More Related Content
Similar to Iv beta agonist in acute asthma
Similar to Iv beta agonist in acute asthma (20)
Iv beta agonist in acute asthma
- 1. DOI 10.1378/chest.122.4.1200
2002;122;1200-1207Chest
Carlos A. Camargo, Jr
Andrew H. Travers, Brian H. Rowe, Samantha Barker, Arthur Jones and
: A Meta-analysis*Emergency Department
Treating Patients With Acute Asthma in the
-Agonists inβThe Effectiveness of IV
http://chestjournal.chestpubs.org/content/122/4/1200.full.html
services can be found online on the World Wide Web at:
The online version of this article, along with updated information and
ISSN:0012-3692
)http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(
written permission of the copyright holder.
this article or PDF may be reproduced or distributed without the prior
Dundee Road, Northbrook, IL 60062. All rights reserved. No part of
Copyright2002by the American College of Chest Physicians, 3300
Physicians. It has been published monthly since 1935.
is the official journal of the American College of ChestChest
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 2. The Effectiveness of IV -Agonists in
Treating Patients With Acute Asthma in
the Emergency Department*
A Meta-analysis
Andrew H. Travers, MD, MSc; Brian H. Rowe, MD, MSc;
Samantha Barker, MD; Arthur Jones, RT; and
Carlos A. Camargo, Jr., MD, DrPH
Objectives: To determine the benefit of IV 2-agonists for severe acute asthma treated in the
emergency department (ED).
Methods: Randomized controlled trials were identified using EMBASE, MEDLINE, and CINAHL;
the Cochrane Airways Review Group database; hand searching; bibliographies; pharmaceutical
companies; and author contact. Studies where IV 2-agonists were compared to placebo and/or
existing standards of care were considered. Where appropriate, trials were combined using odds
ratios (ORs) or weighted mean differences with 95% confidence intervals (CIs).
Results: From 746 identified references, 55 potentially relevant articles were identified and 15
articles were included. All trials were performed outside North America and were published prior to
1997. Three main treatment strategies were reviewed: strategy 1 (three articles), IV 2-agonists with
inhaled 2-agonists vs inhaled 2-agonists; strategy 2 (six articles), IV 2-agonists alone vs inhaled
2-agonists; and strategy 3 (six articles), IV 2-agonists vs IV methylxanthines. Compared to all
treatments, IV 2-agonist use did not lead to clinical or statistical significant differences in vital signs,
pulmonary functions, laboratory measures, adverse effects, or clinical success. Although statistically
nonsignificant, seven methodologically strong studies demonstrated that peak expiratory flows and
heart rates were unchanged following 2-agonist use compared to all other treatments at 60 min
(8.3 L/min [95% CI, 17.6 to 34.2] and 3.65 beats/min [95% CI, 2.9 to 10.2], respectively), with an
increased risk of adverse effects (OR, 1.98; 95% CI, 0.5 to 8.2).
Conclusions: Evidence is lacking to support the use of IV 2-agonists in ED patients with severe acute
asthma. Moreover, the clinical benefit appears questionable, while the potential clinical risks are
obvious. The only recommendations for IV -2agonist use should be in those patients in whom inhaled
therapy is not feasible, or in the context of a controlled clinical trial comparing IV 2-agonists with
standard care vs standard care alone. (CHEST 2002; 122:1200–1207)
Key words: asthma; -agonists; emergency department; IV; pulmonary function; side effects
Abbreviations: ABG ϭ arterial blood gas; CI ϭ confidence interval; CPG ϭ clinical practice guideline; df ϭ degrees of
freedom; ED ϭ emergency department; OR ϭ odds ratio; PEFR ϭ peak expiratory flow rate; PFT ϭ pulmonary function
test; RCT ϭ randomized controlled trial; WMD ϭ weighted mean difference
The general approach to treating patients with
acute asthma is to use inhaled -agonist bron-
chodilators and corticosteroids. For severe acute
asthma, penetration of inhaled -agonists to the
affected small conducting airways may be impeded,
and consequently responses may be a result of drug
reaching the receptors via the systemic circulation.
In these circumstances, if bronchodilatation occurs
*From the Division of Emergency Medicine (Drs. Travers and
Rowe) and Department of Radiology (Dr. Barker), University of
Alberta and Capital Health Authority, Edmonton, AB, Canada;
Respiratory Care Department (Mr. Jones), University of Texas,
San Antonio, TX; and the Department of Emergency Medicine
(Dr. Camargo), Massachusetts General Hospital Boston, MA.
Presented at the American College of Emergency Physicians
Annual Meeting, Las Vegas, NV, October 1999, and the Cana-
dian Association of Emergency Physicians Annual Meeting,
Quebec City, PQ, Canada, October, 1999.
These results have been electronically published by the Airways
Review Group in the Cochrane Collaboration (Cochrane Data-
base of Systematic Reviews. The Cochrane Library, Issue 4,
2001. Oxford, UK: Update Software). Dr. Travers received a
grant from the Canadian Association of Emergency Physicians to
complete this work. Dr. Rowe is supported by a salary award
from the Canadian Institute of Health Research as the Chair in
Emergency Airway Diseases (Ottawa, ON). Dr. Camargo is
supported by grant HL-03533 from the National Institutes of
Health (Bethesda, MD).
Correspondence to: Andrew Travers, MD, MSc, Division of
Emergency Medicine, University of Alberta, 1G1.50 WMC, 8440-
112th St, Edmonton, AB, T6G 2B7 Canada; e-mail: ahtravers@
shaw.ca
1200 Clinical Investigations
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 3. predominantly in response to the systemic distribu-
tion of the drug, IV rather than inhaled administra-
tion of bronchodilators may provide an earlier clini-
cal response.1
For editorial comment see page 1116
The research investigating the role of IV -
agonists in the emergent treatment of asthma has
spanned Ͼ 25 years. At present, each of the clinical
practice guidelines (CPGs) in Europe (British Tho-
racic Society), Canada (Canadian Association of
Emergency Physicians), and the United States (Na-
tional Asthma Education and Prevention Program)
recommend inhaled -agonist therapy for all cases of
asthma that present to the emergency department
(ED).2–5 Each CPG suggests IV and subcutaneous
-agonists as second-line therapy for use in patients
unresponsive to inhaled bronchodilator and systemic
corticosteroid therapy, or if the inhaled route is not
practical for the patient (ie, excessive coughing, too
weak to inspire adequately, or moribund patient).2–5
IV use is not approved in the National Asthma
Education and Prevention Program guidelines.5
Each CPG variously describe “near-death asthma” or
“life-threatening asthma” as qualifying terms for
adult candidates for IV or subcutaneous administra-
tion. These are listed as alternative therapies paral-
leling inhalational anesthetics and IV methylxan-
thines.
However, most of the CPG recommendations for
IV or subcutaneous agents originate from low-grade
and/or low levels of evidence; as a result, debate
regarding the IV route of treatment continues. This
lack of consensus reflects the fact that no systematic
review of the IV or subcutaneous -agonist literature
for the treatment of asthmatic exacerbations has
been published to date. Consequently the objective
of this review was to determine if the evidence from
randomized trials supports the use of IV -agonists
in the treatment of patients with severe acute asthma
who present to the ED.
Materials and Methods
Inclusion Criteria
To be eligible for inclusion in this review, a study had to meet
all of the following criteria: (1) design, randomized controlled
trials (RCTs) or quasi RCTs (allocation on days of the week, or
some other method); (2) population, studies recruiting adult or
pediatric patients with severe acute asthma from the ED (or its
equivalent); (3) interventions, administration of IV (selective or
nonselective) -agonists vs the administration of placebo, other
IV bronchodilators (ie, methylxanthines), or other inhaled selec-
tive or nonselective -agonists; included studies could also use
other recognized standard treatment (ie, corticosteroids); and
(4) outcomes, pulmonary functions, vital signs, adverse effects,
and clinical scores. Agreement for relevance for review was
measured using statistics.
Study Identification
Electronic databases were searched from 1966 to 2000, explod-
ing -agonist treatment (all routes, formulations, and brand
names) and asthma; the search was restricted to RCTs using
standardized and validated strategies.6 This search was per-
formed on MEDLINE, EMBASE, CINAHL, the Controlled
Trials Register of the Cochrane Library, and the Cochrane
Airway Review Group “Asthma and Wheeze” Registry. These
Cochrane registries include studies identified by the Cochrane
Collaboration through standardized searching and hand search-
ing of journals for controlled clinical trials. Reference lists of all
available primary studies and review articles were reviewed to
identify potential relevant citations. Trials were not excluded on
the basis of language. Included authors, major pharmaceutical
producers of asthma medications (AstraZeneca, Boehringer In-
gelheim, Glaxo, 3M Pharmaceuticals), and other asthma re-
searchers were contacted regarding the existence of other pub-
lished, unpublished, or interim results on -agonist research. The
reference lists from the search strategy was independently re-
viewed, and clearly irrelevant articles were discarded. If the title,
abstract, or descriptors suggested any potential relevance, the full
text article was retrieved. Agreement for “relevance for review”
was measured using statistics. Each relevant article was then
assessed by two independent, nonblinded reviewers for inclusion
in this review. Agreement for relevance for inclusion was mea-
sured using statistics. Disagreement was resolved by consensus
or third-party adjudication.
Quality Assessment of Trials
The previously validated Jadad 5-point scale (score 0 to 5) was
used to assess randomization (0 to 2 points), double blinding (0 to
2 points), and withdrawals and dropouts (0 to 1 point).7 For
allocation assessment, concealment was described as either ade-
quate, inadequate, or unclear using Cochrane methodology.8
Two reviewers independently assessed quality, and interrater
reliability was measured by using simple agreement, , and
weighted statistics, with disagreement resolved by third-party
adjudication.
Data Extraction
Data for the trials were independently extracted with a struc-
tured form by two blinded reviewers and entered into the
software program (Review Manager Version 4.0.4; Cochrane
Collaboration; Oxford, UK). Primary study authors were re-
quested to confirm data extraction and provide additional clari-
fication or information for the review. In cases where tables were
unavailable, graphs were enlarged and values were approximated.
Data Analysis
All similar studies were pooled using random effects weighted
mean differences (WMDs) for continuous variables, and random
effects odds ratios (ORs) for dichotomous variables, with 95%
confidence interval (CIs) where appropriate. With pooled effects,
heterogeneity was tested using the Breslow-Day test; p Ͻ 0.05
was considered statistically significant. For those summary effect
outcome measures with statistical heterogeneity, a priori sub-
group analyses were classified on the following basis: (1) popu-
lation, adult vs pediatric and severity of illness based on pulmo-
www.chestjournal.org CHEST / 122 / 4 / OCTOBER, 2002 1201
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 4. nary function test (PFT) results; and (2) intervention, selective vs
nonselective -agonists, IV vs inhaled -agonists, IV with inhaled
vs inhaled -agonists, IV -agonists vs IV methylxanthines, and
infusion vs bolus -agonists. Sensitivity analyses were completed
on the strength of methodologic quality (high vs low) and
statistical method of analysis (random vs fixed effects).
Results
Systematic Review
The Airways Review Group database search
revealed 976 references that represented 740 orig-
inal publications (76%): 258 articles (35%) in
EMBASE, 250 articles (34%) in MEDLINE, 2
articles (0.3%) from CINAHL, 224 articles (30%)
from both MEDLINE and EMBASE, and 6 arti-
cles (0.7%) cited in all three. An independent
review of the abstracts and titles of these publica-
tions identified 31 potentially relevant studies.
The agreement for relevance was high ( ϭ 0.83).
Twenty-four additional references were added
from bibliographic searching of relevant articles
and overviews; a total of 55 full-text articles were
reviewed for inclusion. Unpublished literature was
requested from pharmaceutical companies and the
authors of all included studies, but none were
identified. Of these 55 articles, a total of 15 studies
(27%) were included in the overview ( ϭ 0.87).
Of the 40 studies that were excluded, 30 studies
(55%) were nonrandomized, 7 studies (13%) in-
cluded treatment of patients with nonacute asthma
or nonasthmatics, and 3 studies (5%) examined
non-IV routes of administration. Table 1 illustrates
that the evidence for intervention with IV -
agonists spans a period of 25 years: 7 articles
(47%) published in the 1970s, 5 articles (33%)
from the 1980s, and 3 articles (20%) from the
1990s. Twelve of the studies (80%) were con-
ducted in Europe, 1 study (7%) was conducted
Asia, and 2 studies (13%) were conducted in
Australia. No trials meeting our inclusion criteria
were conducted in North America.
Methodologic Quality
Many of the included articles were double-blind,
controlled trials; however, the methodologic quality
varied across studies. Using the method of Jadad et
al,7 seven studies (47%) were rated as “strong”
(Jadad score 3 to 5) and eight studies (53%) were
rated as “weak” (Jadad score 0 to 2). Agreement
between the two independent assessments of study
quality was high ( ranged from 0.59 to 1.0 for each
domain). There was no significant correlation be-
tween quality scores and the year of publication of
the trial (Pearson r ϭ 0.38, p ϭ 0.17). Regarding
concealment of allocation methodology, 5 studies
(33%) were rated as having clearly blinded allocation
and 10 studies (67%) were rated as having unclear
allocation blinding ( ϭ 1.0). There was no statisti-
cally significant association between those studies
that were rated as strong methodologically and those
that had blinded allocation (2
ϭ 2.04, degrees of
freedom [df] ϭ 1, p Ͼ 0.05).
Study Design
Thirteen of the studies (87%) followed a parallel
protocol, whereas 2 of the studies (13%) followed
a crossover model.9,10 Eleven studies (73%) intro-
duced IV -agonists immediately on entry. The
remaining four studies introduced IV -agonists
within 30 to 75 min of study entry, during which
Table 1—Descriptions of Included Studies
Source Country Quality
Sample
Size Patients Intervention Treatment Comparison Treatment
Bloomfield et al9/1979 Scotland High 20 Adult Salbutamol, 500 g IV bolus Salbutamol, 5 mg inhaled
Browne et al1/1997 Australia High 29 Pediatric Salbutamol, 15 g/kg IV bolus Salbutamol, 2.5–5.0 mg inhaled
Cheong et al11/1988 England High 61 Adult Salbutamol, 12.5 g/min IV Salbutamol, 5 mg inhaled
Femi-Pearse et al20/1977 Nigeria Low 50 Adult Salbutamol, 200 g IV bolus Aminophylline, 250 mg IV
Hambleton and Stone21/1979 England Low 18 Pediatric Salbutamol, 4 g/kg IV bolus Aminophylline, 4 mg/kg IV
Hussein et al17/1986 Germany Low 20 Pediatric Reproterol, 0.2 g/kg/min IV Salbutamol, 75 g/kg inhaled
Johnson et al18/1978 England Low 39 Adult Salbutamol, 10 g/min IV Aminophylline, 1 mg/min
Lawford et al13/1978 England High 13 Adult Salbutamol, 20 g/min IV Salbutamol, 10 mg inhaled
Salmeron et al14/1994 France High 47 Adult Salbutamol, 8.3 g/min IV Salbutamol, 10 mg inhaled
Sharma et al22/1984 India Low 30 Adult Salbutamol, 250 g IV bolus;
terbutaline, 250 g IV bolus
Aminophylline, 250 mg IV
Aminophylline, 250 mg IV
Swedish Society of Medicine15/1990 Sweden Low 176 Adult Salbutamol, 5 g/kg IV bolus Salbutamol, 0.15 mg/kg inhaled
Tribe et al10/1976 Australia High 23 Adult Salbutamol, 100 g IV bolus Aminophylline, 250 mg IV
Van Renterghem et al12/1987 Belgium Low 23 Adult Terbutaline, 6 g/kg IV bolus Terbutaline, 0.1 mg/kg inhaled
Williams et al19/1975 England High 20 Adult Salbutamol, 8.3 g/min IV Aminophylline, 500 mg IV
Williams et al16/1981 England Low 15 Adult Terbutaline, 250 g IV bolus Terbutaline, 2.5 mg inhaled
1202 Clinical Investigations
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 5. time the patients received either inhaled -
agonists1,11,12 or IV aminophylline.12 There were
three main treatment strategies utilized in the
studies under review. Three studies1,11,12 utilized
strategy 1 where IV -agonists were compared to
inhaled -agonist, where both groups of patients
received a “run-in” phase of inhaled -agonist
therapy. Six studies9,13–17 utilized strategy 2, where
IV -agonists were compared with inhaled agents,
with no inhalational therapy in the IV -agonist
arm. The remaining six studies10,18 –22 utilized
strategy 3, where IV -agonists were compared
with IV methylxanthines, where neither group
received inhaled -agonist therapy.
Populations
Participants were selected from a sample of
patients who presented to the ED or its equivalent
with severe acute asthma. All patients were admit-
ted to the hospital. The majority of studies focused
on adult patients only (age range, 15 to 65 years),
with only three studies1,17,21 evaluating children
(age range, 0.8 to 14.7 years). The median sample
size across the studies was 23, with a range of 13 to
176 patients. All studies enrolled patients with
“severe” asthma, though there was variability in
the parameters and definitions used for inclusion
criteria. Nine studies9,11–16,19,20 used vital signs
(heart rate Ͼ 100 beats/min) and PFT results
(Ͻ 20% expected) as primary inclusion criteria.
Five studies12,14,16,19,21 required abnormalities in
arterial blood gas (ABG) measurements. Four
articles10,18,21,22 listed simple clinical symptoms
and signs of “severe shortness of breath or wheez-
ing” as inclusion criteria. The inclusion criteria in
two articles1,14 described standardized clinical
assessment scales for severe asthma. These defini-
tions of severity are described elsewhere.23,24
Interventions
All patients received supplemental oxygen by face
mask and systemic corticosteroids. No patients re-
ceived inhaled steroids or inhaled anticholinergic
agents in any of the studies. All studies used selective
IV 2-agonists. Table 1 demonstrates that nine stud-
ies1,9,10,12,15,16,20–22 administered IV 2-agonists as a
bolus (range, 100 to 500 g, or 4 to 15 g/kg),
whereas six studies11,13,14,18,19,21 administered the IV
2-agonist as an infusion (range, 8.3 to 20 g/min to
total doses of 500 to 3,000 g). Most studies (73%)
used salbutamol; three studies evaluated terbutaline,
and one study evaluated reproterol. One study22 ran
a triple-parallel protocol comparing IV salbutamol vs
IV terbutaline vs IV aminophylline. Consequently,
this study was treated as two studies: IV salbutamol vs
aminophylline, and IV terbutaline vs aminophylline.
Outcomes
Each article evaluated primary outcomes within a
2-h period. Nevertheless, six studies extended the
observation interval longer: 3 h,22 5 h,11 6 h,14
24 h,1,21 and 36 h.17,18 Multiple statistical tests were
performed in each study, with a mean of 24 (varying
from 0 to 80). No mention of adjustments for
multiple testing were identified in these articles, and
11 articles (73%) made no mention of possible type
I errors.
More than 240 individual outcome measurements
were abstracted from the studies. Scores from a
variety of symptom scales were occasionally used to
describe outcomes; however, due to the different
scores used, no pooled analyses were conducted. In
addition, a number of PFT results were employed
(including peak expiratory flow rate [PEFR], FEV1,
FVC, percentage of predicted PEFR, and percent-
age of predicted FEV1); nonetheless, variability in
the type of PFT employed limited comparisons
between studies. There were no descriptions of any
patients who were intubated or died during any of
the study observation periods.
Five trials9,11,16,18,19 used improvements in PFTs
(namely PEFR) as the primary outcome. Five arti-
cles described a primary outcome variable of “clini-
cal improvement,” but the definition varied widely
between studies. Three of these studies10,13,15 relied
on the “impression by the patient or physician of
improvement in symptoms.” The remaining two
studies used predefined clinical determinants of
success. The first article defined three unique pri-
mary clinical measures of success: earlier ED dis-
charge time (defined as the start of hourly inhaled
salbutamol therapy), faster recovery time (to cessa-
tion of nebulae 2-agonists every 30 min, and
60 min), and less oxygen dependence (defined at the
2-h window as the requirement for medical oxygen
to maintain oxygen saturations Ͼ 93%).1 The second
article14 defined “clinical success” as the presence of
at least two of the following points at 60 min: (1) a
decrease in a “clinical index rating” of at least three
points, (2) a decrease in Paco2 of at least 3 mm Hg,
and (3) an increase in PEFR of at least 50 L/min.
Consequent to the variety of outcomes, only seven
domains were analyzed in which sufficient data were
available and similarly derived: serial PEFR, serial
percentage of predicted PEFR, serial FEV1, serial
heart rate, serial ABG values, autonomic side effects,
and clinical improvement.
www.chestjournal.org CHEST / 122 / 4 / OCTOBER, 2002 1203
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 6. Results
Pulmonary Function
Table 2 demonstrates that across the 6-h observa-
tion in the seven articles reporting PEFR, no statis-
tical differences in PEFR were identified between
those patients who received IV 2-agonists vs inhaled
2-agonists or IV methylxanthines. Moreover, differ-
ences between the summary outcome measures in
each stratum were of questionable clinical signifi-
cance with pooled estimates of treatment effect
ranging from a 0.4 to 19.4 L/min. Over the course of
6 h, there were no statistically or clinically significant
differences with respect to FEV1 or percentage of
predicted PEFRs (not shown). There was intermit-
tent heterogeneity present in these analyses, and this
is addressed further in the discussion.
HRs
Nine articles described heart rate results over a
6-h period recorded in Table 2. Over this time, there
were higher heart rates in those patients who re-
ceived IV 2-agonists (range, 4.0 to 12.3 beats/min).
These differences were statistically significant in the
15-min and 45-min periods, and the 2-h to 6-h strata,
each of which provided homogeneous pooled esti-
mates. However, the differences in heart rates are of
questionable clinical significance.
ABG Measurements
Six articles described ABG measurements, and
five articles described carbon dioxide tensions. There
was no statistical difference in either the Pao2 or
Paco2 between IV 2-agonists and comparison treat-
ments. In addition, there was no heterogeneity
across any stratum.
Autonomic Side Effects
Despite concern regarding the potential side ef-
fects of IV 2-agonists, only 10 studies (67%) re-
ported this information. Autonomic effects included
cardiovascular (palpitations, tachycardia, hyperten-
sion), neurologic (tremor, headache), and/or GI ef-
fects (nausea, vomiting). The pooled OR suggests
that adverse effects were experienced approximately
twice as frequently when receiving IV treatment as
with the comparison treatment. Nevertheless, this
result was not statistically significant and significant
heterogeneity was present in the pooled estimate.
Clinical Improvement
Five articles reported a primary outcome variable
of clinical improvement, but there was variability in
the measurement. The pooled OR suggests that the
proportion of patients who did not improve with IV
therapy was the same as the proportion of patients
Table 2—Summary Effect Measures of Included Studies*
Variables WMD† 95% CI REM 2
‡
Continuous variables
Absolute PEFR, L/min
15 min 10.06 Ϫ 1.67, 21.78 4.63 (df ϭ 4), NS
30 min 9.48 Ϫ 10.45, 29.41 5.75 (df ϭ 3), NS
45 min Ϫ 0.42 Ϫ 29.94, 29.10 0.55 (df ϭ 2), NS
60 min 19.42 Ϫ 3.70, 42.55 18.83 (df ϭ 6), p Յ 0.05
120 min 16.91 Ϫ 18.60, 52.42 15.42 (df ϭ 3), p Յ 0.05
2 to 6 h Ϫ 3.38 Ϫ 21.55, 14.79 4.46 (df ϭ 4), NS
Heart rate, beats/min
15 min 7.70 0.87, 14.51 8.69 (df ϭ 4), NS
30 min 4.03 Ϫ 2.98, 11.03 11.81 (df ϭ 4), p Յ 0.05
45 min 13.07 1.56, 24.50 3.59 (df ϭ 2), NS
60 min 3.65 Ϫ 2.90, 10.19 31.23 (df ϭ 8), p Յ 0.05
120 min 3.95 Ϫ 6.85, 14.76 45.21 (df ϭ 5), p Յ 0.05
2 to 6 h 10.82 5.00, 16.64 9.91 (df ϭ 5), NS
ABG, mm Hg
Pao2 Ϫ 3.18 Ϫ 8.69, 2.33 1.11 (df ϭ 5), NS
Paco2 1.66 Ϫ 0.94, 4.25 3.69 (df ϭ 4), NS
Dichotomous variables§
Adverse side effects (OR, 1.98) 0.48, 8.18 36.80 (df ϭ 8), p Յ 0.05
Fail to improve with treatment (OR, 2.08) 0.32, 13.47 24.48 (df ϭ 4), p Յ 0.05
*REM ϭ random effects model; NS ϭ not significant.
†Negative numbers favor IV treatment; positive numbers favor control.
‡Breslow ϭ Day test for heterogeneity.
§OR Ͻ 1 favors IV treatment; OR Ͼ 1 favors control.
1204 Clinical Investigations
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 7. who received the comparison treatment. Significant
heterogeneity was present in this pooled estimate.
Subgroup Analysis
An insufficient number of pediatric articles with
similar outcome measures were identified, and this
precluded any subgroup comparison on the basis of
age. An insufficient number of similar outcomes
prevented any formal comparison of results based on
type or dose of 2-agonists. There was no statistical
difference in any of the outcome domains when
comparing 2-agonists administered as an IV bolus
vs infusion. There was no change in the trends of the
summary statistics for any of the outcome domains
when strategy 2 was compared to strategy 3. Too few
studies with sufficient similar outcomes limited any
meaningful comparison of strategy 1 vs strategy 2 or
strategy 3.
Sensitivity Analysis: Methodologic Quality
Using the methods of Jadad et al7, a “strong”
methodologic study was defined as having a Jadad
score of 3 to 5, and a “weak” study as having a Jadad
score of 0 to 2. From Table 3 it is evident that the
stronger methodologic studies fail to demonstrate a
clinical or statistical difference between IV 2-
agonists or the comparison treatment in terms of
PEFR and clinical success. Moreover, although not
statistically significant, IV 2-agonists appear to have
an increased risk of adverse effects and increased
heart rate compared to the control treatment. By
comparing the two groups, it is clear that the weak
methodologic studies had larger effect sizes, favoring
the control treatment. Although these were statisti-
cally nonsignificant, the treatment effects from the
weak methodologic were orders of magnitude larger
or even discordant from the results of the method-
ologically strong studies. Subgroup analysis by fixed-
effects modeling demonstrated no differences in
results except for more strata with statistically signif-
icant lower serial heart rates for the non-IV groups
(range, 0.1 to 14.1 beats/min).
Discussion
The literature has been conflicting regarding the
use of IV 2-agonists in patients with acute asthma,
and this systematic review is the first to examine the
available evidence of the effect of treating severe
acute asthmatics with IV 2-agonists. The subse-
quent meta-analysis included 15 randomized trials
over 25 years that included 584 adults and children
across nine countries. IV 2-agonists administered
either by bolus or infusion compared to inhaled
Table3—SensitivityAnalysisbyStrongvsWeakMethodologicQuality*
Variables
StrongMethodologicQuality(JadadScore3to5)WeakMethodologicQuality(JadadScore0to2)
No.of
StudiesWMD†orOR‡95%CI2
No.of
StudiesWMD†orOR‡95%CI2
PEFRat60min4WMD8.30L/minϪ17.63–34.222
4.97(dfϭ3)NS3WMD32.67L/min1.18–64.162
5.80(dfϭ2)NS
PEFRat120min2WMDϪ1.27L/minϪ21.42–18.882
0.63(dfϭ1)NS4WMD27.22L/minϪ28.19–82.632
4.66(dfϭ3)NS
PEFRfinal3WMDϪ10.76L/minϪ32.84–11.332
2.14(dfϭ2)NS3WMD27.25L/minϪ6.20–60.692
5.87(dfϭ2)NS
Heartrateat60min5WMD4.89beats/minϪ1.08–10.862
7.12(dfϭ4)NS3WMDϪ0.69beats/minϪ13.41–12.042
10.68(dfϭ2)§
Heartrateat120min4WMD8.92beats/min1.38–16.462
6.03(dfϭ3)NS2WMDϪ4.44beats/minϪ19.03–10.142
5.93(dfϭ1)§
Sideeffects5OR2.250.49–10.392
7.19(dfϭ4)NS5OR0.260.06–1.152
7.19(dfϭ4)NS
Failtoimprove4OR1.170.12–11.662
15.03(dfϭ3)§1OR12.795.32–30.76NS(onestudy)
*FromJadadetal.7SeeTable2forexpansionofabbreviation.
†NegativenumbersfavorIVtreatment;positivenumbersfavorcontrol.
‡ORϽ1favorsIVtreatment;ORϾ1favorscontrol.
§pՅ0.05.
www.chestjournal.org CHEST / 122 / 4 / OCTOBER, 2002 1205
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 8. 2-agonists or IV methylxanthines did not lead to any
statistically significant differences in pulmonary
functions, laboratory measures of ventilation and
oxygenation, or clinical descriptions of improvement.
Subgroup and sensitivity analysis consistently dem-
onstrated that the use of IV 2-agonists was associ-
ated with an increased risk of autonomic side effects
and higher heart rates; however, they were never
shown to be statistically significant in this regard.
When examining the quality of articles involving
IV agents in acute asthmatic presentations, it is
obvious that greater care must be incorporated into
further work if clarity is to emerge. There were
broad discrepancies among outcomes from studies7,8
where methodologic quality was scored using two
accepted methods. Moreover, statistical planning
and sample size calculations were not carefully con-
sidered in most studies. No studies were large
enough to protect against type II error, and sample
size calculations were rarely reported. Furthermore,
multiple statistical testing was performed in many
studies, increasing the risk of type I error.
The literature has examined three treatment strat-
egies involving IV 2-agonists. Originally, IV 2-
agonists were compared to IV aminophylline in most
clinical trials in the 1970s and early 1980s (40% of
the included articles). As the standard of care for
asthma has been refined, the routine use of ami-
nophylline has diminished, and inhaled 2-agonists
have been increasingly used.2–5 Consequently, there
was a shift in focus to compare IV vs nebulae
2-agonists (40% of the included articles). Whether
IV 2-agonists improve bronchodilator response
when administered in addition to nebulae broncho-
dilators was only addressed in three studies (20%)
under review. Although the evidence suggests that
IV 2-agonists alone are no better than inhaled
2-agonists, the role of IV 2-agonists in addition to
inhaled 2-agonists remains unclear.
There are several potential limitations of this
study. First, this review analyzed only the IV route of
administration, and did not evaluate the literature on
subcutaneous routes of administration. Based on the
consistent lack of benefit shown with the IV 2-
agonists, it is unlikely that subcutaneous agents
would differ in effect when compared to nebulized
agents.
Second, there was significant heterogeneity in
pooled estimates for many of the summary outcome
measures despite the demonstration of similarities in
design, populations, interventions, and outcome
measurements between the 15 studies. Nevertheless,
on further sensitivity analysis it appeared that studies
of weak methodologic quality account for the major-
ity of this heterogeneity. In particular, one article
(Swedish Society, 1990)15 was responsible for the
majority of the heterogeneity based on the following
points: (1) differential methodologic quality, the
Swedish Society article was rated as having low
methodologic quality; (2) different populations, all
articles studied patients with extremely severe asth-
ma; however, the majority of studies enrolled pa-
tients with mean PEFRs in the range of 50 to
100 L/min, whereas the Swedish study evaluated
patients with mean PEFRs in the range of 160 to
170 L/min (still defined as “severe Ͻ 200 L/min” by
international guidelines); and (3) different cointer-
ventions, the Swedish study did not administer any
corticosteroid therapy until 2 h into the study proto-
col, whereas all other studies introduced corticoste-
roid therapy at the time of enrollment into the study.
The effects of each of these factors on the homoge-
neity of the outcome domains were confounding in
isolation and in whole by the very large sample size
of the Swedish study (n ϭ 176) in relation to the
relatively smaller studies (sample range, 14 to 71).
When analyzed by strong vs weak methodologic
quality, the treatment effects favoring control were
less pronounced in the methodologically stronger
studies. This would suggest that the methodologi-
cally stronger studies fail to demonstrate a clear
difference between the two comparison treatments.
Third, despite the intensive search strategy em-
ployed, there still exists a possibility of study selec-
tion bias or publication bias in this meta-analysis. For
example, we may be erroneously estimating the
nonsignificant effects of IV 2-agonists due to miss-
ing unpublished negative or positive trial results.
Although a comprehensive search of the published
English and non-English literature for potentially
relevant studies was conducted, using a systematic
strategy to avoid bias, some studies may have still
been missed. In addition, attempts were made to
contact first and corresponding authors. Despite
these endeavors, no unpublished or non-English
articles were uncovered; still, we recognize that they
may exist.
Fourth, the best outcome measure for “success” in
treating acute asthma was measured variably be-
tween studies. Better standardization of this out-
come would improve study comparability. Most
studies included pulmonary functions as their pri-
mary outcome measures. The inherent variability of
these PFTs in acute asthma, emphasizes the need for
further research into alternative and valid measures.
In addition, the evaluation of adverse side effects was
complicated by a lack of standardized reporting.
Conclusion
Despite the methodologic limitations, the results
of this work clarify the use of IV 2-agonists in the
1206 Clinical Investigations
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 9. treatment of severe acute asthma. The use of IV
2-agonists compared to inhaled 2-agonists or IV
methylxanthines did not lead to any significant dif-
ferences in pulmonary functions, laboratory mea-
sures of ventilation and oxygenation, or clinical
failure/success. Although statistically nonsignificant,
IV 2-agonists produced slightly more autonomic
side effects and tachycardia than do comparison
treatments. Consequently, the clinical benefit ap-
pears questionable, while the potential clinical risks
are obvious. The only recommendations for IV 2-
agonist use should be in those patients in whom
inhaled therapy is not feasible, or in the context of a
controlled clinical trial comparing IV 2-agonists
with standard care vs standard care alone.
ACKNOWLEDGMENT: The authors thank Stephen Milan,
Anna Bara, and Jane Dennis of the Cochrane Airways Review
Group. The editorial assistance of Professor Paul Jones
(Cochrane Airways Review Group Coordinating Editor) and the
abstraction of data by Carol Spooner were greatly appreciated.
References
1 Browne GJ, Penna AS, Phung X, et al. Randomized trial of
intravenous salbutamol in early management of acute severe
asthma in children. Lancet 1997; 349:301–305
2 Lipworth BJ. Treatment of acute asthma. Lancet 1997;
350:sii18–sii23
3 Beveridge RC, Grunfeld AF, Hodder RV, et al. Guidelines
for the emergency management of asthma in adults. Can Med
Assoc J 1996; 155:25–37
4 Ernst P, Fitzgerald J, Spier S. Canadian Asthma Consensus
Conference: summary of recommendations. Can Respir J
1996; 3:89–100
5 National Asthma Education and Prevention Program. Expert
panel report 2: guidelines for the diagnosis and management
of asthma. Bethesda, MD: National Institutes of Health,
1997; 1
6 Mulrow C, Oxman A. Cochrane collaboration handbook. The
Cochrane Library. Issue 4, 2001. Oxford, UK: Oxford Update
Software, updated quarterly, 1999
7 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality
or reports of randomized clinical trials: is blinding necessary?
Control Clin Trials 1996; 17:1–12
8 Schultz KF, Chalmers I, Hayes RJ, et al. Empirical evidence
of bias: dimensions of methodological quality associated with
estimates of treatment effects in controlled trials. JAMA 1995;
273:408–412
9 Bloomfield P, Carmichael J, Petrie GR, et al. Comparison of
salbutamol given intravenously and by intermittent positive-
pressure breathing in life-threatening asthma. BMJ 1979;
1:848–850
10 Tribe AE, Wong RM, Robinson JS. A controlled trial on
intravenous salbutamol and aminophylline in acute asthma.
Med J Aust 1976; 2:749–752
11 Cheong B, Reynolds SR, Rajan G, et al. Intravenous -agonist
in severe acute asthma. BMJ 1988; 297:448–450
12 Van Renterghem D, Lamont H, Elinck W, et al. Intravenous
vs nebulized terbutaline in patients with acute severe asthma:
a double-blind randomized study. Ann Allergy 1987; 59:313–
315
13 Lawford P, Jones BJM, Milledge JS. Comparison of intrave-
nous and nebulised salbutamol in initial treatment of severe
asthma [abstract]. BMJ 1978; 1:84
14 Salmeron S, Brochard L, Mal H, et al. Nebulized vs intrave-
nous albuterol in hypercapnic acute asthma: a multicenter,
double-blind randomized study. Am J Respir Crit Care Med
1994; 149:1466–1470
15 Swedish Society of Medicine. High-dose inhaled vs intrave-
nous salbutamol combined with theophylline in severe acute
asthma. Eur Respir J 1990; 3:163–170
16 Williams SJ, Winner SJ, Clark TJH. Comparison of inhaled
and intravenous terbutaline in acute severe asthma. Thorax
1981; 36:629–631
17 Hussein A, von der Hardt H, Muller W, et al. Intravenous
infusion of reproterol in the treatment of acute severe asthma
in children. Monatsschr Kinderheilkd (German) 1986; 134:
192–196
18 Johnson AJ, Spiro SG, Pidgeon J, et al. Intravenous infusion
of salbutamol in severe acute asthma. BMJ 1978; 1:1013–
1015
19 Williams SJ, Parrish RW, Seaton A. Comparison of intrave-
nous aminophylline and salbutamol in severe asthma [ab-
stract]. BMJ 1975; 4:685
20 Femi-Pearse D, George WO, Ilechukwu ST, et al. Compar-
ison if intravenous aminophylline and salbutamol in severe
asthma [abstract]. BMJ 1977; 1:491
21 Hambleton G, Stone MJ. Comparison of IV salbutamol with
IV aminophylline in the treatment of severe, acute asthma in
childhood. Arch Dis Child 1979; 54:391–402
22 Sharma TN, Gupta RB, Gupta PR, et al. Comparison of
intravenous aminophylline, salbutamol, and terbutaline in
acute asthma. Indian J Chest Dis Allied Sci 1984; 26:155–158
23 Chronic bronchitis, asthma, and pulmonary emphysema: a
statement by the Committee on Diagnostic Standards for
Non-tuberculosis Respiratory Disease; American Thoracic
Society. Am Rev Respir Dis 1962; 85:762–768
24 National Asthma Campaign. Initial assessment of severity of
asthma in children. In: Asthma management handbook 1993.
Melbourne, Australia: National Asthma Campaign, 1993
www.chestjournal.org CHEST / 122 / 4 / OCTOBER, 2002 1207
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
- 10. DOI 10.1378/chest.122.4.1200
2002;122; 1200-1207Chest
Carlos A. Camargo, Jr
Andrew H. Travers, Brian H. Rowe, Samantha Barker, Arthur Jones and
: A Meta-analysis*Asthma in the Emergency Department
-Agonists in Treating Patients With AcuteβThe Effectiveness of IV
March 12, 2012This information is current as of
http://chestjournal.chestpubs.org/content/122/4/1200.full.html
Updated Information and services can be found at:
Updated Information & Services
http://chestjournal.chestpubs.org/content/122/4/1200.full.html#ref-list-1
This article cites 21 articles, 12 of which can be accessed free at:
References
http://chestjournal.chestpubs.org/content/122/4/1200.full.html#related-urls
This article has been cited by 7 HighWire-hosted articles:
Cited Bys
http://www.chestpubs.org/site/misc/reprints.xhtml
found online at:
Information about reproducing this article in parts (figures, tables) or in its entirety can be
Permissions & Licensing
http://www.chestpubs.org/site/misc/reprints.xhtml
Information about ordering reprints can be found online:
Reprints
"Services" link to the right of the online article.
Receive free e-mail alerts when new articles cite this article. To sign up, select the
Citation Alerts
PowerPoint slide format. See any online figure for directions.
articles can be downloaded for teaching purposes inCHESTFigures that appear in
Images in PowerPoint format
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from
![The Effectiveness of IV -Agonists in
Treating Patients With Acute Asthma in
the Emergency Department*
A Meta-analysis
Andrew H. Travers, MD, MSc; Brian H. Rowe, MD, MSc;
Samantha Barker, MD; Arthur Jones, RT; and
Carlos A. Camargo, Jr., MD, DrPH
Objectives: To determine the benefit of IV 2-agonists for severe acute asthma treated in the
emergency department (ED).
Methods: Randomized controlled trials were identified using EMBASE, MEDLINE, and CINAHL;
the Cochrane Airways Review Group database; hand searching; bibliographies; pharmaceutical
companies; and author contact. Studies where IV 2-agonists were compared to placebo and/or
existing standards of care were considered. Where appropriate, trials were combined using odds
ratios (ORs) or weighted mean differences with 95% confidence intervals (CIs).
Results: From 746 identified references, 55 potentially relevant articles were identified and 15
articles were included. All trials were performed outside North America and were published prior to
1997. Three main treatment strategies were reviewed: strategy 1 (three articles), IV 2-agonists with
inhaled 2-agonists vs inhaled 2-agonists; strategy 2 (six articles), IV 2-agonists alone vs inhaled
2-agonists; and strategy 3 (six articles), IV 2-agonists vs IV methylxanthines. Compared to all
treatments, IV 2-agonist use did not lead to clinical or statistical significant differences in vital signs,
pulmonary functions, laboratory measures, adverse effects, or clinical success. Although statistically
nonsignificant, seven methodologically strong studies demonstrated that peak expiratory flows and
heart rates were unchanged following 2-agonist use compared to all other treatments at 60 min
(8.3 L/min [95% CI, 17.6 to 34.2] and 3.65 beats/min [95% CI, 2.9 to 10.2], respectively), with an
increased risk of adverse effects (OR, 1.98; 95% CI, 0.5 to 8.2).
Conclusions: Evidence is lacking to support the use of IV 2-agonists in ED patients with severe acute
asthma. Moreover, the clinical benefit appears questionable, while the potential clinical risks are
obvious. The only recommendations for IV -2agonist use should be in those patients in whom inhaled
therapy is not feasible, or in the context of a controlled clinical trial comparing IV 2-agonists with
standard care vs standard care alone. (CHEST 2002; 122:1200–1207)
Key words: asthma; -agonists; emergency department; IV; pulmonary function; side effects
Abbreviations: ABG ϭ arterial blood gas; CI ϭ confidence interval; CPG ϭ clinical practice guideline; df ϭ degrees of
freedom; ED ϭ emergency department; OR ϭ odds ratio; PEFR ϭ peak expiratory flow rate; PFT ϭ pulmonary function
test; RCT ϭ randomized controlled trial; WMD ϭ weighted mean difference
The general approach to treating patients with
acute asthma is to use inhaled -agonist bron-
chodilators and corticosteroids. For severe acute
asthma, penetration of inhaled -agonists to the
affected small conducting airways may be impeded,
and consequently responses may be a result of drug
reaching the receptors via the systemic circulation.
In these circumstances, if bronchodilatation occurs
*From the Division of Emergency Medicine (Drs. Travers and
Rowe) and Department of Radiology (Dr. Barker), University of
Alberta and Capital Health Authority, Edmonton, AB, Canada;
Respiratory Care Department (Mr. Jones), University of Texas,
San Antonio, TX; and the Department of Emergency Medicine
(Dr. Camargo), Massachusetts General Hospital Boston, MA.
Presented at the American College of Emergency Physicians
Annual Meeting, Las Vegas, NV, October 1999, and the Cana-
dian Association of Emergency Physicians Annual Meeting,
Quebec City, PQ, Canada, October, 1999.
These results have been electronically published by the Airways
Review Group in the Cochrane Collaboration (Cochrane Data-
base of Systematic Reviews. The Cochrane Library, Issue 4,
2001. Oxford, UK: Update Software). Dr. Travers received a
grant from the Canadian Association of Emergency Physicians to
complete this work. Dr. Rowe is supported by a salary award
from the Canadian Institute of Health Research as the Chair in
Emergency Airway Diseases (Ottawa, ON). Dr. Camargo is
supported by grant HL-03533 from the National Institutes of
Health (Bethesda, MD).
Correspondence to: Andrew Travers, MD, MSc, Division of
Emergency Medicine, University of Alberta, 1G1.50 WMC, 8440-
112th St, Edmonton, AB, T6G 2B7 Canada; e-mail: ahtravers@
shaw.ca
1200 Clinical Investigations
© 2002 American College of Chest Physicians
by guest on March 12, 2012chestjournal.chestpubs.orgDownloaded from](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)