowler et al. [32], Iglesias et al. [21], Lv et al. [22], Nabil Habib et al. [16], Wani et al. [24], Zabet et al. [37].
l 4/7 trials had overall high risk of bias.
m I2 = 84%, P < 0.00001. Substantial heterogeneity.
n Chang et al. [18], Hwang et al. [20], Iglesias et al. [21], Lv et al. [22], Moskowitz et al. [23], Sevransky et al. [25], Wani et al. [24].

Primary outcome: 28-day mortality

28-day mortality was reported in 14 studies, two of them reported 30-day mortality,we approximated them to the 28-day mortality. They included a total of 1823 patients. The mortality was not significantly different between the vitamin C group and the control group (RR 0.87, 95% CI 0.73 to 1.04, p = 0.12) (Fig. 2). The contour-enhanced funnel plot supported by Harbord’s test showed no publication bias (p = 0.483) (Figure S3).

TSA

TSA showed that the adjusted CI for mortality was 0.70 to 1.08 (I2 = 30%, D2 = 32%, n = 1823), and the diversity-adjusted RIS was 2530 (Fig. 3). The cumulative Z score didn't cross the traditional boundary or adjusted boundaries for benefit, and the RIS had not been reached (72 %).

Subgroup analyses for mortality

Table 3 showed the subgroup analyses for mortality based on a pre-defined subgroup, and the details were shown in Figures S4-6. The mortality was lower in the vitamin C group than in the control group among patients who were treated with vitamin C monotherapy (RR 0.66, 95% CI 0.49 to 0.88, p = 0.004) (Figure S6), and there was a significant difference between vitamin C monotherapy subgroup and vitamin C combination therapy subgroup (p = 0.01, I2 = 83.9%) (Figure S6).

Table 3 Subgroup analyses for mortality

Subgroups

No. of trials

No. of participants

RR

95% CI

p

I2

Test of subgroup

differences 

p

I2

Risk of bias

Low risk of bias

5

1028

0.85

0.67-1.09

0.20

25%

0.84

0%

High risk of bias

5

517

0.82

0.58-1.14

0.24

31%

 

 

Dose of vitamin C

Low dose (≥ 5 g/d)

3

66

1.12

0.73-1.73

0.61

0%

0.22

32.6%

High dose (< 5 g/d)

12

1765

0.84

0.70-1.00

0.05

23%

 

 

Vitamin C regimen

Monotherapy

6

455

0.66

0.49-0.88

0.004

17%

0.01

83.9%

Combination therapy

8

1368

1.01

0.85-1.20

0.91

0%

 

 

RR risk ratio; CI confidence interval

Secondary outcomes

Seven trials with a total of 586 patients reported on duration of vasopressor use. When pooled, the vitamin C was associated with a reduction in duration of vasopressor use (SMD = -0.83, 95% CI -1.28 to -0.38, p = 0.0003, I2 = 84%) (Figure S7). 72-h ΔSOFA score data was available from 7 studies (1226 patients), When pooled, the vitamin C was associated with an increase in 72-h ΔSOFA score (SMD = 0.20, 95% CI 0.07 to 0.32, p = 0.002, I2 = 11%) (Figure S8). ICU LOS was not significantly associated with vitamin C (SMD = -0.09, 95% CI -0.25 to 0.06, p = 0.24, I2 = 41%) when 10 studies were combined (1345 patients) (Figure S9). Ventilator days was not significantly associated with vitamin C (SMD = -0.29, 95% CI -0.79 to 0.22, p = 0.26, I2 = 83%) when 6 studies were combined (445 patients) (Figure S10).

Sensitivity analyses

We systematically and qualitatively analyzed the sensitivity across the included studies to determine the influence of individual trials on the results. We did not detect a significant impact from any single study in the results of mortality, ICU LOS and 72-h ΔSOFA score (Figures S11-12, Figure S15). In the results of ventilator days and duration of vasopressor use, we found that the trial of Nabil Habib et al may led to the high heterogeneity (Figures S13-14), but deleted the trial did not result in significant deviations from the original overall estimate.

Discussion

Our meta-analysis systematically evaluate whether vitamin C improves the prognosis of adult patients with sepsis in randomized controlled trials. Through an analysis of 1823 patients from the 14 included studies, we found that when vitamin C is used as an adjunct method in patients with sepsis, it may not significantly reduce mortality, but when vitamin C is administered monotherapy instead of combination therapy, it may be beneficial for reducing mortality. In addition, we found a statistically significant reduction in SOFA score during the first 72 hours after enrollment.

Two recent meta-analyses showed that vitamin C does not have a positive therapeutic role in critically ill patients [39, 40], but these meta-analyses included various patients, not sepsis patients only; thus, there may have greater heterogeneity. Last year and this year, two meta-analyses showed that the use of vitamin C did not reduce mortality in sepsis patients[41, 42], but they included many retrospective studies, which may have led to lower evidence quality, and several recently published high-level large RCTs was not included, especially the largest study to date including 501 patients (the VICTAS Randomized Clinical Trial) was not included[25].

In animals, studies have shown that when animals are stressed, the synthesis of endogenous vitamin C increases [43, 44], as it does in mice exposed to tumors [45]. Other studies have shown that the synthesis of vitamin C is eight times greater than it is in animals exposed to drugs [46, 47]. It can be seen that when animals are affected by diseases and drugs, the demand for vitamin C increases significantly. This is especially obvious for humans who cannot synthesize vitamin C themselves. Long et al confirmed that the levels of vitamin C are very low in plasma after trauma and infection [48]. In patients with sepsis, as the disease worsens, an excessive inflammatory response increases the metabolism of vitamin C, and vitamin C levels gradually decline [12, 49]. Carr et al found that 88% of septic shock patients had hypovitaminosis C, and 38% were deficient in vitamin C [50]. Therefore, vitamin C supplementation is particularly important for patients with sepsis.

The amount of vitamin C that sepsis patients need to be supplemented with is still inconclusive, ranging from 0.45 g/d to 12 g/d. Under normal physiological conditions, 100–300 mg of vitamin C per day can meet daily needs [51]. However, critically ill patients may need more, and studies have shown that critically ill patients need more than 3 g daily doses to restore normal vitamin C levels [48]. We tried to explore whether the dose of vitamin C affects mortality, but we found that there was no significant difference between the high-dose vitamin C subgroup (≥ 5 g/d) and the low-dose vitamin C subgroup (< 5 g/d). In recent years, Wang et al found that medium doses (3–10 g/d) of vitamin C were associated with decreased mortality in critically ill patients, with neither low doses (< 3 g/d) nor high doses (≥ 10 g/d) having a significant impact [39]. According to the grouping method of Wang et al, we found that high doses can significantly reduce mortality in patients with sepsis, while medium or low doses cannot (Figure S16). However, what is worth to notice is that both studies in the high-dose group used vitamin C monotherapy, this may be a confounding factor.

Recently, cocktail therapy combining vitamin C, thiamine, and corticosteroids has become a hot topic among new therapies for sepsis. Since vitamin C, thiamine, and corticosteroids have the same cellular signaling pathways and metabolic cascades [52], this cocktail therapy is theoretically justified. Since the treatment was proposed by Marik et al in 2016, the combination therapy of vitamin C, thiamine, and corticosteroids in patients with sepsis has received increasing attention. They found that the early use of intravenous vitamin C, together with corticosteroids and thiamine, is effective in preventing progressive organ dysfunction and in reducing the mortality of patients with severe sepsis and septic shock [14]. However, a recent retrospective observational cohort study suggests that incorporating vitamin C, hydrocortisone, and thiamine into standard practice may not improve patient outcomes [53], what is worth to notice is that non-sequential patients were included in the vitamin C group in this study resulting in a severe selection bias which may limit the interpretation. Since these two studies are observational studies, we did not include them in our meta-analysis. Excitingly, several large RCT studies on this cocktail therapy have been published recently, providing new evidence for our meta-analysis. Fujii et al found that the combination of vitamin C, thiamine, and hydrocortisone did not reduce mortality or vasopressor time in a study of 216 sepsis patients [19]. Recent years, Iglesias et al [21], Chang et al [18], Moskowitz et al[23] and Sevransky et al[25] used similar methods and found no significant change in mortality or SOFA score.

Through subgroup analysis, we found that the combined results of six studies using vitamin C monotherapy showed a significant reduction in mortality in patients with sepsis, while the combined results of the other eight studies using vitamin C combined with other drugs, including thiamine and hydrocortisone, mainly showed no significant effect on mortality. We speculate that patients with sepsis using vitamin C monotherapy instead of combination therapy may play a more active role.

It should be noted that our research still has many limitations. First, the included study included a 25-year time span during which significant changes in the recognition and management of sepsis may have had different effects on the trial populations. Second, many studies mentioned that the initial time of vitamin C application in patients with sepsis may have a significant impact on the results, such as mortality. We tried to perform subgroup analysis according to the initial time of medication; unfortunately, it was difficult for us to extract this part of the data. Third, since the vitamin C regimen and control regimen in each study are not the same, it will lead to greater clinical heterogeneity. Fourth, some of the included studies were co-intervention (vitamin E, NAC, etc), it will weaken the relative contribution of vitamin C. Fifth, some secondary results (duration of vasopressor use and 72-h ΔSOFA score) were not reported in the protocol, they were exploratory outcomes and may led to several bias. Sixth, although we performed a comprehensive database search and a manual search and made a funnel plot, which had symmetry, we did not search the gray literature or contact authors to confirm whether there were any unpublished studies. Therefore, we still cannot rule out the existence of publication bias. Additionally, TSA shows that the sample size did not reach the RIS, so the sample size was not enough to draw firm conclusions about the clinical efficacy of vitamin C, and more large multicenter RCTs are needed.

Conclusions

In this meta-analysis of patients with sepsis, the use of vitamin C was not associated with reduction in 28-day mortality, but vitamin C may have a positive effect in improving organ function. As the certainty of evidence was low, Larger RCTs were needed.

Abbreviations

CI: Confidence interval; GRADE: The Grading of Recommendations, Assessment, Development, and Evaluation; ICU: Intensive care unit; LOS: Length of stay; RCTs: Randomized controlled trials; RIS: required information size; RR: Risk ratio; SOFA: Sequential Organ Failure Assessment; SMD: standardized mean difference; TSA: Trial sequential analysis

Declarations

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The datasets generated and analysed during the current study are available from the corresponding author upon a reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

None

Authors’ contributions

HC and PC conceived and designed the research questions, searched the scientific literature, collected the data, assessed quality of the studies. HC drafted the manuscript. PC played an important role in drafting the key questions. HC and KL performed statistical analyses. KL and JS contributed to the data interpretation and differences resolution. JS participated in the design, helped to revise the manuscript and provided technical or material support. All authors have read and approved the final manuscript, and agreed to be accountable for all aspects of the article in ensuring that questions related to the accuracy or integrity of any part of the article were appropriately investigated and resolved.

Acknowledgements

Not applicable.

Authors' information

Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.

2 The medical team of a troop of the Second Mobile Corps, Chinese People's Armed Police Forces, Fuzhou, Fujian 350200, China.

Department of Critical Care Medicine, Northern Jiangsu People’s Hospital; Clinical Medical College, Yangzhou University, No.98 Nantong West Road, Yangzhou, Jiangsu 225001, China.

References

  1. Singer M, Deutschman CS, Seymour CW et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016; 315 (8):801-810.
  2. Fleischmann C, Scherag A, Adhikari NKJ et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016; 193 (3):259-272.
  3. Rhee C, Jones TM, Hamad Y et al. Prevalence, Underlying Causes, and Preventability of Sepsis-Associated Mortality in US Acute Care Hospitals. JAMA Netw Open. 2019; 2 (2):e187571.
  4. Rhee C, Dantes R, Epstein L et al. Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014. JAMA. 2017; 318 (13):1241-1249.
  5. De Backer D, Cecconi M, Lipman J et al. Challenges in the management of septic shock: a narrative review. Intensive Care Med. 2019; 45 (4):420-433.
  6. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014; 311 (13):1308-1316.
  7. Pisoschi AM, Pop A. The role of antioxidants in the chemistry of oxidative stress: A review. Eur J Med Chem. 2015; 97:55-74.
  8. Rizzo AM, Berselli P, Zava S et al. Endogenous antioxidants and radical scavengers. Adv Exp Med Biol. 2010; 698:52-67.
  9. Li J. Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Critical care (London, England). 2018; 22 (1):258.
  10. Metnitz PG, Bartens C, Fischer M et al. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med. 1999; 25 (2):180-185.
  11. Carr AC, Shaw GM, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis: a rationale for vitamin C administration in severe sepsis and septic shock? Critical care (London, England). 2015; 19:418.
  12. Sharshar T, Carlier R, Blanchard A et al. Depletion of neurohypophyseal content of vasopressin in septic shock. Crit Care Med. 2002; 30 (3):497-500.
  13. de Grooth HJS, Spoelstra-de Man AME, Oudemans-van Straaten HM. EARLY PLASMA VITAMIN C CONCENTRATION, ORGAN DYSFUNCTION AND ICU MORTALITY. Intensive Care Med. 2014; 40:S199-S199.
  14. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017; 151 (6):1229-1238.
  15. Fowler AA, Truwit JD, Hite RD et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019; 322 (13):1261-1270.
  16. Nabil Habib T, Ahmed I. Early Adjuvant Intravenous Vitamin C Treatment in Septic Shock may Resolve the Vasopressor Dependence. International Journal of Microbiology & Advanced Immunology. 2017; 5:77–81.
  17. Ferrón-Celma I, Mansilla A, Hassan L et al. Effect of vitamin C administration on neutrophil apoptosis in septic patients after abdominal surgery. The Journal of surgical research. 2009; 153 (2):224-230.
  18. Chang P, Liao Y, Guan J et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock (HYVCTTSSS): A randomized controlled clinical trial. Chest. 2020.
  19. Fujii T, Luethi N, Young PJ et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial. JAMA. 2020.
  20. Hwang SY, Ryoo SM, Park JE et al. Combination therapy of vitamin C and thiamine for septic shock: a multi-centre, double-blinded randomized, controlled study. Intensive Care Med. 2020:1-11.
  21. Iglesias J, Vassallo AV, Patel VV et al. Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis. Chest. 2020.
  22. Lv SJ, Zhang GH, Xia JM, Yu H, Zhao F. Early use of high-dose vitamin C is beneficial in treatment of sepsis. Ir J Med Sci. 2020.
  23. Moskowitz A, Huang DT, Hou PC et al. Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ Injury in Septic Shock: The ACTS Randomized Clinical Trial. JAMA. 2020; 324 (7):642-650.
  24. Wani SJ, Mufti SA, Jan RA et al. Combination of vitamin C, thiamine and hydrocortisone added to standard treatment in the management of sepsis: results from an open label randomised controlled clinical trial and a review of the literature. Infect Dis (Lond). 2020; 52 (4):271-278.
  25. Sevransky JE, Rothman RE, Hager DN et al. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021; 325 (8):742-750.
  26. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339:b2535.
  27. Harbord RM, Egger M, Sterne JAC. A modified test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006; 25 (20):3443-3457.
  28. Brok J, Thorlund K, Gluud C, Wetterslev J. Trial sequential analysis reveals insufficient information size and potentially false positive results in many meta-analyses. J Clin Epidemiol. 2008; 61 (8):763-769.
  29. Brok J, Thorlund K, Wetterslev J, Gluud C. Apparently conclusive meta-analyses may be inconclusive--Trial sequential analysis adjustment of random error risk due to repetitive testing of accumulating data in apparently conclusive neonatal meta-analyses. Int J Epidemiol. 2009; 38 (1):287-298.
  30. Imberger G, Gluud C, Boylan J, Wetterslev J. Systematic Reviews of Anesthesiologic Interventions Reported as Statistically Significant: Problems with Power, Precision, and Type 1 Error Protection. Anesth Analg. 2015; 121 (6):1611-1622.
  31. Wetterslev J, Thorlund K, Brok J, Gluud C. Estimating required information size by quantifying diversity in random-effects model meta-analyses. BMC Med Res Methodol. 2009; 9:86.
  32. Fowler AA, Syed AA, Knowlson S et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014; 12:32.
  33. Hozo SP, Djulbegovic B, Hozo I. Estimating the mean and variance from the median, range, and the size of a sample. BMC Med Res Methodol. 2005; 5:13.
  34. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014; 14:135.
  35. Putzu A, Daems A-M, Lopez-Delgado JC, Giordano VF, Landoni G. The Effect of Vitamin C on Clinical Outcome in Critically Ill Patients: A Systematic Review With Meta-Analysis of Randomized Controlled Trials. Crit Care Med. 2019; 47 (6):774-783.
  36. Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336 (7650):924-926.
  37. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract. 2016; 5 (2).
  38. Galley HF, Howdle PD, Walker BE, Webster NR. The effects of intravenous antioxidants in patients with septic shock. Free Radic Biol Med. 1997; 23 (5):768-774.
  39. Wang Y, Lin H, Lin B-W, Lin J-D. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Annals of intensive care. 2019; 9 (1):58.
  40. Zhang M, Jativa DF. Vitamin C supplementation in the critically ill: A systematic review and meta-analysis. SAGE open medicine. 2018; 6:2050312118807615.
  41. Scholz SS, Borgstedt R, Ebeling N et al. Mortality in septic patients treated with vitamin C: a systematic meta-analysis. Crit Care. 2021; 25 (1):17.
  42. Wei X-B, Wang Z-H, Liao X-L et al. Efficacy of vitamin C in patients with sepsis: An updated meta-analysis. Eur J Pharmacol. 2020; 868:172889.
  43. Lahiri S, Lloyd BB. The effect of stress and corticotrophin on the concentrations of vitamin C in blood and tissues of the rat. The Biochemical journal. 1962; 84:478-483.
  44. Nakano K, Suzuki S. Stress-induced change in tissue levels of ascorbic acid and histamine in rats. The Journal of nutrition. 1984; 114 (9):1602-1608.
  45. Campbell EJ, Vissers MCM, Bozonet S et al. Restoring physiological levels of ascorbate slows tumor growth and moderates HIF-1 pathway activity in Gulo(-/-) mice. Cancer Med. 2015; 4 (2):303-314.
  46. Burns JJ, Mosbach EH, Schulenberg S. Ascorbic acid synthesis in normal and drug-treated rats, studied with L-ascorbic-1-C14 acid. The Journal of biological chemistry. 1954; 207 (2):679-687.
  47. Conney AH, Bray GA, Evans C, Burns JJ. Metabolic interactions between L-ascorbic acid and drugs. Ann N Y Acad Sci. 1961; 92:115-127.
  48. Long CL, Maull KI, Krishnan RS et al. Ascorbic acid dynamics in the seriously ill and injured. The Journal of surgical research. 2003; 109 (2):144-148.
  49. Borrelli E, Roux-Lombard P, Grau GE et al. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk. Crit Care Med. 1996; 24 (3):392-397.
  50. Carr AC, Rosengrave PC, Bayer S et al. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Critical care (London, England). 2017; 21 (1):300.
  51. Levine M, Padayatty SJ, Espey MG. Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr. 2011; 2 (2):78-88.
  52. Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT Therapy) for the Treatment of Sepsis. Focus on Ascorbic Acid. Nutrients. 2018; 10 (11).
  53. Litwak JJ, Cho N, Nguyen HB, Moussavi K, Bushell T. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application. J Clin Med. 2019; 8 (4).