(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: mdolovic{at}mcmaster.ca
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Abstract
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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 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
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Introduction
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The 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 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.
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.
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.
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Methodology
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We undertook a systematic overview of the pertinent literature. The databases that were searched were MEDLINE, Embase, and the Cochrane Library (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 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.
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.
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Results and 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 bronchodilators (ie, albuterol, metaproterenol, or terbutaline). No studies were available that compared 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 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.
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Table 8.. Short-term Nebulizer vs MDI + Spacer/Holding Chamber Studies Using ß2-Agonists for Pediatric Patients in the Acute Care Setting*
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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.
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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
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Table 9.. Short-term Nebulizer vs MDI + Spacer/Holding Chamber Studies Using ß2-Agonists for Adult Patients in the Acute Care Setting*
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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.
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
- 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.
- 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.
- 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.
Summary of RCT Results
- 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
- 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.
- 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.
- Many factors would lead the clinician to appropriately select a particular type of 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.
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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.
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Summary of RCT Results
- 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
- 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.
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.
Summary of RCT Results
- 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
- 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.
- 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.
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Device Selection in the Outpatient Setting
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Short-Acting ß2-Agonists for Asthma in the Outpatient Setting
Twenty-eight RCTs compared devices for the delivery of ß2-agonists to outpatients. Most trials used a crossover design, and all were of type 2a or 2b. In other words, study outcomes assessed the comparability of the effect in the clinical laboratory setting in patients who 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
).
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Table 15.. Trials Comparing MDI vs DPI Studies "Comparable Dose and Drug" ß2-Agonists and Cromolyn Adult Outpatients With Asthma*
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Figure 7.. Weighted standardized mean difference 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 abbreviations not used in the text.
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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.
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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 comparable dose/drug ß2-agonist trials comparing MDI vs DPI. Bottom right, D: WMD mean 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.
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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 ).
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).
Summary of RCT Results
- 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
- 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; strength of recommendation: A.
- 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).
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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.
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Summary of RCT Results
- 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 (quality of evidence: good).
- 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
- 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; strength of recommendation: A.
- 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.
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 M
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Abstract
Introduction
