Intramuscular versus oral corticosteroids to reduce relapses following discharge from the emergency department for acute asthma

Scott W Kirkland; Elfriede Cross; Sandra Campbell; Cristina Villa‐Roel; Brian H Rowe

doi:10.1002/14651858.CD012629.pub2

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Figure 1

Study flow diagram.

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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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Figure 3

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

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Analysis 1.1

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 1 Relapse.

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Analysis 1.2

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 2 Relapse intention to treat.

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Analysis 1.3

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 3 Subgroup analysis: children versus adults.

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Analysis 1.4

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 4 Subgroup analysis: relapse within 10 days and over 10 days post‐discharge.

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Analysis 1.5

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 5 Subgroup analysis: mild/moderate versus severe exacerbations.

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Analysis 1.6

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 6 Sensitivity analysis: risk of bias.

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Analysis 1.7

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 7 Sensitivity analysis: oral corticosteroid prescriptions greater than 5 days.

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Analysis 1.8

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 8 Sensitivity analysis: fixed effects.

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Analysis 1.9

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 9 Sensitivity analysis: corticosteroids in ED.

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Analysis 1.10

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 10 Serious adverse events; hospitalization following discharge.

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Analysis 1.11

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 11 Adverse events.

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Analysis 1.12

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 12 Adverse events: nausea/vomiting/GI distress.

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Analysis 1.13

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 13 Adverse events: insomnia.

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Analysis 1.14

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 14 Adverse events: personality changes.

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Analysis 1.15

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 15 Adverse events: pain.

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Analysis 1.16

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 16 Adverse events: swelling.

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Analysis 1.17

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 17 Adverse events: redness.

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Analysis 1.18

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 18 Pulmonary function: peak expiratory flow (L/min).

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Analysis 1.19

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 19 Pulmonary function: FEV₁/FVC (%).

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Analysis 1.20

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 20 Symptom persistence.

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Analysis 1.21

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 21 Symptom persistence: cough.

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Analysis 1.22

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 22 Symptom persistence: wheezing.

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Analysis 1.23

Comparison 1 Intramuscular versus oral corticosteroids, Outcome 23 24‐hour beta agonist use.

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Summary of findings for the main comparison. Intramuscular corticosteroids compared to Oral corticosteroids for acute asthma

Intramuscular corticosteroids compared to Oral corticosteroids for acute asthma
Patient or population: patients with acute asthma Settings: Acute care settings Intervention: Intramuscular corticosteroids Comparison: Oral corticosteroids
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Oral corticosteroids	Intramuscular corticosteroids
Relapse	201 per 1000	12 fewer per 1000 (from 56 fewer to 48 more)	RR 0.94 (0.72 to 1.24)	804 (9 studies)	⊕⊕⊝⊝ low^1,2
Relapse within 10 days post‐discharge	154 per 1000	40 fewer per 1000 (from 75 fewer to 11 more)	RR 0.74 (0.51 to 1.07)	742 (7 studies)	⊕⊕⊕⊝ moderate¹
Relapse occurring after 10 days post‐discharge	245 per 1000	2 fewer per 1000 (from 64 fewer to 81 more)	RR 0.99 (0.74 to 1.33)	556 (5 studies)	⊕⊕⊝⊝ low^1,2
Adverse events	294 per 1000	50 fewer per 1000 (from 106 fewer to 21 more)	RR 0.83 (0.64 to 1.07)	404 (5 studies)	⊕⊕⊝⊝ low^1,3
Pulmonary function: Peak expiratory flow	The mean pulmonary function: peak expiratory flow ranged across control groups from 304 to 419 litres/min	The mean pulmonary function: peak expiratory flow in the intervention groups was 7.78 liters/min lower (38.83 lower to 23.28 higher)		272 (4 studies)	⊕⊕⊕⊝ moderate²
Symptom persistence	537 per 1000	317 fewer per 1000 (from 461 fewer to 107 more)	RR 0.41 (0.14 to 1.2)	80 (3 studies)	⊕⊕⊝⊝ low^1,3
24‐hour beta agonist use	375 per 1000	172 fewer per 1000 (from 296 fewer to 139 more)	RR 0.54 (0.21 to 1.37)	48 (2 studies)	⊕⊕⊝⊝ low^1,3
The basis for the assumed risk* (e.g. the median control group risk across studies) 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.
¹ Downgraded 1 level for risk of bias. Majority of studies received an unclear risk of bias for random sequence generation and selective outcome reporting ² Downgraded 1 level for imprecision including wide confidence intervals (including both benefit, harm, and no effect) ³ Downgraded 1 level for Imprecision including wide confidence intervals (including both benefit, harm, and no effect) and few events

Summary of findings for the main comparison. Intramuscular corticosteroids compared to Oral corticosteroids for acute asthma

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Table 1. Exacerbation severity

Studies	Pulmonary function: Eligibility criteria	Exacerbation severity
Al‐Wahadneh 2006	Severity estimated using modified scoring system based on GINA guidelines. Reported to enrolling patients with mild‐moderate exacerbations, however baseline pulmonary function of the groups was not reported.	Unable to assess
Chan 2001	Reported mean baseline PEF greater than 200 L/min: IM group: 270 L/min (SD: 103); oral group: 261 L/min (SD: 104).	Mild/moderate
Gordon 2007	Reported to enrolling patients identified as moderate exacerbations, however baseline pulmonary function was not reported.	Unable to assess
Gries 2000	Applied adapted exacerbation severity score (unspecified). Reported to enrolling patients rated as mild/moderate, however baseline pulmonary function of the groups was not reported.	Unable to assess
Hoffman 1988	Reported baseline mean PEF of enrolled patients of less than 150 L/min: IM group: 129 L/min (SD:14); oral group: 141 L/min (SD: 14).	Severe
Klig 1997	Exacerbation severity estimated via pulmonary index score. Study reported to enrolling patients with mild/moderate exacerbations, however baseline pulmonary function was not reported.	Unable to assess
Lahn 2004	Eligibility criteria required patients to have a PEFR of ≤ 70% predicted with a minimum PEFR of ≥ 40%. Reported PEF of enrolled patients was ≥ 200 L/min: IM group: 205 L/min (SD: 70); oral group: 209 L/min (SD: 72).	Mild/moderate
Lee 1993	Reported mean baseline PEF of ≥ 200 L/min: IM group: 210 L/min (SD: 30); oral group: 208 L/min (SD: 26).	Mild/moderate
Schuckman 1998	Reported mean baseline PEF of ≥ 200 L/min: IM group: 243.6 L/min (SD: 64); oral group: 244.7 L/min (SD: 83).	Mild/moderate
Abbreviations: GINA = Global Initiative for Asthma; PEF = Peak expiratory flow; PEFR = Peak expiratory flow rate; IM = intramuscular; SD = standard deviation

Table 1. Exacerbation severity

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Table 2. Study characteristics of included studies

Studies

Location/setting

Co‐interventions

Corticosteroid doses and durations

Methyprednisolone equivalency

Relapse outcome

Al‐Wahadneh 2006

Jordan, ED

Provided in ED: not stated

Provided at discharge: SABA

Dexamethasone (IM)

1.7 mg/kg

Mean dose: 24 mg

Single dose

Prednisolone (oral)

2 mg/kg/day for 5 days

Mean dose: 19.2 mg per day

Total dose: 96 mg

Methylprednisone equivalency: 120 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

76.8 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

1/16

Day 21

Oral group

3/14

Day 21

Chan 2001

Canada, ED

Provided in ED: SABA, methylxanthines, supplemental oral/IV corticosteroids

Provided at discharge: Methylxanthines, unspecified inhaled beta₂‐agonists, and ICS

Betamethasone (IM)

12 mg

Single dose. Received placebo capsules over 7 days.

Prednisone (oral)

50 mg a day for 7 days. Received a single placebo injection

Total dose: 350 mg

Methylprednisone equivalency:

72 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

280 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

12/86

Day 7

Oral group

19/82

Day 7

Gordon 2007

United States, Pediatric ED

Provided in ED: SABA, ipratropium bromide. IV corticosteroids for patients who vomited oral corticosteroids.

Provided at discharge: Inhaled beta₂‐agonists and ICS

Dexamethasone (IM)

0.6 mg/kg (max 16 mg)

Single dose

Prednisolone (oral)

2 mg/kg (max 50 mg) daily for 5 days

Total: 250 mg

Methylprednisone equivalency:

80 mg

Duration: intermediate half‐life (12‐36 hours)

Oral

Methylprednisone equivalency:

200 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

8/69

Day 4

Oral group

11/73

Day 4

IM group

15/68

Day 14

Oral group

16/73

Day 14

Gries 2000

United States, Tertiary medical center

Provided in ED: SABA

Provided at discharge: SABA

Dexamethasone (IM)

Patients 6 to 12 months old received 16 mg.

Patients 13 to 35 months old received 24 mg.

Children ≥ 36 months received 36 mg.

Single dose

Prednisone (oral)

2 mg/kg a day for 5 days

Total dose: unclear

Methylprednisone equivalency:

Unable to assess

Oral

Methylprednisone equivalency:

Unable to assess

IM group

1/15

Day 28

Oral group

3/17

Day 28

Hoffman 1988

United States, ED

Provided in ED: SABA, epinephrine, methylxanthines, IV corticosteroids

Provided at discharge: Methylxanthine and inhaled beta₂‐agonists

Methylprednisonlone (IM)

80 mg

Single dose. Received placebo capsules for 7 days

Methylprednisolone (oral)

Tapering dose over 7 days.

Total dose: 216 mg

Received placebo injection

Methylprednisone equivalency:

80 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

216 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

0/8 day

Day 7

Oral group

2/10

Day 7

Klig 1997

United States, Pediatric ED

Provided in ED: SABA

Provided at discharge: SABA

Dexamethasone (IM)

0.3 mg/kg

Total dose: 15 mg

Single dose

Prednisone (oral)

2 mg/kg a day for 3 days

Total dose: 100 mg

Methylprednisone equivalency:

75 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

80 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

0/21

Day 5

Oral group

0/21

Day 5

Lahn 2004

United States, ED

Provided in ED: inhaled beta₂‐agonists, IV corticosteroids

Provided at discharge: SABA

Methylprednisolone (IM)

160 mg

Single dose. Received placebo capsules for 8 days

Methylprednisolone (oral)

Tapering dose over 8 days.

Total dose: 160 mg (tapering dose 32 mg day 1).

Received placebo injection

Methylprednisone equivalency:

80 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

80 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

13/92

Day 10

Oral group

12/88

Day 10

IM group

17/92

Day 21

Oral group

20/88

Day 21

Lee 1993

Taiwan, ED

Provided in ED: SABA, methylxanthines

Provided at discharge: Methylxanthine and inhaled beta₂‐agonists

Dexamethasone (IM)

10 mg

Single dose. Received placebo capsules for 7 days

Dexamethasone (oral)

Tapering dose over 7 days.

11.75 mg total. Received placebo injection

Methylprednisone equivalency:

50 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

58.8 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

1/17

Day 7

Oral group

0/19

Day 7

Schuckman 1998

United States, ED

Provided in ED: SABA, oral/IV corticosteroids

Provided at discharge: SABA, antibiotics, ICS, cromolyn sodium, ipratropium bromide

Triamcinolone (IM)

40 mg

Single dose. Received placebo capsules for 5 days

Prednisone (oral)

40 mg a day for 5 days.

Total dose: 160 mg

Received placebo injection

Methylprednisone equivalency:

40 mg

Duration: intermediate half‐life (12 to 36 hours)

Oral

Methylprednisone equivalency:

160 mg

Duration: intermediate half‐life (12 to 36 hours)

IM group

7/78

Day 7

Oral group

11/76

Day 7

ED = emergency department; SABA = short‐acting beta₂‐agonists; LABA = long‐acting beta₂‐agonists; IV = intravenous; IM = intramuscular; ICS = inhaled corticosteroids

Table 2. Study characteristics of included studies

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Comparison 1. Intramuscular versus oral corticosteroids

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Relapse Show forest plot	9	804	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.24]

2 Relapse intention to treat Show forest plot	9	821	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.72, 1.26]

3 Subgroup analysis: children versus adults Show forest plot	9	804	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.24]

3.1 Children	4	245	Risk Ratio (M‐H, Random, 95% CI)	0.86 [0.48, 1.53]
3.2 Adults	5	559	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.71, 1.33]
4 Subgroup analysis: relapse within 10 days and over 10 days post‐discharge Show forest plot	9		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4.1 Within 10 days post‐discharge	7	742	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.51, 1.07]
4.2 Greater than 10 days post‐discharge	5	556	Risk Ratio (M‐H, Random, 95% CI)	0.99 [0.74, 1.33]
5 Subgroup analysis: mild/moderate versus severe exacerbations Show forest plot	5	557	Risk Ratio (M‐H, Random, 95% CI)	0.96 [0.70, 1.32]

5.1 Mild/moderate exacerbations	4	539	Risk Ratio (M‐H, Random, 95% CI)	0.98 [0.71, 1.34]
5.2 Severe exacerbations	1	18	Risk Ratio (M‐H, Random, 95% CI)	0.24 [0.01, 4.47]
6 Sensitivity analysis: risk of bias Show forest plot	5	559	Risk Ratio (M‐H, Random, 95% CI)	0.97 [0.71, 1.33]

7 Sensitivity analysis: oral corticosteroid prescriptions greater than 5 days Show forest plot	8	762	Risk Ratio (M‐H, Random, 95% CI)	0.94 [0.72, 1.24]

8 Sensitivity analysis: fixed effects Show forest plot	9	804	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.69, 1.19]

9 Sensitivity analysis: corticosteroids in ED Show forest plot	5	320	Risk Ratio (M‐H, Random, 95% CI)	0.76 [0.45, 1.29]

10 Serious adverse events; hospitalization following discharge Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

11 Adverse events Show forest plot	5	404	Risk Ratio (M‐H, Random, 95% CI)	0.83 [0.64, 1.07]

12 Adverse events: nausea/vomiting/GI distress Show forest plot	3	320	Risk Ratio (M‐H, Random, 95% CI)	0.56 [0.09, 3.59]

13 Adverse events: insomnia Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

14 Adverse events: personality changes Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

15 Adverse events: pain Show forest plot	2	181	Risk Ratio (M‐H, Random, 95% CI)	1.75 [0.32, 9.66]

16 Adverse events: swelling Show forest plot	2	180	Risk Ratio (M‐H, Random, 95% CI)	4.76 [0.57, 39.84]

17 Adverse events: redness Show forest plot	2	175	Risk Ratio (M‐H, Random, 95% CI)	13.5 [0.77, 235.63]

18 Pulmonary function: peak expiratory flow (L/min) Show forest plot	4	272	Mean Difference (IV, Random, 95% CI)	‐7.78 [‐38.83, 23.28]

19 Pulmonary function: FEV₁/FVC (%) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Totals not selected

20 Symptom persistence Show forest plot	3	80	Risk Ratio (M‐H, Random, 95% CI)	0.41 [0.14, 1.20]

21 Symptom persistence: cough Show forest plot	3	178	Risk Ratio (M‐H, Random, 95% CI)	0.69 [0.17, 2.73]

22 Symptom persistence: wheezing Show forest plot	3	177	Risk Ratio (M‐H, Random, 95% CI)	0.59 [0.14, 2.52]

23 24‐hour beta agonist use Show forest plot	2	48	Risk Ratio (M‐H, Random, 95% CI)	0.54 [0.21, 1.37]

Comparison 1. Intramuscular versus oral corticosteroids

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