Abstract
Given the available clinical evidence through the literature search when the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 was being created, we suggested administering vitamin C to such patients. Recently, several randomized control trials have been published, some of which suggested the harmful effect of vitamin C in terms of mortality or persistent organ dysfunction. Therefore, we performed updated systematic reviews and meta-analyses. Accordingly, we revised our recommendation as “We suggest against administering vitamin C to septic patients (GRADE 2D: certainty of evidence = “very low”).”
Supplementary Information
The online version contains supplementary material available at 10.1186/s40560-022-00641-4.
Keywords: Sepsis, Septic shock, Clinical practice guideline, Vitamin C
To the editor,
Given the available clinical evidence through the literature search when the Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG2020) was being created, J-SSCG2020 [1, 2] suggested administering vitamin C to septic patients based on the 11 available randomized control trials (RCT) [3–13].
Recently, Lamontagne et al. conducted a large multi-center RCT, including 872 septic patients, who required vasopressors, to evaluate the effect of high-dose vitamin C [14]. This RCT revealed that the proportion of a composite of death or persistent organ dysfunction at 28 days in the vitamin C group was significantly higher than that in the placebo group. Additionally, several RCTs were published after our meta-analysis on this issue for J-SSCG2020. Therefore, we performed an updated systematic review on 20th June 2022. We identified 12 new RCTs [14–25] and performed an updated meta-analysis using these 23 RCTs (Table 1 and Additional file 1).
Table 1.
Evidence profile
| Certainty assessment | No. of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| No. of studies | Study design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Vitamin C | Placebo | Relative (95% CI) | Absolute (95% CI) | ||
| Long term mortality (more than 60 days) | ||||||||||||
| 6 | Randomized trials | Seriousa | Not serious | Not serious | Not serious | None | 607/1440 (42.2%) | 545/1441 (37.8%) | RR 1.11 (1.02 to 1.22) | 42 more per 1000 (from 8 to 83 more) |
⨁⨁⨁◯ Moderate |
Critical |
| 28 or 30 days mortality | ||||||||||||
| 15 | Randomized trials | Very seriousb | Seriousc | Not serious | Not serious | None | 573/1940 (29.5%) | 584/1916 (30.5%) | RR 0.89 (0.77–1.04) | 34 fewer per 1000 (from 70 fewer to 12 more) |
⨁◯◯◯ Very low |
CRITICAL |
| In-hospital mortality | ||||||||||||
| 12 | Randomized trials | Very seriousb | Seriousd | Not serious | Not serious | None | 383/1194 (32.1%) | 382/1150 (33.2%) | RR 0.94 (0.76 to 1.16) | 20 fewer per 1000 (from 80 fewer to 53 more) |
⨁◯◯◯ Very low |
Critical |
| Length of ICU stay (days) | ||||||||||||
| 16 | Randomized trials | Very seriousb | Very seriouse | Not serious | Not serious | None | 1785 | 1749 | – | MD 0.25 lower (0.72 lower to 0.22 higher) |
⨁◯◯◯ Very low |
Critical |
| Length of hospital stay (days) | ||||||||||||
| 12 | Randomized trials | Very seriousb | Very seriousf | Not serious | Not serious | None | 1722 | 1685 | – | MD 0.24 higher (0.97 lower to 1.45 higher) |
⨁◯◯◯ Very low |
Critical |
| Acute kidney injury | ||||||||||||
| 9 | Randomized trials | Very seriousb | Not serious | Not serious | Not serious | None | 338/1113 (30.4%) | 324/1117 (29.0%) | RR 1.02 (0.93–1.13) | 6 more per 1000 (from 20 fewer to 38 more) |
⨁⨁◯◯ Low |
Critical |
CI confidence interval, MD mean difference, RR risk ratio
aOne study with a high risk of bias was included
bTwo or more studies with high risk of bias were included
cThe I2 value was 39%
dThe I2 value was 50%
eThe I2 value was 68%. We thought that this value is quite large
fThe I2 value was 70%. We thought that this value is quite large
In our updated meta-analysis, the estimated value of the desirable anticipated effect was as follows: the length of ICU stay yielded a mean difference (MD) of 0.25 days shorter (95% confidence interval (CI): 0.72 days shorter–0.22 days longer) (16 RCTs, n = 3534). Thereby, the desirable anticipated effect was thought to be “trivial”. The estimated values of the effects on mortality were as follows: long-term mortality, namely more than 60 days, yielded a risk difference (RD) of 42 more per 1000 (95% CI: 8 more–83 more) (6 RCTs, n = 2881), 28 or 30 days mortality yielded an RD of 34 fewer per 1000 (95% CI: 70 fewer–12 more) (15 RCTs, n = 3856), in-hospital mortality yielded an RD of 20 fewer per 1000 (95% CI: 80 fewer–53 more) (12 RCTs, n = 2344). Of these three mortalities, long-term mortality was chosen as the effect on mortality since we predetermined that the highest certainty of evidence was adopted. Subsequently, the estimated values of the other undesirable anticipated effects were as follows: the length of hospital stay yielded an MD of 0.24 days longer (95% CI: 0.97 days shorter–1.45 days longer) (12 RCTs, n = 3407), and acute kidney injury yielded an RD of 6 more per 1000 (95% CI: 20 fewer–38 more) (9 RCTs, n = 2230). Thereby, the undesirable anticipated effects were “moderate”. Thus, we presumed that administering vitamin C was inferior to the placebo or control. Judgment of values, acceptability, and feasibility were not changed, namely, “probably no important uncertainty or variability”, “probably yes”, and “probably yes”, respectively.
Accordingly, we revised our recommendation to “We suggest against administering vitamin C to septic patients (GRADE 2D: certainty of evidence = “very low”).”
Supplementary Information
Additional file 1. PRISMA flow diagram, risk of bias summary, Forrest plot, funnel plot, and evidence to decision table.
Abbreviations
- J-SSCG2020
The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020
- RCT
Randomized control trial
- MD
Mean difference
- CI
Confidence interval
- RD
Risk difference
Author contributions
All guideline committee members read and approved the final manuscript.
Funding
These guidelines were prepared with financial support from the Japan Society of Intensive Care Medicine and the Japanese Association for Acute Medicine. No member of the Guideline Creation Committee received any form of financial compensation during the preparation of these guidelines. The views and interests of these societies were not reflected in the preparation of the guidelines’ recommendations.
Availability of data and materials
All data generated or analyzed during this study are included in this published article and its additional information files.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
All financial and non-financial competing interests were declared in the J-SSCG2020 [1, 2].
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Japanese Society of Intensive Care Medicine, Email: moriori@tg8.so-net.ne.jp.
Japanese Association for Acute Medicine, Email: ogura@hp-emerg.med.osaka-u.ac.jp.
Japanese Society of Intensive Care Medicine:
Japanese Association for Acute Medicine:
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Additional file 1. PRISMA flow diagram, risk of bias summary, Forrest plot, funnel plot, and evidence to decision table.
Data Availability Statement
All data generated or analyzed during this study are included in this published article and its additional information files.