Scolaris Content Display Scolaris Content Display

Flow diagram.
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Figure 1

Flow diagram.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
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Figure 2

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Figure represents the results from meta‐regression of log of risk ratio of dying and log of the dose of corticosteroids given at day 1 and expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model.Meta‐regression included 26 trials. The trial by Schummer et al was not included.REML estimate of between‐study variance tau2 = .01078.
 % residual variation due to heterogeneity: I2 res = 5.07%
 Proportion of between‐study variance explained Adj R2 = 11.16%
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Figure 3

Figure represents the results from meta‐regression of log of risk ratio of dying and log of the dose of corticosteroids given at day 1 and expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model.

Meta‐regression included 26 trials. The trial by Schummer et al was not included.

REML estimate of between‐study variance tau2 = .01078.
% residual variation due to heterogeneity: I2 res = 5.07%
Proportion of between‐study variance explained Adj R2 = 11.16%

Figure represents results from meta‐regression of log of risk ratio of dying and log of cumulated dose of corticosteroids expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model.Meta‐regression included 26 trials. The trial by Schummer et al was not included.REML estimate of between‐study variance tau2 = .01183
 % residual variation due to heterogeneity I2 res = 6.99%
 Proportion of between‐study variance explained Adj R2 = 2.49%
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Figure 4

Figure represents results from meta‐regression of log of risk ratio of dying and log of cumulated dose of corticosteroids expressed as equivalent mg of hydrocortisone. Estimates from each study are represented by circles. Circle sizes depend on the precision of each estimate (the inverse of its within‐study variance), which is the weight given to each study in the fixed‐effect model.

Meta‐regression included 26 trials. The trial by Schummer et al was not included.

REML estimate of between‐study variance tau2 = .01183
% residual variation due to heterogeneity I2 res = 6.99%
Proportion of between‐study variance explained Adj R2 = 2.49%

Funnel plot of comparison: 1 Steroids versus control, outcome: 1.1 28‐Day all‐cause mortality.
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Figure 5

Funnel plot of comparison: 1 Steroids versus control, outcome: 1.1 28‐Day all‐cause mortality.

Contour‐enhanced funnel plotLog of risk ratio for 28‐day mortality is plotted against its standard error
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Figure 6

Contour‐enhanced funnel plot

Log of risk ratio for 28‐day mortality is plotted against its standard error

Comparison 1 Steroids versus control, Outcome 1 28‐Day all‐cause mortality.
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Analysis 1.1

Comparison 1 Steroids versus control, Outcome 1 28‐Day all‐cause mortality.

Comparison 1 Steroids versus control, Outcome 2 All‐cause mortality by subgroup based on mortality rate.
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Analysis 1.2

Comparison 1 Steroids versus control, Outcome 2 All‐cause mortality by subgroup based on mortality rate.

Comparison 1 Steroids versus control, Outcome 3 28‐Day all‐cause mortality by subgroups based on methodological quality.
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Analysis 1.3

Comparison 1 Steroids versus control, Outcome 3 28‐Day all‐cause mortality by subgroups based on methodological quality.

Comparison 1 Steroids versus control, Outcome 4 28‐Day all‐cause mortality by subgroups based on treatment dose/duration.
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Analysis 1.4

Comparison 1 Steroids versus control, Outcome 4 28‐Day all‐cause mortality by subgroups based on treatment dose/duration.

Comparison 1 Steroids versus control, Outcome 5 28‐Day all‐cause mortality by subgroups based on targeted population.
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Analysis 1.5

Comparison 1 Steroids versus control, Outcome 5 28‐Day all‐cause mortality by subgroups based on targeted population.

Comparison 1 Steroids versus control, Outcome 6 28‐Day mortality in participants with critical illness‐related corticosteroid insufficiency.
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Analysis 1.6

Comparison 1 Steroids versus control, Outcome 6 28‐Day mortality in participants with critical illness‐related corticosteroid insufficiency.

Comparison 1 Steroids versus control, Outcome 7 Intensive care unit mortality.
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Analysis 1.7

Comparison 1 Steroids versus control, Outcome 7 Intensive care unit mortality.

Comparison 1 Steroids versus control, Outcome 8 Hospital mortality.
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Analysis 1.8

Comparison 1 Steroids versus control, Outcome 8 Hospital mortality.

Comparison 1 Steroids versus control, Outcome 9 Number of participants with shock reversal at day 7.
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Analysis 1.9

Comparison 1 Steroids versus control, Outcome 9 Number of participants with shock reversal at day 7.

Comparison 1 Steroids versus control, Outcome 10 Number of participants with shock reversal at 28 days.
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Analysis 1.10

Comparison 1 Steroids versus control, Outcome 10 Number of participants with shock reversal at 28 days.

Comparison 1 Steroids versus control, Outcome 11 SOFA score at day 7.
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Analysis 1.11

Comparison 1 Steroids versus control, Outcome 11 SOFA score at day 7.

Comparison 1 Steroids versus control, Outcome 12 Length of ICU stay for all participants.
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Analysis 1.12

Comparison 1 Steroids versus control, Outcome 12 Length of ICU stay for all participants.

Comparison 1 Steroids versus control, Outcome 13 Length of ICU stay for survivors.
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Analysis 1.13

Comparison 1 Steroids versus control, Outcome 13 Length of ICU stay for survivors.

Comparison 1 Steroids versus control, Outcome 14 Length of hospital stay for all participants.
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Analysis 1.14

Comparison 1 Steroids versus control, Outcome 14 Length of hospital stay for all participants.

Comparison 1 Steroids versus control, Outcome 15 Length of hospital stay for survivors.
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Analysis 1.15

Comparison 1 Steroids versus control, Outcome 15 Length of hospital stay for survivors.

Comparison 1 Steroids versus control, Outcome 16 Number of participants with adverse events.
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Analysis 1.16

Comparison 1 Steroids versus control, Outcome 16 Number of participants with adverse events.

Summary of findings for the main comparison. Steroids versus control for treating sepsis

Steroids versus control for treating sepsis

Patient or population: patients with sepsis
Settings:
Intervention: steroids vs control

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

Number of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Control

Steroids vs control

28‐Day all‐cause mortality
Follow‐up: 14 to 30 days

Study population

RR 0.87
(0.76 to 1)

3176
(27 studies)

⊕⊕⊝⊝
Lowa,b

Trials were conducted over a period from 1976 to 2015. Differences in participant management and in the definition of sepsis were substantial <BR/>18 trial

318 per 1000

276 per 1000
(241 to 318)

28‐Day all‐cause mortality by subgroups based on treatment dose/duration ‐ long course of low‐dose corticosteroids
Follow‐up: 14 to 30 days

Study population

RR 0.87
(0.78 to 0.97)

2266
(22 studies)

⊕⊕⊕⊝
Moderatea

Meta‐regression analysis also showed evidence of a dose response: Low doses were associated with better treatment response

321 per 1000

279 per 1000
(250 to 311)

Hospital mortality
Follow‐up: 14 to 365 days

Study population

RR 0.85
(0.73 to 0.98)

2014
(17 studies)

⊕⊕⊕⊝
Moderatea,c

Low doses of corticosteroids were associated with better treatment response

413 per 1000

351 per 1000
(302 to 405)

Number of participants with shock reversal at day 7
Follow‐up: 7 to 28 days

Study population

RR 1.31
(1.14 to 1.51)

1561
(12 studies)

⊕⊕⊕⊕
High

Low doses of corticosteroids were associated with better treatment response

523 per 1000

685 per 1000
(596 to 790)

SOFA score at day 7
Follow‐up: 7 days

Mean SOFA score at day 7 in intervention groups was
1.53 lower
(2.04 to 1.03 lower)

1132
(8 studies)

⊕⊕⊕⊕
High

Observed reduction in SOFA score was of a magnitude that exceeded any reduction seen with any other treatment for sepsis

Length of ICU stay for survivors
Follow‐up: 14 to 365 days

Mean length of ICU stay for survivors in intervention groups was
2.19 lower
(3.93 to 0.46 lower)

778
(10 studies)

⊕⊕⊕⊕
High

Observed reduction in length of ICU stay was of a magnitude that exceeded any reduction seen with any other treatment for sepsis

Length of hospital stay for survivors
Follow‐up: 14 to 365 days

Mean length of hospital stay for survivors in intervention groups was
4.11 lower
(8.5 lower to 0.28 higher)

710
(9 studies)

⊕⊕⊕⊝
Moderatec

Observed reduction in length of hospital stay was of a magnitude that exceeded any reduction seen with any other treatment for sepsis

Number of participants with adverse events ‐ superinfections
Follow‐up: 14 to 90 days

Study population

RR 1.02
(0.87 to 1.2)

2567
(19 studies)

⊕⊕⊕⊕
High

One large trial suggested increased risk of new sepsis with corticosteroids

161 per 1000

164 per 1000
(140 to 193)

Number of participants with adverse events ‐ hyperglycaemia
Follow‐up: 14 to 90 days

Study population

RR 1.26
(1.16 to 1.37)

2081
(13 studies)

⊕⊕⊕⊕
High

One trial suggested that risk of hyperglycaemia was lower when corticosteroids were given as a continuous perfusion than when they were given as an intravenous bolus

348 per 1000

438 per 1000
(403 to 476)

*The basis for the assumed risk is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: Confidence interval; RR: Risk ratio

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate

aQuality of evidence was downgraded by 1 point owing to some inconsistency; 1 of the 2 largest trials showed no survival benefit

bQuality of evidence was downgraded by 1 point owing to potential publication bias; some asymmetry was noted in the funnel plot
cQuality of evidence was downgraded by 1 point for imprecision, and the upper limit of the confidence interval approached 1

Figures and Tables -
Summary of findings for the main comparison. Steroids versus control for treating sepsis
Comparison 1. Steroids versus control

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 28‐Day all‐cause mortality Show forest plot

27

3176

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.76, 1.00]

2 All‐cause mortality by subgroup based on mortality rate Show forest plot

20

2570

Risk Ratio (M‐H, Fixed, 95% CI)

0.95 [0.86, 1.06]

2.1 Studies reporting 28‐day mortality

18

1966

Risk Ratio (M‐H, Fixed, 95% CI)

0.90 [0.80, 1.00]

2.2 Studies reporting only 14‐day mortality

2

604

Risk Ratio (M‐H, Fixed, 95% CI)

1.21 [0.93, 1.59]

3 28‐Day all‐cause mortality by subgroups based on methodological quality Show forest plot

20

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

3.1 Adequate generation of allocation sequence

19

2342

Risk Ratio (M‐H, Random, 95% CI)

0.97 [0.86, 1.10]

3.2 Adequate allocation concealment

18

2283

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.84, 1.09]

3.3 Blinded trials

18

2259

Risk Ratio (M‐H, Random, 95% CI)

0.95 [0.84, 1.08]

4 28‐Day all‐cause mortality by subgroups based on treatment dose/duration Show forest plot

27

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

4.1 Long course of low‐dose corticosteroids

22

2266

Risk Ratio (M‐H, Fixed, 95% CI)

0.87 [0.78, 0.97]

4.2 Short course of high‐dose corticosteroids

5

910

Risk Ratio (M‐H, Fixed, 95% CI)

0.96 [0.80, 1.16]

5 28‐Day all‐cause mortality by subgroups based on targeted population Show forest plot

26

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

5.1 Sepsis

6

826

Risk Ratio (M‐H, Fixed, 95% CI)

1.11 [0.91, 1.34]

5.2 Septic shock only

12

1444

Risk Ratio (M‐H, Fixed, 95% CI)

0.88 [0.78, 0.99]

5.3 Sepsis and ARDS

3

114

Risk Ratio (M‐H, Fixed, 95% CI)

0.46 [0.25, 0.85]

5.4 Sepsis and community‐acquired pneumonia

5

763

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.38, 1.02]

6 28‐Day mortality in participants with critical illness‐related corticosteroid insufficiency Show forest plot

8

583

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.76, 1.02]

7 Intensive care unit mortality Show forest plot

13

1463

Risk Ratio (M‐H, Random, 95% CI)

0.82 [0.68, 1.00]

8 Hospital mortality Show forest plot

17

2014

Risk Ratio (M‐H, Random, 95% CI)

0.85 [0.73, 0.98]

8.1 Long course of low‐dose corticosteroids

14

1708

Risk Ratio (M‐H, Random, 95% CI)

0.91 [0.82, 1.01]

8.2 Short course of high‐dose corticosteroids

3

306

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.33, 1.60]

9 Number of participants with shock reversal at day 7 Show forest plot

12

1561

Risk Ratio (M‐H, Random, 95% CI)

1.31 [1.14, 1.51]

9.1 Shock reversal at day 7 in trials on long course of low‐dose corticosteroids

10

1258

Risk Ratio (M‐H, Random, 95% CI)

1.34 [1.22, 1.46]

9.2 Shock reversal at day 7 in trials on short course of high‐dose corticosteroids

2

303

Risk Ratio (M‐H, Random, 95% CI)

1.07 [0.64, 1.79]

10 Number of participants with shock reversal at 28 days Show forest plot

7

1013

Risk Ratio (M‐H, Random, 95% CI)

1.11 [1.02, 1.21]

11 SOFA score at day 7 Show forest plot

8

1132

Mean Difference (IV, Random, 95% CI)

‐1.53 [‐2.04, ‐1.03]

12 Length of ICU stay for all participants Show forest plot

12

1384

Mean Difference (IV, Random, 95% CI)

‐1.68 [‐3.27, ‐0.09]

13 Length of ICU stay for survivors Show forest plot

10

778

Mean Difference (IV, Fixed, 95% CI)

‐2.19 [‐3.93, ‐0.46]

14 Length of hospital stay for all participants Show forest plot

12

1802

Mean Difference (IV, Random, 95% CI)

‐0.97 [‐2.55, 0.61]

15 Length of hospital stay for survivors Show forest plot

9

710

Mean Difference (IV, Random, 95% CI)

‐4.11 [‐8.50, 0.28]

16 Number of participants with adverse events Show forest plot

21

Risk Ratio (M‐H, Fixed, 95% CI)

Subtotals only

16.1 Gastroduodenal bleeding

19

2382

Risk Ratio (M‐H, Fixed, 95% CI)

1.24 [0.92, 1.67]

16.2 Superinfections

19

2567

Risk Ratio (M‐H, Fixed, 95% CI)

1.02 [0.87, 1.20]

16.3 Hyperglycaemia

13

2081

Risk Ratio (M‐H, Fixed, 95% CI)

1.26 [1.16, 1.37]

16.4 Hypernatraemia

3

805

Risk Ratio (M‐H, Fixed, 95% CI)

1.64 [1.28, 2.09]

16.5 Neuromuscular weakness

3

811

Risk Ratio (M‐H, Fixed, 95% CI)

0.62 [0.21, 1.88]

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Comparison 1. Steroids versus control