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Selen‐Supplementierung bei lebensbedrohlich erkrankten Erwachsenen

Appendices

Appendix 1. Cochrane Central Register of Controlled Trials search strategy

#1 MeSH descriptor: [Selenium] explode all trees
#2 MeSH descriptor: [Selenium Compounds] explode all trees
#3 selen*
#4 ebselen
#5 #1 or #2 or #3 or #4
#6 #5

Appendix 2. MEDLINE (Ovid SP) and Healthstar search strategy

1. exp Selenium Compounds/ or exp Selenium/ or (selen* or ebselen*).mp.2. (randomized controlled trial.pt. or controlled clinical trial.pt.or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals.sh not (humans.sh and animals.sh))
3. 1 and 2

Appendix 3. EMBASE (Ovid SP) search strategy

1. exp selenium derivative/ or exp selenium/ or (selen* or ebselen*).ti,ab.
2. (placebo.sh. or controlled study.ab. or random*.ti,ab. or trial*.ti,ab. or ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or mask*)).ti,ab.) not (animals not (humans and animals)).sh.
3. 1 and 2

Appendix 4. CAB abstracts search strategy

1. random$.tw
2. trials$.tw
3. placebo$.tw
4. 1 or 2 or 3
5. selen$.tw
6. ebselen.tw
7. 5 or 6
8. 4 and 7

Appendix 5. BIOSIS search strategy

#1 TI=selen* or TI=ebselen*
#2 TS=(random* or trial* or placebo*)
#3 #1 and #2

Appendix 6. CINAHL (EBSCOhost) search strategy

S1 ((MM "Selenium") OR (MM "Selenium Compounds")) or selen* or ebselen*
S2 random* or ((clinical or controlled) N3 trials) or placebo* or multicenter or prospective or ((blind* or mask*) N3 (single or double or triple or treble))
S3 S1 and S2

Study flow diagram for the updated review. (In the original article, Avenell 2004, 10 studies were included and 11 studies were excluded with reasons. Three were awaiting classification, of which one has now been excluded (Kiessling 2006). Two studies are still ongoing).
Figuras y tablas -
Figure 1

Study flow diagram for the updated review. (In the original article, Avenell 2004, 10 studies were included and 11 studies were excluded with reasons. Three were awaiting classification, of which one has now been excluded (Kiessling 2006). Two studies are still ongoing).

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'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.
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Figure 2

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

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'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.
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Figure 3

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

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Funnel plot of comparison: 1.2 Overall mortality (regardless of the follow‐up period).
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Figure 4

Funnel plot of comparison: 1.2 Overall mortality (regardless of the follow‐up period).

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Trial sequential analysis (TSA) of all trials examining the effect of Selenium supplementation on mortality among critically ill. Using a control event proportion of 32% found in the included trials, with a type 1 error of 5% and a 18% relative risk reduction (80% power), the trial sequential monitoring boundary for benefit is not crossed by the z‐curve. However, these lines are very close to crossing each other which may indicate a probability of lack of random error for the conclusion of an effect of 18% relative risk reduction even though the required information size (N = 2605) has not yet been reached. However, caution must be exerted when interpreting the results of this TSA since all included studies are at high risk of bias and the intervention effect is likely to have been overestimated in the traditional meta‐analysis.
Figuras y tablas -
Figure 5

Trial sequential analysis (TSA) of all trials examining the effect of Selenium supplementation on mortality among critically ill. Using a control event proportion of 32% found in the included trials, with a type 1 error of 5% and a 18% relative risk reduction (80% power), the trial sequential monitoring boundary for benefit is not crossed by the z‐curve. However, these lines are very close to crossing each other which may indicate a probability of lack of random error for the conclusion of an effect of 18% relative risk reduction even though the required information size (N = 2605) has not yet been reached. However, caution must be exerted when interpreting the results of this TSA since all included studies are at high risk of bias and the intervention effect is likely to have been overestimated in the traditional meta‐analysis.

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Comparison 1 Selenium versus no selenium, Outcome 1 Overall mortality (regardless of the period of follow‐up).
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Analysis 1.1

Comparison 1 Selenium versus no selenium, Outcome 1 Overall mortality (regardless of the period of follow‐up).

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Comparison 2 Selenium versus no selenium, Outcome 1 Mortality by duration (Selenium).
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Analysis 2.1

Comparison 2 Selenium versus no selenium, Outcome 1 Mortality by duration (Selenium).

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Comparison 2 Selenium versus no selenium, Outcome 2 Mortality by duration (Ebselen).
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Analysis 2.2

Comparison 2 Selenium versus no selenium, Outcome 2 Mortality by duration (Ebselen).

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Comparison 2 Selenium versus no selenium, Outcome 3 Mortality: ICU and pancreatitis (Selenium).
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Analysis 2.3

Comparison 2 Selenium versus no selenium, Outcome 3 Mortality: ICU and pancreatitis (Selenium).

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Comparison 3 Selenium versus no selenium, Outcome 1 Number of infected participants.
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Analysis 3.1

Comparison 3 Selenium versus no selenium, Outcome 1 Number of infected participants.

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Comparison 4 Selenium versus no selenium, Outcome 1 Number of participants with adverse event.
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Analysis 4.1

Comparison 4 Selenium versus no selenium, Outcome 1 Number of participants with adverse event.

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Comparison 4 Selenium versus no selenium, Outcome 2 Length of stay in ICU (Selenium).
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Analysis 4.2

Comparison 4 Selenium versus no selenium, Outcome 2 Length of stay in ICU (Selenium).

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Comparison 4 Selenium versus no selenium, Outcome 3 Number of days on a ventilator (Selenium).
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Analysis 4.3

Comparison 4 Selenium versus no selenium, Outcome 3 Number of days on a ventilator (Selenium).

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Comparison 4 Selenium versus no selenium, Outcome 4 Length of hospital stay (Selenium).
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Analysis 4.4

Comparison 4 Selenium versus no selenium, Outcome 4 Length of hospital stay (Selenium).

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Summary of findings for the main comparison. Summary of findings table 1

Selenium supplementation compared with control for critically ill adults

Patient or population: Patients with critical illnesses

Settings: ICU setting

Intervention: Selenium or ebselen

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No. of participants
(studies)

Quality of the evidence
(GRADE)

Assumed risk

Corresponding risk

Control

Selenium

Overall mortality (regardless of the follow‐up period)

All patients are high risk population

RR 0.82, 95% CI 0.72 to 0.93)

1391
(13)

⊕⊝⊝⊝
very low1,2

ICU length of stay (selenium)

The mean length of stay in an ICU ranged across control groups from
9 days to 26.5 days

The mean length of stay in an ICU ranged across intervention groups from
7.5 days to 22.8 days

MD 0.54, 95% CI ‐2.27 to 3.34

934
(7)

⊕⊝⊝⊝
very low1,3

Days on ventilator (selenium)

The mean days on ventilator ranged across control groups from

6 days to 16 days

The mean days on ventilator ranged across intervention groups from
6 days to 19.8 days

MD ‐0.86, 95% CI ‐4.39 to 2.67

191
(4)

⊕⊝⊝⊝
very low1,4

Length of hospital stay (selenium)

The mean length of hospital stay ranged across control groups from
17 days to 62.8 days

The mean length of hospital stay ranged across intervention groups from
12.5 days to 83 days

MD ‐3.33. 95% CI ‐5.22 to ‐1.44

693
(5)

⊕⊝⊝⊝
very low1,5

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.

Abbreviations: CI: confidence interval; RR: risk ratio; MD: mean difference; ICU: intensive care unit.
1With the exception of SIGNET 2011, all included trials were at high risk of bias. Most studies were small and poorly described.
2The entry refers to: Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Janka 2013; Kuklinski 1991; Lindner 2004; Manzanares 2011; Mishra 2007; Montoya 2009; SIGNET 2011; Valenta 2011; and Zimmermann 1997.
3The entry refers to: Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Manzanares 2011; Mishra 2007; and SIGNET 2011.
4The entry refers to: Angstwurm 1999; Berger 2001; Forceville 2007; and Montoya 2009.
5The entry refers to: Angstwurm 1999; Berger 2001; Forceville 2007; Montoya 2009; and SIGNET 2011.

Figuras y tablas -
Summary of findings for the main comparison. Summary of findings table 1
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Table 1. Length of stay in ICU

Trial

Selenium

Control

Angstwurm 1999

22.8 days (20.8)

26.5 days (22)

Angstwurm 2007

15.1 days (10)

12.7 days (9)

Berger 2001

7,5 days (3.5)

9 days (7.1)

Forceville 2007

22.3 days (9.6)

17 days (8.7)

Manzanares 2011

14 days (11)

13days (6)

Mishra 2007

21.3 days (16.2)

20.8 days (21.8)

SIGNET 2011

14.5 days (4.6)

16.7 days (5.9)

MD 0.54 (95% CI ‐2.27 to 3.34, I² statistic = 72%, random‐effects model)

Analysis 4.2

All findings given as mean (SD). If the original figures were provided in median (range) or interquartile range, we converted them to mean (SD) (Hozo 2005).

Figuras y tablas -
Table 1. Length of stay in ICU
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Table 2. Number of days on a ventilator

Trial

Selenium

Control

Angstwurm 1999

11 days (5.9)

16 (12.6)

Berger 2001

6 days (2.9)

6 days (5.7)

Forceville 2007

19.8 days (7.8)

14.8 days (4.4)

Montoya 2009

9.3 days (1.5)

12 days (1.8)

MD ‐0.86 (95% CI ‐4.39 to 2.67, I² statistic = 89%, random‐effects model)

Analysis 4.3)

All findings given as mean (SD). If the original figures were provided in median (range), we converted them to mean (SD) (Hozo 2005).

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Table 2. Number of days on a ventilator
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Table 3. Length of hospital stay

Trial

Selenium

Control

Angstwurm 1999

38.5 days (24.4)

39.5 days (15.7)

Berger 2001

83 days (73.5)

62.8 days (30.2)

Forceville 2007

31.3 days (18)

32 days (11.6)

Montoya 2009

12.5 days (0.6)

17 days (1.7)

SIGNET 2011

31.7 days (10.9)

33.8 days (12.4)

MD ‐3.33 (95% CI ‐5.22 to ‐1.44, I² statistic = 42%, random‐effects model)

Analysis 4.4

All findings given as mean (SD). If the original figures were provided in median (range) or interquartile range, we converted them to mean (SD) (Hozo 2005).

Figuras y tablas -
Table 3. Length of hospital stay
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Comparison 1. Selenium versus no selenium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Overall mortality (regardless of the period of follow‐up) Show forest plot

16

2084

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.72, 0.93]

1.1 Overall mortality (Selenium)

13

1391

Risk Ratio (M‐H, Fixed, 95% CI)

0.82 [0.72, 0.93]

1.2 Overall mortality (Ebselen)

3

693

Risk Ratio (M‐H, Fixed, 95% CI)

0.83 [0.52, 1.34]
Figuras y tablas -
Comparison 1. Selenium versus no selenium
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Comparison 2. Selenium versus no selenium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mortality by duration (Selenium) Show forest plot

11

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Selenium 28 day

9

1180

Risk Ratio (M‐H, Random, 95% CI)

0.84 [0.69, 1.02]

1.2 Selenium 90 day

3

614

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.78, 1.18]

2 Mortality by duration (Ebselen) Show forest plot

3

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

2.1 Ebselen 30 day

1

105

Risk Ratio (M‐H, Random, 95% CI)

1.78 [0.53, 5.95]

2.2 Ebselen 3 month

2

588

Risk Ratio (M‐H, Random, 95% CI)

0.72 [0.42, 1.22]

3 Mortality: ICU and pancreatitis (Selenium) Show forest plot

11

1255

Risk Ratio (M‐H, Random, 95% CI)

0.87 [0.74, 1.02]

3.1 General intensive care patients

9

1168

Risk Ratio (M‐H, Random, 95% CI)

0.88 [0.77, 1.01]

3.2 Acute pancreatitis

2

87

Risk Ratio (M‐H, Random, 95% CI)

0.40 [0.01, 12.30]
Figuras y tablas -
Comparison 2. Selenium versus no selenium
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Comparison 3. Selenium versus no selenium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of infected participants Show forest plot

9

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Selenium

6

934

Risk Ratio (M‐H, Random, 95% CI)

0.96 [0.75, 1.23]

1.2 Ebselen

3

685

Risk Ratio (M‐H, Random, 95% CI)

0.60 [0.36, 1.02]
Figuras y tablas -
Comparison 3. Selenium versus no selenium
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Comparison 4. Selenium versus no selenium

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Number of participants with adverse event Show forest plot

8

Risk Ratio (M‐H, Random, 95% CI)

Subtotals only

1.1 Selenium

6

925

Risk Ratio (M‐H, Random, 95% CI)

1.03 [0.85, 1.24]

1.2 Ebselen

2

588

Risk Ratio (M‐H, Random, 95% CI)

1.16 [0.40, 3.36]

2 Length of stay in ICU (Selenium) Show forest plot

7

934

Mean Difference (IV, Random, 95% CI)

0.54 [‐2.27, 3.34]

3 Number of days on a ventilator (Selenium) Show forest plot

4

191

Mean Difference (IV, Random, 95% CI)

‐0.86 [‐4.39, 2.67]

4 Length of hospital stay (Selenium) Show forest plot

5

693

Mean Difference (IV, Random, 95% CI)

‐3.33 [‐5.22, ‐1.44]
Figuras y tablas -
Comparison 4. Selenium versus no selenium
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