UMIN-CTR Clinical Trial

Public title

The effect of high-dose vitamin C in patients with sepsis: A systematic review and meta-analysis of randomized controlled trials

Acronym

The effect of high-dose vitamin C in patients with sepsis

Scientific Title

The effect of high-dose vitamin C in patients with sepsis: A systematic review and meta-analysis of randomized controlled trials

Scientific Title:Acronym

The effect of high-dose vitamin C in patients with sepsis

Region

Japan

North America

Condition

Sepsis

Classification by specialty

Intensive care medicine

Classification by malignancy

Others

Genomic information

NO

Narrative objectives1

Sepsis is a dysregulated inflammatory response to an infection and remains a significant public health burden over the world.
Vitamin C has been focused due to its anti-inflammatory and antioxidant properties. A previous randomized controlled trial suggested high-dose vitamin C, compared to low-dose vitamin C and placebo, improved Sequential Organ failure Assessment (SOFA) score in patients with sepsis [J Tlans Med 2014:12(1):32].
Recently, more attention has been paid to vitamin C or the combination therapy of Hydrocortisone, vitamin C (Ascorbic acid) and Thiamin (HAT therapy) as a potential adjunct therapy for sepsis. Marik et al reported significant improvement of survival in septic patients who received HAT therapy in 2017 [CHEST 2017;151(6):1229-1238]. Since this study was a relatively small retrospective before-and-after study, several randomized controlled trials have been conducted to verify this result. However, sample sizes of these randomized trials were not large enough to conclude its effect on the mortality in patients with sepsis. Side effects of high-dose vitamin C were previously reported though it is rare [Clin Nephrol 2017;88:354-358]. Therefore, there is a need to summarize the currently available evidence regarding the use of vitamin C in patients with sepsis. We aimed to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to investigate the effect of vitamin C therapy on mortality in patients with sepsis.

Basic objectives2

Safety,Efficacy

Basic objectives -Others

Trial characteristics_1

Confirmatory

Trial characteristics_2

Others

Developmental phase

Not applicable

Primary outcomes

Short term mortality including 28-day mortality, 30-day mortality, or in-hospital mortality

Key secondary outcomes

ICU length of stay
Hospital length of stay
Duration of vasopressors
Delta SOFA at 72-96 hours
Ventilator-free days
Adverse events
Sub-group analysis based on mean/median control SOFA score.
Sub-group analysis based on HAT therapy vs. non-HAT therapy.

Study type

Others,meta-analysis etc

Basic design

Randomization

Randomization unit

Blinding

Control

Stratification

Dynamic allocation

Institution consideration

Blocking

Concealment

No. of arms

Purpose of intervention

Type of intervention

Interventions/Control_1

Interventions/Control_2

Interventions/Control_3

Interventions/Control_4

Interventions/Control_5

Interventions/Control_6

Interventions/Control_7

Interventions/Control_8

Interventions/Control_9

Interventions/Control_10

Age-lower limit

18

years-old

<=

Age-upper limit

Not applicable

Gender

Male and Female

Key inclusion criteria

We included trials with the following characteristics:
1. Study type: RCT.
2. Patient population: Patients aged above or equal to 18 years with sepsis based on any one of Sepsis-1, Sepsis-2, or Sepsis-3 definitions.
3. Intervention: Intravenous high-dose vitamin C (greater than or equal to 1.5g every 6 hours or 25mg/kg every 6 hours)
4. Control: Placebo or no intervention.

Key exclusion criteria

We excluded articles that included patients <18 years, published in non-English and are conference proceedings.

Target sample size

Name of lead principal investigator

1st name	Ryota
Middle name
Last name	Sato

Organization

Cleveland Clinic

Division name

Critical Care Medicine

Zip code

44195

Address

9500 Euclid Avenue, Cleveland, OH, USA

TEL

1-216-296-8700

Email

st051035@gmail.com

Name of contact person

1st name	Ryota
Middle name
Last name	Sato

Organization

Cleveland Clinic

Division name

Critical Care Medicine

Zip code

44195

Address

9500 Euclid Avenue, Cleveland, OH, USA

TEL

1-216-296-8700

Homepage URL

Email

st051035@gmail.com

Institute

Cleveland Clinic.

Institute

Department

Personal name

Organization

None

Organization

Division

Category of Funding Organization

Other

Nationality of Funding Organization

Co-sponsor

Name of secondary funder(s)

Organization

This research is a systematic review and meta-analysis. Therefore this does no require IRB approval.

Address

N/A

Tel

1-216-296-8700

Email

sator2@ccf.org

Secondary IDs

NO

Study ID_1

Org. issuing International ID_1

Study ID_2

Org. issuing International ID_2

IND to MHLW

Institutions

Date of disclosure of the study information

2020

Year

05

Month

26

Day

URL releasing protocol

https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&recptno=R000046172&t

Publication of results

Published

URL related to results and publications

https://journals.lww.com/ccmjournal/Abstract/2021/12000/Effect_of_IV_High_Dose_Vitamin_C_on_Mortalit

Number of participants that the trial has enrolled

1737

Results

Eleven randomized controlled trials (n = 1,737 patients) were included in this meta-analysis. High-dose IV vitamin C was not associated with a significantly lower short-term mortality (RR, 0.88; 95% CI, 0.73-1.06; p = 0.18; I2 = 29%) but was associated with a significantly shorter duration of vasopressor use (SMD, -0.35; 95% CI, -0.63 to -0.07; p < 0.01; I2 = 80%) and a significantly greater decline in the SOFA score at 72-96 hours (SMD, -0.20; 95% CI, -0.32 to -0.08; p < 0.01; I2 = 16%).

Results date posted

2022

Year

03

Month

13

Day

Results Delayed

Results Delay Reason

Date of the first journal publication of results

2021

Year

12

Month

01

Day

Baseline Characteristics

The reported mean/median age of participants ranged from 54 to 70 years in the vitamin C group and 56 to 69 years in the control group. Furthermore, 47.1 to71.4 percent of participants in the vitamin C group and 39.1 to 78.6 percent of participants in the control group were males. The SOFA score ranged from 8.0 to 11.8 and 7.9 to 12.4 in the vitamin C and control groups, respectively. The median control SOFA score was 9.2, IQR, 8.4 to10.3.

Participant flow

Our systematic search identified 902 articles. After the removal of duplicates, 710 articles were screened. After screening the titles and abstracts, we reviewed 59 articles in detail. Among the remaining 59 articles, 33 were protocol articles, six were different designs, three were conference proceedings, three examined low-dose vitamin C, two examined enteral vitamin C, and one did not provide mortality or any secondary outcomes; all of these were subsequently excluded. Two studies did not provide the number of patients who survived or died, and we were unable to calculate these numbers from provided mortality rates. A total of 11 RCTs enrolling 1,737 patients were included in the final meta-analysis.

Adverse events

HAT therapy was significantly associated with hypernatremia in one study.

Outcome measures

The primary outcome was short-term mortality, which was defined as 28-day mortality, 30 day mortality, or in-hospital mortality, depending on the availability of the data. The secondary outcomes were short-term mortality based on the severity of sepsis, the type of intervention, vasopressor duration, ventilator-free days, ICU length of stay, hospital LOS, delta SOFA score at 72 to 96 hours, and adverse events.

Plan to share IPD

IPD sharing Plan description

Recruitment status

Completed

Date of protocol fixation

2020

Year

05

Month

21

Day

Date of IRB

2020

Year

05

Month

21

Day

Anticipated trial start date

2020

Year

05

Month

21

Day

Last follow-up date

2021

Year

02

Month

25

Day

Date of closure to data entry

Date trial data considered complete

Date analysis concluded

Other related information

A comprehensive search of three major databases of biomedical publications will be performed on 20 April 2020: MEDLINE (source: PubMed, 1966 to April 2020), Cochrane Central Register of Controlled Trials (through April 2020), Embase (1974 to April 2020) with the following keywords in each query: vitamin c, ascorbic acid, antioxidant, sepsis, systemic inflammatory response syndrome, and Multiple Organ Failure. The search terms used were: (ascorbic[tiab] OR ascorbate[tiab] OR vitamin c[tiab] OR ascorbic acid[mesh] OR antioxidant*[tiab]) AND (Sepsis[mesh] OR Sepsis[tiab] OR Systemic inflammatory response syndrome[mesh] OR Systemic inflammatory response syndrome[tiab] OR SIRS[tiab] OR Multiple Organ Failure[mesh] OR Multiple Organ Failure[tiab] OR MOF[tiab]) AND (randomized controlled trial[tiab] OR controlled clinical trial[tiab] OR randomized controlled trials[tiab] OR blind*[tiab] OR clinical trial[tiab] OR clinical trials[tiab] OR placebo*[tiab] OR random*[tiab]).
Two independent reviewers will screen the abstracts and titles of the studies and subsequently review the full-text articles for inclusion on the Rayyan.
Independent reviewers will assess the risk of bias in each trial as the methodological quality of the articles. Disagreements will be resolved by discussion, consensus and the participation of a third author, when necessary.

Registered date

2020

Year

05

Month

26

Day

Last modified on

2022

Year

03

Month

13

Day

Link to view the page

Value
https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000046172