Aerosolterapia. Chest, Guidelines ACCP

DOI 10.1378/chest.127.1.335 2005;127;335-371 Chest

Rajiv Dhand, Joseph L. Rau, Gerald C. Smaldone and Gordon Guyatt Myrna B. Dolovich, Richard C. Ahrens, Dean R. Hess, Paula Anderson,

Allergy, and ImmunologyPhysicians/American College of Asthma, American College of ChestTherapy: Evidence-Based Guidelines: Device Selection and Outcomes of Aerosol

http://chestjournal.org/cgi/content/abstract/127/1/335and services can be found online on the World Wide Web at: The online version of this article, along with updated information

). ISSN: 0012-3692. http://www.chestjournal.org/misc/reprints.shtml(of the copyright holder may be reproduced or distributed without the prior written permission Northbrook IL 60062. All rights reserved. No part of this article or PDFby the American College of Chest Physicians, 3300 Dundee Road,

2007Physicians. It has been published monthly since 1935. Copyright CHEST is the official journal of the American College of Chest

Copyright 2005 by American College of Chest Physicians on April 14, 2008 chestjournal.orgDownloaded from

Device Selection and Outcomes ofAerosol Therapy: Evidence-BasedGuidelines*American College of Chest Physicians/AmericanCollege 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 choicesfor clinicians who are selecting a delivery device for aerosol therapy. There are advantages anddisadvantages associated with each device category. Evidence-based guidelines for the selectionof 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 pressurizedmetered-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 severalcommonly 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) wasundertaken using MEDLINE, EmBase, and the Cochrane Library databases. A broad searchstrategy was chosen, combining terms related to aerosol devices or drugs with the diseases ofinterest in various patient groups and clinical settings. Only RCTs in which the same drug wasadministered 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 254outcomes were tabulated. Of the 131 studies that met the eligibility criteria, only 59 (primarilythose that tested 2-agonists) proved to have useable data.Results: None of the pooled metaanalyses showed a significant difference between devices in anyefficacy outcome in any patient group for each of the clinical settings that was investigated. Theadverse effects that were reported were minimal and were related to the increased drug dose thatwas delivered. Each of the delivery devices provided similar outcomes in patients using thecorrect technique for inhalation.Conclusions: Devices used for the delivery of bronchodilators and steroids can be equallyefficacious. When selecting an aerosol delivery device for patients with asthma and COPD, thefollowing should be considered: device/drug availability; clinical setting; patient age and theability to use the selected device correctly; device use with multiple medications; cost andreimbursement; drug administration time; convenience in both outpatient and inpatient settings;and physician and patient preference. (CHEST 2005; 127:335371)

Key words: aerosols; bronchodilators; corticosteroids; drug delivery systems; dry powder inhalers; metaanalysis;metered-dose inhalers; nebulizers

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

special report

www.chestjournal.org CHEST / 127 / 1 / JANUARY, 2005 335


T he use of inhaled aerosol medications for thetreatment of pulmonary diseases, which becamewell-established in the last half of the 20th century,has advantages over oral and parenteral routes ofdelivery. The use of inhaled aerosols allows selectivetreatment of the lungs directly by achieving highdrug concentrations in the airway while reducingsystemic adverse effects by minimizing systemic druglevels.1 Inhaled 2-agonist bronchodilators producea more rapid onset of action than oral delivery. Somedrugs are only active with aerosol delivery (eg, forasthma patients, cromolyn and ciclesonide; for cysticfibrosis patients, dornase alfa). Aerosol drug deliveryis painless and often convenient. For these reasons,the National Asthma Education and Prevention Pro-

gram guidelines2 favor aerosol inhalation over theoral route or parenteral (ie, subcutaneous, IM, or IV)route. Similarly, the National Heart, Lung, andBlood Institute/World Health Organization GlobalInitiative for Chronic Obstructive Lung Diseaserecommended that bronchodilator medications arecentral to symptom management in COPD patientsand that inhaled therapy is preferred.3There are also disadvantages to aerosol drug ther-

apy. One of the most important disadvantages is thatspecific inhalation techniques are necessary for theproper use of each of the available types of inhalerdevice. A less than optimal technique can result indecreased drug delivery and potentially reducedefficacy.4,5 Improper inhaler technique is commonamong patients.68 The proliferation of inhalationdevices that are available for patients has resulted ina confusing number of choices for the health-careprovider and in confusion for both clinicians andpatients trying to use these devices correctly. Severalstudies have demonstrated lack of physician, nurse,and respiratory therapist knowledge of deviceuse.913 Inhaler devices are less convenient than oraldrug administration insofar as the time required fordrug administration may be longer and some patientsmay find the device less portable. This is particularlytrue for conventional compressed-air nebulizers, theoldest of the currently used types of aerosol deliverydevices.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 haveevolved over time. From the 19th century until 1956,compressed-air nebulizers (also called jet nebulizers)were the only devices that were in common clinicaluse for the administration of inhaled aerosol drugs.In 1955, the pressurized metered-dose inhaler(MDI) was developed at Riker Laboratories (now3M Pharmaceuticals; St. Paul, MN).14 Ultrasonicnebulizers, which utilize high-frequency acousticalenergy 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 ofcromolyn sodium. This and subsequent DPIs havebeen breath-actuated, providing drug only whendemanded by patient inhalation, thus avoiding acommon error with MDI use, the improper timing ofinhaler actuation. Breath-actuated MDI devices (eg,the Autohaler; 3M Pharmaceuticals) are also trig-gered by patient inhalation to release the drug ondemand.Investigators developed open-tube spacer devices,

intended for use with MDIs, in the late 1970s.1820The addition of a one-way valve (holding chamber)18or blind reservoir (ie, reverse-flow spacer)21,22 al-

*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 CriticalCare Medicine (Dr. Anderson), University of Arkansas forMedical 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 ofNew 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 forGlaxoSmithKline and Delex Therapeutics, and has receivedresearch 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 consultingrelationship with the following organizations with a potentialfinancial interest in the subject of the manuscript: AstraZen-eca; Aventis; Boehringer Ingelheim; GlaxoSmithKline; Inno-vata Biomed Limited; Medic-Aid Limited; Monaghan MedicalCorporation; and 3M Corporation. Dr. Hess has served as aconsultant for Pari and has received research funding fromCardinal Health. Dr. Anderson has participated in clinicaltrials for GlaxoSmithKline, Boehringer Ingelheim, Astra-Zen-eca, and Novartis. Dr. Dhand has served as a speaker forGlaxoSmithKline and Boehringer Ingelheim, has sponsoredmeetings for GlaxoSmithKline, Boehringer Ingelheim, andSepracor, and has performed research funded by Sepracor Incand Omron. Dr. Rau has no financial interest or involvementin any organization with a direct financial interest in thesubject of this article, but he has served as a consultant forRespironics, as a speaker for Sepracor Pharmaceutical, and asa consultant and speaker for and performed research fundedby Trudell Medical International and Monaghan MedicalCorporation. Dr. Smaldone has served as a consultant toseveral 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:[email protected]).Correspondence to: Myrna B. Dolovich, PEng, Faculty of HealthSciences, McMaster University, 1200 Main St West, HSC 1V18,Hamilton, ON, Canada L8N 3Z5; e-mail: [email protected]

336 Special Report


lowed the aerosol delivered by the MDI to becontained in the spacer for a finite period of time,thereby circumventing the need for the coordinatedactuation of the MDI with inhalation. Other spacer/holding chamber designs followed, and today thereare several devices that vary in design, shape, size,and assembly. The design of MDIs changed littlebetween 1956 and the 1980s. However, the 1987Montreal protocol mandated the phaseout of the useof chlorofluorocarbons (CFCs) as propellants in allMDIs. This resulted in a redesign of MDIs in the1990s, utilizing hydrofluoroalkane propellants.22Some of these formulations produce aerosols withdifferent characteristics that behave differently inpatients than their predecessors.23

Each type of aerosol device has its own advantagesand disadvantages (Table 1). Nebulizer/compressorsystems require minimal patient cooperation andcoordination, but are cumbersome and time-con-suming to use. Matching nebulizers with associatedair compressors is necessary to assure optimal effi-ciency of drug delivery. MDIs are quicker to use andhighly portable, but require the most patient trainingto ensure coordination for proper use. Up to 70% ofpatients fail to use them properly. The impropertiming of MDI actuation with breath initiation is acommon problem.7 DPIs are easier to use thanMDIs because they are breath-actuated, but requirea relatively rapid rate of inhalation in order toprovide the energy necessary for drug aerosolization.

Table 1Advantages and Disadvantages of Each Type of Aerosol-Generating Device or System ClinicallyAvailable*

Type Advantages Disadvantages

Small-volume jet nebulizer Patient coordination not requiredEffective with tidal breathingHigh dose possibleDose modification possibleNo CFC releaseCan be used with supplemental oxygenCan deliver combination therapies ifcompatible

Lack of portabilityPressurized gas source requiredLengthy treatment timeDevice cleaning requiredContamination possibleNot all medication available in solution formDoes not aerosolize suspensions wellDevice preparation requiredPerformance variabilityExpensive when compressor added in

Ultrasonic nebulizer Patient coordination not requiredHigh dose possibleDose modification possibleNo CFC releaseSmall dead volumeQuietNewer designs small and portableFaster delivery than jet nebulizerNo drug loss during exhalation (breath-actuated devices)

ExpensiveNeed for electrical power source (wall outlet or batteries)Contamination possibleNot all medication available in solution formDevice preparation required before treatmentDoes not nebulize suspensions wellPossible drug degradationPotential for airway irritation with some drugs

Pressurized MDI Portable and compactTreatment time is shortNo drug preparation requiredNo contamination of contentsDose-dose reproducibility highSome can be used with breath-actuated mouthpiece

Coordination of breathing and actuation neededDevice actuation requiredHigh pharyngeal depositionUpper limit to unit dose contentRemaining doses difficult to determinePotential for abuseNot all medications availableMany use CFC propellants in United States

Holding chamber, reverse-flow spacer, or spacer

Reduces need for patient coordinationReduces pharyngeal deposition

Inhalation can be more complex for some patientsCan reduce dose available if not used properlyMore expensive than MDI aloneLess portable than MDI aloneIntegral actuator devices may alter aerosol propertiescompared to native actuator

DPI Breath-actuatedLess patient coordination requiredPropellant not requiredSmall and portableShort treatment timeDose counters in most newer designs

Requires moderate to high inspiratory flowSome units are single doseCan result in high pharyngeal depositionNot all medications available

*Modified from Dolovich et al.142



Younger patients and patients in acute distress maynot be able to generate the necessary flow rates.2,24Breath-actuated MDIs are also easier to use, but arecurrently available in the United States for only asingle drug (ie, the 2-agonist pirbuterol). Holdingchambers used with MDIs remove the necessity ofcareful timing between inhalation and MDI actua-tion. However, they are more bulky to carry than theMDI by itself or a DPI. The improper use of holdingchambers (eg, placing multiple puffs in the chamberbefore inhalation or waiting too long between MDIactuation and inhalation) can actually reduce drugdelivery to the lungs.Several factors can guide clinicians on the choice

of a device for a specific patient. One factor is theage of the subject (Table 2).2 Another factor is theavailability of the drug formulation, as not all drugsare available in each type of aerosol delivery device.The clinical setting (eg, outpatient, emergency de-partment (ED), hospitalized inpatient, or intensivecare setting) and the disease being treated (eg,COPD vs asthma) also influence the choice ofaerosol device.Several systematic reviews and metaanalyses re-

lated to the selection of an aerosol delivery devicehave been published. In a metaanalysis, Turner etal25 concluded that bronchodilator delivery by meansof nebulizer or MDI is equivalent in the treatment ofadults with acute airflow obstruction. A systematicreview by Amirav and Newhouse26 compared MDIswith accessory devices to nebulizers in children withacute asthma. While their results showed no differ-ences between the types of delivery systems, it wasconcluded that the MDI with an accessory device (ie,a spacer or holding chamber) should be consideredthe preferred mode of aerosol delivery. A systematicreview27 of the management of acute exacerbationsof 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 ofspacers and holding chambers vs nebulizers for2-agonist treatment of acute asthma, concludedthat an MDI with a holding chamber produces

outcomes that are at least equivalent to thoseachieved with the use of a nebulizer. Several system-atic reviews3032 have compared MDIs to DPIs andhave concluded that there is no evidence that eitherdevice is superior to the other for bronchodilatortherapy.While systematic reviews provide key evidence

summaries, they do not present specific recommen-dations for practice. The reasons for this include afocus on restricted populations and outcomes, andthe lack of a process to ensure recommendationsreflect patients values and preferences.33 However,clinicians require information and guidance concern-ing the best estimates of benefits and risks ofalternatives, and concerning the explicit tradeoffsbetween these benefits and risks, or, in other words,evidence-based guidelines. Therefore, despite theavailability of the above systematic reviews, we be-lieve that evidence-based guidelines are still needed.Consequently, the intent of this project was to assessthe available scientific evidence addressing the ques-tion of whether device selection affects efficacy andthe adverse effects of treatment. Therefore, we setout to systematically review relevant evidence fromrandomized, placebo-controlled clinical trials and toprovide general recommendations based on thetradeoffs that this evidence provides. Our recom-mendations relate to issues that clinicians shouldconsider in selecting a particular therapeutic aerosoldelivery device for their patients in each of severalcommonly encountered clinical settings.

Methodology

We undertook a systematic overview of the perti-nent literature. The databases that were searchedwere MEDLINE, Embase, and the Cochrane Li-brary (Table 3, available on-line only). A broadsearch strategy was chosen to combine terms relatingto aerosol devices or drugs with those relating to thediseases of interest in various patient groups and in anumber of clinical settings (Fig 1). Only randomizedcontrolled trials (RCTs) in human subjects publishedin English were selected. The search identified aninitial set of approximately 2,100 publications span-ning the years 1972 to 2000. Two reviewers indepen-dently assessed each abstract of these publications todetermine whether they met the eligibility criteria(ie, RCT addressing the relevant population, inter-vention, and outcome). This review identified 394RCTs assessing inhaled corticosteroid, 2-agonist,and anticholinergic agents that were delivered byMDI, MDI with spacer/holding chamber, nebulizer,or DPI. These 394 studies were coded (for setting,population, disease, and device) to provide a second

Table 2General Age Requirements for Correct Use ofAerosol Delivery Device Types*

Aerosol Delivery Method Minimum Age

Small-volume nebulizer 2 yrMDI 5 yrMDI with chamber 4 yrMDI with chamber and mask 4 yrMDI with endotracheal tube NeonateBreath-actuated MDI 5 yrDPI 5 yr

*Based on National Asthma Education and Prevention Program.2

338 Special Report


screening to identify studies in which the same drugwas administered with different devices. Studieswere excluded if they only compared devices of thesame type (eg, DPI with DPI) or only compared oralor parenteral therapy with the aerosol therapy. Datawere 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 similarexpressions of the same measurement, specified ahierarchy of outcomes within this taxonomy. Of the131 studies, only 59 proved to have useable data

(Table 6). These studies primarily tested 2-agonists.Few studies of corticosteroids met our eligibilitycriteria.Separate metaanalyses were carried out for each

specific clinical setting being considered. Theweighted standardized difference between treat-ment groups in the outcome of interest was calcu-lated using the mean scores and their SDs. Wecombined results across end points of FEV1, peakflow, and specific airway conductance (sGaw), andcalculated the effect size in SD units. For studiesthat made measurements at multiple time points,the last time point was used for analysis. Forstudies with multiple doses, analyses using the firstdose and the last dose were performed. All out-comes reported are in SD units. In studies thatprovided data for more than one of these out-comes, we used the outcome that was highest inthe hierarchy. To assess whether the magnitude ofthe heterogeneity of differences in the apparenttreatment effect across studies was greater thanone might expect by chance, we conducted a testbased on the 2 distribution with N 1 degree offreedom, where N is the number of studies. Noimportant effects were seen in any of the groupanalyses, and there was very little heterogeneity inany of the data. In general, our statistical methodsrelied on the approaches described by Fleiss34 andby Hedges and Olkin.35We found that the studies were heterogeneous in

purpose, design, and patient selection, and deter-mined that these descriptors would influence theinterpretation and relevance of the studies for clini-cal use by patients. Therefore, we grouped thestudies that were reviewed into three general types

Figure 1. Studies selected included those overlapping (illus-trated by shaded area) devices or drugs, disease setting, andRCTs.

Table 5Ranked Taxonomy of Outcomes*

Outcome Ranking

FEV1 FEV1; FEV1 % predicted; FEV1 L/% predicted; FEV1/FVC ratio; FEV1 mL; FEV1 % change from initial;FEV1 % predicted % change from initial

PF PF L/min; PEF am pre, PEF pm pre, PEF am post, PEF pm post; we decided there was little tochoose between the additional measures, though in general pre should be chosen over post and am shouldbe chosen over pm

Mechanics sGAW; sGAW s/kPa; the rest were arbitrarySymptoms/physical findings 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 measuresFVC FVC; FVC mL; FVC % predicted; FVC L/% predicted; the following were arbitrary: IVC should be the last

choiceFEF2575% FEV2575 (112) FEF2575; FEF2575 % predicted; the rest were arbitraryBlood gas Sao2; Po2; Pco2; pHAdrenergic use 2-adrenergic use, total No. of doses, BD puffsTechnique/preference Preference for technique, device rating; the following were arbitrary: design should be second to last choice,

taste should be the last choiceHeart rate, BP, ECG Heart rate; pulse rate; heart rate increase

*PF peak flow; PEF peak expiratory flow; IVC inspiratory vital capacity; FEF2575% forced expiratory flow, midexpiratory phase,BD bronchodilator.



(types 1, 2a, and 2b) based on the intended purposeand specific study design used.

Type 1 Trials: Device Performance UnderConditions of Actual Clinical Use

These trials were intended to compare the effec-tiveness of the devices and drug being studied in asetting of real-world clinical use with the measuredoutcomes relevant to the accepted indication for thedrug in this setting. Studies that compared the effectof a 2-agonist agent delivered by nebulizer, DPI,and/or MDI in patients presenting to the ED withacute asthma are an example of this type of study.These studies typically evaluate outcomes such asimprovement in lung function and oxygenation orhospital admission rate. Studies that compare theeffect of inhaled corticosteroids delivered by differ-ent devices over a period of weeks, and assess dailyasthma symptoms, 2-agonist use, and daily peakflow measurement are other examples of suchstudies.

Type 2 Trials: Device Performance in the ClinicalLaboratory Setting

These studies compare drug delivery to the lungsand the clinical response to drugs administered bydifferent devices under carefully controlled clinicallaboratory conditions. These studies were typicallyperformed to satisfy regulatory requirements duringthe process of drug development and registration.Participating patients are usually carefully trained inand monitored for the proper use of the devices.These studies do not directly evaluate the perfor-mance of the devices in settings and conditions inwhich patients actually use them as part of themanagement of their asthma or COPD (eg, a patientwho 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 measureincreases in lung function in response to the 2-agonist in patients who have developed a mild-to-moderate degree of bronchospasm after having theirusual asthma medication withheld. A few measurethe inhibition of bronchial provocation with exercisecompounds (eg, methacholine or histamine). Type 2studies can be divided into two subtypes based onthe kind of analysis performed in the study.

Type 2a Trials: Analyzing Differences in ResponseVariables: These studies typically compare meanincreases in lung function values (eg, FEV1) pro-duced by the different devices. These studies aretermed response axis comparisons by the US Foodand Drug Administration and are now widely recog-nized to be relatively insensitive to true differencesin drug delivery by different devices.36 Typically, thedoses used are near the top of the 2-agonist dose-response curve that patients exhibit in this setting. Asa result, the studies are commonly unable to distin-guish differences in response to either a differentdose via the same device or to delivery by differentdevices.

Type 2b Trials: Estimating Differences in ClinicalPotency: These studies establish dose-responsecurves for each of the devices being compared andthen use differences in the position of these curves toestimate differences in the clinical potency of thedevices (known as the relative potency or potencyratio). The results of this analysis yield statementssuch as 1 actuation (or microgram of drug) deliv-ered from device A is equivalent to X number ofactuations (or micrograms) delivered from deviceB. The analysis also calculates a confidence intervalfor the estimate of the relative potency as an indica-tor of how reliable the estimate is. These studies are

Table 6Reasons Trials Were Not Included in Analysis

ComparisonStudies,No.

Reasons for Exclusion

Total forAnalysis,

No.NotRCT

NotComparisonof Interest

NotIndependentSubgroups

Only UsableBaselineData

NoUseableData

NoComparableTrials orOutcomes

Overall 131 3 20 2 7 30 11 59MDI vs DPI 45 1 0 0 2 12 2 28Nebulizer vs MDI spacer 32 0 0 1 2 6 4 19MDI vs MDI spacer 17 0 1 0 3 7 2 5DPI vs MDI spacer 14 2 0 0 0 4 4 4DPI vs nebulizer 3 0 0 0 0 0 3 0MDI vs nebulizer 5 0 0 0 0 1 4 0Intermittent vs continuous nebulizer 7 0 0 1 0 2 0 4

340 Special Report


termed dose-scale comparisons36 and are recog-nized as being the most reliable way of identifyingtrue difference in drug delivery to the site of actionin the lung.Members of the Writing Committee assumed

responsibility for drafting individual sections of thefinal document, including the recommendations. Tograde the strength of the recommendations, we useda system adopted by the Health and Science PolicyCommittee of the American College of Chest Phy-sicians (Table 7). The draft document was reviewedby 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 inthe Hospital ED: Nineteen RCTs that comparedaerosol delivery devices in the ED met the criteriafor inclusion in the analysis. All used a parallel designand assessed the response to one of three 2-agonist

bronchodilators (ie, albuterol, metaproterenol, orterbutaline). No studies were available that com-pared nebulizers to MDIs alone in patients withacute asthma presenting to the ED. The majority ofthese studies compared delivery by nebulizer to thatby an MDI with a spacer/holding chamber. All weretype 1 studies that enrolled patients presenting to theED with acute asthma symptoms. Only 3 of the 19studies included in the analysis studied delivery byDPI in the ED setting. None of the studies specifi-cally stated that they had screened patients for theirability to use the device correctly. The studies alsoomitted a detailed discussion of the device techniquethat was used to inhale the medications. Most ofthese studies measured acute physiologic responsesto treatment, and a smaller number measured effectson asthma sign/symptom scores. Few studies offerother clinically important outcome measures such ashospital admission rate, time in the ED, and read-missions to the ED. The cost of care and the fractionof patients who cannot use the device correctly werenot reported in any of the studies. Eight stud-

Table 7Scheme 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 ortherapeutic procedure:

A Strong recommendationB Moderate recommendationC Weak recommendationD Negative recommendationI No recommendation possible (inconclusive)E/A Strong recommendation based on expert opinion onlyE/B Moderate recommendation based on expert opinion onlyE/C Weak recommendation based on expert opinion onlyE/D Negative recommendation based on expert opinion only

Quality of the evidenceGood Evidence is based on good RCTs or metaanalysesFair Evidence is based on other controlled trials or RCTs with minor flawsLow Evidence is based on nonrandomized, case-control, or other observational studiesExpert opinion 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 benefitThese levels of net benefit to the patient (adjusted for risk) are based on clinical assessment of the test or procedure:SubstantialIntermediateSmall/weakNoneConflictingNegative

Relationship of strength of the recommendations scale to quality of evidence and net benefits

Quality of Evidence

Net Benefit

Substantial Intermediate Small/Weak None Conflicting Negative

Good A A B D I DFair A B C D I DLow B C C I I DExpert opinion E/A E/B E/C I I E/D



ies3744 randomized pediatric patients to receive a2-agonist agent by nebulizer or MDI with spacer/holding chamber (ie, Aerocell Lactantes [Grunewald-Danes; Chile], AeroChamber [Trudell Medical; Lon-don, ON, Canada], and Volumatic [Glaxo Wellcome;London, UK]) [Table 8]. Collectively, these studiesenrolled patients with ages ranging from 1 to 17years. Most investigators reported no significant differ-ence between these two techniques for pulmonary

function measures (ie, peak flow and FEV1) or symp-tom scores. Metaanalyses of symptom scores and pul-monary function results showed no differences be-tween the nebulizer and the MDI with a spacer/holding chamber (Fig 2, 3). One study40 reportedgreater patient preference for the MDI with a spacer/holding chamber, and another study38 reported shortertreatment times with the use of an MDI and a spacer/holding chamber. None of the studies included in the

Table 8Short-term Nebulizer vs MDI Spacer/Holding Chamber Studies Using 2-Agonists for Pediatric Patientsin the Acute Care Setting*

Study/Year/Study Type

Total Patients/Patients per Group,

No.Lost to Follow-up,

No. (Time) Age Range Drug/Device (Dose)

Pediatric ERPloin et al40/2000/type 1 64/(32/31) 4 MDI: 1251 mo (24.8 mo) Albuterol/MDI Babyhaler spacer

(0.05 mg/kg)NEB: 1156 mo (25.5 mo) Nebulizer (0.15 mg/kg)

Rubilar et al42/2000/type 1 132 9 MDI: 7.2 4.7 mo Albuterol/MDI Aerocell spacer(0.2 mg q10 min)

NEB: 8.5 5.4 mo Hudson Updraft II nebulizer(0.25 mg/kg q13 min)

Schuh et al43/1999/type 1 90/(30/30/30) 16 (517 yr) 517 yr (9.1) Albuterol/MDI AeroChamberspacer:GpI ( 25 kg 0.6 mg;2534 kg 0.8 mg; 34 kg 1 mg:GpII 0.2 mg)

WhisperJet Nebulizer GpIII(0.15 mg/kg to max of 5 g)

Robertson et al41/1998/type 1

58/(155) (412 yr) 412 yrMDI: 6.9 2.4 yr

Albuterol/ 25 kg: MDIVolumatic spacer (0.6 mg)

NEB: 7.0 2.5 yr NEB (2.5 mg) 25 kg: MDIVolumatic spacer (1.2 mg) NEB(5.0 mg)

Williams et al44/1996/type 1 60 0 (6 yr) 6 yr Albuterol/MDI AeroChamber andAeroChamber: 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

Lin and Hsieh39/1995/type 1 117 6 MDI: 516 yr (8.1 yr) Terbutaline/MDI AeroChamberspacer (0.75 mg)

NEB: 515 yr (8.4 yr) 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 ICUBatra et al37/1997/type 1 60 0 112 yr Albuterol/MDIM/S CiPLA

112 yr MDI: 44.1 25.8 mo spacer (0.2 mg)NEB: 51.2 27.1 mo NEB (0.15 mg/kg)

*NS not significant; NEB nebulizer; % pred % predicted. See Table 5 for abbreviations not used in the text.WhisperJet nebulizer, Intec Medical, Ingelwood, CO; Hudson UpDraft nebulizer II, model 1730, Hudson Oxygen Sales, Temecula, CA;Babyhaler spacer, GlaxoSmithKline France, Marly le Roi, France; ACE MDI spacer, DHD Healthcare, Wampsville, NY: M/S CiPLA spacer,M/S. CIPLA Ltd., Salem, Tamilnadu, India.Median value in parentheses.Mean SD values.Weight 25 g.

342 Special Report


analysis evaluated DPI use in pediatric patients pre-senting to the ED.In adult patients reporting to the ED with asthma

symptoms (Table 9), six studies4550 compared 2-agonist delivery by nebulizer to that by an MDI witha spacer/holding chamber. No study reported asignificant difference in pulmonary function re-sponse to the two methods of delivery (Fig 3). Twostudies47,48 addressed other important outcomes andreported no significant differences between devicesfor time in the ED, hospital admission rate, andfrequency of ED discharge at 6 h. Similar findingswere reported in studies5153 including both pediat-ric (ie, adolescent) and adult patients in ED settings.The three studies47,54,55 evaluating the use of a DPI

(eg, Rotahaler [GlaxoSmithKline; Ware, UK] andTurbuhaler [AstraZeneca; Lund, Sweden]) withadult patients in this setting reported no significantdifferences between DPI and the other two deliverymethods for pulmonary function response and forother outcomes such as hours to hospital discharge(Table 10). Similar findings were noted for pediatricpatients presenting to the ED in a study that was notincluded in this analysis.56One study57 evaluated aerosol delivery devices in

an ambulance setting. No significant differenceswere reported in pulmonary function response to anebulizer, an MDI used alone, or an MDI with aspacer/holding chamber, but the effects on respira-tory rate and duration of treatment were significantly

PulmonaryFunction

Vital Signsand

Symptoms Side Effects Concomitant Care Other Measures

Pulmonary index score(p 09.27)

Preference for MDIspacer NEB(p 0.05)

Respiratory rate nebulizerwith MDI spacer (p 0.01)clinical score (NS)

FEV1 % pred (NS) Dyspnea score (NS) Heart rate NEBwith MDI spacer(p 0.005)

Accessory musclescore (NS)

PF NEB MDI spacer(p 0.005) (all patients)

Asthma score better after NEBthan MDI spacer (p 0.001)(all patients)

PF % pred (NS) Respiratory rate (NS)

FEV1 % pred Clinical severity score (NS) Pulse rate (NS) Sao2MDI spacer NEB

(p 0.039); PF % predMDI spacerwith NEB

MDI spacer Nebulizer(p 0.002) FEF2575% %pred (NS)

(p 0.003)

PF % pred (NS) Dyspnea score (NS) Vomiting in ED Minutes to meanSeverity score improvement MDI spacer treatment time MDI(NS) NEB (p 0.05) heart spacer NEB

rate increase MDI (p 0.001)spacer NEB No. of treatments NS(p 0.001) Admission rate NS

Respiratory rate (NS) Heart rate (NS) Sao2 (NS)Dyspnea (NS) Po2 (NS)

Pco2 (NS)



better for the use of the MDI with holding chamberthan for the other two methods.Adverse effects appeared to be more common with

nebulizer use. Heart rate change tended to be greaterin patients using a nebulizer, but the effect acrossstudies was significant only when pediatric and adultstudies were analyzed together (Fig 4). These differ-ences in heart rate between devices tended to be smallin magnitude. One study38 found vomiting to be morecommon with nebulizer use than with use of an MDIwith a spacer/holding chamber, which likely was due tothe larger dose given by nebulizer in these subjects.

Summary of RCT Results

The delivery of 2-agonists in the ED setting bynebulizers or MDIs with holding chambers (eg,AeroChamber, Volumatic, or InspirEase [KeyPharmaceuticals; Kenilworth, NJ]) is equally ef-fective for improving pulmonary function andreducing symptoms of acute asthma in both adultand pediatric patients (quality of evidence: good).

The delivery of 2-agonists in the ED setting by DPI(eg, Rotahaler or Turbuhaler) has been inadequatelystudied, but trials in adults have suggested DPIs maybe as effective as nebulizers or MDIs with spacer/holding chambers (quality of evidence: low).

Nebulizer use in the ED setting is associated withgreater increases in heart rate than with the use ofan MDI with spacer/holding chamber, suggestingthat a larger systemically absorbed dose is admin-istered by nebulizers (quality of evidence: good).

Recommendations1. Both the nebulizer and MDI with spacer/

holding chamber are appropriate for the deliv-ery of short-acting 2-agonists in the ED. Qual-ity of evidence: good; net benefit: substantial;strength of recommendation: A.

2. Because data for DPIs are limited, and highquality data for standard MDIs (without spacer/holding chamber) and breath-actuated MDIs areunavailable, we are unable to recommend the useof these devices in the ED until more informationis available. Quality of evidence: low; net benefit:none; strength of recommendation: I.

3. Many factors would lead the clinician to appro-priately select a particular type of aerosol de-livery device in this setting. These factors in-clude the patients ability to use the devicecorrectly, the preferences of the patient for thedevice, the unavailability of an appropriatedrug/device combination, the compatibility be-tween the drug and delivery device, the lack oftime or skills to properly instruct the patient inthe use of the device or to monitor the appro-priate use, and the cost of therapy. Quality ofevidence: low; net benefit: substantial; strengthof recommendation: B.

Aerosol Delivery of Short-Acting 2-Agonists in theInpatient Hospital Setting

Considering the common use of aerosolized drugsin hospitalized patients, there are surprisingly few

Figure 2. Weighted standardized mean difference (WMD) for symptom scores in ED/ICU trials using2-agonists comparing nebulizer (N) vs MDI spacer/holding chamber (M S/HC).

344 Special Report


studies that have compared aerosol delivery devicesin this setting (Table 11).53,5863 Six type 1 stud-ies53,5861,63 included in the analysis compared nebu-lizers with MDIs having spacer/holding chambers inadult and pediatric patients. These studies reportedno significant differences in pulmonary functionbetween nebulizers and MDIs with spacer/holdingchambers (Fig 5). One study62 compared MDI usedalone with DPI use and also found no significantdifference in peak expiratory flow rate (PEFR).However, as the deposition efficiency of the DPItested was approximately half that of the MDI

tested, the authors elected to compare DPI dosesthat were twice that for the MDI, with the intent ofproducing equal responses. Other outcome variablessuch as length of hospital stay were similar for thenebulizer and MDI with a spacer/holding chamber.Reports of the cost of care are conflicting, withoutclear evidence of one device resulting in a greatercost than another. There is a paucity of data regard-ing the ability of patients to use these devicescorrectly in this setting. For 2-agonists, the impactof the differences in the time required to administerthe therapy on patient responses was not analyzed.

Figure 3. Top: weighted standardized mean difference for peak flow in ED/ICU trials using2-agonists comparing nebulizer vs MDI spacer/holding chamber. Bottom: weighted standardizedmean difference for FEV1 in ED/ICU trials using 2-agonists comparing nebulizer vs MDI spacer/holding chamber. See the legend of Figure 2 for abbreviations not used in the text.



The inpatient setting presents a unique opportunityfor health-care providers to instruct the patient onthe proper use of each device, but the benefit of suchan approach has not been assessed in randomizedtrials.


In the inpatient setting, the available evidencesuggests that there is no difference in the pulmo-nary function response between using a nebulizer

and using an MDI with a spacer/holding chamberfor administering short-acting 2-agonist therapy(quality of evidence: good).

Recommendations

1. Both nebulizers and MDIs with spacer/holdingchambers are appropriate for use in the inpa-tient setting. Quality of evidence: good; netbenefit: substantial; strength of recommenda-tion: A.

Table 9Short-term Nebulizer vs MDI Spacer/Holding Chamber Studies Using 2-Agonists for Adult Patients inthe Acute Care Setting*

Study/Year/Study TypeTotal Patients,

No.

Lost toFollow-Up,

No. Age Range Drug/Device (Dose)

Adult ED studiesColacone et al45/1993/type 1 85 5 MDI: 1881 yr

(41 yr)Albuterol/MDI AeroChamber spacer(0.4 mg q30 min)

NEB: 1883 yr(43 yr)

NEB (2.5 mg q30 min, max 4 doses)

Idris et al46/1993/type 1 35 0 MDI: 1645 yr(25 yr)

Albuterol/MDI InspirEase spacer(0.36 mg q30 min)

NEB: 1045 yr(23 yr)

NEB (2.5 mg q30 min, max 6 doses)

Rodrigo and Rodrigo48/1993/type 1 97 0 MDI: 1850 yr(32.4 12.1 yr)

Albuterol/MDI AeroChamber(0.4 mg q10 min, max 5.61 mg)

NEB: 31.9 12.0 yr) NEB (1.5 mg q15 min, max 11.8 mg)

Salzman et al49/1989/type 1 50 6 MDI: 32.5 12.5 yr Metaproterenol/MDI AeroChamber(1 500 g q5 min, max 1.95 mg)

NEB: 28.9 10.3 yr NEB (15 mg)Raimondi et al47/1997/type 1 18 0 Albuterol/MDI AeroChamber

spacer (0.4 mg)NEB (5.0 mg)

Adult ED/ICUTurner et al50/1988/type 1 COPD group, 22; 0 44 yr Metaproterenol/MDI InspirEase

asthma group, 53 COPD group spacer (1.95 mg)MDI: 55 4 yr: NEB (15 mg)NEB: 57 3 yr

Asthma group:MDI: 38 3 yrNEB: 39 3 yr

Mandelberg et al52/1997/type 1 50 9 MDI: 65.8 13.64 yr Albuterol/MDI Volumatic (0.2 mgalbuterol sulfate)

NEB: 63.3 13 yr NEB (2.5 mg)

Levitt et al51/1995/type 1 40 0 MDI: 18 yr (60.719 yr)

Albuterol/MDI AeroChamber(0.4 mg to max 2.4 mg q60 min for180 min; mean total dose, 23.753.2 mg)

NEB: 41.7 21 yr NEB (15 mg/h for up to 3 hr; meantotal dose, 28.1 7.3 mg)

Summer et al53/1989/type 1 36 4 MDI: 63.19 yr Terbutaline/MDI Brethancer spacer(0.5 mg metaproterenol)

NEB: 62.69 yr NEB (15 mg)

*See Tables 5 and 8 for abbreviations not used in the text.Median values in parentheses.Mean SD values.Manufactured by the Asthma and Respiration Foundation of New Zealand, Wellington, NZ.

346 Special Report


2. Because the data for DPIs, standard MDIs with-out spacer/holding chambers, and breath-actu-atedMDIs have been inadequately studied in thissetting, we are unable to recommend the use ofthese devices in patients requiring hospitalizationfor asthma or COPD until more information isavailable. Quality of evidence: low; net benefit:none; strength of recommendation: I.

3. Many factors would lead the clinician to appro-priately select a particular type of aerosol deliverydevice in this setting. These include the patientsinability to use the device correctly, the prefer-ences of the patient for the device, the unavail-

ability of the drug/device combination, the com-patibility between the drug and the deliverydevice, the lack of time or skills to properlyinstruct the patient in the use of the device or inmonitoring the appropriate use, and the cost oftherapy. Quality of evidence: low; net benefit:substantial; strength of recommendation: B.

Intermittent vs Continuous Nebulizer Delivery of2-Agonists

Continuous aerosol bronchodilator therapy isused occasionally in patients with severe broncho-

Pulmonary Function

Vital Signsand

Symptoms Side Effects Concomitant Care

FEV1 (NS) Dyspnea score (NS) Heart rate 20 beats/min (NS)

FEV1 % pred (NS) Respiratory rate (NS) Heart rate (NS)PF % pred (NS)FVC % pred (NS)

FEV1 (NS) Tremor (NS) 2-adrenergic use (NS)PF (NS) Time in ED (NS)FVC (NS) Hospital admission rate (NS)

FEV1 (NS) Respiratory rate (NS) Pulse rate (NS)FVC (NS)

FEV1 (NS) Hospital discharge at 6 h (NS)

FEV1 (NS) Respiratory rate (NS) Heart rateBorg scale (NS) MDI spacer without NEB

(p 0.05)

FEV1 (NS) Respiratory improvementscore-physician (NS)

Respiratory improvementscore-patient (NS)

PF MDI holding chamber Nebulizer (p 0.005)

Dyspnea score (NS) Tremor (NS); heart rate (NS) Hospital admission rate (NS)

FEV1 (NS) RCP time (NS)PF (NS) Length of stay (NS)FVC (NS) Patient charge (NS)



spasm in the ED or ICU. Its use is limited to themost severe exacerbations of asthma. One system-atic review64 supports the equivalence of continu-ous and intermittent albuterol nebulization in thetreatment of acute adult asthma. Continuous vsintermittent administration of 2-agonists wascompared in six randomized type 1 studies enroll-ing either adult patients or pediatric patients inthe ED and ICUs (Table 12).6570 These six studiesreported no differences in pulmonary functionchanges comparing these administration ap-proaches (Fig 6). Changes in asthma score anddyspnea are also similar for both modalities.65,70Two studies have reported greater staff (eg, respi-ratory therapy) time requirements for intermittentnebulization compared to continuous nebuliza-tion.65,70 One study69 reported a lower hospitaladmission rate with the use of continuous nebuli-zation in an ED setting, but another study65reported no difference in admission rates. De-creased hospital length of stay was associated withthe use of continuous nebulization in one studyenrolling pediatric patients.70 Two studies67,69 re-ported similar heart rate responses with continu-ous and intermittent nebulization.

Summary of RCT Results Pulmonary function and asthma symptom scoresshow similar benefits for continuous and intermit-tent nebulization of short-acting 2-agonists (qual-ity of evidence: good).

The time requirements for staff administrationand maintenance of the therapy are less for con-tinuous nebulization than for intermittent nebuli-zation (quality of evidence: good).

Adverse effects of 2-agonists are similar for con-tinuous and intermittent nebulization of 2-ago-nists (quality of evidence: good).

The effects of continuous vs intermittent nebuli-zation of 2-agonists on hospital admission ratefrom the ED, hospital length of stay, and cost ofcare have not been adequately studied (quality ofevidence: low).

Recommendation1. Frequent intermittent nebulization and contin-

uous nebulization are both appropriate alterna-tives in severely dyspneic patients in the ED orICU. Quality of evidence: good; net benefit:substantial; strength of recommendation: A.

Aerosolized 2-Agonists in Patients ReceivingMechanical Ventilation

Patients in the ICU, particularly those receivingmechanical ventilation, present unique challenges

Tab

le10

Sh

ort-term

DPIStudies

Using2-Agonistsin

theAcute

CareSetting*

Stud

y/Ye

ar/

Stud

yType

Total

Patie

nts,

No.

Lostto

Follow-up

Age

Range,y

rDrug/Device(D

ose)

Pulm

onary

Fun

ction

Vita

lSigns

andSymptom

sSide

Effects

Con

comita

ntCare

Nanaet

al54/1998/type

186

0MDI:1647(37)

Albuterol/M

DI

FEV1(N

S)Symptom

score(N

S)Volum

atic

(1mg)

PIF(N

S)DPI:1

649

(40)

DPI-Turbu

haler(2

mg)

Raimon

diet

al47/1997/type

118

0MDI:33.7

5.6

Albuterol/M

DI

AeroC

hambe

r(0.4

mg)

FEV1(N

S)Hou

rsto

hospita

ldischarge(N

S)DPI:4

2.8

15

DPI-R

otoh

aler

(0.4

mg)

Ton

nesenet

al55/1994/type

168

650

Terbu

talin

e/MDI

FEV1(N

S)Respiratory

rate

(NS)

Heart

rate

(NS)

Neb

uhaler

(2.5

mg)

PF(N

S)Systolic

BP(N

S)DPI-Turbu

haler(2.5

mg)

Raimon

diet

al47/1997/type

118

0DPI:4

2.8

16

Albuterol/D

PI-R

otoh

aler

(0.4

mg)

FEV1(N

S)Hou

rsto

hospita

ldischarge(N

S)NEB:3

9.1

6.5

NEB(5

mg)

*PIF

peak

inspiratoryflo

w.S

eeTables5and8forabbreviatio

nsused

inthetext.

Med

ianvalue.

Mean

SDvalues.

348 Special Report


for aerosol delivery. Both MDIs and nebulizerscan be adapted for use in ventilator circuits, theformer requiring a spacer or connector with anintegral actuator. Because of compatibility issues,it is currently not possible to use DPIs andbreath-actuated MDIs to deliver inhalant medica-tions via a ventilator circuit. Only three RCTs(Table 13) comparing these devices in mechani-cally ventilated patients were available for analysis.All were type I studies. These compared theeffects of short-acting 2-agonists on pulmonarymechanics in infants with bronchiolitis, and inadults with asthma and COPD.7173 None of thesetrials compared other outcomes such as the dura-tion of mechanical ventilation, the length of stay inthe ICU, the length of hospital stay, the costof treatment, clinician preference, the relief ofdyspnea, or the occurrence of pulmonary compli-cations.Albuterol was the drug employed in each of the

three RCTs included in the analysis. The out-comes evaluated included changes in respiratorysystem compliance, airway resistance, and expira-tory flows. In two of the studies,71,72 there were nodifferences in the response to albuterol betweenMDIs and nebulizers. In the other study,73 theadministration of up to 10 mg albuterol by MDIhad no effect, whereas, the administration of 2.5 to7.5 mg albuterol with a nebulizer produced signif-icant reductions in airway resistance. In this study,however, the adapter employed to connect theMDI to the ventilator circuit had a very low drug

delivery efficiency.73 This underscores the need togive careful attention to the specific details of thesystem used to deliver aerosolized drugs to intu-bated, mechanically ventilated patients.74Observational trials75 have reported that the

administration of albuterol with an MDI andchamber spacer produced responses that werecomparable to those obtained with albuterol ad-ministered by nebulizer. In one randomized cross-over study (published following the literaturesearch for these evidence-based guidelines), Du-arte et al76 reported that the airway response toalbuterol via MDI with spacer and nebulizer weresimilar in duration and magnitude for mechani-cally ventilated patients with COPD. Although it iscommonly accepted that an endotracheal tube mayaffect aerosol deposition patterns by providing afiner aerosol at the tube exit, the presence ofairway disease may overwhelm this advantage.77There are no deposition/dose-response compara-tive studies in patients receiving mechanical ven-tilation, and, thus, no clear recommendations forthe dosing of -agonists in this setting can bemade.The adverse effects of 2-agonist administration

during mechanical ventilation were determined intwo studies. In one,72 no adverse effects werefound after the administration of 270 g albuterolfrom an MDI or 2.5 mg administered with anebulizer. In the study by Manthous et al,73premature beats and sinus tachycardia or tremorswere noted after the administration of 7.5 mg

Figure 4. Weighted standardized mean difference for heart rate in ED/ICU trials using 2-agonistscomparing nebulizer vs MDI spacer/holding chamber. See the legend of Figure 2 for abbreviationsnot used in the text.



albuterol with a nebulizer. All of the patients whoreceived a cumulative dose of 15 mg albuterol witha nebulizer developed tachycardia and prematureheart beats. No changes in BP or other side effectshave been described from albuterol administrationin this group of patients.Although evaluated only in non-RCT studies, several

factors are known to have clinically important effects onaerosol delivery during mechanical ventilation. Theseinclude the position at which the nebulizer is placed inthe circuit,78,79 the nebulizer brand and its fill volume,80the humidification of the inspired gas,80 the treatmenttime,80 the inspiratory time (duty cycle),79,80 intermit-tent vs continuous nebulization,79 the ventilatorbrand,81 and the density of the carrier gas.82 It has beenreported that the response to albuterol administered byMDI to mechanically ventilated patients with COPDwas not affected by inspiratory flow pattern, pressure-

controlled ventilation vs volume-controlled ventila-tion,83 the level of inspiratory flow,84 the delivered tidalvolume,85 or the addition of an end-inspiratory pause.86When an MDI is used during mechanical ventilation,the use of a spacer device has been shown to increasedeposition compared to other in-line actuators.87Noninvasive positive-pressure ventilation (NPPV)

is increasingly used in the care of patients with acuteexacerbations of COPD. No RCT has compared thedelivery of aerosol medications by nebulizer or MDIin this setting. There have, however, been reports ofthe use of nebulizers88 or MDIs89 in conjunctionwith the use of NPPV.


In children and adults receiving mechanical ven-tilation, the outcomes of 2-agonist administration

Table 11Aerosol Delivery in Hospitalized Patients*

Study/Year/Study Type Setting

TotalPatients,

No.

Lost toFollow-up,


Short-term nebulizer vs MDI spacer/holding chamberPediatricFuglsang and Pedersen60/

1986/type 1Pediatric, inpatient 21 714 yr Terbutaline/NEB: Pari Inhaler

Boy (0.10 mg/kg)MDI Nebuhaler (0.10 mg/kg)

Parkin et al58/1995/type 1 Pediatric, inpatient 60 9 15 yr (35 mo) Albuterol ipratroprium/MDI AeroChamber (0.5 mg albuterol0.04 mg ipratroprium)

NEB (0.15 mg/kg albuterol0.125 mg ipratroprium)

AdultBerry et al61/1989/type 1 Adult COPD, inpatient 20 0 6091 yr (67.9 Albuterol/MDI InspirEase (0.36 mg)

7.1 yr) NEB (2.5 mg)

Pediatric/adultSummer et al53/1989/type 1 Adult/Pediatric, inpatient 36 4 MDI: 62.69 yr Terbutaline/MDI Brethancer

spacer 0.5 mg metaproterenolNEB: 63.13 yr Nebulizer: 15 mg

Jasper et al59/1987/type 1 Adult/Pediatric, inpatient 38 4 MDI: 52.7 21.4 yr

Metaproterenol/MDI InspirEase (1.3 mg)

NEB: 49.33 9.1 yr

NEB (15 mg)

Long-term nebulizer vs MDI spacer/holding chamberDewar et al63/1999/type 1 Pediatric, inpatient 78 16 3 yr Salbutamol/MDI Volumatic

NEB: 8.04 yr (0.1 mg)MDI: 6.9 yr NEB (5 mg)

Long-term MDI vs DPIRuggins et al62/1993/type 1 Pediatric, inpatient 51 2 413 yr (9 yr) Albuterol/MDI (Autohaler) (0.2 mg)

DPI-Rotohaler (0.4 mg)

*Sao2 arterial oxygen saturation. See Table 8 for abbreviations not used in the text.Manufactured by Pari GmbH, Starnberg, Germany.Median values.Mean SD values.

350 Special Report


using an MDI with or without a spacer/holdingchamber are no different than those observedfollowing 2-agonist administration with a nebu-lizer (quality of evidence: fair).

High doses of 2-agonists administered with anebulizer are associated with a higher incidence oftachycardia and premature heart beats in mechan-ically ventilated patients, but there is no differencein adverse effects observed after the administra-tion of albuterol with an MDI compared to thoseobserved after the administration of the drug witha nebulizer (quality of evidence: fair).

There is insufficient evidence to guide the choiceof MDI or nebulizer for patients receiving NPPV(quality of evidence: low).

Recommendations

1. Both nebulizers and MDIs can be used todeliver 2-agonists to mechanically ventilatedpatients. Quality of evidence: fair; net benefit:substantial; strength of recommendation: A.

2. Careful attention to details of the techniqueemployed for administering drugs by MDI ornebulizer to mechanically ventilated patients iscritical, since multiple technical factors mayhave clinically important effects on the effi-ciency of aerosol delivery. Quality of evidence:low; net benefit: substantial; strength of recom-mendation: B.

Device Selection in the OutpatientSetting

Short-Acting 2-Agonists for Asthma in theOutpatient Setting

Twenty-eight RCTs compared devices for the deliv-ery of 2-agonists to outpatients. Most trials used acrossover design, and all were of type 2a or 2b. In otherwords, study outcomes assessed the comparability ofthe effect in the clinical laboratory setting in patientswho had been carefully trained in and screened forproper use of the device. Consequently, they did not

Pulmonary Function

VitalSigns/

Symptoms Side Effects Concomitant CareOther

Measures

FEV1 MDI HC NEB(p 0.05)

Heart rate NS

Asthma score (NS) Hours to Q4h (NS)Symptoms at 7 d (NS) Total number of doses (NS)Symptoms at 14 d (NS) Hours to discharge (NS)

FEV1 (NS) Borg scale (NS)FVCMDI spacer NEB

(p 0.01)

FEV1 (NS) RCP time (NS)PF (NS) Length of stay (NS)FVC (NS) Patient charge (NS)FEV1 (NS) Annual hospital costs (NS)FVC (NS)

Hospital length of stay (NS)cost NEB MDI spacer(p 0.001)

Nighttime asthma morbidityNEB MDI spacer(p 0.05)

PEFR (NS) Heart rate increaseMDI DPI (p 0.001)

Sao2 MDI DPI(p 0.05)



directly assess effectiveness as quick relief treatmentfor outpatient asthma symptoms (the primary role thatthese agents play in the treatment of asthma).2,3 Some

were single-dose studies in which each treatment wasadministered only once, with measurements beingmade before and after this treatment. In other studies,

Figure 5. Weighted standardized mean difference for FEV1 in inpatient trials using 2-agonistscomparing nebulizer vs MDI spacer/holding chamber. See the legend of Figure 2 for abbreviationsnot used in the text.

Table 12Intermittent vs Continuous Nebulizers Studies Using 2-Agonists*

Study/Year/Study Type Setting Total Patients, No.

Lost toFollow-up,

No. Age Range

Khine et al65/1996/type 1 Pediatric, ER/ICU 73 3 218 yrContinuous: 86 46 moIntermittent: 97 50 mo

Shrestha et al66/1996/type 1 Adult 165 0 High dose: 34.6 10.6 yrAsthma, ER/ICU St. Dose: 35.3 10.7 yr

Low dose: 32.4 10.80 yrSt. dose: 35.1 10.4 yr

Reisner et al67/1995/type 1 Adult 22 2 Continuous: 30 3.9 yrAsthma, ER/ICU Intermittent: 39 6.0 yr

Lin et al68/1993/type 1 Adult 38 0 Continuous: 39.8 13.2 yrAsthma, ER/ICU Intermittent: 40.6 14.1 yr

Rudnitsky et al69/1993/type 1 Adult 99 0 Continuous: 35 14 yrAsthma, ER/ICU Intermittent: 36 15 yr

Papo et al70/1993/type 1 Pediatric, ER/ICU 17 0 Continuous: 1.816 yr (6 yr)Intermittent: 2.515 yr (4 yr)

*RVU relative value unit; St standard; RT respiratory therapist. See Table 8 for abbreviations not used in the text.Mean SD values.Median values.

352 Special Report


treatments were administered on a scheduled dailybasis over varying periods of time from as short as 1 dayup to a few months. With both of these approaches,however, the primary outcome assessed changes inlung function in the clinical laboratory. Daily asthmasymptom scores and adverse effects, mainly changes inheart rate, were assessed in only a few trials.Twenty-three studies9099,101103,106115 (both type

2a and 2b) compared the responses to short-acting2-agonists using a DPI vs those using an MDI(without a spacer/holding chamber) in adults withasthma (Tables 14, 15). Outcomes included sometype of pulmonary function measurement in all butone trial. In that one study, cough score was the onlyuseable outcome. Metaanalyses comparing FEV1,PEFR, and sGaw responses from these studiesshowed no significant differences between devices,either by separate analysis or when pooled (Fig 7).Six of the trials comparing MDI with DPI were

analyzed separately because they employed similar(comparable) doses of the same drug in the twodevices (Table 15).95,102,103,108,110,114 This allowedfor a more direct assessment of device efficiencyand effectiveness than in the studies that useddifferent doses and/or drugs in the devices beingcompared. An analysis of these comparable dosestudies also found no differences in FEV1, PEFR,FVC, or symptoms (see Fig 8 on-line). For trials inwhich multiple sequential doses were adminis-tered by each device, the metaanalysis was per-

formed for both the lowest dose and for thehighest dose administered (in 16 trials). Again, nodifferences were found for FEV1, PEFR, sGaw, orFVC. Two studies compared cough or other symp-toms,90,101 and three studies compared changes inheart rate changes.92,98,115 No differences werefound between the MDI and the DPI in pooledanalyses of these studies. However, one study116reported greater improvements in FEV1 for DPIuse compared with MDI use, and another study90reported greater improvement in cough score forDPI use compared with MDI use.Four studies compared the MDIs and DPIs in

pediatric patients. Two studies117,118 investigatedterbutaline delivered by MDI and by DPI (Turbu-haler). Another study119 evaluated fenoterol deliveryby MDI and DPI. The fourth study120 enrolled bothpediatric and adult patients. None of these studies,either individually or when combined, showed adifference between use of the MDI and use of theDPI.Fewer data are available comparing the effects of

2-agonists inhaled via an MDI without a spacerdevice vs those inhaled via an MDI with a spacerdevice in adults or children with asthma in theoutpatient setting,100,121 and only one study121 metcriteria for inclusion in the analysis. This studyshowed no difference between the two routes for theoutcomes FEV1, PEFR, or FVC (Table 16).Eight type 2b studies that compared short-acting

Drug/Device (dose)PulmonaryFunction

VitalSigns/

Symptoms Side Effects Concomitant Care

Albuterol/NEB(0.3 mg/kg/h)

Asthma score (NS) Hospital admissionrate (NS)

RT time (p 0.001intermittent continuous)

Albuterol/NEB:Continuous(2.5, 7.5 mg/h)

FEV1 (p 0.05comparing all groups)

Intermittent (2.5, 7.5 mg)Albuterol/NEB FEV1 % pred (NS) Respiratory rate (NS) Heart rate (NS)Continuous (7.5 mg/h) PF % pred (NS)Intermittent (2.5 mg)Albuterol/NEB: FEV1 (NS)Continuous (15.0 mg/h)Intermittent (5.0 mg)Albuterol/NEB: PF (NS) Heart rate (NS) Admission rateContinuous (5.0 mg/h) (p 0.03 intermittent Intermittent (2.5 mg) continuous)Albuterol (0.3 mg/kg/h) Dyspnea score (NS) RVU respiratory care time

Time to dyspnea score 5 (p 0.001 intermittent (p 0.03 intermittent continuous)continuous) Length of stay (p 0.04

intermittent continuous)



-agonist delivery by different devices were evaluatedseparately (Table 17). Three studies that compared thedose delivered by nebulizer and MDI with holdingchamber each concluded that more than two MDIactuations are required to equal one nebulizer treat-ment. Pedersen and Bundgaard122 and Madsen et al123estimated that approximately four terbutaline MDIactuations are required to equal a single nebulizedtreatment with 2.5 to 4.0 mg of terbutaline. Blake et

al124 estimated that approximately 10 MDI actuationsof albuterol are required to equal one nebulizer treat-ment with 2.5 mg albuterol. It is for this reason themore than two MDI actuations are typically used inED studies comparing MDIs with spacers/holdingchambers and nebulizers (Table 8). Type 2B studies byWong et al,125 Lofdahl et al,126 and Bondesson et al127compared albuterol delivery via DPI (Turbuhaler) andCFC MDI (Ventolin). All three studies estimated that

Figure 6. Top: weighted standardized mean difference for FEV1 in ED/ICU trials of 2-agonistscomparing intermittent (Int) vs continuous (Cont) nebulization. Bottom: weighted standardized meandifference for peak flow in ED/ICU trials of 2-agonists comparing intermittent vs continuousnebulizers. See the legend of Figure 2 for abbreviations not used in the text.

354 Special Report


the dose delivered by the DPI was greater (1.38-fold,1.98-fold, and 2.0-fold greater, respectively). Confi-dence intervals for these three estimates overlapped inthe region, indicating a twofold to threefold greaterpotency for the Turbuhaler. In contrast, two type 2Bstudies112,128 comparing a Spiros DPI (Elan Pharma-ceuticals; Dublin, Ireland) with a CFCMDI (Ventolin)estimated that these devices were approximately equi-potent. This draws attention to the fact that differencesin the relative amount of drug delivered to the lungdepends not only on the general type of device used(DPI vs MDI) but also on the specific brand of devicebeing compared (eg, Spiros DPI or Turbuhaler DPI).


In the adult and pediatric outpatient populationwith asthma, available evidence comparing short-acting 2-agonist delivery by MDI and DPI showno differences in pulmonary function responses,symptom scores, or heart rate. This remains truewhen analysis is restricted to type 2b studies thatestimate the doses required to produce equallevels of response (called dose-axis comparisons)[quality of evidence: good].

In a limited number of type 2 studies comparingshort-acting 2-agonists administered with an MDIto that with an MDI using a spacer or holdingchamber, pulmonary function responses were foundto be comparable (quality of evidence: low).

The use of nebulizers for the delivery of short-acting 2-agonists in the outpatient setting has notbeen adequately studied in RCTs (quality of evi-dence: low).

Recommendations

1. For treatment of asthma in the outpatientsetting, both the MDI, used with or withoutspacer/holding chamber, and the DPI are ap-propriate for the delivery of short-acting 2-agonists. Quality of evidence: good; net benefit:substantial; strength of recommendation: A.

2. The appropriate selection of a particular type ofaerosol delivery device in this setting includesthe patients 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 deliv-ery device, the lack of time or skills to properlyinstruct the patient in the use of the device orto monitor the appropriate use, the cost of thetherapy, and the potential for reimbursement.Quality of evidence: low; net benefit: substan-tial; strength of recommendation: B.

Tab

le13

Aerosol

Deliveryin

PatientsReceiving

Mecha

nicalVentilation

*

Stud

y/Ye

ar/

Stud

yType

Setting

Patie

nts,

No.

Lostto

Follow-up,

No.

Age

Drug/Device(D

ose)

Side

Effects

Con

comita

ntCare

Other

Measures

Torreset

al71/

Pediatric,

ICU

165

5.3

7.6mo

Albuterol/M

DI

AirLife

Raw

(NS)

1997/ty

pe1

(0.44yr)

Med

ispacer

(0.36mg)

compliance(N

S)NEB(1.5

mg)

Manthou

set

al73/

Adu

lt/pe

diatric,

100

66.3

9.75

yr

Albuterol/M

DI

1996

Toxic

effects(N

S)Resistancepressure

1993/ty

pe1

ICU

Intersurgicalswivel

(NS)

Elbow

spacer

(1.0,2

.0,3

.0,

4.0mgq3

0min;c

umulative

dose

9mgor

100pu

ffs)

NEB(2.5,7

.5,1

5.0mgq3

0min,

cumulativedo

se15

mg)

Gay

etal

72/1991/type

1Pe

diatric/adult,

202

69yr

Albuterol/M

DI(0.27mg)

Tim

eforadministration

Expiratoryflo

wIC

UNEB(2.5

mg)

(NS)

atisorecoilprs

Costof

unitdo

se(N

S)6and10

cmH

2O(N

S)

*Raw

airw

aysresistance;p

rs

pressure.S

eeTable

8forabbreviatio

nsno

tused

inthetext.

Meanage.

Mean

SDvalues.

Manufacturedby

BaxterHealth

care,D

eerfield,IL.



Inhaled Corticosteroids for Asthma

Four trials90,104,105,106,129 comparing the use of a DPIwith that of an MDI plus spacer for the inhalation ofinhaled corticosteroids in adult90,104,105,129 asthmaticpatients in the outpatient setting met the criteria forstudy inclusion (Table 18). No studies enrolling chil-

dren were eligible for inclusion. To be able to accu-rately compare device performance and efficacy, werequired that the same drug be delivered via MDI/spacer and DPI, and this greatly limited the number ofuseable trials. In these four trials, the same dose of thesame corticosteroid was used for the two deliveryroutes. The durations of these type 1 trials were

Table 14MDI vs DPI Using 2-Agonists in Adult Outpatients With Asthma*

Study/Year/Study Type

TotalPatients,

No.

Lost toFollow-up,


Haahtela et al109/1994/type 2A 20 0 2366 yr (50 yr) Salbutamol/DPI-Easyhaler (0.09, 0.18, 0.36,0.72 mg)

Bauer et al115/1993/type 2A 16 0 3761 yr (4725 1.6 yr) Fenoterol/MDI DPI (0.4 mg)DPI (Spinhaler): (10.0 mg colforsin)

Zainudin et al111/1990/type 2A 9 0 2068 yr Salbutamol/DPI-Rotahaler (0.4 mg)

Johnsen and Weeke92/1988/type 2A 9 0 2046 yr (30 yr) Terbutaline/DPI-Turbuhaler (0.25, 0.5, 1.0, 2.0,4.0 mg)

Persson et al93/1988/type 2A 13 1 2059 yr (39 yr) Terbutaline/DPI-Turbuhaler (0.25, 0.5, 1.0, 2.0,4.0 mg)

Lahdensuo et al94/1986/type 2A 20 0 4576 yr (62 yr) Fenoterol/DPI-Fio2 (0.2 mg)

Bundgaard et al97/1983/type 2A 18 0 2049 yr (37 yr) Fenoterol/DPI-Fio2 (0.6, 1.0 mg)

Dirksen and Groth98/1983/type 2A 9 0 2765 yr (47 4 yr) Fenoterol/DPI-Fio2 (0.05, 0.1, 0.2, 0.4 mg)

Bundgaard and Schmidt99/1982/type 2A 18 3 2155 yr (39 yr) Fenoterol/DPI-Fio2 (0.2, 0.4 mg)Geoffroy et al112/1999/type 2B 60 16 1865 yr (29.7 10.5 yr) Albuterol/DPI-Spiros (0.09 mg)

Tammivaara et al101/1997/type 1 115 2 DPI: 49 13 yr Albuterol/DPI (0.2 mg)MDI: 45 14 yr

Vidgren et al106/1995/type 2A 40 0 1878 yr (39 yr) Salbutamol/DPI-Easyhaler (0.1 mg)

Jackson et al107/1994/type 2A 10 0 1966 yr (42 yr) Terbutaline/Turbuhaler (0.25 mg)Nieminen et al113/1994/type 2A 21 4 2073 yr (51 yr) Salbutamol/DPI-Easyhaler (0.18 mg)

Boe et al90/1992/type 1 179 56 1878 yr (51 yr) Terbutaline/Turbuhaler (0.5 mg)

Osterman et al91/1989/type 1 23 4 2066 yr (46 yr) TerbutalineTurbuhaler (0.5 mg)

Kiveranta96/1985/type 2A 20 1857 yr (35 yr) Fenoterol/DPI-Fio2 (0.3 mg)

*pre pretreatment; post posttreatment; Fio2 fraction of inspired oxygen; Tmax time to maximum response. See Table 8 forabbreviations not used in the text.Median values.Mean SD values.

356 Special Report


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). Twoof the trials addressed subject preference, and therewas a significant preference for the DPI over theMDI/spacer combination (p 0.01) [see Fig 10on-line]. We deem the incidence of oral candidiasisto be a crucial outcome, and no trial addressed thisissue. There were no randomized control trials thatwere eligible for study inclusion that addressed other

device comparisons using inhaled corticosteroids(MDI vs MDI with spacer/holding chamber, andMDI used alone vs DPI).

Summary of RCT Results For adult patients with asthma in the outpatientsetting, there are no differences in pulmonaryfunction response or symptom scores when thesame dose of the same corticosteroid is used in aDPI or MDI with spacer/holding chamber (qualityof evidence: good).

PulmonaryFunction

VitalSigns/

Symptoms Side Effects Concomitant Care Design/Duration

FEV1 (NS) Adverse events (NS) Crossover cumulativePF (NS) dose/1 dFVC (NS)FEV1 (NS) Heart rate (NS) Tremor amplitude Crossover/120 min

MDI DPI (p 0.05)Serum K (NS)

FEV1 (NS) Crossover/60 minPF (NS)FVC (NS)FEV1 (NS) Heart rate (NS) Tremor amplitude Taste (NS) Crossover cumulativeFVC (NS) MDI DPI (p 0.05) dose/1 dFEV1 (NS) Tremor amplitude (NS) Crossover cumulativeFVC (NS) dose/1 dFEV1 Crossover/5, 15, 60 minMDI DPI

(p 0.01)PF (NS)PF (NS) Tremor (NS) Crossover dose

FEV1 (NS) Heart rate (NS) Crossover, cumulativedose

PF (NS) Crossover, doseFEV1 (NS) Tmax (NS) Crossover/5 d

Duration of effect (NS)Onset time (NS)

FEV1 (NS) Symptom score (day) (NS) 2-adrenergic use (NS) Parallel/21, 84 dPF (NS) Symptom score (night) (NS)FEV1 (NS) Tmax (NS) Crossover/2 dPF (NS) Preference for technique (NS)FVC (NS)

Crossover/3 dFEV1 (NS) Adverse events (NS) Ease of use (NS) Crossover/2 dPF (NS)FVC (NS)

Cough Throat irritation Taste MDI DPI Crossover/14 dMDI DPI (p 0.05) MDI DPI (p 0.05) Device rating MDI DPI

Mouth irritation (p 0.001)MDI DPI(p 0.05)

Difficulty learning to usMDI DPI (p 0.001)

PEF am pre (NS) Tremor (NS) 2-adrenergic use (NS) Crossover/14 dPEF pm pre (NS) Preference for technique (NS)PEF am post-MDI

DPI (p 0.05)PEFR-am (NS) Preference for technique (NS) Crossover/35 dPEFR-pm (NS)



Two studies indicated a significant patient pref-erence for use of the DPI over that of the MDIwith spacer/holding chamber (quality of evidence:good).

No RCT adequately addressed the incidence oforal candidiasis (quality of evidence: low).

Recommendations

1. For the treatment of asthma in the outpatientsetting, both the MDI with a spacer/holdingchamber and the DPI are appropriate devicesfor the delivery of inhaled corticosteroids. Qual-ity of evidence: good; net benefit: substantial;strength of recommendation: A.

2. For outpatient asthma therapy, the selection ofan appropriate aerosol delivery device for in-haled corticosteroids includes the patientsability to use the device correctly, the prefer-ences of the patient for the device, the avail-ability of the drug/device combination, thecompatibility between the drug and deliverydevice, the lack of time or skills to properlyinstruct the patient in the use of the device ormonitor the appropriate use, the cost of therapy,and the potential for reimbursement. Quality ofevidence: low; net benefit: substantial; strength ofrecommendation: B.

2-Agonists and Anticholinergic Agents for COPD

Proving device efficacy can be difficult in COPDpatients because the airway obstruction in such

patients shows limited reversibility with drug ther-apy. Seven studies130136 comparing different de-livery devices met the criteria for entry into thisanalysis (Table 19). Pooled analysis of these stud-ies showed no evidence for superiority of anyaerosol delivery device (nebulizer, MDI, or MDIwith spacer in patients) for outpatients withCOPD. While the data are quite limited for COPDpatients, the experience in asthma patients sup-ports the conclusions for COPD.Turner et al,50 in an acute setting adult trial,

reported a significantly greater increase in heartrate for nebulizers compared to MDI withoutimportant differences in efficacy. Similar findingswere reported by Berry et al61 for inpatients withCOPD, but data are lacking for COPD patientstreated in the outpatient setting. In an outpatientstudy of patients with COPD, Pauwels et al131compared the use of an MDI and that of an MDIwith a valved holding chamber following the inha-lation of terbutaline, and reported that the MDIwith holding chamber may be more effective thanMDI alone. In an outpatient study of patients withasthma or COPD, Dorow and Hidinger et al132reported no differences between the use of anMDI and that of MDI with a valved holdingchamber.Device differences have not been adequately stud-

ied for combination bronchodilator therapy (eg,Combivent; Boehringer-Ingelheim; Ridgefield, CT)or for steroid preparations in outpatients withCOPD. Delivery systems for long-acting bronchodi-

Table 15Trials Comparing MDI vs DPI Studies Comparable Dose and Drug 2-Agonists andCromolyn Adult Outpatients With Asthma*

Study/Year/Study Type Total Patients, No. Lost to Follow-up, No. Age Range Drug/Device (Dose)

Nelson et al114/1999/type 2A 283 43 DPI Albuterol/MDI (0.09 mg)34.2 13.4 yr DPI-Spiros (0.108 mg)MDI34.6 15.4 yrPlacebo32.4 14.1 yr

Svedmyr et al95/1982/type 2A 7 0 3166 yr (51.28) Salbutamol/MDI (0.1, 0.3, 0.8, 2.0, 4.4 mg)DPI-Rotahaler (0.2, 0.6, 1.8, 4.2, 9.0 mg)

Vilsvik et al103/1991/type 2A 21 5 1655 yr (30.6) Albuterol/MDI (0.2 mg)Terbutaline/DPI-Turbuhaler (0.5 mg)

Mathieu et al102/1992/type 2A 12 1 31.6 yr Salbutamol/MDI (0.2 mg)DPI-Diskhaler (0.4 mg)

Lantos et al110/1993/type 2A 15 0 1854 yr (34) Cromolyn/MDI (2.0 mg)DPI-Spinhaler (20.0 mg)

Lindsay et al108/1994/type 1 47 1 Adults Salbutamol/MDI (0.2 mg)51 11 yr Terbutaline/DPI-Turbuhaler (0.5 mg)Children11 2 yr

*AUC area under the curve. See Table 8 for abbreviations not used in the text.Mean SD values.Median values.

358 Special Report


lators (eg, salmeterol and formoterol) also have notbeen adequately studied in this patient population.The selection of an aerosol delivery device for the

treatment of outpatients with COPD is determinedby the formulation, the needs of the patient, clinicianbiases, and reimbursement. Although use of an MDI(with spacer and mask if necessary) may producesimilar results, nebulizers are often used in sickerand less cooperative patients.


In the outpatient management of COPD patientswith 2-agonist and anticholinergic agents, theavailable evidence shows no differences in pulmo-nary function responses between delivery devices(quality of evidence: good).

Increases in heart rate were greater after theadministration of albuterol by nebulizer than afteradministration by MDI (quality of evidence:good).

Recommendations

1. For the treatment of COPD in the outpatientsetting, the MDI, with or without spacer/holding chamber, the nebulizer, and the DPIare all appropriate for the delivery of inhaled2-agonist and anticholinergic agents. Qualityof evidence: good; net benefit: substantial;strength of recommendation: A.

2. For outpatient COPD therapy, the selection ofan appropriate aerosol delivery device for in-haled 2-agonist and anticholinergic agentsincludes the patients ability to use the device

correctly, the preferences of the patient for thedevice, the availability of the drug/device com-bination, the compatibility between the drugand the delivery device, the lack of time orskills to properly instruct the patient in the useof the device or monitor its appropriate use,the cost of therapy, and the potential forreimbursement. Quality of evidence: low; netbenefit: substantial; strength of recommenda-tion: B.

Discussion

The results of this systematic review of RCTswere essentially the same in each of the clinicalsettings evaluated above. None of the pooledmetaanalyses (Tables 20 and 21, available on-lineonly) showed a significant difference betweendevices in any efficacy outcome in any patientgroup. Thus, the relative effectiveness of deliverymethods does not provide a clear basis for select-ing one device over another. This does not meanthat the device choice for a specific patient doesnot seem to matter. In essence, this says that eachof the devices studied can work equally well in thatsetting in patients who can use them appropri-ately. This is an important statement because moststudies, especially in the outpatient setting, selectfor patients who are capable of using each of thedevices with the appropriate technique or trainpatients to use the appropriate technique. TheRCTs included in this systematic review do notprovide much information about who is likely to

Pulmonary Function Vital Signs/Symptoms Side Effects Concomitant Care Design/Duration

AUC serial FEV1(p 0.44)

Parallel/12 wk

FEV1 (NS) Heart rate (NS) Crossover/2 dFVC (NS)PF (NS) Crossover/15 min

FEV1 % pred (NS) Crossover/unspecifiedVC % pred (NS)PF % pred (NS) Dyspnea episode duration (NS) 2-adrenergic use (NS) Crossover/4 wk

FEV1 % pred (NS) Wheeze (NS) Adverse events (NS) Preference for technique (NS) Crossover/4 wkPF % pred (NS) Sleep disturbance (NS)FVC % pred (NS) Total symptom score (NS)



use one device or another properly, nor do theyaddress many other considerations that are impor-tant for choosing a delivery device for a specificpatient in a specific clinical situation. These in-clude the ability to use the device, patient prefer-ence, the availability of equipment, and cost.While the clinician is still left to select the methodof delivery based on these other considerations, wehave made general recommendations based on theresults of the metaanalysis to guide the clinician inhis/her selection of a delivery system. In addition,there are some obvious situations in which deviceselection clearly does matter. For example, in eachof the clinical situations studied, there are somedevices that were studied little or not at all. Thisappears to indicate a consensus that RCTs are notneeded to determine that some devices are inap-propriate for that clinical situation. For example, itis clear that infants and toddlers have virtually nochance of using an MDI (without spacer or hold-ing chamber) or a DPI properly. Similarly, thereare virtually no RCTs studying the MDI (withoutspacer or holding chamber) in the ED since mostclinicians believe that the severe dyspnea experi-enced by many asthma patients in that settingwould prevent them from using this device prop-erly.Consideration of the circumstances under which

studies were performed is an important factor forinterpreting the results of our systematic review.All of the RCTs performed in the acute care

settings (ie, ED, inpatient unit, or ICU) are type 1trials (ie, they were performed under conditions ofactual clinical use in the ED, inpatient unit, orICU). These studies are reassuring in that both anebulizer and an MDI with a valved holdingchamber can work well in that setting. Similarly,MDIs with a reverse-flow spacer can be success-fully used in these settings but not in intubatedpatients, unless they incorporate an interface tothe ventilator circuit. Similarly, studies of inhaledcorticosteroid use in outpatients, while limited innumber, are type 1 studies that are performedunder conditions of actual clinical use. The resultsare reassuring in that each device can work well inpatients who know how to use them correctly.Studies of 2-agonist use for outpatient asthma

and COPD are less reassuring since virtually all ofthese were type 2 studies that were performedunder laboratory conditions rather than conditionsof actual clinical use. The studies indicate thatunder ideal conditions and in patients who aresuccessfully taught to use the devices correctly,the devices being compared can each deliversufficient quantities of drug to the airway to elicitthe same response. However, the relationshipbetween these laboratory studies and the use ofthe device in patients daily lives is not clear. Manyof these studies were performed for regula

Aerosolterapia. Chest, Guidelines ACCP

Documents

Transcript of Aerosolterapia. Chest, Guidelines ACCP