The Outcome of IV Vitamin C Therapy in Patients with Sepsis or Septic Shock: A Meta-Analysis of Randomized Controlled Trials

DOI: https://doi.org/10.21203/rs.3.rs-2240090/v1

Abstract

Background: To update a meta-analysis of randomized controlled trials (RCTs) and further explore the outcome of IV vitamin C (IVVC) administration in sepsis or septic shock patients.

Methods: This study is a meta-analysis of RCTs. The RCTs of vitamin C therapy in sepsis were searched in PubMed, EMBASE and Clinical Trials.gov since August 16, 2022. We registered the protocol with PROSPERO (CRD42022354875). The primary outcome was mortality included 28-day, 30-day, or in hospital mortality. Two reviewers independently assessed RCTs according to eligibility criteria: 1) Study type: RCT; 2) patient population: patients ≥18 years with sepsis or septic shock; 3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention, or  placebo (defined as control group) ; 4) the RCT described primary outcome. Then, two authors independently extracted related information from RCTs.

Results: Eighteen RCTs (n=2980 patients) were identified in this meta-analysis. Treatment with IVVC was not shown to improve mortality (odds ratio,0.87; 95% CI, 0.75–1.02; p=0.09; I2=44%) regardless of different dose or type of therapy, whereas there was significant effects in duration of vasopressor use (MD, –15.31; 95% CI, –21.92 to –8.69; p<0.00001; I2 =59%) and change in the Sequential Organ Failure Assessment (SOFA) score from baseline to 72–96 hours (MD, –0.64; 95% CI, –1.15 to –0.13; p=0.01; I2=65%), and was relatively safe in sepsis or septic shock patients (OR, 1.22; 95% CI, 0.98–1.51; p=0.08; I2=40%).

Conclusion: In this meta-analysis, IVVC in sepsis or septic shock patients was relatively safe and significantly shorten the duration of vasopressor use and improved the change of SOFA score, whereas it was not associated with reduction in mortality.

Background

Sepsis is a life-threatening organ dysfunction related to a dysregulated host response to infection [1], and septic shock is a type of sepsis with a higher risk of mortality. This disorder contributes to 11 million deaths worldwide every year [2], which is considered as a primary health threat by the World Health Organization [3]. Despite significant advances in sepsis, no other treatment beyond basic therapy, such as source of infection control, fluid resuscitation and vasoactive drugs has sufficient evidence to support to improve mortality [4], and sepsis survivors often suffer from residual organ injury [5]. Consequently, it is very necessary to find effective, safe, and economical adjuvant treatments to reduce mortality and financial burden for sepsis.

Vitamin C is a powerful antioxidant drug and a cofactor in the production of numerous biosynthetic enzymes needed for the survival of shock, which participates in the synthesis of intrinsic vasopressin and norepinephrine [6]. Vitamin C cannot be synthesized by the human, and the levels are low in many critically ill patients. As a readily available, inexpensive, and few side effects of treatment option, vitamin C supplementation during sepsis has specifically gained increasing interest for years. Early studies confirmed IV vitamin C (IVVC) is associated with decreased inflammatory response and ameliorated outcomes in sepsis [7–8]. In addition, favorable outcomes in the vitamin C group was reported in some meta-analysis [9–10]. However, the available evidence remains inconsistent. In another recent meta-analysis, it was reported that IVVC suggested no efficacy in sepsis [11]. 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) [15–17] with a larger population of patients to provide better evidence.

Because of increasing updated researches and inconsistent results in many studies, it is essential to reassess the present evidence about the efficacy and safety of IVVC in sepsis or septic shock patients. The purpose of this meta-analysis of RCTs is to research the impact of IVVC in sepsis patients and carry out subgroup analyses to further explore the efficacy of IVVC with different dose and type of therapy.

Methods

This study performed based on the Preferred Reporting Items for Meta-Analyses (PRISMA) statement [18]. The protocol was prospectively registered in PROSPERO (CRD42022354875).

Study protocol

We chose randomized clinical trials (RCTs) to increase statistical power according to the below criteria: 1) Study type: RCT; 2) patient population: patients ≥ 18 years with sepsis or septic shock; 3) intervention: IVVC at any doses as monotherapy or combined with thiamine or and hydrocortisone compared with standard of care, no intervention, or placebo (defined as control group) ; 4) the RCT described primary outcome. Only English articles were included and conference papers were excluded.

Literature research and data extraction

We comprehensively conducted search of PubMed, EMBASE and Clinical Trials.gov to identify RCTs using subject terms and free terms. The search was last updated on August 16, 2022. Supplemental data for a full list of subject terms and free terms was presented the search strategy (Supplemental eTable 1) .

NoteExpress software was utilized to process articles and remove duplicate articles. Two reviewers independently assessed the titles and abstracts to see if they fulfilled the inclusion criteria. When there were disagreements between them, a third party reviewer was consulted for adjudication to deal with the problems.

The data was retrieved using excel independently by two authors. The relevant information was collected including first author, year of publication, intervention, age, sex, the type of sepsis, SOFA score and so on.

We chose short-term mortality as primary outcome. The short-term mortality was defined as 28- or 30-day mortality, and when unavailable, hospital mortality was eligible. We further extracted the data including different dose (≥ 10g/d and < 10g/d) and type of therapy (monotherapy and combined therapy) for subgroup analyses to investigate the source of heterogeneity in the effect of IVVC on outcomes as they may exert different treatment effect.

The secondary outcomes were change in SOFA score from baseline to 72-96h, duration of vasopressor, vitamin C level and adverse events.

Risk of bias assessment

The Cochrane Risk of Bias tool was used to evaluate the methodological quality of included RCTs to determine the risk of bias independently by two authors [19]. The Cochrane Risk of Bias includes seven areas: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome data, incomplete outcome data, selective reporting and other bias. When there were disagreements, a third author was participated in the discussion.

Statistical analysis

RevMan 5.5 was used for all analyses with the Mantel-Haenszel (M-H) and inverse variance random-effects or fix-effects models for binary and continuous outcomes based on heterogeneity, respectively. Odds ratio (OR) for dichotomous outcomes or mean difference (MD) for continuous outcomes was adopted with 95% confifidence intervals (CIs). The medians and interquartile ranges (IQRs) were transformed to means and standard deviation (SD). We evaluated the existence of statistical heterogeneity through the M-H chi-square test and the inconsistency (I2) statistic. The heterogeneity of I2 is not considered statistically significant if it is not exceed 50%. The heterogeneity has three degrees of low (25%), medium (50%), and high (75%) classified by Guinot et al [20]. Substantial heterogeneity was identified as p < 0.05 or I2 > 50%.

We performed a subgroup analysis focusing on the dose of vitamin C (≥ 10g/d and < 10g/d) and vitamin C therapy regimens (monotherapy and combined therapy) .

Reasons for heterogeneity were planned to explore by conducting sensitivity analyses. To assess publication bias, we conducted funnel plots for outcomes to detect the symmetry of the funnel plots, otherwise, we further used Egger regression test to examine bias. For outcomes with publication bias, we examined the stability using Trim and Fill Analysis and further found out trials with high or unknown risk of bias by Influence Analysis (metaninf). All statistical analyses and assessments of bias risk were conducted by Review RevMan 5.5 and STATA software V12. p < 0.05 was defined as statistical signifificance.

Certainty of evidence assessment

We utilized the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) [21] methodology to evaluate the quality of evidence. The GRADE encompasses methodological limitations, inconsistency, imprecision, indirectness and publication bias to divide quality of evidence as very low, low, moderate, or high from RCTs. The summary of table was generated through the GRADEpro GDT software.

Results

Eligible studies and study characteristics

We initially identified 803 records, and 192 identical duplicate articles were deleted before screening. 582 studies were excluded by screening titles and abstracts. 11 studies were further removed during the assessment of the full text. Ultimately, 18 eligible RCTs [15–17, 22–36] enrolling 2980 patients were included in this meta-analysis. The PRISMA 2020 flowchart of this study is presented in Fig. 1.

A total of 18 RCTs including 8 multicenter RCT studies and 10 single center studies were involved with initial Vitamin C intervention plan, Classification of diseases, initial SOFA score, vasopressors use and mechanical ventilation were evaluated. The main characteristics are given in Supplemental Table S1.

Risk of bias assessment

For random sequence generation, 18 literatures are all low risk of bias; In terms of allocation concealment, 12 articles had low bias risk, and 5 article had unclear bias risk, 1 article had high bias risk; In terms of blinding the subjects and experimenters, 12 literatures are low risk of bias, 2 article had high bias risk and 4 article had unclear bias risk; In terms of blinding the outcome evaluators, 14 literatures are low risk of bias, 2 article had high bias risk and 2 article had unclear bias risk; In terms of incomplete result data, 17 literatures are low risk of bias, 1 article had unclear bias risk; selective reporting of research results, the 18 literatures are all low risk of bias; For other bias, 6 literatures are low risk of bias and 12 article had high bias risk as shown in Fig. 2.

Primary outcomes

Short-term mortality of all included 18 RCTs was presented in Fig. 3. The pooled result indicated that compared with control, IVVC was not associated with a statistically significant reduction in short-term mortality (OR, 0.87; 95% CI, 0.75–1.02; p = 0.09; I2 = 44%).

Subgroup analysis of mortality

≥ 10g/d Versus < 10g/d. Three studies [15, 33, 36] administered ≥ 10g/d IVVC (at a dose of 50 mg/kg every 6 hours), and 15 studies [16, 17, 22–32, 34, 35] administered < 10g/d IVVC (at a dose of 25 mg/kg every 6 hours, 1.5 g every 6 hours). Low dose IVVC administration (< 10g/d) was associated with reduced mortality (OR, 0.79; 95% CI, 0.65–0.97; p = 0.02; I2 = 36%) as shown in Fig. 4, whereas high dose IVVC (≥ 10g/d) did not produce remarkable result (OR, 1.02; 95% CI,0.79–1.32; p = 0.85; I2 = 68%).

IVVC combined therapy versus monotherapy. Ten studies [22–29, 31, 32] analyzed IVVC combined with hydrocortisone and thiamine (combined therapy), among them, one study included only vitamin C and thiamine [26]. Eight studies [15–17, 30, 33–36] tested IVVC alone (monotherapy group). As shown in Fig. 5, there was no prominent effect on mortality in either the combined therapy subgroup (OR, 0.93; 95% CI, 0.74–1.17; p = 0.52; test for heterogeneity I2 = 0%) or monotherapy subgroup (OR, 0.83; 95% CI, 0.66–1.17; p = 0.09; I2 = 67%).

Secondary outcomes

Ten studies reported the vasopressor use duration [16, 17, 23–25, 27, 29, 30, 34, 35], and IVVC demonstrated remarkable shorter vasopressor use duration (MD, − 15.31; 95% CI, − 21.92 to − 8.69; p < 0.00001; I2 = 59%) (Fig. 6). 17 studies described a change of SOFA score [15–17, 22–33, 35, 36], and the use of IVVC was associated with improve change in the SOFA score (MD, − 0.64; 95% CI, − 1.15 to − 0.13; p = 0.01; I2 = 65%) (Fig. 7). Six studies reported IVVC level [16, 26, 31, 33, 35, 36], and the vitamin C level was associated with a significantly increase (MD, 771; 95% CI, 155.47 to 642.43; p = 0.001; I2 = 99%) (Fig. 8). Night studies reported adverse events [15, 17, 22, 25–28, 32, 36] with no significant difference between two groups (OR, 1.22; 95% CI, 0.98–1.51; p = 0.08; I2 = 40%) (Fig. 9). Notably, substantial heterogeneity were observed in the vasopressor use duration (I2 = 59%), SOFA score change (I2 = 65%), and vitamin C level (I = 99%).

Publication bias and sensitivity analysis

A funnel plot was conducted to evaluate for publication bias for short-term mortality, and we detected asymmetry when visually assessing. We also statistically evaluated publication bias through Egger’s test. The result revealed that there was publication bias in the RCTs on mortality (p = 0.007). The meta-analysis result for mortality was robust in further trim and fill analysis. To find out the source of heterogeneity, we used sensitivity analysis for included RCTs and suggested that Lamontagne’s study was the source of heterogeneity (Fig. 10).

Meta-regressions analysis

Meta-regressions analysis was performed to find out the specific influencing factors of heterogeneity. The results of meta-regressions analysis showed that different dose (p = 0.032) and type of therapy (p = 0.018) were significantly affected mortality factors (Fig. 11).

Certainty of the evidence

There was no statistically difference in IVVC administration reduction in short-term mortality, compared with control, however, Low dose IVVC administration (< 10g/d) was associated with significantly reduced mortality compared with high dose IVVC. IVVC treated with hydrocortisone and thiamine indicated no remarkable effect on mortality in the combined therapy subgroup. Compared to control group, treatments containing vitamin C were associated with significant short vasopressor duration requirement and reduction in the change of SOFA scores. The summary of primary outcome and secondary outcomes were presented in Table 1 and Table 2.

Table 1

Summary of results for the primary outcome

Outcomes

Relative Risk (95% CI)

Risk Difference (95% CI)

No. of Studies

(Total Patients)

Certainty

(GRADE)

Vitamin C

Control

Overall Mortality

OR = 0.87(0.75 to 1.02)

284 per 1000

314 per 1000

2980 (18 studies)

moderate

Mortality vitaminC -dose -≥10g/d

OR = 1.03 (0.79 to 1.33)

346 per 1000

339 per 1000

1029(3 studies)

low

Mortality vitaminC-dose -<10g/d

OR = 0.79 (0.65 to 0.97)

253 per 1000

300 per 1000

1951(15 studies)

moderate

Mortality of therapy-Monotherapy

OR = 0.83 (0.66 to 1.03)

317 per 1000

359 per 1000

1402(8 studies)

low

Mortality of therapy-Combined therapy

OR = 0.93 (0.74 to 1.17)

259 per 1000

273 per 1000

1578(10 studies)

moderate

Table 2

Summary of results for secondary outcomes

Outcomes

Number of Studies

Sample Size

Absolute Effect Size (95% CI)

Certainty

(GRADE)

Vitamin C

Control

Change in SOFA score

17

1427

1413

0.64 lower

(1.15 to 0.13 lower)

moderate

Duration of vasopressor use

10

409

409

15.31 lower

(21.92 to 8.69 lower)

moderate

Adverse drug reaction

9

1122

1128

OR 1.22

(0.98 to 1.51)

moderate

Vitamin C concentration

6

230

233

398.95 higher

(155.47 to 642.43 higher)

very low

Discussion

We carried out this meta-analysis of the most recent RCTs to analyze the efficacy of IVVC in sepsis or septic shock patients. Eighteen RCTs with 2980 patients were included in the final analysis. The primary outcome analysis revealed IVVC in patients was not associated with improved mortality. There was no statistically difference between IVVC combination therapy and monotherapy. The primary outcome was contrary to the study of Marik et al [8], which suggested that combined treatment could decrease hospital mortality.

Triple therapy of vitamin C, hydrocortisone and thiamine has biological rationality in sepsis, however, our primary outcome was insignificant in contrast to studies which concluded that coadministration offered acceptable outcomes in sepsis or septic shock patients [8, 23]. On the other hand, several large RCTs of vitamin C in sepsis or septic shock did not produce a remarkable reduction in mortality [15, 22, 28, 32]. Despite the large multicenter trial of VITAMINS, there was a concern about the time of combined therapy initiation [28]. Individual trial of combination treatment had shown a decrease in 28-day mortality in the prespecified subgroup of sepsis patients within 48 hours speculate that administering vitamin C as soon as possible may be meaningful [27]. However, this result has not been replicated. Recent meta-analyses [11, 13, 37–39] also failed to find improved mortality among patients with sepsis, no matter combined therapy or monotherapy. Different inclusion criterion, patient populations and timing of administration explain the heterogeneity of different research results to some extent.

We attempted to determine whether there may be some significant differences between high and low dose of vitamin C by performing a subgroup analysis comparing mortality. Interestingly, our results revealed that low dose (< 10g/d) IVVC, compared with high-dose (≥ 10g/d), was associated with improved mortality, which was contrary to previous meta-analysis that high-dose (≥ 10g/d) IVVC was benefit for mortality. CITRIS-ALI trial revealed that compared with placebo, high-dose vitamin C (50mg/kg every 6 hours) had a lower 28-day mortality in exploratory analysis [33], while the larger scale LOVIT trial did not improve 28-day mortality [15]. In addition, a component network meta-analysis demonstrated high-dose (6g/d) and very-high dose vitamin C (> 12g/d) were associated with decreased mortality but with low certainty [40]. The exact mechanism by which low dose vitamin C works has not been clarified. However, these studies populations of previous meta-analysis included critically ill patients. It is unclear whether higher doses confer greater benefits, although low dose was used in VITAMINS trial [28], the vitamin C level reached almost the same concentration at 6 hours [41] as published in CITRIS-ALI trial [33] of a high dosing regimen at 48 hours.

In spite of mortality, this meta-analysis indicated promising results that IVVC could significantly short duration of vasopressor use and improve the change of SOFA score. Our results were contrary to meta-analysis of Cai et al [11] that vitamin C did not produce obvious effect on duration of vasopressor use, however, the meta-analysis comprised 6 cohort studies. Corticosteroids decrease vasopressor requirements in septic shock [42, 43], and the hemodynamic improvement may be due to corticosteroids [32]. Changes in SOFA score would suggest whether organ function has improved. Vitamin C has numerous effects including antioxidant, immune-supporting, anti-inflammatory and improving vascular endothelial cell function [6, 44]. As is well known that vitamin C is a cofactor in the production of biosynthetic enzymes that can increase vasopressin synthesis [6, 45]. Therefore, the vital role of vitamin C may be the reason that vitamin C therapy could shorten duration of vasopressor use and improve the change in SOFA score. Although there were medium degree of heterogeneity in the pool results of duration of vasopressor use and the change of SOFA score, no publication bias were found in the assessment of Egger’s test.

Hypovitaminosis is generally recognized as vitamin C level below 23 µmol/L [25]. A previous study showed that patients with sepsis need 3g/day of vitamin C to reach normal plasma level [34]. Six researches enrolled in our meta-analysis showed the vitamin C level in intervention group at 32-96h were increased significantly, but did not translate into improved clinical mortality. A previous study suggested that some patients may develop vitamin deficiency within 48 hours after discontinuing vitamin C infusion in spite of the dosing regimen [46], which may result in no improvement in mortality.

Adverse effects of vitamin C were rare. Driny et al believed that vitamin C was safe, tolerable and would not cause patients withdraw from the study [35]. On the basis of this study, Fowler et al. reported that different doses of vitamin C would not lead to any serious adverse events [7]. No studies have shown that IVVC increase adverse events, except that Chang’s study was discontinued due to the high incidence of severe hypernatremia after interim analysis, which was attributed to the adverse effects of hydrocortisone [27]. Our meta-analysis also demonstrated that vitamin C in sepsis is considered relatively safe.

We acknowledge some limitations. First of all, 10 RCTs [16, 23, 24, 27, 29–31, 34–36] were all single center studies with small sample size, which may result in selective bias or introduce small sample effect, so as to obtain a large beneficial therapeutic effect conclusion. Second, RCTs in this meta-analysis used different doses of vitamin C. Most RCTs administered 1.5 g vitamin C every 6 hours or 25 mg/kg every 6 hours, whereas other RCTs administered 50 mg/kg every 6 hours or 200 mg/kg daily. We consider that the difference dose of vitamin C was likely to affect the efficacy of the meta-analysis as our subgroup and meta-regressions analysis indicated that dose was associated with mortality. Third, the duration of vitamin C may have obvious impact on the outcome. Many patients in the intervention group did not administrate the entire duration of IVVC [16, 32], which may reduce benefit of the treatment group to some extent. Moreover, some trials [22, 27, 36] early terminated their RCTs for reasons, which may also be one of the reasons for different outcomes.

Conclusion

To our knowledge, this is the most comprehensive meta-analysis including the newest and largest RCT of Famontagne to update of vitamin C treatment in sepsis or septic shock. In this meta-analysis, regardless of the different doses or combinations of thiamine and hydrocortisone, IVVC treatment did not show improvement in the mortality for patients with sepsis or septic shock, whereas it significantly shorten the duration of vasopressor use and improved the change of SOFA score, and was relatively safe in sepsis or septic shock patients.

Abbreviations

RCTs: Randomized controlled trials; IVVC: IV vitamin C; SOFA: Sequential Organ Failure Assessment; OR: Odds ratio; MD: Mean difference; CIs: Confifidence intervals; IQRs: Interquartile ranges; SD: Standard deviation; GRADE: Grading of Recommendations, Assessment, Development and Evaluations.

Declarations

Acknowledgements

All authors approved the submission of the final article. The authors have disclosed that they do not have any potential conflicts of interest.

Author’s contributions

B.F.L. performed the literature search, supplemented key intellectual content, performed the analysis, and wrote the manuscript. J.W.S performed the literature search, extracted the data independently, performed assessment of bias and certainty of evidence. H.Q.S. provided critical criteria for elemental intellectual features and supplemented key intellectual content. H.Y.C. extracted the data independently and supported the statistical analysis. B.C.X. conceived the study, analyzed the data and corrected the manuscript. All authors read and approved the final manuscript. 

Funding 

This research received no specific grant or funding. 

Availability of data and materials 

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. 

Ethics approval and consent to participate 

Not applicable. 

Consent for publication 

All authors have read and approved the submission of the manuscript. 

Competing interest 

All authors report no competing interests. 

Author details 

1. Department of Hospital Infection Control, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong, China. 2. Department of Clinical Pharmacy, Dongguan Tungwah Hospital, Dongguan, Guangdong, China. 3. Department of Critical Care Medicine, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong, China. 4. Department of Clinical Pharmacy, Affiliated Dongguan Hospital, Southern Medical University, Dongguan, Guangdong, China.

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