Holding chambers (spacers) versus nebulisers for beta‐agonist treatment of acute asthma

Christopher J Cates; Emma J Welsh; Brian H Rowe

doi:10.1002/14651858.CD000052.pub3

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Figure 1

Study 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

Funnel plot of comparison: 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies), outcome: 1.1 Hospital admission.

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Figure 4

Forest plot of comparison: 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies), outcome: 1.1 Hospital admission.

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Figure 5

Forest plot of comparison: 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies), outcome: 1.3 Duration in emergency department (minutes). [mins].

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Figure 6

Forest plot of comparison: 1 Spacer (chamber) versus Nebuliser (Multiple treatment studies), outcome: 1.9 Rise in pulse rate (% baseline) [%].

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Analysis 1.1

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 1 Hospital admission.

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Analysis 1.2

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 2 Hospital admission or poor response to treatment.

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Analysis 1.3

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 3 Duration in emergency department (minutes)..

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Analysis 1.4

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 4 Final rise in FEV₁ (% predicted).

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Analysis 1.5

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 5 30 minute rise in FEV₁ (% predicted).

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Analysis 1.6

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 6 Severe asthmatics final rise in FEV₁ (% predicted).

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Analysis 1.7

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 7 Final rise in peak flow (% predicted).

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Analysis 1.8

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 8 30 minute rise in peak flow (% predicted).

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Analysis 1.9

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 9 Rise in pulse rate (% baseline).

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Analysis 1.10

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 10 % Oxygen saturation (change from baseline).

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Analysis 1.11

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 11 Number of participants developing tremor.

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Analysis 1.12

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 12 Number of participants given steroids.

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Analysis 1.13

Comparison 1 Spacer (chamber) versus nebuliser (multiple‐treatment studies), Outcome 13 Rise in respiratory rate (breaths per minute).

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Analysis 2.1

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 1 Hospital admission.

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Analysis 2.2

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 2 Final peak flow (% predicted).

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Analysis 2.3

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 3 30 minute rise in FEV₁ (% predicted).

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Analysis 2.4

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 4 15 minute rise in FEV₁ (% predicted).

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Analysis 2.5

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 5 30 minute rise in peak flow (% predicted).

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Analysis 2.6

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 6 15 minute rise in peak flow (% predicted).

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Analysis 2.7

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 7 Rise in pulse rate (% baseline).

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Analysis 2.8

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 8 Number of participants developing tremor.

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Analysis 2.9

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 9 Number of participants with deterioration in blood gases.

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Analysis 2.10

Comparison 2 Spacer (chamber) versus nebuliser (single‐treatment studies), Outcome 10 Rise in respiratory rate.

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Analysis 3.1

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 1 Duration of hospital admission (days).

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Analysis 3.2

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 2 Number of hours until reached 4‐hourly dosing regimen.

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Analysis 3.3

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 3 Total number of inhaled doses received.

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Analysis 3.4

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 4 Number of participants returning to normal PEFR and respiratory score levels (end of study).

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Analysis 3.5

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 5 Number of symptom‐free participants 14 days post‐discharge.

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Analysis 3.6

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 6 Readmissions in the subsequent 12 months.

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Analysis 3.7

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 7 Clinical asthma score (end of trial).

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Analysis 3.8

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 8 Maximum percentage decrease in respiratory score.

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Analysis 3.9

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 9 Respiratory rate at discharge.

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Analysis 3.10

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 10 Heart rate at discharge.

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Analysis 3.11

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 11 Oxygen saturations at discharge.

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Analysis 3.12

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 12 30 minute rise in FEV₁.

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Analysis 3.13

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 13 Final rise in FEV₁.

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Analysis 3.14

Comparison 3 Spacer (chamber) versus nebuliser (inpatient studies), Outcome 14 Final rise in peak flow (% change from baseline).

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Analysis 4.1

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 1 Hospital admission.

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Analysis 4.2

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 2 Hospital admission or poor response to treatment.

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Analysis 4.3

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 3 Duration in emergency department (minutes)..

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Analysis 4.4

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 4 Final rise in FEV₁ (% predicted).

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Analysis 4.5

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 5 30 minute rise in FEV₁ (% predicted).

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Analysis 4.6

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 6 Severe asthmatics final rise in FEV₁ (% predicted).

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Analysis 4.7

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 7 Final rise in peak flow (% predicted).

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Analysis 4.8

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 8 30 minute rise in peak flow (% predicted).

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Analysis 4.9

Comparison 4 Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups), Outcome 9 Rise in pulse rate (% baseline).

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Summary of findings for the main comparison. Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for children with acute asthma

Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for children with acute asthma
Patient or population: children with acute asthma Settings: Community or Emergency Department Intervention: Multiple treatments with beta₂‐agonist via spacer (chamber) Comparison: Multiple treatments with beta₂‐agonist via nebuliser
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Nebuliser	Multiple treatment of beta₂ ‐agonist via spacer (chamber)
Hospital admission	110 per 1000	78 per 1000 (52 to 119)	RR 0.71 (0.47 to 1.08)	757 (9 studies)	⊕⊕⊝⊝ low^1,2	Large increases in the proportion of children admitted to hospital on spacer in comparison to nebuliser are ruled out by this 95% confidence interval.
Duration in emergency department (minutes)	The mean duration in emergency department (minutes) in the control groups was 103 minutes	The mean duration in emergency department (minutes) in the intervention groups was 33 minutes shorter (43 minutes shorter to 24 minutes shorter)		396 (3 studies)	⊕⊕⊕⊝ moderate¹	There was a consistent direction of shortening of time in ED in all 3 studies, and although the size of this effect varied between studies (I² = 66%), we felt that the mean difference was important in all studies.
Final rise in FEV₁ (% predicted)	The mean final rise in FEV₁ (% predicted) in the control groups was 27% predicted at baseline	The mean final rise in FEV₁ (% predicted) in the intervention groups was 0.92% higher (4.96% lower to 6.79% higher)		48 (2 studies)	⊕⊕⊝⊝ low^1,2
Rise in pulse rate (% baseline)	The mean rise in pulse rate (% baseline) in the control groups was 7% rise from baseline	The mean rise in pulse rate (% baseline) in the intervention groups was 5.62% lower (7.52% to 3.72% lower)		670 (9 studies)	⊕⊕⊕⊝ moderate¹
Number of participants developing tremor	142 per 1000	91 per 1000 (62 to 135)	RR 0.64 (0.44 to 0.95)	254 (4 studies)	⊕⊕⊕⊝ moderate¹
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 Mostly open label studies ² Wide confidence intervals

Summary of findings for the main comparison. Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for children with acute asthma

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Summary of findings 2. Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for adults with acute asthma

Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for adults with acute asthma
Patient or population: Adults with acute asthma Settings: Community or Emergency Department Intervention: Multiple treatments with beta₂‐agonist via spacer (chamber) Comparison: Multiple treatments with beta₂‐agonist via nebuliser
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Nebuliser	Multiple treatment of beta₂ ‐agonist via spacer (chamber)
Hospital admission	109 per 1000	103 per 1000 (67 to 156)	RR 0.94 (0.61 to 1.43)	582 (9 studies)	⊕⊕⊕⊝ moderate^1,2
Duration in emergency department (minutes).	The mean duration in emergency department (minutes) in the control groups was 109 minutes	The mean duration in emergency department (minutes) in the intervention groups was 2 minutes longer (23 minutes shorter to 27 longer)		132 (2 studies)	⊕⊕⊕⊝ moderate²
Final rise in FEV₁(% predicted)	The mean final rise in FEV₁ (% predicted) in the control groups was 22 % predicted FEV₁	The mean final rise in FEV1 (% predicted) in the intervention groups was 0.96% higher (2.54 lower to 4.46 higher)		307 (6 studies)	⊕⊕⊕⊕ high^3,4
Rise in pulse rate (% baseline)	The mean rise in pulse rate (% baseline) in the control groups was ‐2% of baseline	The mean rise in pulse rate (% baseline) in the intervention groups was 1.23 lower (4.06 lower to 1.6 higher)		376 (7 studies)	⊕⊕⊕⊕ high^3,4
Number of participants developing tremor	185 per 1000	207 per 1000 (122 to 351)	RR 1.12 (0.66 to 1.9)	234 (4 studies)	⊕⊕⊕⊝ moderate^2,3
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 Mostly double‐blind studies. ² Confidence intervals too wide to assess whether either treatment is better. ³ All double‐blind studies. ⁴ Very small absolute differences.

Summary of findings 2. Multiple treatment of beta₂‐agonist via spacer (chamber) compared to nebuliser for adults with acute asthma

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Table 1. Details of spacers, design and location

Study ID	Spacer Type	Spacer Volume (mL)	Adults of Children	Number of subjects	Multiple or Single Treatments	Location	Study design
Ba 1989	Nebuhaler	750	Children	27	Multiple	Inpatients	Double dummy
Batra 1997	Volumatic	750	Children	60	Multiple	Casualty	Open
Burrows 2004	Volumatic	750	Children	29	Multiple	Inpatients	Open
Chong‐Neto 2005	Aerochamber and home‐made	145 or 500	Children	30	Multiple	Community	Dummy dry powder given to spacer group
Chou 1995	Aerochamber	145	Children	152	Multiple	Casualty	Open
Coker 1995	Volumatic	750	Children	24	Multiple	Inpatients	Open
Colacone 1993	Aerochamber	145	Adults	80	Multiple	Casualty	Double‐dummy
Dewar 1999	Volumatic	750	Children	62	Multiple	Inpatients	Open
Dhuper 2008	Lite Aire	160	Adults	58	Multiple	Casualty	Double‐dummy
Direkwatanachai 2008	Volumatic	750	Children	145	Multiple	Casualty & Outpatient Clinic	Open
Duarte 2002	home‐made	500	Children	196	Multiple	Casualty	Open
Ferrés 1989	unknown	750	Children	100	Single	Casualty	Open
Freelander 1984	Nebuhaler	750	Children	28	Single	Casualty	Open
Hussein 2002	"Large volume"	NS	Children	60	Single	Casualty	Open
Idris 1993	Inspirease	650	Adults	35	Multiple	Casualty	Double‐dummy
Jamalvi 2006	Babyhaler	350	Children	150	Multiple	Casualty	Open
Kerem 1993	Volumatic	750	Children	33	Single	Casualty	Double‐dummy
Leversha 2000	Aerochamber	145	Children	60	Multiple	Casualty	Double dummy
Lin 1995	Aerochamber	145	Children	111	Single	Casualty	Open
Maldano 1997	unknown	NS	Children	42	Multiple	Casualty	Open
Morley 1988	Inspirease	650	Adults	28	Multiple	Inpatients	Open
Morrone 1990	unknown	500	Adults	44	Single	Community	Open
Parkin 1995	Aerochamber	145	Children	65	Multiple	Inpatients	Open
Pendergast 1989	Nebuhaler	750	Children	27	Multiple	Casualty	Open
Ploin 2000	Babyhaler	350	Children	64	Multiple	Casualty	Double‐dummy
Raimondi 1997	Aerochamber	145	Adults	27	Multiple	Casualty	Open
Rao 2002	unknown	NS	Adults	50	Multiple	Casualty	Double‐dummy
Robertson 1998	Volumatic	750	Children	155	Single	Casualty	Double‐dummy
Rodrigo 1993	Volumatic	750	Adults	97	Multiple	Casualty	Double‐dummy
Rogrigo 1998	Volumatic	750	Adults	22	Multiple	Casualty	Double‐dummy
Rodriguez 1999	Volumatic	750	Adults	69	Multiple	Casualty	Open
Salzman 1989	Aerochamber	145	Adults	44	Single	Casualty	Double‐dummy
Sannier 2007	Varied according to child's home use	NS	Children	79	Multiple	Casualty	Open
Turner 1988	Inspirease	650	Adults	53	Multiple	Casualty	Double‐dummy
Valencia 1999	home‐made	500	Children	70	Multiple	Casualty	Open
Vazquez 1992	Volumatic	750	Children	18	Multiple	Casualty	Open
Vivek 2003	Nebuhaler	750	Adults	122	Multiple	Casualty	Open
Williams 1996	Aerochamber	145	Children	60	Multiple	Casualty	Open
Yasmin 2012	Home‐made spacer	250	Children	50	Multiple	Department of Paediatrics	Open

Table 1. Details of spacers, design and location

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Comparison 1. Spacer (chamber) versus nebuliser (multiple‐treatment studies)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospital admission Show forest plot	18		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Adults	9	582	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.61, 1.43]
1.2 Children	9	757	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.47, 1.08]
2 Hospital admission or poor response to treatment Show forest plot	21		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Adults	9	582	Risk Ratio (M‐H, Fixed, 95% CI)	0.94 [0.61, 1.43]
2.2 Children	12	937	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.75, 1.33]
3 Duration in emergency department (minutes). Show forest plot	5		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Adults	2	132	Mean Difference (IV, Random, 95% CI)	1.75 [‐23.45, 26.95]
3.2 Children	3	396	Mean Difference (IV, Random, 95% CI)	‐33.48 [‐43.32, ‐23.65]
4 Final rise in FEV₁ (% predicted) Show forest plot	8		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 Adults	6	307	Mean Difference (IV, Fixed, 95% CI)	0.96 [‐2.54, 4.46]
4.2 Children	2	48	Mean Difference (IV, Fixed, 95% CI)	0.92 [‐4.96, 6.79]
5 30 minute rise in FEV₁ (% predicted) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 Adults	3	200	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐3.18, 2.78]
6 Severe asthmatics final rise in FEV₁ (% predicted) Show forest plot	4		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 Adults	4	94	Mean Difference (IV, Fixed, 95% CI)	1.60 [‐4.49, 7.69]
7 Final rise in peak flow (% predicted) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.1 Adults	3	139	Mean Difference (IV, Fixed, 95% CI)	‐0.49 [‐4.60, 3.63]
7.2 Children	3	166	Mean Difference (IV, Fixed, 95% CI)	‐2.99 [‐8.88, 2.91]
8 30 minute rise in peak flow (% predicted) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

8.1 Adults	2	147	Mean Difference (IV, Fixed, 95% CI)	0.92 [‐2.68, 4.51]
9 Rise in pulse rate (% baseline) Show forest plot	16		Mean Difference (IV, Random, 95% CI)	Subtotals only

9.1 Adults	7	376	Mean Difference (IV, Random, 95% CI)	‐1.23 [‐4.06, 1.60]
9.2 Children	9	670	Mean Difference (IV, Random, 95% CI)	‐5.41 [‐8.34, ‐2.48]
10 % Oxygen saturation (change from baseline) Show forest plot	6		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

10.1 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Children	6	476	Mean Difference (IV, Fixed, 95% CI)	‐0.19 [‐0.61, 0.24]
11 Number of participants developing tremor Show forest plot	8		Risk Ratio (IV, Random, 95% CI)	Subtotals only

11.1 Adults	4	234	Risk Ratio (IV, Random, 95% CI)	0.82 [0.28, 2.37]
11.2 Children	4	254	Risk Ratio (IV, Random, 95% CI)	0.64 [0.44, 0.95]
12 Number of participants given steroids Show forest plot	4		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12.1 Adults	2	88	Risk Ratio (M‐H, Random, 95% CI)	0.71 [0.08, 6.02]
12.2 Children	2	297	Risk Ratio (M‐H, Random, 95% CI)	1.12 [0.95, 1.32]
13 Rise in respiratory rate (breaths per minute) Show forest plot	13		Mean Difference (IV, Random, 95% CI)	Subtotals only

13.1 Adults	5	257	Mean Difference (IV, Random, 95% CI)	0.28 [‐2.29, 2.84]
13.2 Children	8	686	Mean Difference (IV, Random, 95% CI)	‐0.94 [‐2.84, 0.97]

Comparison 1. Spacer (chamber) versus nebuliser (multiple‐treatment studies)

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Comparison 2. Spacer (chamber) versus nebuliser (single‐treatment studies)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospital admission Show forest plot	5		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

1.1 Adults	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
1.2 Children	4		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2 Final peak flow (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 30 minute rise in FEV₁ (% predicted) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 15 minute rise in FEV₁ (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

4.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 30 minute rise in peak flow (% predicted) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

5.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Children	2		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 15 minute rise in peak flow (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

6.1 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Rise in pulse rate (% baseline) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Children	2		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Number of participants developing tremor Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

8.1 Children	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Number of participants with deterioration in blood gases Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

9.1 Children	2		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
10 Rise in respiratory rate Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

10.1 Adults	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 2. Spacer (chamber) versus nebuliser (single‐treatment studies)

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Comparison 3. Spacer (chamber) versus nebuliser (inpatient studies)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Duration of hospital admission (days) Show forest plot	3		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

1.1 Adults	1	18	Mean Difference (IV, Fixed, 95% CI)	‐0.60 [‐3.23, 2.03]
1.2 Children	2	75	Mean Difference (IV, Fixed, 95% CI)	0.33 [‐0.10, 0.76]
2 Number of hours until reached 4‐hourly dosing regimen Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

2.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3 Total number of inhaled doses received Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

3.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Number of participants returning to normal PEFR and respiratory score levels (end of study) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Adults	0		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Children	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5 Number of symptom‐free participants 14 days post‐discharge Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

5.1 Adults	0		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
5.2 Children	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6 Readmissions in the subsequent 12 months Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

6.1 Adults	0		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
6.2 Children	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
7 Clinical asthma score (end of trial) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

7.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
7.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8 Maximum percentage decrease in respiratory score Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
8.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Respiratory rate at discharge Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

9.1 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9.2 Children	2	75	Mean Difference (IV, Fixed, 95% CI)	‐0.91 [‐3.20, 1.38]
10 Heart rate at discharge Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

10.1 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
10.2 Children	2	76	Mean Difference (IV, Fixed, 95% CI)	1.06 [‐5.48, 7.61]
11 Oxygen saturations at discharge Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

11.1 Adults	0	0	Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
11.2 Children	2	76	Mean Difference (IV, Fixed, 95% CI)	0.12 [‐0.42, 0.66]
12 30 minute rise in FEV₁ Show forest plot	2		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected

12.1 Adults	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
12.2 Children	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13 Final rise in FEV₁ Show forest plot	2		Std. Mean Difference (IV, Fixed, 95% CI)	Totals not selected

13.1 Adults	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
13.2 Children	1		Std. Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14 Final rise in peak flow (% change from baseline) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

14.1 Adults	0		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
14.2 Children	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 3. Spacer (chamber) versus nebuliser (inpatient studies)

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Comparison 4. Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Hospital admission Show forest plot	16		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Adults with other spacers	6	366	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.55, 2.84]
1.2 Adults with Volumatic	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.51, 1.38]
1.3 Children with other spacers	6	515	Risk Ratio (M‐H, Fixed, 95% CI)	0.61 [0.39, 0.96]
1.4 Children with Volumatic	2	163	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.05, 6.11]
2 Hospital admission or poor response to treatment Show forest plot	19		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2.1 Adults with other spacers	6	366	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.55, 2.84]
2.2 Adults with Volumatic	2	166	Risk Ratio (M‐H, Fixed, 95% CI)	0.84 [0.51, 1.38]
2.3 Children with other spacers	8	635	Risk Ratio (M‐H, Fixed, 95% CI)	0.80 [0.55, 1.16]
2.4 Children with Volumatic	3	223	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.79, 2.13]
3 Duration in emergency department (minutes). Show forest plot	4		Mean Difference (IV, Random, 95% CI)	Subtotals only

3.1 Adults with other spacers	1	35	Mean Difference (IV, Random, 95% CI)	‐9.0 [‐42.91, 24.91]
3.2 Adults with Volumatic	1	97	Mean Difference (IV, Random, 95% CI)	15.00 [‐22.65, 52.65]
3.3 Children with other spacers	2	348	Mean Difference (IV, Random, 95% CI)	‐29.89 [‐40.47, ‐19.32]
4 Final rise in FEV₁ (% predicted) Show forest plot	7		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 Adults with other spacers	3	168	Mean Difference (IV, Fixed, 95% CI)	0.30 [‐4.70, 5.30]
4.2 Adults with Volumatic	2	119	Mean Difference (IV, Fixed, 95% CI)	1.20 [‐4.13, 6.53]
4.3 Children with other spacers	1	30	Mean Difference (IV, Fixed, 95% CI)	0.0 [‐6.17, 6.17]
4.4 Children with Volumatic	1	18	Mean Difference (IV, Fixed, 95% CI)	9.8 [‐9.41, 29.01]
5 30 minute rise in FEV₁ (% predicted) Show forest plot	2		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

5.1 Adults with other spacers	1	53	Mean Difference (IV, Fixed, 95% CI)	‐3.80 [‐8.51, 0.91]
5.2 Adults with Volumatic	1	97	Mean Difference (IV, Fixed, 95% CI)	1.5 [‐3.07, 6.07]
6 Severe asthmatics final rise in FEV₁ (% predicted) Show forest plot	4		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

6.1 Adults with other spacers	3	55	Mean Difference (IV, Fixed, 95% CI)	0.86 [‐6.77, 8.48]
6.2 Adults with Volumatic	1	39	Mean Difference (IV, Fixed, 95% CI)	2.90 [‐7.21, 13.01]
7 Final rise in peak flow (% predicted) Show forest plot	5		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

7.1 Adults with Volumatic	2	119	Mean Difference (IV, Fixed, 95% CI)	‐0.39 [‐4.77, 3.98]
7.2 Children with other spacers	2	148	Mean Difference (IV, Fixed, 95% CI)	‐3.75 [‐9.95, 2.45]
7.3 Children with Volumatic	1	18	Mean Difference (IV, Fixed, 95% CI)	4.10 [‐14.81, 23.01]
8 30 minute rise in peak flow (% predicted) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Totals not selected

8.1 Adults with Volumatic	1		Mean Difference (IV, Fixed, 95% CI)	0.0 [0.0, 0.0]
9 Rise in pulse rate (% baseline) Show forest plot	13		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

9.1 Adults with other spacers	3	168	Mean Difference (IV, Fixed, 95% CI)	‐2.28 [‐7.81, 3.24]
9.2 Adults with Volumatic	3	188	Mean Difference (IV, Fixed, 95% CI)	‐0.16 [‐3.89, 3.58]
9.3 Children with other spacers	5	464	Mean Difference (IV, Fixed, 95% CI)	‐6.80 [‐9.14, ‐4.45]
9.4 Children with Volumatic	2	78	Mean Difference (IV, Fixed, 95% CI)	‐6.73 [‐11.24, ‐2.23]

Comparison 4. Spacer (chamber) versus nebuliser (multiple‐treatment studies with Volumatic subgroups)

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