Dolovich

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(Chest. 2005;127:335-371.)
© 2005 American College of Chest Physicians
Device Selection and Outcomes of Aerosol Therapy:

Evidence-Based Guidelines*
American College of Chest Physicians/American College of Asthma,
Allergy, and Immunology
Myrna B. Dolovich, PEng; Richard C. Ahrens, MD; Dean R. Hess, PhD, RRT,
FCCP; Paula Anderson, MD, FCCP; Rajiv Dhand, MD, FCCP; Joseph L.
Rau, PhD, RRT; Gerald C. Smaldone, MD, PhD, FCCP and Gordon Guyatt,
MD, FCCP
*
From the Faculty of Health Sciences (Professor Dolovich) and the Department of Clinical Epidemiology
and Biostatistics (Dr. Guyatt), McMaster University, Hamilton, ON, Canada; the Division of Pediatric
Allergy and Pulmonary Diseases (Dr. Ahrens), Roy J. and Lucille A. Carver College of Medicine,
University of Iowa, Iowa City IA; Harvard Medical School (Dr. Hess), Boston, MA; the Division of
Pulmonary and Critical Care Medicine (Dr. Anderson), University of Arkansas for Medical Sciences,
Little Rock, AK; the Division of Pulmonary, Critical Care, and Environmental Medicine (Dr. Dhand),
University of Missouri-Columbia, Columbia, MO; Cardiopulmonary Care Sciences (Dr. Rau), Georgia
State University, Atlanta, GA; and the Department of Medicine (Dr. Smaldone), Pulmonary/Critical Care
Division, State University of New York at Stony Brook, Stony Brook, NY.
Correspondence to: Myrna B. Dolovich, PEng, Faculty of Health Sciences, McMaster University, 1200
Main St West, HSC 1V18, Hamilton, ON, Canada L8N 3Z5; e-mail: [email protected]
Abstract TOP
Abstract
Introduction
Methodology
Background: The proliferation of inhaler devices has
Results and Recommendations
resulted in a confusing number of choices for clinicians Device Selection in the...
who are selecting a delivery device for aerosol therapy. Discussion
There are advantages and disadvantages associated with Summaries and Results
each device category. Evidence-based guidelines for the References
selection of the appropriate aerosol delivery device in specific clinical settings are
needed.
Aim: (1) To compare the efficacy and adverse effects of treatment using nebulizers vs
pressurized metered-dose inhalers (MDIs) with or without a spacer/holding chamber vs
dry powder inhalers (DPIs) as delivery systems for ß-agonists, anticholinergic agents,
and corticosteroids for several commonly encountered clinical settings and patient
populations, and (2) to provide recommendations to clinicians to aid them in selecting a
particular aerosol delivery device for their patients.
Methods: A systematic review of pertinent randomized, controlled clinical trials (RCTs)

was undertaken using MEDLINE, EmBase, and the Cochrane Library databases. A
broad search strategy was chosen, combining terms related to aerosol devices or drugs
with the diseases of interest in various patient groups and clinical settings. Only RCTs in
which the same drug was administered with different devices were included. RCTs (394
trials) assessing inhaled corticosteroid, ß2-agonist, and anticholinergic agents delivered
by an MDI, an MDI with a spacer/holding chamber, a nebulizer, or a DPI were
identified for the years 1982 to 2001. A total of 254 outcomes were tabulated. Of the
131 studies that met the eligibility criteria, only 59 (primarily those that tested ß2-
agonists) proved to have useable data.
Results: None of the pooled metaanalyses showed a significant difference between

devices in any efficacy outcome in any patient group for each of the clinical settings that
was investigated. The adverse effects that were reported were minimal and were related
to the increased drug dose that was delivered. Each of the delivery devices provided
similar outcomes in patients using the correct technique for inhalation.
Conclusions: Devices used for the delivery of bronchodilators and steroids can be
equally efficacious. When selecting an aerosol delivery device for patients with asthma
and COPD, the following should be considered: device/drug availability; clinical
setting; patient age and the ability to use the selected device correctly; device use with
multiple medications; cost and reimbursement; drug administration time; convenience in
both outpatient and inpatient settings; and physician and patient preference.
Key Words: aerosols • bronchodilators • corticosteroids • drug delivery systems • dry

powder inhalers • metaanalysis • metered-dose inhalers • nebulizers
Introduction
TOP
Abstract
The use of inhaled aerosol medications for the treatment Introduction
Methodology
of pulmonary diseases, which became well-established
in the last half of the 20th century, has advantages over Device Selection in the...
oral and parenteral routes of delivery. The use of inhaled Discussion
aerosols allows selective treatment of the lungs directly Summaries and Results
by achieving high drug concentrations in the airway References
while reducing systemic adverse effects by minimizing
systemic drug levels.1 Inhaled ß2-agonist bronchodilators produce a more rapid onset of
action than oral delivery. Some drugs are only active with aerosol delivery (eg, for
asthma patients, cromolyn and ciclesonide; for cystic fibrosis patients, dornase alfa).
Aerosol drug delivery is painless and often convenient. For these reasons, the National
Asthma Education and Prevention Program guidelines2 favor aerosol inhalation over the
oral route or parenteral (ie, subcutaneous, IM, or IV) route. Similarly, the National
Heart, Lung, and Blood Institute/World Health Organization Global Initiative for
Chronic Obstructive Lung Disease recommended that bronchodilator medications are
central to symptom management in COPD patients and that inhaled therapy is
preferred.3
There are also disadvantages to aerosol drug therapy. One of the most important
disadvantages is that specific inhalation techniques are necessary for the proper use of
each of the available types of inhaler device. A less than optimal technique can result in
decreased drug delivery and potentially reduced efficacy.45 Improper inhaler technique
is common among patients.678 The proliferation of inhalation devices that are available
for patients has resulted in a confusing number of choices for the health-care provider
and in confusion for both clinicians and patients trying to use these devices correctly.
Several studies have demonstrated lack of physician, nurse, and respiratory therapist
knowledge of device use.910111213 Inhaler devices are less convenient than oral drug
administration insofar as the time required for drug administration may be longer and
some patients may find the device less portable. This is particularly true for
conventional compressed-air nebulizers, the oldest of the currently used types of aerosol
delivery devices.
Device manufacturers have long been aware of the importance of portability and ease of
use with aerosol delivery devices. As a result, these devices have evolved over time.
From the 19th century until 1956, compressed-air nebulizers (also called jet nebulizers)
were the only devices that were in common clinical use for the administration of inhaled
aerosol drugs. In 1955, the pressurized metered-dose inhaler (MDI) was developed at
Riker Laboratories (now 3M Pharmaceuticals; St. Paul, MN).14 Ultrasonic nebulizers,
which utilize high-frequency acoustical energy for the aerosolization of a liquid, were
introduced in the 1960s.1516 In 1971, Bell and colleagues17 introduced the first dry
powder inhaler (DPI), known as the Spinhaler, for the inhalation of cromolyn sodium.
This and subsequent DPIs have been "breath-actuated," providing drug only when
demanded by patient inhalation, thus avoiding a common error with MDI use, the
improper timing of inhaler actuation. Breath-actuated MDI devices (eg, the Autohaler;
3M Pharmaceuticals) are also triggered by patient inhalation to release the drug on
demand.
Investigators developed open-tube spacer devices, intended for use with MDIs, in the
late 1970s.181920 The addition of a one-way valve (holding chamber)18 or blind reservoir
(ie, reverse-flow spacer)2122 allowed the aerosol delivered by the MDI to be contained in
the spacer for a finite period of time, thereby circumventing the need for the coordinated
actuation of the MDI with inhalation. Other spacer/holding chamber designs followed,
and today there are several devices that vary in design, shape, size, and assembly. The
design of MDIs changed little between 1956 and the 1980s. However, the 1987
Montreal protocol mandated the phaseout of the use of chlorofluorocarbons (CFCs) as
propellants in all MDIs. This resulted in a redesign of MDIs in the 1990s, utilizing
hydrofluoroalkane propellants.22 Some of these formulations produce aerosols with
different characteristics that behave differently in patients than their predecessors.23
Each type of aerosol device has its own advantages and disadvantages (Table 1 ).
Nebulizer/compressor systems require minimal patient cooperation and coordination,
but are cumbersome and time-consuming to use. Matching nebulizers with associated
air compressors is necessary to assure optimal efficiency of drug delivery. MDIs are
quicker to use and highly portable, but require the most patient training to ensure
coordination for proper use. Up to 70% of patients fail to use them properly. The
improper timing of MDI actuation with breath initiation is a common problem.7 DPIs are
easier to use than MDIs because they are breath-actuated, but require a relatively rapid
rate of inhalation in order to provide the energy necessary for drug aerosolization.
Younger patients and patients in acute distress may not be able to generate the necessary
flow rates.224 Breath-actuated MDIs are also easier to use, but are currently available in
the United States for only a single drug (ie, the ß2-agonist pirbuterol). Holding chambers
used with MDIs remove the necessity of careful timing between inhalation and MDI
actuation. However, they are more bulky to carry than the MDI by itself or a DPI. The
improper use of holding chambers (eg, placing multiple puffs in the chamber before
inhalation or waiting too long between MDI actuation and inhalation) can actually
reduce drug delivery to the lungs.
View this Table 1. Advantages and Disadvantages of Each Type of Aerosol-

table: Generating Device or System Clinically Available*
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Several factors can guide clinicians on the choice of a device for a specific patient. One
factor is the age of the subject (Table 2 ).2 Another factor is the availability of the drug
formulation, as not all drugs are available in each type of aerosol delivery device. The
clinical setting (eg, outpatient, emergency department (ED), hospitalized inpatient, or
intensive care setting) and the disease being treated (eg, COPD vs asthma) also influence
the choice of aerosol device.
View this Table 2. General Age Requirements for Correct Use of Aerosol
table: Delivery Device Types*
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Several systematic reviews and metaanalyses related to the selection of an aerosol
delivery device have been published. In a metaanalysis, Turner et al25 concluded that
bronchodilator delivery by means of nebulizer or MDI is equivalent in the treatment of
adults with acute airflow obstruction. A systematic review by Amirav and Newhouse26
compared MDIs with accessory devices to nebulizers in children with acute asthma.
While their results showed no differences between the types of delivery systems, it was
concluded that the MDI with an accessory device (ie, a spacer or holding chamber)
should be considered the preferred mode of aerosol delivery. A systematic review27 of
the management of acute exacerbations of COPD concluded that there is insufficient
evidence that either an MDI or a nebulizer is superior. Cates et al28 and Cates,29 in
systematic reviews of spacers and holding chambers vs nebulizers for ß2-agonist
treatment of acute asthma, concluded that an MDI with a holding chamber produces
outcomes that are at least equivalent to those achieved with the use of a nebulizer.
Several systematic reviews303132 have compared MDIs to DPIs and have concluded that
there is no evidence that either device is superior to the other for bronchodilator therapy.
While systematic reviews provide key evidence summaries, they do not present specific
recommendations for practice. The reasons for this include a focus on restricted
populations and outcomes, and the lack of a process to ensure recommendations reflect
patients’ values and preferences.33 However, clinicians require information and guidance
concerning the best estimates of benefits and risks of alternatives, and concerning the
explicit tradeoffs between these benefits and risks, or, in other words, evidence-based
guidelines. Therefore, despite the availability of the above systematic reviews, we
believe that evidence-based guidelines are still needed. Consequently, the intent of this
project was to assess the available scientific evidence addressing the question of
whether device selection affects efficacy and the adverse effects of treatment. Therefore,
we set out to systematically review relevant evidence from randomized, placebo-
controlled clinical trials and to provide general recommendations based on the tradeoffs
that this evidence provides. Our recommendations relate to issues that clinicians should
consider in selecting a particular therapeutic aerosol delivery device for their patients in
each of several commonly encountered clinical settings.
Methodology
We undertook a systematic overview of the pertinent TOP

literature. The databases that were searched were Abstract
MEDLINE, Embase, and the Cochrane Library (Table 3 Introduction
Methodology
, available on-line only). A broad search strategy was
chosen to combine terms relating to aerosol devices or Device Selection in the...
drugs with those relating to the diseases of interest in Discussion
various patient groups and in a number of clinical Summaries and Results
settings (Fig 1 ). Only randomized controlled trials References
(RCTs) in human subjects published in English were
selected. The search identified an initial set of
approximately 2,100 publications spanning the years 1972 to 2000. Two reviewers
independently assessed each abstract of these publications to determine whether they
met the eligibility criteria (ie, RCT addressing the relevant population, intervention, and
outcome). This review identified 394 RCTs assessing inhaled corticosteroid, ß2-agonist,
and anticholinergic agents that were delivered by MDI, MDI with spacer/holding
chamber, nebulizer, or DPI. These 394 studies were coded (for setting, population,
disease, and device) to provide a second screening to identify studies in which the same
drug was administered with different devices. Studies were excluded if they only
compared devices of the same type (eg, DPI with DPI) or only compared oral or
parenteral therapy with the aerosol therapy. Data were then extracted from the
remaining 131 studies. A total of 254 outcomes were tabulated (Table 4 , available on-
line only). Because this proved unwieldy, we created a taxonomy of 10 categories
(Table 5 ) and, as many of the outcomes were similar expressions of the same
measurement, specified a hierarchy of outcomes within this taxonomy. Of the 131
studies, only 59 proved to have useable data (Table 6 ). These studies primarily tested
ß2-agonists. Few studies of corticosteroids met our eligibility criteria.
View this table: Table 3A. Search Strategies for RCTs*

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View this table: Table 3B. PubMed Search Strategy

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View this table: Table 3C. EMBASE Search Strategy

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Figure 1. Studies selected included those

overlapping (illustrated by shaded area) devices or
drugs, disease setting, and RCTs.
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View this table: Table 4. Outcome Categories*

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View this table: Table 5. Ranked Taxonomy of Outcomes*

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View this table: Table 6. Reasons Trials Were Not Included in Analysis
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Separate metaanalyses were carried out for each specific clinical setting being
considered. The weighted standardized difference between treatment groups in the
outcome of interest was calculated using the mean scores and their SDs. We combined
results across end points of FEV1, peak flow, and specific airway conductance (sGaw),
and calculated the effect size in SD units. For studies that made measurements at
multiple time points, the last time point was used for analysis. For studies with multiple
doses, analyses using the first dose and the last dose were performed. All outcomes
reported are in SD units. In studies that provided data for more than one of these
outcomes, we used the outcome that was highest in the hierarchy. To assess whether the
magnitude of the heterogeneity of differences in the apparent treatment effect across
studies was greater than one might expect by chance, we conducted a test based on the
2
distribution with N – 1 degree of freedom, where N is the number of studies. No
important effects were seen in any of the group analyses, and there was very little
heterogeneity in any of the data. In general, our statistical methods relied on the
approaches described by Fleiss34 and by Hedges and Olkin.35
We found that the studies were heterogeneous in purpose, design, and patient selection,
and determined that these descriptors would influence the interpretation and relevance
of the studies for clinical use by patients. Therefore, we grouped the studies that were
reviewed into three general types (types 1, 2a, and 2b) based on the intended purpose
and specific study design used.
Type 1 Trials: Device Performance Under Conditions of Actual Clinical Use
These trials were intended to compare the effectiveness of the devices and drug being
studied in a setting of "real-world" clinical use with the measured outcomes relevant to
the accepted indication for the drug in this setting. Studies that compared the effect of a
ß2-agonist agent delivered by nebulizer, DPI, and/or MDI in patients presenting to the
ED with acute asthma are an example of this type of study. These studies typically
evaluate outcomes such as improvement in lung function and oxygenation or hospital
admission rate. Studies that compare the effect of inhaled corticosteroids delivered by
different devices over a period of weeks, and assess daily asthma symptoms, ß2-agonist
use, and daily peak flow measurement are other examples of such studies.
Type 2 Trials: Device Performance in the Clinical Laboratory Setting

These studies compare drug delivery to the lungs and the clinical response to drugs
administered by different devices under carefully controlled clinical laboratory
conditions. These studies were typically performed to satisfy regulatory requirements
during the process of drug development and registration. Participating patients are
usually carefully trained in and monitored for the proper use of the devices. These
studies do not directly evaluate the performance of the devices in settings and conditions
in which patients actually use them as part of the management of their asthma or COPD
(eg, a patient who awakens in the night with acute bronchospasm). The most common
examples of this type of study are outpatient evaluations of devices containing short-
acting ß2-agonists. Most of these studies measure increases in lung function in response
to the ß2-agonist in patients who have developed a mild-to-moderate degree of
bronchospasm after having their usual asthma medication withheld. A few measure the
inhibition of bronchial provocation with exercise compounds (eg, methacholine or
histamine). Type 2 studies can be divided into two subtypes based on the kind of
analysis performed in the study.
Type 2a Trials: Analyzing Differences in Response Variables:

These studies typically compare mean increases in lung function values (eg, FEV1)
produced by the different devices. These studies are termed response axis comparisons
by the US Food and Drug Administration and are now widely recognized to be
relatively insensitive to true differences in drug delivery by different devices.36
Typically, the doses used are near the top of the ß2-agonist dose-response curve that
patients exhibit in this setting. As a result, the studies are commonly unable to
distinguish differences in response to either a different dose via the same device or to
delivery by different devices.
Type 2b Trials: Estimating Differences in Clinical Potency:

These studies establish dose-response curves for each of the devices being compared
and then use differences in the position of these curves to estimate differences in the
clinical potency of the devices (known as the relative potency or potency ratio). The
results of this analysis yield statements such as "1 actuation (or microgram of drug)
delivered from ‘device A’ is equivalent to ‘X’ number of actuations (or micrograms)
delivered from ‘device B.’" The analysis also calculates a confidence interval for the
estimate of the relative potency as an indicator of how reliable the estimate is. These
studies are termed "dose-scale comparisons"36 and are recognized as being the most
reliable way of identifying true difference in drug delivery to the site of action in the
lung.
Members of the Writing Committee assumed responsibility for drafting individual
sections of the final document, including the recommendations. To grade the strength of
the recommendations, we used a system adopted by the Health and Science Policy
Committee of the American College of Chest Physicians (Table 7 ). The draft document
was reviewed by all members of the Writing Committee for content and accuracy.
View this table: Table 7. Scheme Used to Grade Recommendations

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Device Selection in the Hospital Acute Care Setting
Aerosol Delivery of Short-Acting ß2-Agonists in the Hospital ED:
Nineteen RCTs that compared aerosol delivery devices in the ED met the criteria for
inclusion in the analysis. All used a parallel design and
assessed the response to one of three ß2-agonist TOP
bronchodilators (ie, albuterol, metaproterenol, or Abstract
terbutaline). No studies were available that compared Introduction
nebulizers to MDIs alone in patients with acute asthma Methodology
presenting to the ED. The majority of these studies Device Selection in the...
compared delivery by nebulizer to that by an MDI with Discussion
a spacer/holding chamber. All were type 1 studies that Summaries and Results
enrolled patients presenting to the ED with acute asthma References
symptoms. Only 3 of the 19 studies included in the
analysis studied delivery by DPI in the ED setting. None
of the studies specifically stated that they had screened patients for their ability to use
the device correctly. The studies also omitted a detailed discussion of the device
technique that was used to inhale the medications. Most of these studies measured acute
physiologic responses to treatment, and a smaller number measured effects on asthma
sign/symptom scores. Few studies offer other clinically important outcome measures
such as hospital admission rate, time in the ED, and readmissions to the ED. The cost of
care and the fraction of patients who cannot use the device correctly were not reported
in any of the studies.
Eight studies3738394041424344 randomized pediatric patients to receive a ß2-agonist agent by

nebulizer or MDI with spacer/holding chamber (ie, Aerocell Lactantes [Grünewald-
Danes; Chile], AeroChamber [Trudell Medical; London, ON, Canada], and Volumatic
[Glaxo Wellcome; London, UK]) [Table 8 ]. Collectively, these studies enrolled patients
with ages ranging from < 1 to 17 years. Most investigators reported no significant
difference between these two techniques for pulmonary function measures (ie, peak flow
and FEV1) or symptom scores. Metaanalyses of symptom scores and pulmonary
function results showed no differences between the nebulizer and the MDI with a
spacer/holding chamber (Fig 2, 3 ). One study40 reported greater patient preference for
the MDI with a spacer/holding chamber, and another study38 reported shorter treatment
times with the use of an MDI and a spacer/holding chamber. None of the studies
included in the analysis evaluated DPI use in pediatric patients presenting to the ED.
View this Table 8. Short-term Nebulizer vs MDI + Spacer/Holding Chamber

table: Studies Using ß2-Agonists for Pediatric Patients in the Acute Care
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Figure 2. Weighted standardized mean difference

(WMD) for symptom scores in ED/ICU trials
using ß2-agonists comparing nebulizer (N) vs MDI
+ spacer/holding chamber (M + S/HC).

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Figure 3. Top: weighted standardized mean difference

for peak flow in ED/ICU trials using ß2-agonists
comparing nebulizer vs MDI + spacer/holding chamber.
Bottom: weighted standardized mean difference for
FEV1 in ED/ICU trials using ß2-agonists comparing
nebulizer vs MDI + spacer/holding chamber. See the
legend of Figure 2 for abbreviations not used in the text.
View larger version

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In adult patients reporting to the ED with asthma symptoms (Table 9 ), six

studies454647484950 compared ß2-agonist delivery by nebulizer to that by an MDI with a
spacer/holding chamber. No study reported a significant difference in pulmonary
function response to the two methods of delivery (Fig 3). Two studies4748 addressed other
important outcomes and reported no significant differences between devices for time in
the ED, hospital admission rate, and frequency of ED discharge at 6 h. Similar findings
were reported in studies515253 including both pediatric (ie, adolescent) and adult patients
in ED settings. The three studies475455 evaluating the use of a DPI (eg, Rotahaler
[GlaxoSmithKline; Ware, UK] and Turbuhaler [AstraZeneca; Lund, Sweden]) with
adult patients in this setting reported no significant differences between DPI and the
other two delivery methods for pulmonary function response and for other outcomes
such as hours to hospital discharge (Table 10 ). Similar findings were noted for pediatric
patients presenting to the ED in a study that was not included in this analysis.56
View this Table 9. Short-term Nebulizer vs MDI + Spacer/Holding Chamber

table: Studies Using ß2-Agonists for Adult Patients in the Acute Care
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View this table: Table 10. Short-term DPI Studies Using ß2-Agonists in the Acute
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One study57 evaluated aerosol delivery devices in an ambulance setting. No significant

differences were reported in pulmonary function response to a nebulizer, an MDI used
alone, or an MDI with a spacer/holding chamber, but the effects on respiratory rate and
duration of treatment were significantly better for the use of the MDI with holding
chamber than for the other two methods.
Adverse effects appeared to be more common with nebulizer use. Heart rate change
tended to be greater in patients using a nebulizer, but the effect across studies was
significant only when pediatric and adult studies were analyzed together (Fig 4 ). These
differences in heart rate between devices tended to be small in magnitude. One study38
found vomiting to be more common with nebulizer use than with use of an MDI with a
spacer/holding chamber, which likely was due to the larger dose given by nebulizer in
these subjects.
for heart rate in ED/ICU trials using ß2-agonists
comparing nebulizer vs MDI + spacer/holding
chamber. See the legend of Figure 2 for
abbreviations not used in the text.

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Summary of RCT Results

The delivery of ß2-agonists in the ED setting by nebulizers or MDIs with holding
chambers (eg, AeroChamber, Volumatic, or InspirEase [Key Pharmaceuticals;
Kenilworth, NJ]) is equally effective for improving pulmonary function and
reducing symptoms of acute asthma in both adult and pediatric patients (quality
of evidence: good).
The delivery of ß2-agonists in the ED setting by DPI (eg, Rotahaler or
Turbuhaler) has been inadequately studied, but trials in adults have suggested
DPIs may be as effective as nebulizers or MDIs with spacer/holding chambers
(quality of evidence: low).
Nebulizer use in the ED setting is associated with greater increases in heart rate
than with the use of an MDI with spacer/holding chamber, suggesting that a
larger systemically absorbed dose is administered by nebulizers (quality of
evidence: good).
Recommendations
1. Both the nebulizer and MDI with spacer/holding chamber are appropriate for the
delivery of short-acting ß2-agonists in the ED. Quality of evidence: good; net
benefit: substantial; strength of recommendation: A.
2. Because data for DPIs are limited, and high quality data for standard MDIs
(without spacer/holding chamber) and breath-actuated MDIs are unavailable, we
are unable to recommend the use of these devices in the ED until more
information is available. Quality of evidence: low; net benefit: none; strength of
recommendation: I.
3. Many factors would lead the clinician to appropriately select a particular type of
aerosol delivery device in this setting. These factors include the patient’s ability
to use the device correctly, the preferences of the patient for the device, the
unavailability of an appropriate drug/device combination, the compatibility
between the drug and delivery device, the lack of time or skills to properly
instruct the patient in the use of the device or to monitor the appropriate use, and
the cost of therapy. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Aerosol Delivery of Short-Acting ß2-Agonists in the Inpatient Hospital Setting

Considering the common use of aerosolized drugs in hospitalized patients, there are
surprisingly few studies that have compared aerosol delivery devices in this setting
(Table 11 ).53585960616263 Six type 1 studies535859606163 included in the analysis compared
nebulizers with MDIs having spacer/holding chambers in adult and pediatric patients.
These studies reported no significant differences in pulmonary function between
nebulizers and MDIs with spacer/holding chambers (Fig 5 ). One study62 compared MDI
used alone with DPI use and also found no significant difference in peak expiratory flow
rate (PEFR). However, as the deposition efficiency of the DPI tested was approximately
half that of the MDI tested, the authors elected to compare DPI doses that were twice
that for the MDI, with the intent of producing equal responses. Other outcome variables
such as length of hospital stay were similar for the nebulizer and MDI with a
spacer/holding chamber. Reports of the cost of care are conflicting, without clear
evidence of one device resulting in a greater cost than another. There is a paucity of data
regarding the ability of patients to use these devices correctly in this setting. For ß2-
agonists, the impact of the differences in the time required to administer the therapy on
patient responses was not analyzed. The inpatient setting presents a unique opportunity
for health-care providers to instruct the patient on the proper use of each device, but the
benefit of such an approach has not been assessed in randomized trials.
View this table: Table 11. Aerosol Delivery in Hospitalized Patients*

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for FEV1 in inpatient trials using ß2-agonists
comparing nebulizer vs MDI + spacer/holding
chamber. See the legend of Figure 2 for

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In the inpatient setting, the available evidence suggests that there is no difference
in the pulmonary function response between using a nebulizer and using an MDI
with a spacer/holding chamber for administering short-acting ß2-agonist therapy
(quality of evidence: good).
Recommendations
1. Both nebulizers and MDIs with spacer/holding chambers are appropriate for use
in the inpatient setting. Quality of evidence: good; net benefit: substantial;
strength of recommendation: A.
2. Because the data for DPIs, standard MDIs without spacer/holding chambers, and
breath-actuated MDIs have been inadequately studied in this setting, we are
unable to recommend the use of these devices in patients requiring
hospitalization for asthma or COPD until more information is available. Quality
of evidence: low; net benefit: none; strength of recommendation: I.
aerosol delivery device in this setting. These include the patient’s inability to use
the device correctly, the preferences of the patient for the device, the
unavailability of the drug/device combination, the compatibility between the drug
and the delivery device, the lack of time or skills to properly instruct the patient
in the use of the device or in monitoring the appropriate use, and the cost of
therapy. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Intermittent vs Continuous Nebulizer Delivery of ß2-Agonists

Continuous aerosol bronchodilator therapy is used occasionally in patients with severe
bronchospasm in the ED or ICU. Its use is limited to the most severe exacerbations of
asthma. One systematic review64 supports the equivalence of continuous and intermittent
albuterol nebulization in the treatment of acute adult asthma. Continuous vs intermittent
administration of ß2-agonists was compared in six randomized type 1 studies enrolling
either adult patients or pediatric patients in the ED and ICUs (Table 12 ).656667686970 These
six studies reported no differences in pulmonary function changes comparing these
administration approaches (Fig 6 ). Changes in asthma score and dyspnea are also
similar for both modalities.6570 Two studies have reported greater staff (eg, respiratory
therapy) time requirements for intermittent nebulization compared to continuous
nebulization.6570 One study69 reported a lower hospital admission rate with the use of
continuous nebulization in an ED setting, but another study65 reported no difference in
admission rates. Decreased hospital length of stay was associated with the use of
continuous nebulization in one study enrolling pediatric patients.70 Two studies6769
reported similar heart rate responses with continuous and intermittent nebulization.
View this table: Table 12. Intermittent vs Continuous Nebulizers Studies Using
[in this window] ß2-Agonists*
[in a new
window]
Figure 6. Top: weighted standardized mean difference for
FEV1 in ED/ICU trials of ß2-agonists comparing
intermittent (Int) vs continuous (Cont) nebulization.
Bottom: weighted standardized mean difference for peak
flow in ED/ICU trials of ß2-agonists comparing
intermittent vs continuous nebulizers. See the legend of
Figure 2 for abbreviations not used in the text.
View larger version

(15K):
[in this window]
[in a new window]

Pulmonary function and asthma symptom scores show similar benefits for
continuous and intermittent nebulization of short-acting ß2-agonists (quality of
evidence: good).
The time requirements for staff administration and maintenance of the therapy
are less for continuous nebulization than for intermittent nebulization (quality of
evidence: good).
Adverse effects of ß2-agonists are similar for continuous and intermittent
nebulization of ß2-agonists (quality of evidence: good).
The effects of continuous vs intermittent nebulization of ß2-agonists on hospital
admission rate from the ED, hospital length of stay, and cost of care have not
been adequately studied (quality of evidence: low).
Recommendation
1. Frequent intermittent nebulization and continuous nebulization are both

appropriate alternatives in severely dyspneic patients in the ED or ICU. Quality
of evidence: good; net benefit: substantial; strength of recommendation: A.
Aerosolized ß2-Agonists in Patients Receiving Mechanical Ventilation

Patients in the ICU, particularly those receiving mechanical ventilation, present unique
challenges for aerosol delivery. Both MDIs and nebulizers can be adapted for use in
ventilator circuits, the former requiring a spacer or connector with an integral actuator.
Because of compatibility issues, it is currently not possible to use DPIs and breath-
actuated MDIs to deliver inhalant medications via a ventilator circuit. Only three RCTs
(Table 13 ) comparing these devices in mechanically ventilated patients were available
for analysis. All were type I studies. These compared the effects of short-acting ß2-
agonists on pulmonary mechanics in infants with bronchiolitis, and in adults with asthma
and COPD.717273 None of these trials compared other outcomes such as the duration of
mechanical ventilation, the length of stay in the ICU, the length of hospital stay, the cost
of treatment, clinician preference, the relief of dyspnea, or the occurrence of pulmonary
complications.
View this table: Table 13. Aerosol Delivery in Patients Receiving Mechanical
[in this window] Ventilation*
[in a new
window]
Albuterol was the drug employed in each of the three RCTs included in the analysis.
The outcomes evaluated included changes in respiratory system compliance, airway
resistance, and expiratory flows. In two of the studies,7172 there were no differences in
the response to albuterol between MDIs and nebulizers. In the other study,73 the
administration of up to 10 mg albuterol by MDI had no effect, whereas, the
administration of 2.5 to 7.5 mg albuterol with a nebulizer produced significant
reductions in airway resistance. In this study, however, the adapter employed to connect
the MDI to the ventilator circuit had a very low drug delivery efficiency.73 This
underscores the need to give careful attention to the specific details of the system used to
deliver aerosolized drugs to intubated, mechanically ventilated patients.74
Observational trials75 have reported that the administration of albuterol with an MDI and
chamber spacer produced responses that were comparable to those obtained with
albuterol administered by nebulizer. In one randomized crossover study (published
following the literature search for these evidence-based guidelines), Duarte et al76
reported that the airway response to albuterol via MDI with spacer and nebulizer were
similar in duration and magnitude for mechanically ventilated patients with COPD.
Although it is commonly accepted that an endotracheal tube may affect aerosol
deposition patterns by providing a finer aerosol at the tube exit, the presence of airway
disease may overwhelm this advantage.77 There are no deposition/dose-response
comparative studies in patients receiving mechanical ventilation, and, thus, no clear
recommendations for the dosing of ß-agonists in this setting can be made.
The adverse effects of ß2-agonist administration during mechanical ventilation were

determined in two studies. In one,72 no adverse effects were found after the
administration of 270 µg albuterol from an MDI or 2.5 mg administered with a
nebulizer. In the study by Manthous et al,73 premature beats and sinus tachycardia or
tremors were noted after the administration of 7.5 mg albuterol with a nebulizer. All of
the patients who received a cumulative dose of 15 mg albuterol with a nebulizer
developed tachycardia and premature heart beats. No changes in BP or other side effects
have been described from albuterol administration in this group of patients.
Although evaluated only in non-RCT studies, several factors are known to have
clinically important effects on aerosol delivery during mechanical ventilation. These
include the position at which the nebulizer is placed in the circuit,7879 the nebulizer brand
and its fill volume,80 the humidification of the inspired gas,80 the treatment time,80 the
inspiratory time (duty cycle),7980 intermittent vs continuous nebulization,79 the ventilator
brand,81 and the density of the carrier gas.82 It has been reported that the response to
albuterol administered by MDI to mechanically ventilated patients with COPD was not
affected by inspiratory flow pattern, pressure-controlled ventilation vs volume-
controlled ventilation,83 the level of inspiratory flow,84 the delivered tidal volume,85 or
the addition of an end-inspiratory pause.86 When an MDI is used during mechanical
ventilation, the use of a spacer device has been shown to increase deposition compared
to other in-line actuators.87
Noninvasive positive-pressure ventilation (NPPV) is increasingly used in the care of

patients with acute exacerbations of COPD. No RCT has compared the delivery of
aerosol medications by nebulizer or MDI in this setting. There have, however, been
reports of the use of nebulizers88 or MDIs89 in conjunction with the use of NPPV.
In children and adults receiving mechanical ventilation, the outcomes of ß2-

agonist administration using an MDI with or without a spacer/holding chamber
are no different than those observed following ß2-agonist administration with a
nebulizer (quality of evidence: fair).
High doses of ß2-agonists administered with a nebulizer are associated with a
higher incidence of tachycardia and premature heart beats in mechanically
ventilated patients, but there is no difference in adverse effects observed after the
administration of albuterol with an MDI compared to those observed after the
administration of the drug with a nebulizer (quality of evidence: fair).
There is insufficient evidence to guide the choice of MDI or nebulizer for
patients receiving NPPV (quality of evidence: low).
Recommendations
1. Both nebulizers and MDIs can be used to deliver ß2-agonists to mechanically

ventilated patients. Quality of evidence: fair; net benefit: substantial; strength of
recommendation: A.
2. Careful attention to details of the technique employed for administering drugs by
MDI or nebulizer to mechanically ventilated patients is critical, since multiple
technical factors may have clinically important effects on the efficiency of
aerosol delivery. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Device Selection in the Outpatient Setting
TOP
Short-Acting ß2-Agonists for Asthma in the Abstract
Outpatient Setting Introduction
Twenty-eight RCTs compared devices for the delivery Methodology
of ß2-agonists to outpatients. Most trials used a Results and Recommendations
crossover design, and all were of type 2a or 2b. In other Device Selection in the...
words, study outcomes assessed the comparability of the Discussion
Summaries and Results
effect in the clinical laboratory setting in patients who References
had been carefully trained in and screened for proper
use of the device. Consequently, they did not directly
assess effectiveness as "quick relief" treatment for outpatient asthma symptoms (the
primary role that these agents play in the treatment of asthma).23 Some were single-dose
studies in which each treatment was administered only once, with measurements being
made before and after this treatment. In other studies, treatments were administered on a
scheduled daily basis over varying periods of time from as short as 1 day up to a few
months. With both of these approaches, however, the primary outcome assessed changes
in lung function in the clinical laboratory. Daily asthma symptom scores and adverse
effects, mainly changes in heart rate, were assessed in only a few trials.
Twenty-three studies90919293949596979899101102103106107108109110111112113114115 (both type 2a and 2b)

compared the responses to short-acting ß2-agonists using a DPI vs those using an MDI
(without a spacer/holding chamber) in adults with asthma (Tables 14, 15 ). Outcomes
included some type of pulmonary function measurement in all but one trial. In that one
study, cough score was the only useable outcome. Metaanalyses comparing FEV1,
PEFR, and sGaw responses from these studies showed no significant differences
between devices, either by separate analysis or when pooled (Fig 7 ).
View this table: Table 14. MDI vs DPI Using ß2-Agonists in Adult Outpatients
[in this window] With Asthma*
[in a new
window]
View this Table 15. Trials Comparing MDI vs DPI Studies "Comparable Dose
table: and Drug" ß2-Agonists and Cromolyn Adult Outpatients With
[in this Asthma*
window]
[in a new
window]

for combined end point (FEV1, PEFR, or sGaw) in
outpatient ß2-agonist trials comparing MDI (M) vs
DPI (D). See the legend of Figure 2 for

[in this window]
[in a new window]
Six of the trials comparing MDI with DPI were analyzed separately because they
employed similar ("comparable") doses of the same drug in the two devices (Table
15).95102103108110114 This allowed for a more direct assessment of device efficiency and
effectiveness than in the studies that used different doses and/or drugs in the devices
being compared. An analysis of these comparable dose studies also found no differences
in FEV1, PEFR, FVC, or symptoms (see Fig 8 on-line). For trials in which multiple
sequential doses were administered by each device, the metaanalysis was performed for
both the lowest dose and for the highest dose administered (in 16 trials). Again, no
differences were found for FEV1, PEFR, sGaw, or FVC. Two studies compared cough
or other symptoms,90101 and three studies compared changes in heart rate changes.9298115
No differences were found between the MDI and the DPI in pooled analyses of these
studies. However, one study116 reported greater improvements in FEV1 for DPI use
compared with MDI use, and another study90 reported greater improvement in cough
score for DPI use compared with MDI use.
Figure 8. Top left, A: weighted standardized mean

difference for FEV1 in outpatient comparable
dose/drug ß2-agonist trials comparing MDI vs DPI
(D). Top right, B: WMD mean difference for peak
flow in outpatient comparable dose/drug ß2-
agonist trials comparing MDI vs DPI. Bottom left,
C: WMD mean difference for FVC in outpatient
View larger version (19K): comparable dose/drug ß2-agonist trials comparing
[in this window] MDI vs DPI. Bottom right, D: WMD mean
[in a new window] difference for symptoms in outpatient comparable
dose/drug ß2-agonist trials comparing MDI vs DPI.
See legends of Figures 2and 7 for abbreviations
not used in the text.
Four studies compared the MDIs and DPIs in pediatric patients. Two studies117118
investigated terbutaline delivered by MDI and by DPI (Turbuhaler). Another study119
evaluated fenoterol delivery by MDI and DPI. The fourth study120 enrolled both
pediatric and adult patients. None of these studies, either individually or when
combined, showed a difference between use of the MDI and use of the DPI.
Fewer data are available comparing the effects of ß2-agonists inhaled via an MDI
without a spacer device vs those inhaled via an MDI with a spacer device in adults or
children with asthma in the outpatient setting,100121 and only one study121 met criteria for
inclusion in the analysis. This study showed no difference between the two routes for
the outcomes FEV1, PEFR, or FVC (Table 16 ).
View this Table 16. MDI vs MDI + Spacer Studies Using ß2-Agonists in
table: Adult Outpatients With Asthma*
[in this
window]
[in a new
window]
Eight type 2b studies that compared short-acting ß-agonist delivery by different devices
were evaluated separately (Table 17 ). Three studies that compared the dose delivered
by nebulizer and MDI with holding chamber each concluded that more than two MDI
actuations are required to equal one nebulizer treatment. Pedersen and Bundgaard122 and
Madsen et al123 estimated that approximately four terbutaline MDI actuations are
required to equal a single nebulized treatment with 2.5 to 4.0 mg of terbutaline. Blake et
al124 estimated that approximately 10 MDI actuations of albuterol are required to equal
one nebulizer treatment with 2.5 mg albuterol. It is for this reason the more than two
MDI actuations are typically used in ED studies comparing MDIs with spacers/holding
chambers and nebulizers (Table 8). Type 2B studies by Wong et al,125 Lofdahl et al,126
and Bondesson et al127 compared albuterol delivery via DPI (Turbuhaler) and CFC MDI
(Ventolin). All three studies estimated that the dose delivered by the DPI was greater
(1.38-fold, 1.98-fold, and 2.0-fold greater, respectively). Confidence intervals for these
three estimates overlapped in the region, indicating a twofold to threefold greater
potency for the Turbuhaler. In contrast, two type 2B studies112128 comparing a Spiros DPI
(Elan Pharmaceuticals; Dublin, Ireland) with a CFC MDI (Ventolin) estimated that
these devices were approximately equipotent. This draws attention to the fact that
differences in the relative amount of drug delivered to the lung depends not only on the
general type of device used (DPI vs MDI) but also on the specific brand of device being
compared (eg, Spiros DPI or Turbuhaler DPI).
View this table: Table 17. Type 2B Studies Comparing Short-Acting ß-Agonist
[in this window] Delivery*
[in a new
window]

In the adult and pediatric outpatient population with asthma, available evidence
comparing short-acting ß2-agonist delivery by MDI and DPI show no differences
in pulmonary function responses, symptom scores, or heart rate. This remains
true when analysis is restricted to type 2b studies that estimate the doses required
to produce equal levels of response (called dose-axis comparisons) [quality of
evidence: good].
In a limited number of type 2 studies comparing short-acting ß2-agonists
administered with an MDI to that with an MDI using a spacer or holding
chamber, pulmonary function responses were found to be comparable (quality of
evidence: low).
The use of nebulizers for the delivery of short-acting ß2-agonists in the outpatient
setting has not been adequately studied in RCTs (quality of evidence: low).
Recommendations
1. For treatment of asthma in the outpatient setting, both the MDI, used with or
without spacer/holding chamber, and the DPI are appropriate for the delivery of
short-acting ß2-agonists. Quality of evidence: good; net benefit: substantial;
2. The appropriate selection of a particular type of aerosol delivery device in this
setting includes the patient’s ability to use the device correctly, the preferences of
the patient for the device, the availability of the drug/device combination, the
compatibility between the drug and delivery device, the lack of time or skills to
properly instruct the patient in the use of the device or to monitor the appropriate
use, the cost of the therapy, and the potential for reimbursement. Quality of
evidence: low; net benefit: substantial; strength of recommendation: B.
Inhaled Corticosteroids for Asthma

Four trials90104105106129 comparing the use of a DPI with that of an MDI plus spacer for the
inhalation of inhaled corticosteroids in adult90104105129 asthmatic patients in the outpatient
setting met the criteria for study inclusion (Table 18 ). No studies enrolling chil-dren
were eligible for inclusion. To be able to accurately compare device performance and
efficacy, we required that the same drug be delivered via MDI/spacer and DPI, and this
greatly limited the number of useable trials. In these four trials, the same dose of the
same corticosteroid was used for the two delivery routes. The durations of these type 1
trials were relatively short. One trial was of 2 weeks duration, and the other three were
of 4 weeks duration. Metaanalysis reported no difference for FEV1, PEFR, or symptom
scores (see Fig 9 on-line). Two of the trials addressed subject preference, and there was
a significant preference for the DPI over the MDI/spacer combination (p < 0.01) [see
Fig 10 on-line]. We deem the incidence of oral candidiasis to be a crucial outcome, and
no trial addressed this issue. There were no randomized control trials that were eligible
for study inclusion that addressed other device comparisons using inhaled
corticosteroids (MDI vs MDI with spacer/holding chamber, and MDI used alone vs
DPI).
View this Table 18. MDI + Spacer vs DPI Studies Using Corticosteroids in
table: Adult Outpatients With Asthma*
[in this
window]
[in a new
window]
Figure 9. Top, A: weighted mean standardized difference for
FEV1 in outpatient steroid trials comparing DPI vs MDI +
spacer/holding chamber. Middle, B: weighted mean
standardized difference for peak flow in outpatient steroid trials
comparing DPI vs MDI + spacer/holding chamber. Bottom, C:
Weighted mean standardized difference for symptoms in
outpatient steroid trials comparing DPI vs MDI + spacer/holding
chamber. See legends of Figures 2and 7 for abbreviations not
used in the text.
View larger
version (14K):
[in this window]
[in a new
window]
Figure 10. Weighted mean standardized difference

for preference in outpatient steroid trials
comparing DPI vs MDI + spacer/holding chamber.
See legends of Figures 2and 7 for abbreviations
not used in the text.

[in this window]
[in a new window]

For adult patients with asthma in the outpatient setting, there are no differences
in pulmonary function response or symptom scores when the same dose of the
same corticosteroid is used in a DPI or MDI with spacer/holding chamber
Two studies indicated a significant patient preference for use of the DPI over that
of the MDI with spacer/holding chamber (quality of evidence: good).
No RCT adequately addressed the incidence of oral candidiasis (quality of
evidence: low).
Recommendations
1. For the treatment of asthma in the outpatient setting, both the MDI with a
spacer/holding chamber and the DPI are appropriate devices for the delivery of
inhaled corticosteroids. Quality of evidence: good; net benefit: substantial;
2. For outpatient asthma therapy, the selection of an appropriate aerosol delivery
device for inhaled corticosteroids includes the patient’s ability to use the device
correctly, the preferences of the patient for the device, the availability of the
drug/device combination, the compatibility between the drug and delivery
device, the lack of time or skills to properly instruct the patient in the use of the
device or monitor the appropriate use, the cost of therapy, and the potential for
reimbursement. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
ß2-Agonists and Anticholinergic Agents for COPD

Proving device efficacy can be difficult in COPD patients because the airway
obstruction in such patients shows limited reversibility with drug therapy. Seven
studies130131132133134135136 comparing different delivery devices met the criteria for entry
into this analysis (Table 19 ). Pooled analysis of these studies showed no evidence for
superiority of any aerosol delivery device (nebulizer, MDI, or MDI with spacer in
patients) for outpatients with COPD. While the data are quite limited for COPD patients,
the experience in asthma patients supports the conclusions for COPD.
View this table: Table 19. Outpatient COPD Studies*

[in this window]
[in a new window]
Turner et al,50 in an acute setting adult trial, reported a significantly greater increase in
heart rate for nebulizers compared to MDI without important differences in efficacy.
Similar findings were reported by Berry et al61 for inpatients with COPD, but data are
lacking for COPD patients treated in the outpatient setting. In an outpatient study of
patients with COPD, Pauwels et al131 compared the use of an MDI and that of an MDI
with a valved holding chamber following the inhalation of terbutaline, and reported that
the MDI with holding chamber may be more effective than MDI alone. In an outpatient
study of patients with asthma or COPD, Dorow and Hidinger et al132 reported no
differences between the use of an MDI and that of MDI with a valved holding chamber.
Device differences have not been adequately studied for combination bronchodilator
therapy (eg, Combivent; Boehringer-Ingelheim; Ridgefield, CT) or for steroid
preparations in outpatients with COPD. Delivery systems for long-acting
bronchodilators (eg, salmeterol and formoterol) also have not been adequately studied in
this patient population.
The selection of an aerosol delivery device for the treatment of outpatients with COPD
is determined by the formulation, the needs of the patient, clinician biases, and
reimbursement. Although use of an MDI (with spacer and mask if necessary) may
produce similar results, nebulizers are often used in sicker and less cooperative patients.
In the outpatient management of COPD patients with ß2-agonist and

anticholinergic agents, the available evidence shows no differences in pulmonary
function responses between delivery devices (quality of evidence: good).
Increases in heart rate were greater after the administration of albuterol by
nebulizer than after administration by MDI (quality of evidence: good).
Recommendations
1. For the treatment of COPD in the outpatient setting, the MDI, with or without
spacer/holding chamber, the nebulizer, and the DPI are all appropriate for the
delivery of inhaled ß2-agonist and anticholinergic agents. Quality of evidence:
good; net benefit: substantial; strength of recommendation: A.
2. For outpatient COPD therapy, the selection of an appropriate aerosol delivery
device for inhaled ß2-agonist and anticholinergic agents includes the patient’s
ability to use the device correctly, the preferences of the patient for the device,
the availability of the drug/device combination, the compatibility between the
drug and the delivery device, the lack of time or skills to properly instruct the
patient in the use of the device or monitor its appropriate use, the cost of therapy,
and the potential for reimbursement. Quality of evidence: low; net benefit:
substantial; strength of recommendation: B.
Discussion
The results of this systematic review of RCTs were essentially the same in each of the
clinical settings evaluated above. None of the pooled metaanalyses (Tables 20and 21 ,
available on-line only) showed a significant difference between devices in any efficacy
outcome in any patient group. Thus, the relative effectiveness of delivery methods does
not provide a clear basis for selecting one device over another. This does not mean that
the device choice for a specific patient does not seem to matter. In essence, this says that
each of the devices studied can work equally well in that
setting in patients who can use them appropriately. This TOP
is an important statement because most studies, Abstract
especially in the outpatient setting, select for patients Introduction
Methodology
who are capable of using each of the devices with the
appropriate technique or train patients to use the Device Selection in the...
appropriate technique. The RCTs included in this Discussion
systematic review do not provide much information Summaries and Results
about who is likely to use one device or another References
properly, nor do they address many other considerations
that are important for choosing a delivery device for a
specific patient in a specific clinical situation. These include the ability to use the
device, patient preference, the availability of equipment, and cost. While the clinician is
still left to select the method of delivery based on these other considerations, we have
made general recommendations based on the results of the metaanalysis to guide the
clinician in his/her selection of a delivery system. In addition, there are some obvious
situations in which device selection clearly does matter. For example, in each of the
clinical situations studied, there are some devices that were studied little or not at all.
This appears to indicate a consensus that RCTs are not needed to determine that some
devices are inappropriate for that clinical situation. For example, it is clear that infants
and toddlers have virtually no chance of using an MDI (without spacer or holding
chamber) or a DPI properly. Similarly, there are virtually no RCTs studying the MDI
(without spacer or holding chamber) in the ED since most clinicians believe that the
severe dyspnea experienced by many asthma patients in that setting would prevent them
from using this device properly.
View this table: Table 20. Summary of Metaanalyses*

[in this window]
[in a new window]
View this table: Table 21. Comparison of Trials Included and Not Included in
[in this window] Metaanalysis*
[in a new
window]
Consideration of the circumstances under which studies were performed is an important

factor for interpreting the results of our systematic review. All of the RCTs performed in
the acute care settings (ie, ED, inpatient unit, or ICU) are type 1 trials (ie, they were
performed under conditions of actual clinical use in the ED, inpatient unit, or ICU).
These studies are reassuring in that both a nebulizer and an MDI with a valved holding
chamber can work well in that setting. Similarly, MDIs with a reverse-flow spacer can
be successfully used in these settings but not in intubated patients, unless they
incorporate an interface to the ventilator circuit. Similarly, studies of inhaled
corticosteroid use in outpatients, while limited in number, are type 1 studies that are
performed under conditions of actual clinical use. The results are reassuring in that each
device can work well in patients who know how to use them correctly.
Studies of ß2-agonist use for outpatient asthma and COPD are less reassuring since
virtually all of these were type 2 studies that were performed under laboratory
conditions rather than conditions of actual clinical use. The studies indicate that under
ideal conditions and in patients who are successfully taught to use the devices correctly,
the devices being compared can each deliver sufficient quantities of drug to the airway
to elicit the same response. However, the relationship between these laboratory studies
and the use of the device in patient’s daily lives is not clear. Many of these studies were
performed for regulatory purposes as part of the evaluation of new formulations. These
kinds of studies are typically designed to demonstrate equivalence with an existing
device. The doses used were typically selected to ensure this, particularly in the
nebulizer vs MDI RCTs.53596162 Thus, it is not surprising when these type 2 studies fail to
show differences. It is also likely that the doses used in many of these laboratory-based
studies produced responses that were near the plateau of the dose-response curve.
Therefore, differences in drug delivery would not be reflected as a difference in
response. However, these studies do not indicate that the device would perform equally
well in more adverse, real-world situations, such as when a patient awakens at night
with more bronchospasm and lower lung function than is typically studied in the clinical
laboratory.137138 Furthermore, these studies routinely exclude patients who cannot
correctly use the devices being compared. The results clearly apply just to the
subpopulation of patients who can use the device effectively.
Differences in systemic adverse effects were present only between the nebulizer and the
MDI with holding chamber for albuterol delivery in the ED, and between the nebulizer
and the MDI (used alone) for albuterol delivery in COPD outpatients. Heart rate was
higher with nebulizer delivery. Vomiting was greater after nebulized albuterol
administration than after albuterol administered by MDI with a valved holding chamber
in children in the ED. These findings are most likely due to the larger doses of albuterol
administered by the nebulizer compared to those administered by the MDI, resulting in
greater systemic absorption.
We did not assess the power of individual studies a priori. Although it is likely that
many studies were underpowered, the metaanalysis of these studies consistently fails to
show a significant difference between devices. Moreover, our findings are consistent
with those reported in other systematic reviews.25262728303164139 However, our interpretation
of these results differs from those offered by authors of some of the reviews. Notably,
Turner et al25 concluded that because no clear differences between devices could be
found in the systematic review of RCTs, cost alone should drive the choice between
devices. This interpretation of the results of the systematic review was subsequently
criticized in a number of letters to the editor,140141 although the review itself was not. In
their review, Amirav and Newhouse26 also found no differences in pulmonary function
response to nebulized albuterol and albuterol administered by an MDI with holding
chamber in children treated in the ED setting. They also interpreted their results as
demonstrating that cost alone should be the determining factor for the choice of device.
The interpretation of our systematic review as well as those of other authors in existence
is open to debate. While we make general recommendations, they are based on the
metaanalysis of the data from the RCTs considered. We have avoided making specific
recommendations that are not directly supported by the RCT results.
How then, in practice, does one select an aerosol delivery device for the patient? In
other words, what practical advice can be given for device selection when the best
evidence shows no difference in outcomes between devices? In the following list, we
review the important issues for clinicians to consider when selecting an aerosol delivery
device.
When selecting an aerosol delivery device, the following questions should be

considered:
1. In what devices is the desired drug available?

2. What device is the patient likely to be able to use properly, given the patient’s
age and the clinical setting?
3. For which device and drug combination is reimbursement available?
4. Which devices are the least costly?
5. Can all types of inhaled asthma/COPD drugs that are prescribed for the patient
(eg, short-acting ß-agonist, corticosteroid, anticholinergic, and long-acting ß-
agonist) be delivered with the same type of device (eg, nebulizer, manually
actuated MDI, MDI with spacer/holding chamber, or breath-actuated device [ie,
automatically activated MDI or DPI])? Using the same type of device for all
inhaled drugs may facilitate patient teaching and decrease the chance for
confusion among devices that require different inhalation techniques.
6. Which devices are the most convenient for the patient, family (outpatient use), or
medical staff (acute care setting) to use, given the time required for drug
administration and device cleaning, and the portability of the device?
7. How durable is the device?
8. Does the patient or clinician have any specific device preferences?
Finally, whichever device is chosen, it is clear that proper patient education on its use is
critical and that the assessment of inhalation technique should be part of subsequent
visits to the physician.142 Therefore, physicians, respiratory therapists, and nurses caring
for patients with respiratory diseases should be familiar with issues related to
performance and with the correct use of aerosol delivery devices. Patients must be
adequately instructed in the correct use of aerosol delivery devices. If the selected
delivery device should fail to provide satisfactory treatment or result in unacceptable
side effects for the patient, both clinician and patient should recognize that there are
other effective options.
TOP
Abstract
Introduction
Methodology
Device Selection in the...
Discussion
References
Aerosol Delivery of Short-Acting ß2-Agonists in the Hospital ED

Summary of RCT Results:
The delivery of ß2-agonists in the ED setting by nebulizers or MDIs with holding

chambers (eg, AeroChamber, Volumatic, or InspirEase) is equally effective for
improving pulmonary function and reducing symptoms of acute asthma in both
adult and pediatric patients (quality of evidence: good).
The delivery of ß2-agonists in the ED setting by DPI (eg, Rotahaler or
Turbuhaler) has been inadequately studied, but trials in adults have suggested
DPIs may be as effective as nebulizers or MDIs with spacer/holding chambers
(quality of evidence: low).
Nebulizer use in the ED setting is associated with greater increases in heart rate
than with the use of an MDI with spacer/holding chamber, suggesting that a
larger systemically absorbed dose is administered by nebulizers (quality of
evidence: good).
Recommendations:
1. Both the nebulizer and MDI with spacer/holding chamber are appropriate for the
delivery of short-acting ß2-agonists in the ED. Quality of evidence: good; net
benefit: substantial; strength of recommendation: A.
2. Because data for DPIs are limited, and high quality data for standard MDIs
(without spacer/holding chamber) and breath-actuated MDIs are unavailable, we
are unable to recommend the use of these devices in the ED until more
information is available. Quality of evidence: low; net benefit: none; strength of
recommendation: I.
aerosol delivery device in this setting. These factors include the patient’s ability
to use the device correctly, the preferences of the patient for the device, the
unavailability of an appropriate drug/device combination, the compatibility
between the drug and delivery device, the lack of time or skills to properly
instruct the patient in the use of the device or to monitor the appropriate use, and
the cost of therapy. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Aerosol Delivery of Short-Acting ß2-Agonists in the Inpatient Hospital Setting

In the inpatient setting, the available evidence suggests that there is no difference
in the pulmonary function response between using a nebulizer and using an MDI
with a spacer/holding chamber for administering short-acting ß2-agonist therapy
Recommendations:
1. Both nebulizers and MDIs with spacer/holding chambers are appropriate for use
in the inpatient setting. Quality of evidence: good; net benefit: substantial;
2. Because the data for DPIs, standard MDIs without spacer/holding chambers, and
breath-actuated MDIs have been inadequately studied in this setting, we are
unable to recommend the use of these devices in patients requiring
hospitalization for asthma or COPD until more information is available. Quality
of evidence: low; net benefit: none; strength of recommendation: I.
aerosol delivery device in this setting. These include the patient’s inability to use
the device correctly, the preferences of the patient for the device, the
unavailability of the drug/device combination, the compatibility between the drug
and the delivery device, the lack of time or skills to properly instruct the patient
in the use of the device or in monitoring the appropriate use, and the cost of
therapy. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Intermittent vs Continuous Nebulizer Delivery of ß2-Agonists

Pulmonary function and asthma symptom scores show similar benefits for
continuous and intermittent nebulization of short-acting ß2-agonists (quality of
evidence: good).
The time requirements for staff administration and maintenance of the therapy
are less for continuous nebulization than for intermittent nebulization (quality of
evidence: good).
Adverse effects of ß2-agonists are similar for continuous and intermittent
nebulization of ß2-agonists (quality of evidence: good).
The effects of continuous vs intermittent nebulization of ß2-agonists on hospital
admission rate from the ED, hospital length of stay, and cost of care have not
been adequately studied (quality of evidence: low).
Recommendation:
1. Frequent intermittent nebulization and continuous nebulization are both

appropriate alternatives in severely dyspneic patients in the ED or ICU. Quality
of evidence: good; net benefit: substantial; strength of recommendation: A.
Aerosolized ß2-Agonists in Patients Receiving Mechanical Ventilation

In children and adults receiving mechanical ventilation, the outcomes of ß2-

agonist administration using an MDI with or without a spacer/holding chamber
are no different than those observed following ß2-agonist administration with a
nebulizer (quality of evidence: fair).
High doses of ß2-agonists administered with a nebulizer are associated with a
higher incidence of tachycardia and premature heart beats in mechanically
ventilated patients, but there is no difference in adverse effects observed after the
administration of albuterol with an MDI compared to those observed after the
administration of the drug with a nebulizer (quality of evidence: fair).
There is insufficient evidence to guide the choice of MDI or nebulizer for
patients receiving NPPV (quality of evidence: low).
Recommendations:
1. Both nebulizers and MDIs can be used to deliver ß2-agonists to mechanically

ventilated patients. Quality of evidence: fair; net benefit: substantial; strength of
recommendation: A.
2. Careful attention to details of the technique employed for administering drugs by
MDI or nebulizer to mechanically ventilated patients is critical, since multiple
technical factors may have clinically important effects on the efficiency of
aerosol delivery. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
Short-Acting ß2-Agonists for Asthma in the Outpatient Setting

In the adult and pediatric outpatient population with asthma, available evidence
comparing short-acting ß2-agonist delivery by MDI and DPI show no differences
in pulmonary function responses, symptom scores, or heart rate. This remains
true when analysis is restricted to type 2b studies that estimate the doses required
to produce equal levels of response (called dose-axis comparisons) [quality of
evidence: good].
In a limited number of type 2 studies comparing short-acting ß2-agonists
administered with an MDI to that with an MDI using a spacer or holding
chamber, pulmonary function responses were found to be comparable (quality of
evidence: low).
The use of nebulizers for the delivery of short-acting ß2-agonists in the outpatient
setting has not been adequately studied in RCTs (quality of evidence: low).
Recommendations:
1. For treatment of asthma in the outpatient setting, both the MDI, used with or
without spacer/holding chamber, and the DPI are appropriate for the delivery of
short-acting ß2-agonists. Quality of evidence: good; net benefit: substantial;
2. The appropriate selection of a particular type of aerosol delivery device in this
setting includes the patient’s ability to use the device correctly, the preferences of
the patient for the device, the availability of the drug/device combination, the
compatibility between the drug and delivery device, the lack of time or skills to
properly instruct the patient in the use of the device or to monitor the appropriate
use, the cost of the therapy, and the potential for reimbursement. Quality of
evidence: low; net benefit: substantial; strength of recommendation: B.
Inhaled Corticosteroids for Asthma

For adult patients with asthma in the outpatient setting, there are no differences
in pulmonary function response or symptom scores when the same dose of the
same corticosteroid is used in a DPI or MDI with spacer/holding chamber
Two studies indicated a significant patient preference for use of the DPI over that
of the MDI with spacer/holding chamber (quality of evidence: good).
No RCT adequately addressed the incidence of oral candidiasis (quality of
evidence: low).
Recommendations:
1. For the treatment of asthma in the outpatient setting, both the MDI with a
spacer/holding chamber and the DPI are appropriate devices for the delivery of
inhaled corticosteroids. Quality of evidence: good; net benefit: substantial;
2. For outpatient asthma therapy, the selection of an appropriate aerosol delivery
device for inhaled corticosteroids includes the patient’s ability to use the device
correctly, the preferences of the patient for the device, the availability of the
drug/device combination, the compatibility between the drug and delivery
device, the lack of time or skills to properly instruct the patient in the use of the
device or monitor the appropriate use, the cost of therapy, and the potential for
reimbursement. Quality of evidence: low; net benefit: substantial; strength of
recommendation: B.
ß2-Agonists and Anticholinergic Agents for COPD
In the outpatient management of COPD patients with ß2-agonist and

anticholinergic agents, the available evidence shows no differences in pulmonary
function responses between delivery devices (quality of evidence: good).
Increases in heart rate were greater after the administration of albuterol by
nebulizer than after administration by MDI (quality of evidence: good).
Recommendations:
1. For the treatment of COPD in the outpatient setting, the MDI, with or without
spacer/holding chamber, the nebulizer, and the DPI are all appropriate for the
delivery of inhaled ß2-agonist and anticholinergic agents. Quality of evidence:
good; net benefit: substantial; strength of recommendation: A.
2. For outpatient COPD therapy, the selection of an appropriate aerosol delivery
device for inhaled ß2-agonist and anticholinergic agents includes the patient’s
ability to use the device correctly, the preferences of the patient for the device,
the availability of the drug/device combination, the compatibility between the
drug and the delivery device, the lack of time or skills to properly instruct the
patient in the use of the device or monitor its appropriate use, the cost of therapy,
and the potential for reimbursement. Quality of evidence: low; net benefit:
substantial; strength of recommendation: B.
Device Selection
When selecting an aerosol delivery device, the following questions should be
considered:
1. In what devices is the desired drug available?

2. What device is the patient likely to be able to use properly, given the patient’s
age and the clinical setting?
3. For which device and drug combination is reimbursement available?
4. Which devices are the least costly?
5. Can all types of inhaled asthma/COPD drugs that are prescribed for the patient
(eg, short-acting ß-agonist, corticosteroid, anticholinergic, and long-acting ß-
agonist) be delivered with the same type of device (eg, nebulizer, manually
actuated MDI, MDI with spacer/holding chamber, or breath-actuated device [ie,
automatically activated MDI or DPI])? Using the same type of device for all
inhaled drugs may facilitate patient teaching and decrease the chance for
confusion among devices that require different inhalation techniques.
6. Which devices are the most convenient for the patient, family (outpatient use), or
medical staff (acute care setting) to use, given the time required for drug
administration and device cleaning, and the portability of the device?
7. How durable is the device?
8. Does the patient or clinician have any specific device preferences?
Acknowledgements
The authors thank Angela Eady and Lauren Griffith (Department of Clinical
Epidemiology and Biostatistics and Medicine, McMaster University, Hamilton, ON,
Canada) and James B Fink, MS, Fellow, Respiratory Science, Aerogen, Inc (Mountain
View, CA).
Footnotes
Abbreviations: CFC = chlorofluorocarbon; DPI = dry powder inhaler; ED = emergency

department; MDI = metered-dose inhaler; NPPV = noninvasive positive pressure
ventilation; PEFR = peak expiratory flow rate; RCT = randomized controlled trial;
sGaw = specific airway conductance
Professor Dolovich has served as a speaker for Forest Laboratories, 3M Pharma, and
Aventis, and as a consultant for GlaxoSmithKline and Delex Therapeutics, and has
received research funding from 3M Pharma, Trudell Medical International, and Altana
Pharma. Dr. Ahrens, in the past 12 months, has received research funding from or has
had a consulting relationship with the following organizations with a potential financial
interest in the subject of the manuscript: AstraZeneca; Aventis; Boehringer Ingelheim;
GlaxoSmithKline; Innovata Biomed Limited; Medic-Aid Limited; Monaghan Medical
Corporation; and 3M Corporation. Dr. Hess has served as a consultant for Pari and has
received research funding from Cardinal Health. Dr. Anderson has participated in
clinical trials for GlaxoSmithKline, Boehringer Ingelheim, Astra-Zeneca, and Novartis.
Dr. Dhand has served as a speaker for GlaxoSmithKline and Boehringer Ingelheim, has
sponsored meetings for GlaxoSmithKline, Boehringer Ingelheim, and Sepracor, and has
performed research funded by Sepracor Inc and Omron. Dr. Rau has no financial
interest or involvement in any organization with a direct financial interest in the subject
of this article, but he has served as a consultant for Respironics, as a speaker for
Sepracor Pharmaceutical, and as a consultant and speaker for and performed research
funded by Trudell Medical International and Monaghan Medical Corporation. Dr.
Smaldone has served as a consultant to several device and pharmaceutical companies
that are connected to aerosol therapy, primarily the nebulization of drugs. Those
companies with a direct financial interest in nebulization include Monaghan/Trudell
Medical International, Aerogen, Pari, and Profile Therapeutics.
Received for publication February 25, 2004. Accepted for publication August 25, 2004.
References
TOP
Abstract
Introduction
Methodology
Device Selection in the...
Discussion
1. Newhouse, MT, Dolovich, MB (1986) Control
of asthma by aerosols. N Engl J Med 315,870- References
874[ISI][Medline]
1. National Asthma Education and Prevention Program. Expert panel report 2:
guidelines for the diagnosis and management of asthma. Bethesda, MD:
National Heart, Lung, and Blood Institute, April 1997; NIH Publication No. 97–
4051
1. National Heart, Lung, and Blood Institute/World Health Organization.. Global
strategy for the diagnosis, management, and prevention of chronic obstructive
pulmonary disease: National Heart, Lung, and Blood Institute and World Health
Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD);
workshop summary. Am J Respir Crit Care Med 2001;163,1256-1276[Free
Full Text]
1. Dolovich, M, Ruffin, RE, Roberts, R, et al Optimal delivery of aerosols from
metered dose inhalers. Chest 1981;80(suppl),911-915
1. Newman, SP, Pavia, D, Clarke, SW How should a pressurized beta-adrenergic
bronchodilator be inhaled? Eur J Respir Dis 1981;62,3-21[ISI][Medline]
1. Crompton, GK Problems patients have using pressurized aerosol inhalers. Eur J
Respir Dis 1982;63(suppl),101-104
1. De Blaquiere, P, Christensen, DB, Carter, WB, et al Use and misuse of metered-
dose inhalers by patients with chronic lung disease: a controlled, randomized
trial of two instruction methods. Am Rev Respir Dis 1989;140,910-916[ISI]
[Medline]
1. Kamps, AW, van Ewijk, B, Roorda, RJ, et al Poor inhalation technique, even
after inhalation instructions, in children with asthma. Pediatr Pulmonol
2000;29,39-42[CrossRef][ISI][Medline]
1. Guidry, CG, Brown, WD, Stogner, SW, et al Incorrect use of metered dose
inhalers by medical personnel. Chest 1992;101,31-33[Abstract]
1. Hanania, NA, Wittman, R, Kesten, S, et al Medical personnel’s knowledge of
and ability to use inhaling devices: metered-dose inhalers, spacing chambers,
and breath- actuated dry powder inhalers. Chest 1994;105,111-116[Abstract]
1. Kesten, S, Zive, K, Chapman, KR Pharmacist knowledge and ability to use
inhaled medication delivery systems. Chest 1993;104,1737-1742[Abstract]
1. Lindgren, S, Bake, B, Larsson, S Clinical consequences of inadequate inhalation
technique in asthma therapy. Eur J Respir Dis 1987;70,93-98[ISI][Medline]
1. McFadden, ER, Jr Improper patient techniques with metered dose inhalers:
clinical consequences and solutions to misuse. J Allergy Clin Immunol
1995;96,278-282[ISI][Medline]
1. Freedman, T Medihaler therapy for bronchial asthma: a new type of aerosol
therapy. Postgrad Med J 1956;20,667-673
1. Mercer, TT Production of therapeutic aerosols: principles and techniques. Chest
1981;80,S813-S817
52018. Muers, MF Overview of nebuliser treatment. Thorax 1997;52,S25-

S30[Free Full Text]
1. Bell, JH, Hartley, PS, Cox, JSG Dry powder aerosols: I. A new powder
inhalation device. J Pharm Sci 1971;60,1559-1564[ISI][Medline]
1. Corr, D, Dolovich, M, McCormack, D, et al Design and characteristics of a
portable breath-actuated particle size selective medical aerosol inhaler. J Aerosol
Sci 1982;13,1-7[CrossRef][ISI]
1. Morén, F Drug deposition of pressurized inhalation aerosols: I. Influence of

actuator tube design. Int J Pharm 1978;1,205-212[CrossRef][ISI]
1. Newman, SP, Morén, F, Pavia, D, et al Deposition of pressurized suspension

aerosols inhaled through extension devices. Am Rev Respir Dis 1981;124,317-
320[ISI][Medline]
1. Tobin, MJ, Jenouri, G, Danta, I, et al Response to bronchodilator drug

administration by a new reservoir aerosol delivery system and a review of other
auxiliary delivery systems. Am Rev Respir Dis 1982;126,670-675[ISI][Medline]
1. Leach, CL Approaches and challenges to use freon propellant replacements.

Aerosol Sci Technol 1995;22,328-334[ISI]
1. Dolovich, M New delivery systems and propellants. Can Respir J 1999;6,290-

295[Medline]
1. Pedersen, S How to use a rotahaler. Arch Dis Child 1986;61,11-14[Abstract]
1. Turner, MO, Patel, A, Ginsburg, S, et al Bronchodilator delivery in acute airflow

obstruction: a meta-analysis. Arch Intern Med 1997;157,1736-1744[Abstract]
1. Amirav, I, Newhouse, MT Metered-dose inhaler accessory devices in acute
asthma: efficacy and comparison with nebulizers; a literature review. Arch
Pediatr Adolesc Med 1997;151,876-882[Abstract]
1. Bach, PB, Brown, C, Gelfand, SE, et al Management of acute exacerbations of
chronic obstructive pulmonary disease: a summary and appraisal of published
evidence. Ann Intern Med 2001;134,600-620[Abstract/Free Full Text]
1. Cates CJ, Rowe BH, Bara A. Holding chambers versus nebulisers for beta-
agonist treatment of acute asthma. Cochrane Database Syst Rev (database
online). Issue 2, 2002
1. Cates, C Spacers and nebulisers for the delivery of beta-agonists in non-life-
threatening acute asthma. Respir Med 2003;97,762-769[CrossRef][ISI]
[Medline]
1. Ram, FSF, Wright, J, Brocklebank, D, et al Systematic review of clinical
effectiveness of pressurised metered dose inhalers versus other hand held inhaler
devices for delivering ß2-agonists bronchodilators in asthma. BMJ
2001;323,901-905[Abstract/Free Full Text]
1. Ram FS, Brocklebank DM, Muers M, et al. Pressurised metered-dose inhalers
versus all other hand-held inhalers devices to deliver bronchodilators for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev (database online).
Issue 1, 2002
&'()* Ram FS, Brocklebank DM, White J, et al. Pressurised metered dose inhalers versus all
other hand-held inhaler devices to deliver ß2 agonist bronchodilators for non-acute
asthma. Cochrane Database Syst Rev (database online). Issue 1, 2002
1. Guyatt, G, Hayward, R, Richardson, WS, et al Moving from evidence to action.
Guyatt, G Rennie, D eds. The user’s guides to the medical literature: a manual
for evidence-based clinical practice 2002 AMA Publications. Chicago, IL:
1. Fleiss, JL The statistical basis of meta-analysis. Stat Methods Med Res
1993;2,121-145[Medline]
1. Hedges, LV, Olkin, I Statistical methods for meta-analysis. 1985 Academic
Press. San Diego, CA:
1. Ahrens, RC On comparing inhaled ß adrenergic agonists. Ann Allergy
1991;67,296-298[ISI][Medline]
1. Batra, V, Sethi, GR, Sachdev, HP Comparative efficacy of jet nebulizer and
metered dose inhaler with spacer device in the treatment of acute asthma. Indian
Pediatr 1997;34,497-503[Medline]
1. Chou, KJ, Cunningham, SJ, Crain, EF Metered-dose inhalers with spacers vs
nebulizers for pediatric asthma. Arch Pediatr Adolesc Med 1995;149,201-
205[published erratum appears in Arch Pediatr Adolesc Med 1995; 149:545]
[Abstract]
1. Lin, YZ, Hsieh, KH Metered dose inhaler and nebuliser in acute asthma. Arch
Dis Child 1995;72,214-218[Abstract]
1. Ploin, D, Chapuis, FR, Stamm, D, et al High-dose albuterol by metered-dose
inhaler plus a spacer device versus nebulization in preschool children with
recurrent wheezing: a double-blind, randomized equivalence trial. Pediatrics
1. Robertson, CF, Norden, MA, Fitzgerald, DA, et al Treatment of acute asthma:
salbutamol via jet nebuliser vs spacer and metered dose inhaler. J Paediatr Child
Health 1998;34,142-146[CrossRef][ISI][Medline]
1. Rubilar, L, Castro-Rodriguez, JA, Girardi, G Randomized trial of salbutamol via
metered-dose inhaler with spacer versus nebulizer for acute wheezing in children
less than 2 years of age. Pediatr Pulmonol 2000;29,264-269[CrossRef][ISI]
[Medline]
1. Schuh, S, Johnson, DW, Stephens, D, et al Comparison of albuterol delivered by
a metered dose inhaler with spacer versus a nebulizer in children with mild acute
asthma. J Pediatr 1999;135,22-27[ISI][Medline]
1. Williams, JR, Bothner, JP, Swanton, RD Delivery of albuterol in a pediatric
emergency department. Pediatr Emerg Care 1996;12,263-267[ISI][Medline]
1. Colacone, A, Afilalo, M, Wolkove, N, et al A comparison of albuterol
administered by metered dose inhaler (and holding chamber) or wet nebulizer in
acute asthma. Chest 1993;104,835-841[Abstract]
1. Idris, AH, McDermott, MF, Raucci, JC, et al Emergency department treatment
of severe asthma: metered-dose inhaler plus holding chamber is equivalent in
effectiveness to nebulizer. Chest 1993;103,665-672[Abstract]
1. Raimondi, AC, Schottlender, J, Lombardi, D, et al Treatment of acute severe
asthma with inhaled albuterol delivered via jet nebulizer, metered dose inhaler
with spacer, or dry powder. Chest 1997;97,24-28
1. Rodrigo, G, Rodrigo, C Comparison of salbutamol delivered by nebulizer or
metered-dose inhaler with a pear-shaped spacer in acute asthma. Curr Ther Res
Clin Exp 1993;54,797-808[ISI]
1. Salzman, GA, Steele, MT, Pribble, JP, et al Aerosolized metaproterenol in the
treatment of asthmatics with severe airflow obstruction: comparison of two
delivery methods. Chest 1989;95,1017-1020[Abstract]
1. Turner, JR, Corkery, KJ, Eckman, D, et al Equivalence of continuous flow
nebulizer and metered-dose inhaler with reservoir bag for treatment of acute
airflow obstruction. Chest 1988;93,476-481[Abstract]
1. Levitt, MA, Gambrioli, EF, Fink, JB Comparative trial of continuous
nebulization versus metered dose inhaler in the treatment of acute
bronchospasm. Ann Emerg Med 1995;26,273-277[ISI][Medline]
1. Mandelberg, A, Chen, E, Noviski, N, et al Nebulized wet aerosol treatment in
emergency department: is it essential? Comparison with large spacer device for
metered-dose inhaler. Chest 1997;112,1501-1505[Abstract/Free Full Text]
1. Summer, W, Elston, R, Tharpe, L, et al Aerosol bronchodilator delivery
methods: relative impact on pulmonary function and cost of respiratory care.
Arch Intern Med 1989;149,618-623[Abstract]
1. Nana, A, Youngchaiyud, P, Maranetra, N, et al ß2-agonists administered by a dry
powder inhaler can be used in acute asthma. Respir Med 1998;92,167-
172[CrossRef][ISI][Medline]
1. Tonnesen, F, Laursen, LC, Evald, T, et al Bronchodilating effect of terbutaline
powder in acute severe bronchial obstruction. Chest 1994;105,697-
700[Abstract]
1. Delgado, A, Chou, KJ, Silver, E, et al Nebulizers vs metered-dose inhalers with
spacers for bronchodilator therapy to treat wheezing in children aged 2 to 24
months in a pediatric emergency department. Arch Pediatr Adolesc Med
1. Campbell, IA, Colman, SB, Mao, JH, et al An open, prospective comparison of
beta2 agonists given via nebuliser, Nebuhaler, or pressurised inhaler by
ambulance crew as emergency treatment. Thorax 1995;50,79-80[Abstract]
1. Parkin, PC, Saunders, NR, Diamond, SA, et al Randomised trial spacer v
nebuliser for acute asthma. Arch Dis Child 1995;72,239-240[Abstract]
1. Jasper, AC, Mohsenifar, Z, Kahan, S, et al Cost-benefit comparison of aerosol
bronchodilator delivery methods in hospitalized patients. Chest 1987;91,614-
618[Abstract]
1. Fuglsang, G, Pedersen, S Comparison of Nebuhaler and nebulizer treatment of
acute severe asthma in children. Eur J Respir Dis 1986;69,109-113[ISI]
[Medline]
1. Berry, RB, Shinto, RA, Wong, FH, et al Nebulizer vs spacer for bronchodilator
delivery in patients hospitalized for acute exacerbations of COPD. Chest
1989;96,1241-1246[Abstract]
1. Ruggins, NR, Milner, AD, Swarbrick, A An assessment of a new breath actuated
inhaler device in acutely wheeze children. Arch Dis Child 1993;68,477-
480[Abstract]
1. Dewar, AL, Stewart, A, Cogswell, JJ, et al A randomised controlled trial to
assess the relative benefits of large volume spacers and nebulisers to treat acute
asthma in hospital. Arch Dis Child 1999;80,421-423[Abstract/Free Full Text]
1. Rodrigo, GJ, Rodrigo, C Continuous vs intermittent ß-agonists in the treatment
of acute adult asthma: a systematic review with meta-analysis. Chest
1. Khine, H, Fuchs, SM, Saville, AL Continuous vs intermittent nebulized
albuterol for emergency management of asthma. Acad Emerg Med 1996;3,1019-
1024[Abstract]
1. Shrestha, M, Bidadi, K, Gourlay, S, et al Continuous vs intermittent albuterol, at
high and low doses, in the treatment of severe acute asthma in adults. Chest
1996;109,42-47
1. Reisner, C, Kotch, A, Dworkin, G Continuous versus frequent intermittent
nebulization of albuterol in acute asthma: a randomized, prospective study. Ann
Allergy Asthma Immunol 1995;75,41-47[ISI][Medline]
1. Lin, RY, Sauter, D, Newman, T, et al Continuous versus intermittent albuterol
nebulization in the treatment of acute asthma. Ann Emerg Med 1993;22,1847-
1853[ISI][Medline]
1. Rudnitsky, GS, Eberlein, RS, Schoffstall, JM, et al Comparison of intermittent
and continuously nebulized albuterol for treatment of asthma in an urban
emergency department. Ann Emerg Med 1993;22,1842-1846[ISI][Medline]
1. Papo, MC, Frank, J, Thompson, AE A prospective, randomized study of
continuous versus intermittent nebulized albuterol for severe status asthmaticus
in children. Crit Care Med 1993;21,1479-1486[ISI][Medline]
1. Torres, A, Jr, Anders, M, Anderson, P, et al Efficacy of metered-dose inhaler
administration of albuterol in intubated infants. Chest 1997;112,484-
490[Abstract/Free Full Text]
1. Gay, PC, Patel, HG, Nelson, SB, et al Metered dose inhalers for bronchodilator
delivery in intubated, mechanically ventilated patients. Chest 1991;99,66-
71[Abstract]
1. Manthous, CA, Hall, JB, Schmidt, GA, et al Metered-dose inhaler versus
nebulized albuterol in mechanically ventilated patients. Am Rev Respir Dis
1993;148,1567-1570[ISI][Medline]
1. Diot, P, Morra, L, Smaldone, GC Albuterol delivery in a model of mechanical
ventilation: comparison of metered-dose inhaler and nebulizer efficiency. Am J
Respir Crit Care Med 1995;152,1391-1394[Abstract]
1. Dhand, R, Tobin, MJ Inhaled bronchodilator therapy in mechanically ventilated
patients. Am J Respir Crit Care Med 1997;156,3-10[Free Full Text]
1. Duarte, AG, Momii, K, Bidani, A Bronchodilator therapy with metered-dose
inhaler and spacer versus nebulizer in mechanically ventilated patients:
comparison of magnitude and duration of response. Respir Care 2000;45,817-
823[Medline]
1. Dolovich, MB Influence of inspiratory flow rate, particle size, and airway
caliber on aerosolized drug delivery to the lung. Respir Care 2000;45,597-
608[Medline]
1. Hughes, JM, Saez, J Effects of nebulizer mode and position in a mechanical
ventilator circuit on dose efficiency. Respir Care 1987;32,1131-1135
1. O’Doherty, MJ, Thomas, SH, Page, CJ, et al Delivery of a nebulized aerosol to a
lung model during mechanical ventilation: effect of ventilator settings and
nebulizer type, position, and volume of fill. Am Rev Respir Dis 1992;146,383-
388[ISI][Medline]
1. O’Riordan, TG, Greco, MJ, Perry, RJ, et al Nebulizer function during
mechanical ventilation. Am Rev Respir Dis 1992;145,1117-1122[ISI][Medline]
1. McPeck, M, O’Riordan, TG, Smaldone, GC Choice of mechanical ventilator:
influence on nebulizer performance. Respir Care 1993;38,887-895
1. Good, M, Fink, JB, Dhand, R, et al Improvement in aerosol delivery with
helium-oxygen mixtures during mechanical ventilation. Am J Respir Crit Care
Med 2001;163,109-114[Abstract/Free Full Text]
1. Mouloudi, E, Prinianakis, G, Kondili, E, et al Bronchodilator delivery by
metered dose inhaler in mechanically ventilated patients: influence of flow
pattern. Eur Respir J 2000;16,263-268[Abstract/Free Full Text]
1. Mouloudi, E, Prinianakis, G, Kondili, E, et al Effect of inspiratory flow rate on
ß2-agonist induced bronchodilation in mechanically ventilated COPD patients.
Intensive Care Med 2001;27,42-46[CrossRef][ISI][Medline]
1. Mouloudi, E, Katsanoulas, K, Anastasaki, M, et al Bronchodilator delivery by
metered-dose inhaler in mechanically ventilated COPD patients: influence of
tidal volume. Intensive Care Med 1999;25,1215-1221[CrossRef][ISI][Medline]
1. Mouloudi, E, Katsanoulas, K, Anastasaki, M, et al Bronchodilator delivery by
metered-dose inhaler in mechanically ventilated COPD patients: influence of
end-inspiratory pause. Eur Respir J 1998;12,165-169[Abstract/Free Full Text]
1. Fuller, HD, Dolovich, MB, Turpie, FH, et al Efficiency of bronchodilator
aerosol delivery to the lungs from the metered dose inhaler in mechanically
ventilated patients: a study comparing four different actuator devices. Chest
1994;105,214-218[Abstract]
1. Pollack, CV, Jr, Fleisch, KB, Dowsey, K Treatment of acute bronchospasm with
beta-adrenergic agonist aerosols delivered by a nasal bilevel positive airway
pressure circuit. Ann Emerg Med 1995;26,552-557[ISI][Medline]
1. Nava, S, Karakurt, S, Rampulla, C, et al Salbutamol delivery during non-
invasive mechanical ventilation in patients with chronic obstructive pulmonary
disease: a randomised, controlled study. Intensive Care Med 2001;27,1627-
1635[CrossRef][ISI][Medline]
1. Boe, J, Stiksa, G, Svensson, K, et al New method of evaluating patient
preference for different inhalation delivery systems. Ann Allergy 1992;68,255-
260[ISI][Medline]
1. Osterman, K, Norborg, AM, Stahl, E A multiple dose powder inhaler
(Turbuhaler) compared with a conventional aerosol: an acceptance study in
asthmatics. Allergy 1989;44,294-297[ISI][Medline]
1. Johnsen, CR, Weeke, ER Turbuhaler: a new device for dry powder terbutaline
inhalation. Allergy 1988;48,392-395
1. Persson, G, Gruvstad, E, Stahl, E A new multiple dose powder inhaler,
(Turbuhaler), compared with a pressurized inhaler in a study of terbutaline in
asthmatics. Eur Respir J 1988;1,681-684[Abstract]
1. Lahdensuo, A, Sovijarvi, A, Muittari, A Inhaled powder and aerosol salbutamol
in methacholine-induced bronchial obstruction. Eur J Respir Dis Suppl
1983;128,515-517[Medline]
1. Svedmyr, N, Lofdahl, CG, Svedmyr, K The effect of powder aerosol compared
to pressurized aerosol. Eur J Respir Dis Suppl 1982;119,81-82[Medline]
1. Kiviranta, K Fenoterol inhalation powder and aerosol in the treatment of asthma.
Allergy 1985;40,305-307[ISI][Medline]
1. Bundgaard, A, Schmidt, A Pretreatment of exercise-induced asthma with
sequential inhalations of fenoterol as aerosol and as powder (first of two parts).
Eur J Respir Dis Suppl 1983;130,59-65[Medline]
1. Dirksen, H, Groth, S Fenoterol inhalation powder as an alternative to treatment
with the metered dose inhaler. Eur J Respir Dis Suppl 1983;130,48-53[Medline]
1. Bundgaard, A, Schmidt, A Pretreatment of exercise-induced asthma by fenoterol
delivered as inhalation powder and pressurized aerosol. Ann Allergy 1982;48,36-
39[ISI][Medline]
1. Nelson, HS, Loffert, DT Comparison of the bronchodilator response to albuterol
administered by the OptiHaler, the AeroChamber, or by metered dose inhaler
alone. Ann Allergy 1994;72,337-340[ISI][Medline]
1. Tammivaara, R, Aalto, E, Lehtonen, K, et al Comparison of a novel salbutamol
multidose powder inhaler with a salbutamol metered dose inhaler in patients
with asthma. Curr Ther Res Clin Exp 1997;58,734-744[ISI]
1. Mathieu, M, Goldman, M, Lellouche, N, et al Kinetics of action of salbutamol
inhaled from a metered dose inhaler (MDI) and a "diskhaler". Eur J Clin
Pharmacol 1992;42,435-438[ISI][Medline]
1. Vilsvik, J, Schaanning, J, Stahl, E, et al Comparison between Bricanyl
Turbuhaler and ventolin metered dose inhaler in the treatment of exercise-
induced asthma in adults. Ann Allergy 1991;67,315-318[ISI][Medline]
1. Nieminen, MM, Lahdensuo, A Inhalation treatment with budenoside in asthma:
a comparison of Turbuhaler and metered dose inhalation with Nebuhaler. Acta
Ther 1995;21,179-192[ISI]
1. Vidgren, P, Silvasti, M, Poukkula, A, et al Easyhaler powder inhaler—a new
alternative in the anti-inflammatory treatment of asthma. Acta Therapeutica
1994;20(3–4),117-131
1. Vidgren, M, Silvasti, M, Korhonen, P, et al Clinical equivalence of a novel
multiple dose powder inhaler versus a conventional metered dose inhaler on
bronchodilating effects of salbutamol. Arzneimittelforschung 1995;45,44-
47[Medline]
1. Jackson, L, Stahl, E, Holgate, ST Terbutaline via pressurised metered dose
inhaled (P-MDI) and Turbuhaler in highly reactive asthmatic patient. Eur Respir
J 1994;7,1598-1601[Abstract/Free Full Text]
1. Lindsay, DA, Russell, NL, Thompson, JE, et al A multicentre comparison of the
efficacy of terbutaline Turbuhaler and salbutamol pressurized metered dose
inhaler in hot, humid regions. Eur Respir J ;7,342-345194
1. Haahtela, T, Vidgren, M, Nyberg, A, et al A novel multiple dose powder inhaler:
salbutamol powder and aerosol give equal bronchodilatation with equal doses.
Ann Allergy 1994;72,178-182[ISI][Medline]
1. Lantos, A, Tarjan, E, Varnai, Z, et al Use of Taleum 1-mg inhalation aerosol in
bronchial asthma patient. Ther Hung 1993;41,146-149[Medline]
1. Zainudin, BMZ, Biddiscombe, M, Tolfree, SEJ, et al Comparison of
bronchodilator responses and deposition patterns of salbutamol inhaled from a
pressurised metered dose inhaler, as a dry powder, and as a nebulised solution.
Thorax 1990;45,469-473[Abstract]
1. Geoffroy, P, Lalonde, RL, Ahrens, R, et al Clinical comparability of albuterol
delivered by the breath-actuated inhaler (Spiros) and albuterol by MDI in
patients with asthma. Ann Allergy Asthma Immunol 1999;82,377-382[ISI]
[Medline]
1. Nieminen, MM, Vidgren, M, Laurikainen, K, et al Easyhaler, a novel multiple
dose powder inhaler: clinically equivalent to salbutamol metered dose inhaler
and easier to us. Respiration 1994;61,37-41[ISI][Medline]
1. Nelson, H, Kemp, JP, Bieler, S, et al Comparative efficacy and safety of
albuterol sulfate Spiros inhaler and albuterol metered-dose inhaler in asthma.
Chest 1999;115,329-335[Abstract/Free Full Text]
1. Bauer, K, Dietersdorfer, F, Sertl, K, et al Pharmacodynamic effects of inhaled
dry powder formulations of fenoterol and colforsin in asthma. Clin Pharmacol
Ther 1993;53,76-83[ISI][Medline]
1. Lahdensuo, A, Muittari, A Bronchodilator effects of a fenoterol metered dose
inhaler and fenoterol powder in asthmatics with poor inhaler technique. Eur J
Respir Dis 1986;68,332-335[ISI][Medline]
1. Hirsch, T, Peter-Kern, M, Koch, R, et al Influence of inspiratory capacity on
bronchodilatation via Turbuhaler or pressurized metered-dose inhaler in
asthmatic children: a comparison. Respir Med 1997;91,341-346[CrossRef][ISI]
[Medline]
1. Svenonius, E, Arborelius, M, Wiberg, R, et al A comparison of terbutaline
inhaled by Turbuhaler and by a chlorofluorocarbon (CFC) inhaler in children
with exercise-induced asthma. Allergy 1994;46,408-412
1. Chambers, S, Dunbar, J, Taylor, B Inhaled powder compared with aerosol
administration of fenoterol in asthmatic children. Arch Dis Child 1980;80,73-74
1. Reiser, J, Frame, MH, Warner, JO The potential value of a 750-ml spacer for the
administration of inhaled corticosteroids to children. Pediatric Pulmonol
1986;2,237-243[ISI][Medline]
1. Bloomfield, P, Crompton, GK, Winsey, NJ A tube spacer to improve inhalation
of drugs from pressurised aerosols. BMJ 1979;2,1479
1. Pedersen, JZ, Bundgaard, A Comparative efficacy of different methods of
nebulising terbutaline. Eur J Clin Pharmacol 1983;25,739-742[ISI][Medline]
1. Madsen, EB, Bundgaard, A, Hidinger, KG Cumulative dose-response study
comparing terbutaline pressurized aerosol administered via a pearshaped spacer
and terbutaline in a nebulized solution. Eur J Clin Pharmacol 1982;23,27-
30[ISI][Medline]
1. Blake, KV, Hoppe, M, Harman, E, et al Relative amount of albuterol delivered
to lung receptors from a metered-dose inhaler and nebulizer solution: bioassay
by histamine bronchoprovocation. Chest 1992;101,309-315[Abstract]
1. Wong, AG, O’Byrne, PM, Lindbladh, C, et al Dose-response protective effect of
salbutamol on methacholine airway responsiveness using pressurized metered
dose inhalers and Turbuhalers. Can Respir J 1998;5,119-123[Medline]
1. Lofdahl, CG, Andersson, L, Bondesson, E, et al Differences in bronchodilating
potency of salbutamol in Turbuhaler as compared with a pressurized metered-
dose inhaler formulation in patients with reversible airway obstruction. Eur
Respir J 1997;10,2474-2478[Abstract/Free Full Text]
1. Bondesson, E, Friberg, K, Soliman, S, et al Safety and efficacy of a high
cumulative dose of salbutamol inhaled via Turbuhaler or via a pressurized
metered-dose inhaler in patients with asthma. Respir Med 1998;92,325-330[ISI]
[Medline]
1. Ahrens, RC, Hendeles, L, Clarke, WR, et al Therapeutic equivalence of Spiros
dry powder inhaler and Ventolin metered dose inhaler: a bioassay using
methacholine. Am J Respir Crit Care Med 1999;160,1238-1243[Abstract/Free
Full Text]
1. Morice, AH, Andrews, B, Taylor, M Comparison of the effect on bronchial
hyperresponsiveness of beclomethasone dipropionate administered via a novel
multidose dry-powder inhaler or a conventional pressurised metered dose
inhaler. Respiration 2000;67,298-305[CrossRef][ISI][Medline]
1. Hansen, NC Terbutaline as powder inhalation from Bricanyl Turbuhaler
compared to terbutaline as nebulizer solution in severe chronic airways
obstruction. Eur Respir J 1989;2,716-720[Abstract]
1. Pauwels, R, Lamont, H, Hidinger, K, et al Influence of an extension tube on the
bronchodilator efficacy of terbutaline delivered from a metered dose inhaler.
Respiration 1984;45,61-66[ISI][Medline]
1. Dorow, P, Hidinger, KG Terbutaline aerosol from a metered dose inhaler via a
750 ml spacer: effect on large and small airways. Eur J Clin Pharmacol
1982;22,511-514[CrossRef][ISI][Medline]
1. Gimeno, F, van Veenen, R, Berg, WC, et al A placebo-controlled comparison

between the bronchodilatory effects of ipratropium bromide inhaled as a dry
powder and by metered dose inhaler in chronic obstructive pulmonary disease.
Ann Allergy 1988;61,341-343[ISI][Medline]
2. Rammeloc, RHU, Luursema, PB, Sips, AP, et al Therapeutic equivalence of a

fenoterol/lpratropium bromide combination (Berodual) inhaled as a dry powder
and by metered dose inhaler in chronic obstructive airway disease. Respiration
1992;59,322-326[ISI][Medline]
3. Formgren, H, Sjokvist, A, Stahl, E, et al Terbutaline in COPD comparison
between Turbuhaler and chlorofluorocarbon (CFC) inhaler. Lung 1994;172,271-
280[ISI][Medline]
4. Balzano, G, Battiloro, R, Biraghi, M, et al Effectiveness and acceptability of a
domiciliary multidrug inhalation treatment in elderly patients with chronic
airflow obstruction: metered dose inhaler versus jet nebulizer. J Aerosol Med
2000;13,25-33[ISI][Medline]
5. Beaty, R, Harman, E, Molino, L, et al The dose-response of albuterol MDI
during acute attacks of nocturnal asthma [abstract].Am Rev Respir Dis
1992;145,A66
6. Nelson, HS, Busse, WW, de Boisblanc, BP, et al Fluticasone propionate powder:
oral corticosteroid-sparing effect and improved lung function and quality of life
in patients with severe chronic asthma. J Allergy Clin Immunol 1999;103,267-
275[ISI][Medline]
7. Ram FSF, Brocklebank D, Muers MF, et al. Pressurized metered-dose inhalers
versus all other hand-held inhalers devices to deliver bronchodilators for chronic
obstructive pulmonary disease. Cochrane Database Syst Rev (database online).
Issue 1, 2002
8. Lipworth B, Williams I, Senn S, et al. Electronic letters. BMJ 2001. Available
at: http://bmj.bmjjournals.com/cqi/eletters/323/7318/896
1. Agarwal S. Electronic letter. BMJ 2002. Available at: http://
bmj.bmjjournals.com/cqi/eletters/323/7318/901 Accessed April 4, 2002
2. Dolovich, MB, MacIntyre, NR, Andersen, PJ, et al Consensus statement:
aerosols and delivery devices; American Association for Respiratory Care.
Respir Care 2000;45,589-593[Medline]
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Device Selection and Outcomes of Aerosol Therapy:

Methods: A systematic review of pertinent randomized, controlled clinical trials (RCTs)

Results: None of the pooled metaanalyses showed a significant difference between

Key Words: aerosols • bronchodilators • corticosteroids • drug delivery systems • dry

View this Table 1. Advantages and Disadvantages of Each Type of Aerosol-

We undertook a systematic overview of the pertinent TOP

View this table: Table 3A. Search Strategies for RCTs*

View this table: Table 3B. PubMed Search Strategy

View this table: Table 3C. EMBASE Search Strategy

Figure 1. Studies selected included those

View this table: Table 4. Outcome Categories*

View this table: Table 5. Ranked Taxonomy of Outcomes*

Type 2 Trials: Device Performance in the Clinical Laboratory Setting

Type 2a Trials: Analyzing Differences in Response Variables:

Type 2b Trials: Estimating Differences in Clinical Potency:

View this table: Table 7. Scheme Used to Grade Recommendations

Results and Recommendations

Eight studies3738394041424344 randomized pediatric patients to receive a ß2-agonist agent by

View this Table 8. Short-term Nebulizer vs MDI + Spacer/Holding Chamber

Figure 2. Weighted standardized mean difference

View larger version (25K):

Figure 3. Top: weighted standardized mean difference

View larger version

In adult patients reporting to the ED with asthma symptoms (Table 9 ), six

View this Table 9. Short-term Nebulizer vs MDI + Spacer/Holding Chamber

One study57 evaluated aerosol delivery devices in an ambulance setting. No significant

View larger version (20K):

Summary of RCT Results

Aerosol Delivery of Short-Acting ß2-Agonists in the Inpatient Hospital Setting

View this table: Table 11. Aerosol Delivery in Hospitalized Patients*

Figure 5. Weighted standardized mean difference

View larger version (15K):

Summary of RCT Results

Intermittent vs Continuous Nebulizer Delivery of ß2-Agonists

View larger version

Summary of RCT Results

1. Frequent intermittent nebulization and continuous nebulization are both

Aerosolized ß2-Agonists in Patients Receiving Mechanical Ventilation

The adverse effects of ß2-agonist administration during mechanical ventilation were

Noninvasive positive-pressure ventilation (NPPV) is increasingly used in the care of

Summary of RCT Results

In children and adults receiving mechanical ventilation, the outcomes of ß2-

1. Both nebulizers and MDIs can be used to deliver ß2-agonists to mechanically

Device Selection in the Outpatient Setting

Twenty-three studies90919293949596979899101102103106107108109110111112113114115 (both type 2a and 2b)

Figure 7. Weighted standardized mean difference

View larger version (35K):

Figure 8. Top left, A: weighted standardized mean

Summary of RCT Results

Inhaled Corticosteroids for Asthma

Figure 10. Weighted mean standardized difference

View larger version (11K):

Summary of RCT Results

ß2-Agonists and Anticholinergic Agents for COPD

View this table: Table 19. Outpatient COPD Studies*

Summary of RCT Results

In the outpatient management of COPD patients with ß2-agonist and