aastma anticolinergic

7/27/2019 aastma anticolinergic

1/79

Combined inhaled anticholinergics and beta2-agonists for

initial treatment of acute asthma in children (Review)

Plotnick L, Ducharme F

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published inThe Cochrane Library2008, Issue 4http://www.thecochranelibrary.com

Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review)

Copyright 2008 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
http://www.thecochranelibrary.com/http://www.thecochranelibrary.com/


2/79

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

10DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11AUTHORS CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

12REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

35DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE,

Outcome 1 Admission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42


Outcome 2 -(Change in % Pred FEV1 at 60 minutes after IB) +/- 15 minutes. . . . . . . . . . . . 43


Outcome 3 - (Change in % Pred FEV1 at 120 minutes after IB) +/- 30 minutes. . . . . . . . . . . . 44


Outcome 4 - (% Change in FEV1 at 60 minutes after IB) +/- 15 minutes. . . . . . . . . . . . . . 45

Analysis 1.5. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE,Outcome 5 - (% Change in FEV1 at 120 minutes after IB) +/- 30 minutes. . . . . . . . . . . . . 46


Outcome 6 % Change in Respiratory resistance at 60 minutes after IB +/- 15 minutes. . . . . . . . . 47


Outcome 7 % Change in Respiratory resistance at 120 minutes after IB +/- 30 minutes. . . . . . . . . 48


Outcome 8 Change in clinical score at 60 minutes +/- 15 minutes. . . . . . . . . . . . . . . . 49


Outcome 9 Change in clinical score at 120 minutes +/- 30 minutes. . . . . . . . . . . . . . . . 50

Analysis 1.10. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST

ALONE, Outcome 10 O2 Saturation


3/79

Analysis 2.1. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST

ALONE - FIXED PROTOCOL, Outcome 1 Admission. . . . . . . . . . . . . . . . . . . . 58Analysis 2.2. Comparison 2 ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST

ALONE - FIXED PROTOCOL, Outcome 2 - (Change in % Pred FEV1 at 60 minutes after last IB) +/- 20 minutes. 59


ALONE - FIXED PROTOCOL, Outcome 4 - (% Change in FEV1 or PEFR at 60 minutes after last IB) +/- 15

minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60


ALONE - FIXED PROTOCOL, Outcome 5 -( % Change in FEV1 or PEFR at 120 minutes after last IB) +/- 30

minutes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61


ALONE - FIXED PROTOCOL, Outcome 7 Change in clinical score at 120 minutes +/- 30 minutes. . . . 62


ALONE - FIXED PROTOCOL, Outcome 8 O2 Saturation = 4 inhalations required prior to disposition. . . . . . . 71

Analysis 3.3. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS

ALONE - TITRATRATION PROTOCOL, Outcome 3 Need for corticosteroids in emergency department prior to

disposition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Analysis 3.4. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE

- TITRATRATION PROTOCOL, Outcome 4 Tremor. . . . . . . . . . . . . . . . . . . . 72


- TITRATRATION PROTOCOL, Outcome 5 Vomiting. . . . . . . . . . . . . . . . . . . 73


- TITRATRATION PROTOCOL, Outcome 6 Nausea. . . . . . . . . . . . . . . . . . . . 74Analysis 3.7. Comparison 3 ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE

- TITRATRATION PROTOCOL, Outcome 7 Admission. . . . . . . . . . . . . . . . . . . 75

75WHATS NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

75HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

76INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iiCombined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review)



4/79

[Intervention Review]

Combined inhaled anticholinergics and beta2-agonists forinitial treatment of acute asthma in children

Laurie Plotnick1, Francine Ducharme2

1Department of Paedriatrics, The Montreal Childrens Hospital, McGill University, Montreal, Canada. 2Department of Pediatrics,

McGill University Health Centre, Montreal, Canada

Contact address: Laurie Plotnick, Department of Paedriatrics, The Montreal Childrens Hospital, McGill University, Room C538E,

2300 Tupper Street, Montreal, Quebec, H3H 1P3, [email protected].

Editorial group:Cochrane Airways Group.Publication status and date: Edited (no change to conclusions), published in Issue 4, 2008.

Review content assessed as up-to-date: 24 April 2000.

Citation: Plotnick L, Ducharme F. Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in

children.Cochrane Database of Systematic Reviews2000, Issue 3. Art. No.: CD000060. DOI: 10.1002/14651858.CD000060.


A B S T R A C T

Background

Several randomized controlled trials have examined, with conflicting results, the efficacy of the addition of anticholinergics to beta2agonists in acute pediatric asthma. The pooling for a larger number of randomized controlled trials may provide not only greater power

for detecting group differences and also provide better insight into the influence of patients characteristics and treatment modalities

on efficacy.

Objectives

The aims of this study were to estimate the therapeutic and adverse effects attributable to the addition of inhaled anticholinergics to

beta2 agonists in acute pediatric asthma.

Search strategy

We searched MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000), CINAHL (1982 to April 2000) and reference lists of

studies. We also contacted drug manufacturers and trialists.

Selection criteriaRandomised trials comparing the combination of inhaled anticholinergics and beta2 agonists with beta2 agonists alone in children

aged 18 months to 17 years with acute asthma.

Data collection and analysis

Assessments of trial quality and data extraction were done by two reviewers independently.

Main results

Of the 40 identified trials, 13 were relevant and eight of these were of high quality. The addition of a single dose of anticholinergic

to beta2 agonists did not reduce hospital admission [RR=0.93 (95% CI: 0.65, 1.32)]. However, significant group differences in lung

function supporting the combination of anticholinergics and beta2-agonists were observed 60 minutes [SMD=0.57 (95% CI:0.21,

0.93)] and 120 minutes [SMD=0.53 (95% CI: 0.17, 0.90)] after the dose of anticholinergic. In contrast, the addition of multiple doses

of anticholinergics to beta2 agonists reduced the risk of hospital admission by 25% [RR=0.75 (95% CI: 0.62,0.89)] in children with

1Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children (Review)

mailto:[email protected]:[email protected]


5/79

predominantly moderate and severe exacerbations. Twelve (95% CI: 8, 32) children would need to be treated to avoid one admission.

When restricting this strategy to children with severe exacerbations, seven (95% CI: 5, 20) children need to be treated to avoid anadmission. At 60 minutes after the last anticholinergic inhalation, a weighted mean group difference of 9.68 in change in % predicted

FEV1 [95% CI:5.70, 13.68] favoured anticholinergic use. In the two studies where anticholinergics were systematically added to every

beta2 agonist inhalation, irrespective of asthma severity, no group differences were observed for the few available outcomes. There was

no increase in the amount of nausea, vomiting or tremor in patients treated with anticholinergics.

Authors conclusions

A single dose of an anticholinergic agent is not effective for the treatment of mild and moderate exacerbations and is insufficient for

the treatment of severe exacerbations. Adding multiple doses of anticholinergics to beta2 agonists appears safe, improves lung function

and would avoid hospital admission in 1 of 12 such treated patients. Although multiple doses should be preferred to single doses of

anticholinergics, the available evidence only supports their use in school-aged children with severe asthma exacerbation. There is no

conclusive evidence for using multiple doses of anticholinergics in children with mild or moderate exacerbations.

P L A I N L A N G U A G E S U M M A R Y

Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children

In an asthma attack, the airways (passages to the lungs) narrow from muscle spasms. Bronchodilators (reliever inhalers) relax the muscles

in the airways, opening the airways so breathing is easier. Anti-cholinergic drugs can also affect these muscles, and so are sometimes

used as well as bronchodilators when children have severe asthma attacks. The review of trials found using both drugs together improves

outcomes forchildrenwith severeasthma attacks, although there is notenough evidence about effectsfor children with mild or moderate

attacks. More research on possible adverse effects of the extra drug is needed, although it seems safe.

B A C K G R O U N D

The initial management of acute pediatricasthma exacerbations in

children focuses on the rapid relief of bronchospasm using inhaled

or nebulized bronchodilators (BMA 1992;Boulet 1999; Guide-

lines, 1993; Mitchell 1992; Rachelefsky 1993; Warner 1989).

Children who are incompletely responsive to bronchodilators re-

quire the addition of glucocorticoids (Scarfone 1993;Tal 1990).

Beta2- agonists are clearly the most effective bronchodilators due

to their rapid onset of action and the magnitude of achieved bron-chodilation (Sears 1992 SVedmyr 1985). Anticholinergic agents,

such as ipratropium bromide and atropine sulfate, have a slower

onset of action and weaker bronchodilating effect, but may specif-

ically relieve cholinergic bronchomotor tone and decrease mucosal

edema and secretions (Chapman 1996; Gross 1988;Silverman

1990). Thus, the combination of inhaled anticholinergics with

beta2 agonists may yield enhanced and prolonged bronchodila-

tion.

Several randomized controlled trials (RCTs) have examined, with

conflicting results, the efficacy of the addition of anticholinergics

to beta2 agonists in acute pediatric asthma (Cook 1985, Guill

1987;Reisman 1988,Watson 1988). The conflicting results were

attributed to differences in the asthma severity, intensity of anti-

cholinergic treatment, co-intervention with glucocorticoids, and

study power. The pooling for a larger number of RCTs may pro-

vide not only greater power for detecting group differences in hos-

pitaladmission, butalso betterinsight forthe influence of patients

characteristics and treatment modalities on efficacy (Greenhalgh

1997;Peto 1995;Sackett 1995).

A systematic review of RCTs published until 1992 concluded to a

12% greater improvement in % predicted FEV1 with anticholin-ergic use but with no reduction in hospital admission (Osmond

1995). Our previous Cochrane Review published in 1997 con-

cluded to a significant reduction in hospital admissions in school-

aged children with severe exacerbations receiving intensive anti-

cholinergic treatment. Because three more trials have been pub-

lished since our original Cochrane review, an update was required.

O B J E C T I V E S

The aim of this systematic review was to determine whether the

addition of inhaled anticholinergics to beta2 agonists provides




6/79

clinical improvement and affects the incidence of adverse effects

in children with acute asthma exacerbations. Moreover, we wishedto determine whether the intensity of treatment, severity of the

exacerbation and concomitant use of glucocorticoids influenced

the magnitudeof the effectattributableto inhaled anticholinergics.

M E T H O D S

Criteria for considering studies for this review

Types of studiesAll randomized controlled clinical trials conducted in an emer-

gency department setting, comparing the combination of inhaled

anticholinergic agents and beta2 agonists with short-acting beta2

agonists alone in the treatment of an acute unprovoked asthma

exacerbation, were considered for this review.

Types of participants

Children aged 18 months to 17 years presenting to an emergency

department withan acuteunprovoked (spontaneous) exacerbation

of asthma.

Types of interventions

Treatment group: Single or repeated doses of nebulized or inhaled

short-acting anticholinergic and beta2 agonists.

Control group: Single or repeated doses of nebulized or inhaled

placebo and short-acting beta2 agonists.

Types of outcome measures

Primary outcomes

Hospital admission

Secondary outcomes

1. Change from baseline in %Predicted FEV1, 60 and 120

minutes after the last combined anticholinergic and beta2

agonist inhalation

2. Percent change from baseline in FEV1, 60 and 120 minutes

after the last combined inhalation

3. Change from baseline in respiratory resistance, 60 and 120

minutes after the last combined inhalation

4. Change from baseline in clinical score, 60 and 120 minutes

after the last combined inhalation

5. Oxygen Saturation, 60 and 120 minutes after the last

combined inhalation6. Number of additional bronchodilator treatments required

after the intervention/placebo protocol, prior to disposition

7. Need for systemic corticosteroids

8. Adverse effects such as nausea, vomiting and tremor

9. Relapse rate

Search methods for identification of studies

Electronic searches

MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000)and CINAHL (1982 to April 2000) were searched using the fol-

lowing MeSH, full text, and keyword terms: [asthma, wheez* or

respiratory sounds] and [random*, trial*, placebo*, comparative

study, controlled study, double-blind, single-blind] and [child* or

infan* or adolescen* or pediatr* or paediatr*] and [emergenc* or

acute*] and [ipratropium* or anticholinerg* or atropin*].

Searching other resources

Randomized controlled trials identified by the hand-searching of

medical journals through the Cochrane Collaboration were sur-

veyed using the same terms.

Bibliographies of all trials and review articles identified above werechecked to identify potentially relevant citations.

Inquiries were made to Boehringer Ingelheim, producer of iprat-

ropium bromide, regarding other published or unpublished trials

conducted worldwide and supported by this company or its sub-

sidiaries.

Personal contact was made with trialists working in the field of

pediatric asthma to identify potentially relevant trials.

Data collection and analysis

Selection of studies

Each citation (title and abstract) identified through one of the

above strategies was then reviewed by one reviewer and classified

as definite, possible, or clearly not randomized controlled trial.

The complete article of all citations identified as definite or possi-

ble randomized controlled trials was obtained, irrespective of lan-

guage of publication. These were assessed independently by two

reviewers to determine if the study met the inclusion criteria and,

if so, to evaluate methodological quality and extract data. Review-

ers were masked to the authors names and affiliations, name of

journal, date of publication, and sources of funding for the study.

Disagreement between the reviewers was settled by consensus.




7/79

Data extraction and management

Two authors independently extracted data from eligible studies.For most outcomes, the data was stratified based on the use of cor-

ticosteroids (presence/absence/not described) as co-intervention.

The need for corticosteroids was also added as an outcome for

study protocols which left the choice of such co-intervention to

the discretion of the treating physician. In this case, the addition

of corticosteroids to the standard protocol is generally viewed as

an indicator of poor patient response. In addition, whenever pos-

sible, studies were stratified based on the baseline severity of the

patients (mild, moderate or severe asthma) using spirometry or

clinical score.

Assessment of risk of bias in included studiesWe have assessed the risk of bias for each study according to the

allocation procedures and blinding. Each judgement is listed for

each study inCharacteristics of included studies.

The methodological quality of each trial was assessed by two dif-

ferent methods. First, the quality of blinding was ranked using

the Cochrane Approach and recorded under Allocation Conceal-

ment: A refers to adequate concealment, B refers to uncer-

tainty about adequacy of concealment, C refers to clearly inad-

equate concealment.

Jadads 5-point instrument was also used to evaluate the reported

quality of randomization and blinding, and the description of

withdrawals and dropouts. (Jadad 1995) This blind assessment

has been shown to be valid and associated with high inter-raterreliability. Jadads score was recorded for each study under Table

of included studies: Method (maximum=5, minimum=0).

Inter-reviewer agreement in the assessment of methodological

quality was calculated using the weighted kappa with quadratic

means.

Dealing with missing data

The reviewersattemptedto contact the firstauthor, or all coauthors

in cases of non-response, of each RCT, by post, fax or e-mail, on

at least three occasions to verify study methodology and extracted

information and to provide additional data, if necessary.

Data synthesis

Data were entered into Review Manager software.

Treatment effects for dichotomous outcomes were reported as

pooled relative risks (RR) using the fixed effect model (Greenland

1985) or, in case of heterogeneity, the random effect model

(DerSimonian 1986). The Dersimonian and Laird model was ap-

plied to estimate the pooled absolute risk reduction and, therefore,

estimate the number of patients needed to treat to prevent the

adverse outcome of interest (DerSimonian 1986).

For continuous outcomes, the weighted mean difference or the

standardized weighted mean difference was used to estimate the

pooled effect size (Olkin 1995). The weighted mean difference

was reported for pulmonary function tests using the same unit ofmeasure: it is the weighted sum of each trials difference between

the mean of the experimental and the control group, reported

in the same scale as the pulmonary function test (Olkin 1995).

The standardized mean difference, reported in standard deviation

units, was used when the change in the same pulmonary function

test was reported in different units (change in % predicted FEV1

and % change in FEV1): it is the weighted sum of each trials

group mean difference divided by its pooled standard deviation

(Hasselblad 1995). The contribution of each trial to the pooled

estimate is proportional to the inverse of the variance (Robins

1986). Homogeneity of effect sizes were tested with the Dersimo-

nian and Laird method with P=0.10 as the cut-off for significance

(DerSimonian 1986); heterogeneity was reported whenever iden-tified. In an effort to detect possible biases, funnel plot symmetry

was examined for trials contributing data to hospital admission

(Egger 1997). The pooled effect sizes are presented with the 95%

Confidence Interval (CI).

In order to evaluate the effectof baseline severity on the magnitude

of response to the intervention, each study was also ranked numer-

ically in increasing order of severity using the admission rate ob-

served in the control group. The admission rate is reported in the

user-defined order. If the admission rate for a particular study

was not available, that study was not ranked. Ranking of severity

based on admission rate in the control group corresponded very

closely to ranking based on mean baseline % predicted FEV1 in

the studies which reported it. Ranking on admission rate permit-ted the inclusion of studies which did not use spirometry or did

not report mean baseline % predicted FEV1.

Subgroup analysis and investigation of heterogeneity

Five factors were a prioribelieved to potentially influence the mag-

nitude and/or direction of the therapeutic response, namely the

1) intensity of anticholinergic treatment, 2) co-intervention with

glucocorticoids, 3) severity of exacerbation, 4) methodological

quality, and 5) publication status. RCTs were therefore grouped

according to the intensity of anticholinergic protocol and, within

each group, stratified on the presence/absence of systemic glu-cocorticoids. Whenever reported, the baseline percent predicted

forced expiratory volume in 1 second (FEV1) and hospital admis-

sion rate in the control groups were recorded as indicators of sever-

ity and examined for their potential interaction with therapeutic

effect.

Sensitivity analysis

Sensitivity analyses were performed to examine the effect on re-

sults of excluding unpublished trials and those with poor method-

ological quality.




8/79

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excluded

studies.

Results of the search

Forty studies were reviewed in full text for possible inclusion; 37

studies were identified by the literature search and bibliographies

and 3 studies were identified by contact with trialists. A total of

13 randomized controlled trials were selected for inclusion.

Included studies

Trials were grouped according to the intensity of the anticholin-

ergic protocol: trials testing the addition of a single dose of an-

ticholinergic to the beta2 agonist inhalations were grouped un-

der single dose protocol, trials testing multiple doses in a pre-

determined fixed regimen were grouped under multiple dose-

fixed protocol, while trials testing the systematic addition of an-

ticholinergics to every beta2 agonist inhalation, leaving the num-

ber of inhalations determined by the patients needs, were named

multiple dose-flexible protocol. One trial, which tested two pro-

tocols, contributed to the first two strata (Schuh 1995). With oneexception (Guill 1987), ipratropium bromide was used as the an-

ticholinergic agent.

Five trials contributed data to the single dose protocol. The

patients enrolled to this protocol were aged 3-17 years and varied

from mild to severe asthma severity, based on spirometry and/

or clinical score. Two trials (Beck 1985; Schuh 1995) focused

on children with severe exacerbations with a baseline FEV1 of


9/79

Figure 1. Methodological quality summary: review authors judgements about each methodological quality

item for each included study.




10/79

The inter-rater agreement on methodological quality (Jadadsscore) was high (weighted kappa = 0.93). When scoring the qual-

ity of the studies, disagreement arose with one study (Cook 1985)

and the quality score was easily achieved by consensus. Method-

ology of nine of the thirteen trials was confirmed by the authors

(Calvo 1998;Cook 1985;Ducharme 1998;Guill 1987;Peterson

1996; Qureshi 1997; Qureshi 1998 (sev); Schuh 1995; Zorc 1999

(mod)) and most (N=8) were of high quality (Jadads quality score

>=4) (see Table of Included Studies).

Studies were ranked in increasing order of severity using the ad-

mission rate of the control group as user-defined order. The rank-

ing varied from 0 to 0.53. Four studies were not ranked because

admission rates were not provided (Beck 1985;Cook 1985,Guill

1987;Phanichyakam 1990).RANDOMIZATION

Randomization wasperformed using computer-generated random

numbers in four studies (Ducharme 1998;Guill 1987;Peterson

1996; Zorc JJ 1999 (mil)), tablesof randomnumbersin three trials

(Qureshi 1997;Qureshi 1998 (mod),Schuh 1995), 1 trial (Calvo

1998) used non-randomized consecutive assignment; and the re-

maining four studies failed to describe the method of random-

ization. Regarding means of allocation, nine studies used num-

ber-coded solutions supplied by the pharmacy (Beck 1985;Calvo

1998;Ducharme 1998;Peterson 1996;Qureshi 1997;Qureshi

1998 (sev); ;Reisman 1988;Schuh 1995,Zorc 1999 (sev)), one

study used opaque consecutive numbered envelopes containing

assignment (Guill 1987) and three studies did not describe the

means of allocation.

BLINDING

Eleven studies claimed double-blinding while the other two

claimed triple-blinding (Ducharme 1998; Peterson 1996). Ten

studies used an identical placebo in the control group, one study

described a similarly-looking intervention and placebo solutions

(Cook 1985), andtwo studies failedto provide details of the blind-

ing (Phanichyakam 1990;Watson 1988).

WITHDRAWAL/DROPOUT

Ten studies reported the presence/absence of patient withdrawal

or dropout and the reasons for the attrition if applicable (Calvo

1998;Cook 1985;Ducharme 1998;Guill 1987;Peterson 1996;Qureshi 1997;Qureshi 1998 (mod);Schuh 1995;Watson 1988;

Zorc 1999 (sev)).

Effects of interventions

SINGLE DOSE PROTOCOLS (N=5)

Five trials totaling 453 patients examined the efficacy of adding a

single dose of 250ug ipratropium bromide to beta2-agonists. With

regards to the primary endpoint, no reduction in hospital admis-

sion was observed when pooling two trials (allocating participants

to three treatment-control comparisons) RR 0.93 95% CI 0.65 to

1.32,Figure 2; with no apparent heterogeneity. Both trials were

published and of high methodological quality.




11/79

Figure 2. Forest plot of comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-

AGONIST ALONE, outcome: 1.1 Admission.

Stratification on the presence/absence of co-intervention with cor-

ticosteroids suggested a trend towards a reduced risk of admission

in children not so treated [RR 0.73 (0.46, 1.17)] as compared to

those treated with systemic corticosteroids [RR 1.22 (0.69, 2.55)].

This suggests that co-intervention with corticosteroids may be a

confounder for admission.

Four trials examined response to treatment using pulmonary func-

tion tests. In the two trials reporting the % change in FEV1 a dif-

ference of 16.10% [95% CI: 5.54, 26.66]% between group means

was documented at 60 minutes and of 17.49% (4.46, 30.53)% at

120 minutes after the inhalation of anticholinergics, both favour-

ing anticholinergic use (Beck 1985;Phanichyakam 1990). How-ever, when combining the three trials reporting change in lung

function, either as change in % predicted FEV1 or % change

from baseline FEV1, significant improvement, equivalent to half

a standard deviation in change, was still apparent at 60 minutes

[standardized mean difference=0.57 (0.21, 0.93)] and at 120 min-

utes [standardized mean difference=0.53 (0.17, 0.90)] after the

dose of anticholinergics (Beck 1985 Phanichyakam 1990;Schuh

1995). In the single trial examining the intervention in the two

strata of children with mild to moderate exacerbations, the ab-

sence of group difference observed at 60 minutes [WMD=0.02

(-0.02,0.07)] and at 120 minutes [WMD=-0.01 ( -0.09, 0.07)]

confidently ruled out any important change in respiratory re-

sistance due to treatment (Ducharme 1998).There were no sig-

nificant group differences in clinical score at 60 minutes [N=

2; WMD=-0.06 (-0.26, 0.14)] or 120 minutes [N=2; WMD =

0.13 (-0.22,0.48)], in oxygen saturation at 60 minutes [N=2; RR=

0.75 (0.55,1.01)] or 120 minutes [N=2; RR=1.10 (0.76,1.60)],

in the need for additional inhalation(s) after the standard pro-

tocol prior to disposition to admission or discharge [N=2; RR=

1.05 (0.78,1.41): ] and relapse to additional care [N=2; RR=1.17

(0.56,2.45)].

The addition of a singledose of anticholinergics was notassociatedwith increased tremor [N=2; RR =1.18 (0.72, 1.94)]. Due to the

insufficient (


12/79


13/79


14/79

identification of a significant reduction in hospital admission in

patients with moderate exacerbations (baseline FEV1 of 50-70%predicted or moderate clinical score or 25-30% admission rate in

the control population).

Regarding lung function, significant group differences favouring

the combination treatment were also observed, whether the re-

sponse was expressed as change in % predicted FEV1 or as %

change in FEV1 in trials examining children with baseline FEV1

of 30-70%of predicted. While modest, theextent of improvement

in lung function is probably clinically meaningful as it was asso-

ciated with a substantial reduction in hospital admissions. Three

studies systematically administered glucocorticoids to all enrolled

children (Qureshi 1997; Qureshi 1998 (sev); Zorc 1999 (sev)).

All these studies showed favourable effects of the combination of

multiple doses of anticholinergics and beta2 agonist that were sus-tained in the presence of glucocorticoids. Furthermore, in two tri-

als which enrolled children with all spectrum of severity, the use

of combination therapy resulted in a significant 19% reduction in

the need for additional inhalations after the fixed protocol prior

to disposition: In other words, 8 (95% CI: 5, 29) children would

need to be treated with 2 to 3 doses of anticholinergics to prevent

one or more additional inhalations.

Multiple Dose-Flexible Protocols

Two small trials examined the efficacy of systematically adding

anticholinergics to every beta2 agonist inhalation, tailoring the

number of inhalations to patients response. The systematic addi-tion of anticholinergics to every inhalation was associated with a

non-significant trend towards reducing the number of inhalations

needed. No data could be pooled regarding hospital admission or

other measures of efficacy. Although this protocol most closely re-

flects physicians treatment preference when dealing with children

with mild to moderate asthma, more trials are required to confirm

these trends before any conclusion can be drawn.

Side Effects

No apparent increase in the occurrence of nausea, vomiting or

tremor were observed among subjects treated with either the sin-

gle or multiple dose protocols. Clinically important adverse ef-fects, such as tachycardia or hypertension, were reported too in-

frequently to permit any analyses.

Strengths and Limitations

Like all systematic reviews, this meta-analysis is limited by the

quality of existing data (Khan 1996). Fortunately, most trials (8/

13) were of high quality. Exclusion of trials with lower reported

methodological quality did not affect the conclusions. Funnel plot

failed to identify any publication or other bias, although its sensi-

tivity is somewhat limited by the small number trials. With 10 of

the 13 trials originating from North America, the generalisability

of study results to other countries should be considered, partic-

ularly with regards to the hospital admission. Large geographicalvariations in hospital admission rates have been predominantly at-

tributed to differences in asthma severity, use of daily prophylaxis,

intensity of emergency treatment, and admission criteria (Payne

1995;Homer 1996). Clearly, important international variations

in these factors could influence the anticipated response to treat-

ment.

Our thorough systematic search for published and unpublished

trials resulted in identification of important trials, thus increasing

the power and scope of the review (Cook 1993). Our review is

strengthened by the direct confirmation of methodology and of

extracted data with the authors of nine of thirteen trials. Never-

theless, the number and size of studies being pooled under each

protocol remains small. Obviously, the present conclusions maybe modified in the light of future trials.

The present review summarizes the best evidence available to April

2000. This first update identified 3 new trials not included in

our first Cochrane review published in 1997. Our conclusion re-

garding the single dose protocol remains unchanged due to the

absence of new trials. With two additional trials in the multiple-

dose fixed protocol, we confirmed our prior findings supporting

the addition of multiple doses of anticholinergics to beta2-ago-

nists for reducing hospital admission and improving lung func-

tion in children with severe exacerbations. A new finding indicates

that the use of an intensive fixed protocol also reduces the need

for additional bronchodilator inhalations. However, it is unclear

whether the avoidance of additional bronchodilator inhalationsis mainly observed in the children with severe exacerbations or

also pertains to children with moderate asthma. Despite a new

trial contributing to the multiple dose flexible protocol, no firm

conclusion can be drawn regarding the systematic combination of

anticholinergics and beta2-agonists in every inhalation, because of

variation in reporting outcomes.

A U T H O R S C O N C L U S I O N S

Implications for practiceThe addition of multiple doses of anticholinergics to beta2 agonist

inhalations is indicated in the initial management of children with

severe exacerbations of asthma (


15/79

Little evidence exists to support the systematic addition of anti-

cholinergics to every beta2 agonist inhalation, irrespective of pa-tients disease severity.

The use of anticholinergics was not associated with increased in

the following side effects, namely nausea, vomiting, and tremor.

No comments regarding clinically important adverse effects, such

as tachycardia or hypertension, can be made due to infrequent

reporting.

Implications for research

Future trials should improve on three main aspects: interventions,

choice of outcomes, and stratified reporting of results by asthma

severity level.

Firstly, because systematic glucocorticoids are now the standard

treatment of children with severe exacerbations, they should be

systematically given withbeta2agonistsin future trials. In children

with mild and moderate exacerbations,trials are needed to evaluate

the potential benefit of adding multiple doses of anticholinergics

to beta2 agonist inhalations in a fixed and/or flexible (i.e., titrating

the number of inhalations to patients response) protocol.

Secondly, as admission and relapse are relatively gross measures of

efficacy, subject to practice variation, future trials should include

more sensitive and reliable endpoints such as number of bron-

chodilator inhalations and oxygenation (during the emergency de-partment treatment), duration of symptoms, functional status and

quality of life (for discharged patients), and duration of hospital-

ization and duration of need for intensive (at


16/79


17/79

Vichyanond 1990 {published data only}

Vichyanond p, Sladek WA, Sur S, Hill MR, Szefler SJ, Nelson HS.Efficacy of Atropine Methylnitrate alone and in combination with

Albuterol in children with asthma. Chest1990;98:63742.

Wilson 1984 {published data only}

Wilson N, Dixon C, Silverman M. Bronchial responsiveness to

hyperventilation in children with asthma:inhibition by ipratropium

bromide.Thorax1984;39:58893.

Additional references

BMA 1992

British Medical Association. Asthma: a follow up statement from

an international paediatric asthma consensus group. Archives of

Diseases of Childhood. 1992; Vol. 67:2408.

Boulet 1999Boulet LP, Becker A, Berube D, Beveridge R, Ernst P. Canadian

asthma consensus report, 1999. Canadian Medical Association

Journal1999;161(11 Suppl):S1S72.

CAEP/CTS 1996

Beveridge RC, Grunfeld AF, Hodder RV, Verbeek PR. Guidelines

for the emergency management of asthma in adults. Canadian

Medical Association Journal1996;155:2537.

Chapman 1996

Chapman K. An international perspective on anticholinergic

therapy. American Journal of Medicine1996;100:24S.

Cook 1993

Cook DJ, Guyatt GH, Ryan G, Clifton J, Buckingham L, Willan

A, et al.Should unpublished data be included in meta-analyses?

Current convictions and controversies. Journal of the American

Medical Association1993;269:274953.

DerSimonian 1986

DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled

Clinical Trials1986 1986;7:17788.;7:17788.

Egger 1997

Egger M, Smith GD, Schneider M, Minder C. Bias in meta-

analysis detected by a simple, graphical test. BMJ BMJ 1997;315:

629-34. 1997;315:62934.

Greenhalgh 1997

Greenhalgh T. Papers that summarize other papers (systematic

reviews and meta-analyses). British Medical Journal1997;315:

6725.

Greenland 1985Greenland S, Robins JM. Estimation of a common effect parameter

from sparse follow-up data. Biometrics1985;41:5568.

Gross 1988

Gross NJ. Ipratropium Bromide. New England Journal of Medicine

1988;8:48694.

Hasselblad 1995

Hasselblad V, Hedges LV. Meta-analysis of screening and diagnostic

tests.Psychol Bulletin1995;117:16778.

Homer 1996

Homer CJ, Szilagyi P, Rodewald L, Bloom SR, Greenspan P,

Yazdgerdi S, et al.Does quality of care affect rates of hospitalization

for childhood asthma?. Pediatrics1996;98:1823.

Jadad 1995

Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds JM,Gavaghan DJ, McQuay HJ. Assessing the quality of reports of

randomized controlled trials: Is blinding necessary. Controlled

Clinical Trials1995;134:112.

Khan 1996

Khan KS, Daya S, Jahad AR. The importance of quality of primary

studies in producing unbiased systematic reviews. Archives of

Internal Medicine1996;156:6616.

Mitchell 1992

Mitchell EA. Consensus on acute asthma management in children.

Ad Hoc Pediatric Group. New Zealand Medical Journal 1992; Vol.

105:3535.

NHLBI 1997

National Heart, Lung and Blood Institute. New NHLBI guidelines

for the diagnosis and management of asthma. Lippincott Health

Promotion Letter1997;2:19.

Olkin 1995

Olkin I. Statistical and theoretical considerations in meta-analysis.

Journal of Clinical Epidemiology1995 1995;48:13346.;48:13346.

Osmond 1995

Osmond MH, Klassen TP. Efficacy of ipratropium bromide in

acute childhood asthma - a meta-analysis. Academic Emergency

Medicine1995;2:6516.

Payne 1995

Payne SM, Donahue C, Rappo P, McNamara JJ, Bass J, First L, et

al.Variations in pediatric pneumonia and bronchitis/asthma

admission rates. Is appropriateness a factor?. Archives of Pediatric

and Adolescent Medicine1995;149:1629.Peto 1995

Peto R, Collins R, Gray R. Large-scale randomized evidence: large,

simple trials and overviews of trials. Journal of Clinical Epidemiology

1995;48:2340.

Rachelefsky 1993

Rachelefsky GS, Warner JO. International consensus on the

management of pediatric asthma: a summary statement. Pediatric

Pulmonology. 1993; Vol. 15:1257.

Robins 1986

Robins J, Breslow N, Greenland S. Estimators of the Mantel-

Haenszel variance consistent in both sparse data and large-strata

limiting models. Biometrics1986;42:31123.

Sackett 1995Sackett DL. Applying overviews and meta-analyses at the bedside.

Journal of Clinical Epidemiology1995;48:616.

Scarfone 1993

Scarfone RJ, Fuchs SM, Nager AL, Shane SA. Controlled trial of

oral prednisone in the emergency department treatment of children

with acute asthma. Pediatrics1993;92:5138.

Sears 1992

Sears MR. Clinical application of beta-agonists. Practical Allergy

and Immunology1992;7:98100.

Silverman 1990

Silverman M. The role of anticholinergic antimuscarinic

bronchodilator therapy in children. Lung1990;168:3049.




18/79

Sim 1996

Sim I, Hlatky MA. Growing pains of meta-analysis. British MedicalJournal1996;313:7023.

Stern 1997

Stern JM, SImes RJ. Publication bias: evidence of delayed

publication in a cohort study of clinical research projects. British

Medical Journal1997;315:6405.

SVedmyr 1985

Svedmyr N. A beta2-adrenergic agonist for use in asthma

pharmacology, pharmacokinetics, clinical efficacy and adverse

effects.Pharmacotherapy1985;5:10926.

Tal 1990

Tal A, Levy N, Bearman JE. Methylprednisolone therapy for acuteasthma in infants and toddlers: a controlled clinical trial. Pediatrics

1990;86:3506.

Warner 1989

Warner JO, Gotz M, Landau LI, Levison H, Milner AD, Pedersen

S, et al.Management of asthma: a consensus statement. Archives of

Diseases of Childhood1989;64:106579.

Warner 1992

Warner JO. Asthma: a follow up statement from an international

paediatric asthma consensus group. Archives of Diseases of

Childhood. 1992; Vol. 67:2408. Indicates the major publication for the study




19/79

C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Beck 1985

Methods RANDOMIZATION

- Method: not described

- Means: number-coded solutions supplied by pharmacy

BLINDING - double-blind; identical placebo

WITHDRAWAL/DROPOUT - not described

JADADs quality score=3

Participants N = 25

AGE - 6-17.5 years old

BASELINE SEVERITY -


20/79

Beck 1985 (Continued)

Allocation concealment? Yes number-coded solutions supplied by pharmacy

Blinding?

All outcomes

Yes Identical placebo used

Calvo 1998

Methods No RANDOMIZATION

-Method:consecutive assignment


BLINDING-double-blinding, identical placebo

WITHDRAWAL/DROPOUTS

- none

JADADS quality score=3

Participants N=80

AGE - 5-14 yo

BASELINE SEVERITY - =5

COUNTRY - Chile

Interventions PROTOCOL - Titrated to patient until symptoms controlled

TEST GROUP

- Salbutamol 200mcg +IB 40 mcg q15 minutes x 4 then q20 minutes x 3

CONTROL GROUP

- Salbutamol 200mcg q15 minutes x 4 then q20 minutes x 3

CO-INTERVENTION (other medications used during study)

- some patients received systemic corticosteroids

(prednisone 1mg/kg/dose: max=40 mg) at 60 min after beginning treatment if no clinical or

laboratory improvement

DEVICE

- inhalation

Outcomes PULMONARY FUNCTION TESTS

- peak flow

CLINICAL SCORE- Tal score

VITAL SIGNS - pulse, respiratory rate

ADVERSE EFFECTS - tremor, mydriatic reaction, dryness of the oral membrane, pharyngeal

irritation, nausea, vomiting

# PATIENTS NEEDING CORTICOSTEROIDS

ADMISSION

Notes Author (GMC) contacted

Confirmation by GMC of methodology and data extraction - obtained

Risk of bias




21/79

Calvo 1998 (Continued)

Item Authors judgement Description

Adequate sequence generation? No Consecutive assignment

Allocation concealment? No Number-coded solutions supplied by pharmacy

Blinding?

All outcomes

Yes Identical placebo

Cook 1985

Methods RANDOMIZATION - method and means not described

BLINDING - double-blind; all solutions were 2.5 ml, no other details

WITHDRAWAL/DROPOUT - described


Participants N = 30

AGE - 18 months - 12 years old

BASELINE SEVERITY - moderately severe (not defined), excluded if needed iv medication

COUNTRY - Australia

Interventions PROTOCOL

- Fixed:

- Observation period: 120 minutes

- Single dose

TEST GROUP

- Fenoterol 0.125 ml (1-4 y.o.)/0.25 ml (5-8 y.o.)/0.5 ml (9-12 y.o.)

+ IB 1 ml (1-4 y.o.)/1.5 ml (5-8 y.o.)/2.0 ml (9-12 y.o.)

CONTROL GROUP

- Fenoterol 0.125 ml (1-4 y.o.)/0.25 ml (5-8 y.o.)/0.5 ml (9-12 y.o.) + placebo


- Systemic corticosteroids:- none

- Other medications:- stopped

DEVICE - nebulizer


- Peak Flow Rates (not obtained routinely)

CHANGE IN CLINICAL SCORE - Overall score of wheeze, air entry and respiratory distress


NEED FOR REPEAT TREATMENTS AFTER STANDARD PROTOCOL PRIOR TO DIS-

POSITION

Notes Co-author (KPD) - contacted

Confirmation by KPD of methodology - obtained

Confirmation of data extraction - pending

For change in clinical score, no values for t=0 minutes, therefore used t=5 minutes as baseline

Risk of bias




22/79


23/79

Ducharme 1998 (Continued)

NEED FOR CORTICOSTEROIDS PRIOR TO DISCHARGE

ADMISSION

RELAPSE - within 72 hours

ADMISSION

RELAPSE

ADVERSE EFFECTS - not described

Notes Author (FMD)

- contacted

Confirmation by FMD of methodology and data extraction - obtained

Factorial design - tested 2 interventions simultaneously (frequent low doses of Salbutamol &

combination therapy with IB); no interaction observed between the 2 interventions

Risk of bias


Adequate sequence generation? Yes Computer-generated random numbers

Allocation concealment? Yes Coded solutions

Blinding?

All outcomes


Guill 1987


- Method: computer-generated random numbers

- Means: opaque consecutive numbered envelopes containing assignment

BLINDING - double-blind, identical placebo

WITHDRAWAL/DROPOUT- all participants completed the trial and were included in the anal-

ysis


Participants N = 35 participants, 44 visits

AGE - 13 months - 12 years old

BASELINE SEVERITY - not describedCOUNTRY - USA

Interventions PROTOCOL - Titrated to patient until symptoms controlled or patient admitted

TEST GROUP

- Metaproterenol 0.2 ml (=12 y.o.) + Atropine Sulfate 0.05-0.1 mg/kg (max 2

mg)

CONTROL GROUP

- Metaproterenol 0.2 ml (=12 y.o.)


- Systemic corticosteroids: not mentioned

DEVICE - nebulizer




24/79

Guill 1987 (Continued)


- Change in %Predicted PEF

CLINICAL SCORE

- Pulmonary Index

NUMBER OF REPEAT TREATMENTS REQUIRED PRIOR TO DISPOSITION

ADVERSE EFFECTS - no details in study given but data confirmed

ADMISSION - data not available

RELAPSE - data not available

Notes Author (MFG) - contacted

Confirmation by MFG of methodology and data extraction - obtained

Risk of bias


Adequate sequence generation? Yes Computer-generated random numbers

Allocation concealment? Yes Opaque consecutive numbered envelopes con-

taining assignment

Blinding?

All outcomes

Yes Identical placebos used

Peterson 1996


- Method: computer generated random numbers

- Means: number-coded solutions supplied by the pharmacy

BLINDING - triple-blinding, identical placebo



Participants N = 163

AGE - 5-12 years old

BASELINE SEVERITY -


25/79


26/79


27/79


28/79

Qureshi 1998 (mod)


- Method: table of random numbers


BLINDING

- double-blinding, identical placebo

WITHDRAWAL/DROPOUTS

- described


Participants N=163

AGE - 2-18 yo

BASELINE SEVERITY- 50-70% PEFR or asthma score=8-11COUNTRY - USA


- Fixed:60 minutes

- Observation period: up to 248 minutes

- Multiple doses

TEST GROUP

- Albuterol 2.5mg (20kg) q20 minutes x 3 &

IB 500 mcg at 20 and 40 minutes

CONTROL GROUP


Saline at 20 and 40 minutes

CO-INTERVENTION (other medications used during the study)- Systemic corticosteroids - all received oral steroids at 20 minutes

DEVICE - nebulizer


- % Change in PEFR

CHANGE IN CLINICAL SCORE

O2 SATURATION

# NEBULIZER TXs UNTIL DISPOSITION

TIME TO DISPOSITION


ADMISSION RELAPSE

Notes Author (FQ)- contacted

Confirmation by FQ of methodology and data extraction - obtained

Risk of bias


Adequate sequence generation? Yes Table of random numbers

Allocation concealment? Yes Number-coded solutions supplied by pharmacy




29/79

Qureshi 1998 (mod) (Continued)

Blinding?

All outcomes


Qureshi 1998 (sev)




BLINDING

- double-blinding, identical placebo

WITHDRAWAL/DROPOUTS- described


Participants N=271

AGE - 2-18 yo

BASELINE SEVERITY-


30/79

Qureshi 1998 (sev) (Continued)


Allocation concealment? Yes Number-coded solutions supplied by pharmacy

Blinding?

All outcomes

Unclear Identical placebo

Reisman 1988


- Method: not described- Means: number-coded solutions supplied by the pharmacy

BLINDING - double-blinding, identical placebo

WITHDRAWAL/DROPOUT - not fully described


Participants N = 24


BASELINE SEVERITY -


31/79

Reisman 1988 (Continued)


Adequate sequence generation? Unclear Described as randomised; no other information

available

Allocation concealment? Yes Number-coded solutions supplied by the phar-

macy

Blinding?

All outcomes


Schuh 1995







Participants N = 120


BASELINE SEVERITY -


32/79

Schuh 1995 (Continued)

VITAL SIGNS - heart rate, respiratory rate

ADVERSE EFFECTS - nausea, tremor, conjunctivitis, coughing spasm with syncope

NEED FOR CORTICOSTEROIDS PRIOR TO DISPOSITION

ADMISSION - described

RELAPSE - within 72 hours

Notes Author (SS) contacted

Confirmation of methodology and data extraction - obtained

Risk of bias




macy

Blinding?

All outcomes


Watson 1988

Methods RANDOMIZATION - method and means not describedBLINDING - double-blind, not described

WITHDRAWAL/DROPOUT - none


Participants N = 31


BASELINE SEVERITY - 30-70% Pred FEV1

COUNTRY - Canada

OTHER - ability to perform spirometry consistently


- Fixed: 60 minutes

- Observation period: 120 minutes total

- Multiple doses

TEST GROUP

- Fenoterol 625 mcg + IB 250 mcg combined q60 minutes x 2

CONTROL GROUP

- Fenoterol 625 mcg q 60 minutes x 2

CO-INTERVENTION (other medications usd during study)

- Systemic corticosteroids: none

- Theophylline: none

DEVICE - nebulizer




33/79

Watson 1988 (Continued)


- Change in %Predicted FEV1

- % Change in FEV1

OXYGEN SATURATION - no details given

CHANGE IN CLINICAL SCORE - Pulmonary Index, no details given

ADVERSE EFFECTS - tremor, no adverse effects but none other specified

ADMISSION - described

RELAPSE - not mentioned

Notes Author (WTAW) - contacted

Confirmation by WTAW of methodology and data extraction - pending

Risk of bias


Adequate sequence generation? Unclear Described as randomised; no other information

available

Allocation concealment? Unclear Information not available

Blinding?

All outcomes

Unclear Information not available

Zorc 1999 (mod)







Participants N=194


BASELINE SEVERITY -

initial severity score of 4-6,excluded if required initial therapy in addition to the Critical Pathway

- initial severity score was incomplete/missing for 14% of the total 427 participants of the full study

COUNTRY - USA


- Fixed: 60 minutes


- Multiple doses

TEST GROUP



CONTROL GROUP




34/79

Zorc 1999 (mod) (Continued)



CO-INTERVENTION (other medications used during the study)

- Systemic corticosteroids : all received oral steroids at 20 minutes

DEVICE - nebulizer

Outcomes # NEBULIZER TXs UNTIL DISPOSITION

TIME TO DISPOSITION

ADMISSION

- to ward, to ICU

RELAPSE

Notes Author (MP) - contacted

Confirmation by MP of methodology and data extraction - obtained

Risk of bias


Adequate sequence generation? Yes Computer generated random numbers


macy

Blinding?

All outcomes


Zorc 1999 (sev)







Participants N=51AGE - 1-17 years old

BASELINE SEVERITY - initial severity score of 7-9, excluded patients if respiratory failure or

required initial therapy in addition to the Critical Pathway


COUNTRY - USA


- Fixed: 60 minutes


- Multiple doses

TEST GROUP





35/79

Zorc 1999 (sev) (Continued)


CONTROL GROUP




- Systemic corticosteroids: all received oral steroids at 20 minutes

DEVICE - nebulizer


TIME TO DISPOSITION

ADMISSION

- to ward, to ICURELAPSE



Risk of bias




macy

Blinding?

All outcomes


Zorc JJ 1999 (mil)







Participants N=117


BASELINE SEVERITY - initial severity score of 1-3, excluded patients if required initial therapy

in addition to the Critical Pathway


COUNTRY - USA


- Fixed: 60 minutes


- Multiple doses




36/79

Zorc JJ 1999 (mil) (Continued)

TEST GROUP



CONTROL GROUP




- Systemic corticosteroids: all received oral steroids at 20 minutes

DEVICE - nebulizer


TIME TO DISPOSITIONADMISSION

- to ward, to ICU

RELAPSE



Risk of bias




macy

Blinding?

All outcomes

Unclear Identical placebo

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Boner 1987 The study pertained to stable asthmatics.

Bratteby 1986 The study pertained to chronic asthmatics.

Caubet 1989 The study pertained to chronic asthmatics.

Davis 1984 The study pertained to stable asthmatics.

Delacourt 1994 The study was not a randomized controlled trial.

DeStefano 1989 The study pertained to chronic asthmatics.




37/79

(Continued)

Ekwo 1978 The study was not a randomized controlled trial.

Freeman 1989 The study pertained to patients who were already admitted.

Friberg 1989 The study pertained to chronic asthmatics.

Greenough 1986 The study pertained to chronic asthmatics.

Groggins 1981 The study pertained to stable asthmatics.

Hodges 1981 The study pertained to infants.

Lenney 1986 The study pertained to chronic asthmatics.

Mann 1982 The study pertained to chronic asthmatics.

Rayner 1987 The study pertained to patients who were already admitted.

Stokes 1983 The study did not combine anticholinergic inhalations and beta2-agonist inhalations.

Storr 1986 The study pertained to patients who were already admitted.

Vichyanond 1990 The study pertained to chronic asthmatics.

Wilson 1984 The study pertained to non-acute asthmatics.




38/79

D A T A A N D A N A L Y S E S

Comparison 1. ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST ALONE

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Admission 2 378 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.65, 1.32]

1.1 Co-intervention:

Corticosteroids during study

1 171 Risk Ratio (M-H, Fixed, 95% CI) 1.22 [0.69, 2.15]

1.2 Co-intervention: Nocorticosteroids


1.3 Corticosteroid use

variable/not described

0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

2 -(Change in % Pred FEV1 at

60 minutes after IB) +/- 15

minutes

1 76 Mean Difference (IV, Fixed, 95% CI) -6.6 [-13.73, 0.53]


Corticosteroids during the

previous 60 minutes

0 0 Mean Difference (IV, Fixed, 95% CI) Not estimable

2.2 Co-intervention: No

corticosteroids



Corticosteroid use variable/ not

described


3 - (Change in % Pred FEV1 at

120 minutes after IB) +/- 30

minutes




previous 120 minutes



corticosteroids



variable/ not described


4 - (% Change in FEV1 at 60minutes after IB) +/- 15

minutes

2 45 Mean Difference (IV, Fixed, 95% CI) -16.10 [-26.66, -5.54]



previous 60 minutes



corticosteroids




2 45 Mean Difference (IV, Fixed, 95% CI) -16.10 [-26.66, -

5.54]

5 - (% Change in FEV1 at 120

minutes after IB) +/- 30

minutes


4.46]




39/79


Corticosteroids during theprevious 120 minutes



corticosteroids





4.46]

6 % Change in Respiratory

resistance at 60 minutes after

IB +/- 15 minutes

1 294 Mean Difference (IV, Fixed, 95% CI) 0.02 [-0.02, 0.07]



previous 60 minutes



corticosteroids





7 % Change in Respiratory

resistance at 120 minutes after

IB +/- 30 minutes







corticosteroids





8 Change in clinical score at 60

minutes +/- 15 minutes




previous 60 minutes



corticosteroids













corticosteroids





10 O2 Saturation


40/79


corticosteroids



Corticosteroid use variable/not

described


11 O2 Saturation =1 additional treatment 2 328 Peto Odds Ratio (Peto, Fixed, 95% CI) 1.08 [0.68, 1.71]

13 Tremor 2 105 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.72, 1.94]

14 Vomiting 1 292 Risk Ratio (M-H, Fixed, 95% CI) 0.64 [0.28, 1.45]





corticosteroids


14.3 Corticosteroid usevariable/not described


15 Nausea 1 241 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.28, 1.06]





corticosteroids





16 Need for corticosteroids in

emergency department prior to

disposition


17 Relapse 2 295 Risk Ratio (M-H, Fixed, 95% CI) 1.17 [0.56, 2.45]


Corticosteroids upon discharge



corticosteroids








41/79

Comparison 2. ANTICHOLINERGIC (multiple doses) + BETA-2-AGONIST vs BETA-2-AGONIST ALONE -

FIXED PROTOCOL


studies

No. of


1 Admission 10 1162 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.62, 0.89]





corticosteroids


1.3 Corticosteroid usevariable/not described



60 minutes after last IB) +/- 20

minutes




previous 60 minutes



corticosteroids






120 minutes after last IB) +/-

30 minutes







corticosteroids





4 - (% Change in FEV1 or PEFR

at 60 minutes after last IB) +/-

15 minutes

2 121 Std. Mean Difference (IV, Fixed, 95% CI) -0.51 [-0.87, -0.14]

4.1 Co-intervention:Corticosteroids during the

previous 60 minutes



corticosteroids




0 0 Std. Mean Difference (IV, Fixed, 95% CI) Not estimable

5 -( % Change in FEV1 or PEFR

at 120 minutes after last IB) +/-

30 minutes

2 174 Std. Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.32, 0.28]




2 174 Std. Mean Difference (IV, Fixed, 95% CI) -0.02 [-0.32, 0.28]




42/79


corticosteroids










previous 60 minutes



corticosteroids













corticosteroids





8 O2 Saturation


43/79


Corticosteroids during studyprior to vomiting



corticosteroids





13 Nausea 3 334 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.30, 1.14]



prior to vomiting



corticosteroids







disposition


15 Relapse 8 616 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.49, 1.53]





corticosteroids





Comparison 3. ANTICHOLINERGIC (multiple) + BETA-2-AGONISTS vs. BETA-2-AGONISTS ALONE -

TITRATRATION PROTOCOL


studies

No. of


1 2 to 3 inhalations required prior

to disposition


1.1 Co-intervention: nocorticosteroids



Corticosteroids



corticosteroid use variable/not

described


2 >= 4 inhalations required prior

to disposition


2.1 Co-intervention: no

corticosteroids



Corticosteroids





44/79


corticosteroid use variable/notdescribed




disposition


4 Tremor 2 111 Risk Ratio (M-H, Fixed, 95% CI) Not estimable

5 Vomiting 2 111 Risk Ratio (M-H, Fixed, 95% CI) Not estimable



prior to vomiting



corticosteroids





6 Nausea 2 111 Risk Ratio (M-H, Fixed, 95% CI) Not estimable



prior to vomiting



corticosteroids





7 Admission 1 80 Risk Ratio (M-H, Fixed, 95% CI) Not estimable




7.2 Co-intervention: Nocorticosteroids





8 Relapse 0 0 Risk Ratio (M-H, Fixed, 95% CI) Not estimable





corticosteroids








45/79

Analysis 1.1. Comparison 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs. BETA-2-AGONIST

ALONE, Outcome 1 Admission.

Review: Combined inhaled anticholinergics and beta2-agonists for initial treatment of acute asthma in children

Comparison: 1 ANTICHOLINERGIC (single dose) + BETA-2-AGONIST vs

aastma anticolinergic

Documents