special report
`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
`
`Background: The proliferation of inhaler devices has resulted in a confusing number of choices
`for clinicians who are selecting a delivery device for aerosol therapy. There are advantages and
`disadvantages associated with each device category. Evidence-based guidelines for the 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 ␤-agonists, anticholinergic agents, and corticosteroids for several
`commonly encountered clinical settings and patient populations, and (2) to provide recommen-
`dations 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 cortico-
`steroid, ␤
`2-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 ␤
`2-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.
`(CHEST 2005; 127:335–371)
`
`Key words: aerosols; bronchodilators; corticosteroids; drug delivery systems; dry powder inhalers; metaanalysis;
`metered-dose inhalers; nebulizers
`
`inhaler; ED ⫽ emergency
`Abbreviations: CFC ⫽ chlorofluorocarbon; DPI ⫽ dry
`department;
`powder
`MDI ⫽ metered-dose inhaler; NPPV ⫽ noninvasive positive pressure ventilation; PEFR ⫽ peak expiratory flow rate;
`RCT ⫽ randomized controlled trial; sGaw ⫽ specific airway conductance
`
`www.chestjournal.org
`
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`
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`T he use of inhaled aerosol medications for the
`
`treatment of pulmonary diseases, which became
`well-established in the last half of the 20th century,
`has advantages over oral and parenteral routes of
`delivery. The use of inhaled aerosols allows selective
`treatment of the lungs directly by achieving high
`drug concentrations in the airway while reducing
`systemic adverse effects by minimizing systemic drug
`levels.1 Inhaled ␤
`2-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 Pro-
`
`*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; Cardiopul-
`monary Care Sciences (Dr. Rau), Georgia State University,
`Atlanta, GA; and the Department of Medicine (Dr. Smal-
`done), Pulmonary/Critical Care Division, State University of
`New York at Stony Brook, Stony Brook, NY.
`Professor Dolovich has served as a speaker for Forest Labo-
`ratories, 3M Pharma, and Aventis, and as a consultant for
`GlaxoSmithKline and Delex Therapeutics, and has received
`research funding from 3M Pharma, Trudell Medical Interna-
`tional, 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: AstraZen-
`eca; Aventis; Boehringer Ingelheim; GlaxoSmithKline; Inno-
`vata 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-Zen-
`eca, 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 con-
`nected to aerosol therapy, primarily the nebulization of drugs.
`Those companies with a direct financial interest in nebuliza-
`tion include Monaghan/Trudell Medical International, Aero-
`gen, Pari, and Profile Therapeutics.
`Manuscript received February 25, 2004; revision accepted Au-
`gust 25, 2004.
`Reproduction of this article is prohibited without written permis-
`sion from the American College of Chest Physicians (e-mail:
`permissions@chestnet.org).
`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: mdolovic@mcmaster.ca
`
`gram 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 ther-
`apy. 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.4,5 Improper inhaler technique is common
`among patients.6 – 8 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.9 –13 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 aero-
`sol 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 intro-
`duced in the 1960s.15,16 In 1971, Bell and col-
`leagues17 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 trig-
`gered by patient inhalation to release the drug on
`demand.
`Investigators developed open-tube spacer devices,
`intended for use with MDIs, in the late 1970s.18 –20
`The addition of a one-way valve (holding chamber)18
`or blind reservoir (ie, reverse-flow spacer)21,22 al-
`
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`lowed 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-con-
`suming to use. Matching nebulizers with associated
`air compressors is necessary to assure optimal effi-
`ciency 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.
`
`Table 1—Advantages and Disadvantages of Each Type of Aerosol-Generating Device or System Clinically
`Available*
`
`Type
`
`Advantages
`
`Disadvantages
`
`Small-volume jet nebulizer
`
`Ultrasonic nebulizer
`
`Pressurized MDI
`
`Patient coordination not required
`Effective with tidal breathing
`High dose possible
`Dose modification possible
`No CFC release
`Can be used with supplemental oxygen
`Can deliver combination therapies if
`compatible
`
`Patient coordination not required
`High dose possible
`Dose modification possible
`No CFC release
`Small dead volume
`Quiet
`Newer designs small and portable
`Faster delivery than jet nebulizer
`No drug loss during exhalation (breath-
`actuated devices)
`Portable and compact
`Treatment time is short
`No drug preparation required
`No contamination of contents
`Dose-dose reproducibility high
`Some can be used with breath-
`actuated mouthpiece
`
`Holding chamber, reverse-
`flow spacer, or spacer
`
`Reduces need for patient coordination
`Reduces pharyngeal deposition
`
`DPI
`
`Breath-actuated
`Less patient coordination required
`Propellant not required
`Small and portable
`Short treatment time
`Dose counters in most newer designs
`
`*Modified from Dolovich et al.142
`
`www.chestjournal.org
`
`Lack of portability
`Pressurized gas source required
`Lengthy treatment time
`Device cleaning required
`Contamination possible
`Not all medication available in solution form
`Does not aerosolize suspensions well
`Device preparation required
`Performance variability
`Expensive when compressor added in
`Expensive
`Need for electrical power source (wall outlet or batteries)
`Contamination possible
`Not all medication available in solution form
`Device preparation required before treatment
`Does not nebulize suspensions well
`Possible drug degradation
`Potential for airway irritation with some drugs
`
`Coordination of breathing and actuation needed
`Device actuation required
`High pharyngeal deposition
`Upper limit to unit dose content
`Remaining doses difficult to determine
`Potential for abuse
`Not all medications available
`Many use CFC propellants in United States
`Inhalation can be more complex for some patients
`Can reduce dose available if not used properly
`More expensive than MDI alone
`Less portable than MDI alone
`Integral actuator devices may alter aerosol properties
`compared to native actuator
`Requires moderate to high inspiratory flow
`Some units are single dose
`Can result in high pharyngeal deposition
`Not all medications available
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`Younger patients and patients in acute distress may
`not be able to generate the necessary flow rates.2,24
`Breath-actuated MDIs are also easier to use, but are
`currently available in the United States for only a
`single drug (ie, the ␤
`2-agonist pirbuterol). Holding
`chambers used with MDIs remove the necessity of
`careful timing between inhalation and MDI actua-
`tion. 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.
`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 de-
`partment (ED), hospitalized inpatient, or intensive
`care setting) and the disease being treated (eg,
`COPD vs asthma) also influence the choice of
`aerosol device.
`Several systematic reviews and metaanalyses re-
`lated 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 differ-
`ences 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 evi-
`dence 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
`␤
`2-agonist treatment of acute asthma, concluded
`that an MDI with a holding chamber produces
`
`Table 2—General Age Requirements for Correct Use of
`Aerosol Delivery Device Types*
`
`Aerosol Delivery Method
`
`Minimum Age
`
`ⱕ 2 yr
`Small-volume nebulizer
`⬎ 5 yr
`MDI
`⬎ 4 yr
`MDI with chamber
`ⱕ 4 yr
`MDI with chamber and mask
`Neonate
`MDI with endotracheal tube
`⬎ 5 yr
`Breath-actuated MDI
`ⱖ 5 yr
`DPI
`*Based on National Asthma Education and Prevention Program.2
`
`to those
`least equivalent
`outcomes that are at
`achieved with the use of a nebulizer. Several system-
`atic reviews30 –32 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 recommen-
`dations 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 concern-
`ing 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 be-
`lieve that evidence-based guidelines are still needed.
`Consequently, the intent of this project was to assess
`the available scientific evidence addressing the ques-
`tion 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 recom-
`mendations 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 perti-
`nent literature. The databases that were searched
`were MEDLINE, Embase, and the Cochrane Li-
`brary (Table 3, available on-line only). A broad
`search strategy was chosen to combine terms relating
`to aerosol devices or drugs with those relating to the
`diseases of interest in various patient groups and in a
`number of clinical settings (Fig 1). Only randomized
`controlled trials (RCTs) in human subjects published
`in English were selected. The search identified an
`initial set of approximately 2,100 publications span-
`ning the years 1972 to 2000. Two reviewers indepen-
`dently assessed each abstract of these publications to
`determine whether they met the eligibility criteria
`(ie, RCT addressing the relevant population, inter-
`vention, and outcome). This review identified 394
`RCTs assessing inhaled corticosteroid, ␤
`2-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
`
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`(Table 6). These studies primarily tested ␤
`2-agonists.
`Few studies of corticosteroids met our eligibility
`criteria.
`Separate metaanalyses were carried out for each
`specific clinical setting being considered. The
`weighted standardized difference between treat-
`ment groups in the outcome of interest was calcu-
`lated 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 out-
`comes reported are in SD units. In studies that
`provided data for more than one of these out-
`comes, 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 deter-
`mined that these descriptors would influence the
`interpretation and relevance of the studies for clini-
`cal use by patients. Therefore, we grouped the
`studies that were reviewed into three general types
`
`Figure 1. Studies selected included those overlapping (illus-
`trated by shaded area) devices or drugs, disease setting, and
`RCTs.
`
`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 un-
`wieldy, 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
`
`Outcome
`
`Ranking
`
`Table 5—Ranked Taxonomy of Outcomes*
`
`FEV1
`
`PF
`
`Mechanics
`Symptoms/physical findings
`
`FVC
`
`FEF25–75%
`Blood gas
`Adrenergic use
`Technique/preference
`
`FEV1; FEV1 % predicted; FEV1 L/% predicted; FEV1/FVC ratio; FEV1 mL; FEV1 % change from initial;
`FEV1 % predicted % change from initial
`PF L/min; PEF ⫺ am pre, PEF ⫺ pm pre, PEF ⫺ am post, PEF ⫺ pm post; we decided there was little to
`choose between the additional measures, though in general pre should be chosen over post and am should
`be chosen over pm
`sGAW; sGAW s/kPa; the rest were arbitrary
`Asthma score, dyspnea score, wheeze, sleep disturbances, and dyspnea on exertion; the rest were arbitrary
`within the following categories: shortness of breath, unspecified symptoms, cough, physiologic measures
`FVC; FVC mL; FVC % predicted; FVC L/% predicted; the following were arbitrary: IVC should be the last
`choice
`FEV25–75 (112) ⫹ FEF25–75; FEF25–75 % predicted; the rest were arbitrary
`Sao2; Po2; Pco2; pH
`␤
`2-adrenergic use, total No. of doses, BD puffs
`Preference for technique, device rating; the following were arbitrary: design should be second to last choice,
`taste should be the last choice
`Heart rate; pulse rate; heart rate increase
`Heart rate, BP, ECG
`*PF ⫽ peak flow; PEF ⫽ peak expiratory flow; IVC ⫽ inspiratory vital capacity; FEF25–75%
`BD ⫽ bronchodilator.
`
`www.chestjournal.org
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`CHEST / 127 / 1 /JANUARY, 2005
`
`339
`
`⫽ forced expiratory flow, midexpiratory phase,
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`Table 6—Reasons Trials Were Not Included in Analysis
`
`Reasons for Exclusion
`
`Comparison
`
`Studies,
`No.
`
`Not
`RCT
`
`Not
`Comparison
`of Interest
`
`Not
`Independent
`Subgroups
`
`Only Usable
`Baseline
`Data
`
`No
`Useable
`Data
`
`No
`Comparable
`Trials or
`Outcomes
`
`Total for
`Analysis,
`No.
`
`Overall
`MDI vs DPI
`Nebulizer vs MDI ⫹ spacer
`MDI vs MDI ⫹ spacer
`DPI vs MDI ⫹ spacer
`DPI vs nebulizer
`MDI vs nebulizer
`Intermittent vs continuous nebulizer
`
`131
`45
`32
`17
`14
`3
`5
`7
`
`3
`1
`0
`0
`2
`0
`0
`0
`
`20
`0
`0
`1
`0
`0
`0
`0
`
`2
`0
`1
`0
`0
`0
`0
`1
`
`7
`2
`2
`3
`0
`0
`0
`0
`
`30
`12
`6
`7
`4
`0
`1
`2
`
`11
`2
`4
`2
`4
`3
`4
`0
`
`59
`28
`19
`5
`4
`0
`0
`4
`
`(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 effec-
`tiveness 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 ␤
`2-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 differ-
`ent devices over a period of weeks, and assess daily
`asthma symptoms, ␤
`2-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 perfor-
`mance 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 ␤
`2-agonists. Most of these studies measure
`increases in lung function in response to the ␤
`2-
`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) pro-
`duced by the different devices. These studies are
`termed response axis comparisons by the US Food
`and Drug Administration and are now widely recog-
`nized to be relatively insensitive to true differences
`in drug delivery by different devices.36 Typically, the
`doses used are near the top of the ␤
`2-agonist dose-
`response curve that patients exhibit in this setting. As
`a result, the studies are commonly unable to distin-
`guish 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) deliv-
`ered 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 indica-
`tor of how reliable the estimate is. These studies are
`
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`
`

`

`termed “dose-scale comparisons”36 and are recog-
`nized as being the most reliable way of identifying
`true difference in drug delivery to the site of action
`in the lung.
`the Writing Committee assumed
`Members of
`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 Phy-
`sicians (Table 7). The draft document was reviewed
`by all members of the Writing Committee for con-
`tent and accuracy.
`
`Results and Recommendations
`Device Selection in the Hospital Acute Care Setting
`Aerosol Delivery of Short-Acting ␤
`2-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 ␤
`2-agonist
`
`bronchodilators (ie, albuterol, metaproterenol, or
`terbutaline). No studies were available that com-
`pared nebulizers to MDIs alone in patients with
`acute asthma presenting to the ED. The majority of
`these studies compared delivery by nebulizer to that
`by an MDI with a spacer/holding chamber. All were
`type 1 studies that enrolled patients presenting to the
`ED with acute asthma symptoms. Only 3 of the 19
`studies included in the analysis studied delivery by
`DPI in the ED setting. None of the studies specifi-
`cally 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 read-
`missions 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 stud-
`
`Table 7—Scheme Used to Grade Recommendations
`
`Grading of the strength of the recommendations is based on both the quality of the evidence and the net benefit of the diagnostic or
`therapeutic procedure:
`
`A
`B
`C
`D
`I
`E/A
`E/B
`E/C
`E/D
`Quality of the evidence
`Good
`Fair
`Low
`Expert opinion
`
`Strong recommendation
`Moderate recommendation
`Weak recommendation
`Negative recommendation
`No recommendation possible (inconclusive)
`Strong recommendation based on expert opinion only
`Moderate recommendation based on expert opinion only
`Weak recommendation based on expert opinion only
`Negative recommendation based on expert opinion only
`
`Evidence is based on good RCTs or metaanalyses
`Evidence is based on other controlled trials or RCTs with minor flaws
`Evidence is based on nonrandomized, case-control, or other observational studies
`Evidence is based the consensus of the carefully selected panel of experts in the topic field.
`There are no studies that meet the criteria for inclusion in the literature review.
`
`Net benefit
`These levels of net benefit to the patient (adjusted for risk) are based on clinical assessment of the test or procedure:
`Substantial
`Intermediate
`Small/weak
`None
`Conflicting
`Negative
`Relationship of strength of the recommendations scale to quality of evidence and net benefits
`
`Net Benefit
`
`Quality of Evidence
`
`Substantial
`
`Intermediate
`
`Small/Weak
`
`None
`
`Conflicting
`
`Negative
`
`Good
`Fair
`Low
`Expert opinion
`
`www.chestjournal.org
`
`A
`A
`B
`E/A
`
`A
`B
`C
`E/B
`
`B
`C
`C
`E/C
`
`D
`D
`I
`I
`
`I
`I
`I
`I
`
`D
`D
`D
`E/D
`
`CHEST / 127 / 1 /JANUARY, 2005
`
`341
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`Table 8—Short-term Nebulizer vs MDI ⴙ Spacer/Holding Chamber Studies Using ␤
`2-Agonists for Pediatric Patients
`in the Acute Care Setting*
`
`Total Patients/
`Patients per Group,
`No.
`
`Lost to Follow-up,
`No. (Time)
`
`Study/Year/Study Type
`
`Pediatric ER
`Ploin et al40/2000/type 1
`
`64/(32/31)
`
`4
`
`9
`
`Rubilar et al42/2000/type 1
`
`132
`
`Schuh et al43/1999/type 1
`
`90/(30/30/30)
`
`16 (5–17 yr)
`
`Robertson et al41/1998/
`type 1㛳
`
`58/(155)
`
`(4–12 yr)
`
`Williams et al44/1996/type 1
`
`60
`
`0 (6 yr)
`
`Lin and Hsieh39/1995/type 1
`
`117
`
`6
`
`Age Range
`
`Drug/Device† (Dose)
`
`MDI: 12–51 mo (24.8 mo)‡ Albuterol/MDI ⫹ Babyhaler spacer
`(0.05 mg/kg)
`NEB: 11–56 mo (25.5 mo)‡ Nebulizer (0.15 mg/kg)
`
`MDI: 7.2 ⫾ 4.7 mo§
`
`NEB: 8.5 ⫾ 5.4 mo§
`
`5–17 yr (9.1)‡
`
`4–12 yr
`MDI: 6.9 ⫾ 2.4 yr§
`NEB: 7.0 ⫾ 2.5 yr§
`
`Albuterol/MDI ⫹ Aerocell spacer
`(0.2 mg q10 min)
`Hudson Updraft II nebulizer
`(0.25 mg/kg q13 min)
`Albuterol/MDI ⫹ AeroChamber
`spacer:GpI (⬍ 25 kg 0.6 mg;
`25–34 kg 0.8 mg; ⬎ 34 kg 1 mg:
`GpII 0.2 mg)
`WhisperJet Nebulizer GpIII
`(0.15 mg/kg to max of 5 g)
`Albuterol/⬍ 25 kg: MDI ⫹
`Volumatic spacer (0.6 mg)
`NEB (2.5 mg) ⬎ 25 kg: MDI ⫹
`Volumatic spacer (1.2 mg) NEB
`(5.0 mg)
`Albuterol/MDI ⫹ AeroChamber and
`⬎ 6 yr
`AeroChamber: 9.2 ⫾ 2.8 yr§ ACE spacer (0.36 mg q20 min)
`ACE: 10.5 ⫾ 31 yr§
`NEB (2.5 mg q 30 min)
`NEB: 11.5 ⫾ 3.3 yr§
`MDI: 5–16 yr (8.1 yr)
`
`NEB: 5–15 yr (8.4 yr)‡
`
`Terbutaline/MDI ⫹ AeroChamber
`spacer (0.75 mg)
`NEB (2.5 mg)
`
`Chou et al38/1995/type 1
`
`152
`
`0 (2 yr)
`
`⬎ 2 yr
`
`Albuterol/MDI ⫹ AeroChamber
`(0.3 mg)
`NEB (0.15 mg/kg up to 5.0 mg)
`
`Pediatric ER and ICU
`Batra et al37/1997/type 1
`
`60
`1–12 yr
`
`0