Corticosteroids for treating sepsis

Djillali Annane; Eric Bellissant; Pierre Edouard Bollaert; Josef Briegel; Didier Keh; Yizhak Kupfer

doi:10.1002/14651858.CD002243.pub3

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Figure 1

Flow diagram.

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Figure 2

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

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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%

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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%

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Figure 5

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

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Figure 6

Contour‐enhanced funnel plot

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

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Analysis 1.1

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

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Analysis 1.2

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

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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.

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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.

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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.

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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.

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Analysis 1.7

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

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Analysis 1.8

Comparison 1 Steroids versus control, Outcome 8 Hospital mortality.

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Analysis 1.9

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

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Analysis 1.10

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

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Analysis 1.11

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

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Analysis 1.12

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

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Analysis 1.13

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

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Analysis 1.14

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

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Analysis 1.15

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

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Analysis 1.16

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

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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)	⊕⊕⊝⊝ Low^a,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)	⊕⊕⊕⊝ Moderate^a	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)	⊕⊕⊕⊝ Moderate^a,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)	⊕⊕⊕⊝ Moderate^c	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

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

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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]

Comparison 1. Steroids versus control

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