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 creating, J‐SSCG2020 1 , 2 suggested administering vitamin C to septic patients based on the 11 available randomized control trials (RCT). 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13
Recently, Lamontagne et al. 14 conducted a large multi‐center RCT, including 872 septic patients, who required vasopressors, to evaluate the effect of high‐dose vitamin C. 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 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 and performed an updated meta‐analysis using these 23 RCTs (Table 1 and Appendix S1).
Table 1.
Evidence profile
| Certainty assessment | № of patients | Effect | Certainty | Importance | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| № 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 | Serious † | Not serious | Not serious | Not serious | None | 607/1,440 (42.2%) | 545/1,441 (37.8%) | RR 1.11 (1.02 to 1.22) | 42 more per 1,000 (from 8 more to 83 more) | ⨁⨁⨁◯ Moderate | CRITICAL |
| 28 or 30 days mortality | ||||||||||||
| 15 | Randomized trials | Very serious ‡ | Serious § | Not serious | Not serious | None | 573/1,940 (29.5%) | 584/1,916 (30.5%) | RR 0.89 (0.77 to 1.04) | 34 fewer per 1,000 (from 70 fewer to 12 more) | ⨁◯◯◯Very low | CRITICAL |
| In‐hospital mortality | ||||||||||||
| 12 | Randomized trials | Very serious ‡ | Serious ¶ | Not serious | Not serious | None | 383/1,194 (32.1%) | 382/1,150 (33.2%) | RR 0.94 (0.76 to 1.16) | 20 fewer per 1,000 (from 80 fewer to 53 more) | ⨁◯◯◯Very low | CRITICAL |
| Length of ICU stay (days) | ||||||||||||
| 16 | Randomized trials | Very serious ‡ | Very serious †† | Not serious | Not serious | NONE | 1,785 | 1,749 | ‐ | MD 0.25 lower (0.72 lower to 0.22 higher) | ⨁◯◯◯Very low | CRITICAL |
| Length of hospital stay (days) | ||||||||||||
| 12 | Randomized trials | Very serious ‡ | Very serious ‡‡ | Not serious | Not serious | None | 1,722 | 1,685 | ‐ | MD 0.24 higher (0.97 lower to 1.45 higher) | ⨁◯◯◯Very low | CRITICAL |
| Acute kidney injury | ||||||||||||
| 9 | Randomized trials | Very serious ‡ | Not serious | Not serious | Not serious | None | 338/1,113 (30.4%) | 324/1,117 (29.0%) | RR 1.02 (0.93 to 1.13) | 6 more per 1,000 (from 20 fewer to 38 more) | ⨁⨁◯◯Low | CRITICAL |
CI, confidence interval; MD, mean difference; RR, risk ratio.
One study with a high risk of bias was included.
Two or more studies with high risk of bias were included.
The I 2 value was 39%.
The I 2 value was 50%.
The I 2 value was 68%. We thought that this value is quite large.
The I 2 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 = 3,534). 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 1,000 (95% CI: 8 more–83 more; 6 RCTs, n = 2,881), 28 or 30 days mortality yielded an RD of 34 fewer per 1,000 (95% CI: 70 fewer–12 more; 15 RCTs, n = 3,856), in‐hospital mortality yielded an RD of 20 fewer per 1,000 (95% CI: 80 fewer–53 more; 12 RCTs, n = 2,344). 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 = 3,407), and acute kidney injury yielded an RD of 6 more per 1,000 (95% CI: 20 fewer–38 more; 9 RCTs, n = 2,230). 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”).”
DECLARATIONS
Ethics approval and consent to participate: Not applicable.
Consent for publication: Not applicable.
DISCLOSURE
Conflicts of Interest (COIs) and members' roles: All financial and non‐financial competing interests were declared in the J‐SSCG2020. 1 , 2
Supporting information
Appendix S1. PRISMA flow diagram, risk of bias summary, forrest plot, funnel plot, and evidence to decision table.
Funding information
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.
DATA AVAILABILITY STATEMENT
All data generated or analyzed during this study are included in this published article and its Appendix S1 files.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1. 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 Appendix S1 files.