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Exacerbations in chronic obstructivepulmonary disease (COPD) and asth-ma account for a substantial clinical

and economic burden and are often associ-ated with events that ultimately result inmorbidity and mortality.1 As such, guide-lines in the overall treatment of both COPDand asthma offer specific recommendationsfor the management of these acute episodes.

The more recent guidelines for the treat-ment of COPD published by the NationalHeart, Lung, and Blood Institute of theNational Institutes of Health and the WorldHealth Organization’s (NHLBI/WHO) GlobalInitiative for Chronic Obstructive LungDisease (GOLD), the American College ofPhysicians-American Society of InternalMedicine, and the American College ofChest Physicians (ACCP) are based onexpert panel consensus and empirical evi-dence.2,3 Although numerous other recom-mendations have been developed, morerecent consensus guidelines for asthma havebeen developed by the National AsthmaEducation and Prevention Program (NAEPP)at the NHLBI and through collaborativeefforts between NHLBI/WHO’s GlobalInitiative for Asthma (GINA).4-9

Treatment regimens for acute exacerba-tions generally follow stepwise approachesto therapy with the goals of rapidly reducingairway obstruction and restoring or main-taining lung function. Achieving optimalclinical outcomes through therapeuticapproaches requires the consideration ofpatient characteristics and risk factors, fail-ure of initial treatment, treatment setting,and the severity of the exacerbation itself.Pharmacotherapeutic interventions empha-size the use of bronchodilators, althoughsystemic corticosteroids, oxygen, andnumerous other agents may be considered.Prevention and risk-factor modificationremain of key importance in long-term care.Many therapies that target underlyinginflammatory processes are in developmentand may offer disease-modifying strategiesto reduce the number of substantially pre-

VOL. 10, NO. 5, SUP. THE AMERICAN JOURNAL OF MANAGED CARE S139

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An Assessment of Therapeutic Regimens in theTreatment of Acute Exacerbations in

Chronic Obstructive Pulmonary Diseaseand Asthma

Grant H. Skrepnek, PhD, RPh; and Stan V. Skrepnek, MD

AbstractAcute exacerbations in chronic obstructive pul-

monary disease (COPD) and asthma are potentiallylife-threatening clinical events that may result insubstantial morbidity and mortality. Treatment ofthese episodes requires the rapid reversal of airwayobstruction by decreasing bronchoconstriction andinflammation. Consensus guidelines and recommen-dations build on stepwise approaches to care, withthe mainstay of therapeutic interventions involvingbrochodilators and often including systemic corti-costeroids, oxygen, and other treatments, dependingon severity and setting. Future therapies that targetinflammatory processes may offer improved efficacyand potential disease-modifying effects. The purposeof this article is to assess the treatment options foracute exacerbations in COPD and asthma within thescope of current consensus guidelines and recom-mendations (eg, Global Initiative for ChronicObstructive Lung Disease, National AsthmaEducation and Prevention Program, Global Initiativefor Asthma). Although bronchodilators and cortico-steroids are the primary therapies discussed, anti-biotics, oxygen, magnesium sulfate, noninvasivepositive pressure ventilation, and helium/oxygenmixtures are also addressed. Preventive approachesfor future exacerbations are considered in the over-all approach to achieve optimal outcomes.

(Am J Manag Care. 2004;10:S139-S152)

mature deaths and hospitalizations whileimproving quality of life in patients withCOPD or asthma.

Given the importance of managing COPDand asthma, the purpose of this article is toassess the treatment options for exacerba-tions within the scope of current consensusguidelines and recommendations. Althoughan emphasis is placed on the management ofthese acute events, preventive approachesand future treatments are also highlighted.Providing important background for thisdiscussion, the epidemiology, clinical andeconomic burden of illness, and clinicalpresentation of COPD and asthma have beendiscussed elsewhere in this supplement.1

The discussion offered herein establishesinsight into relevant material; consensusrecommendations and additional sourcesshould guide clinical decision making. Manyfacets beyond exacerbations are importantto the management of COPD and asthma,

although these issues are beyond the scopeof this article.

General Considerations of AcuteExacerbations in COPD and Asthma

Guidelines for COPD. Several factorsmust be considered before treating COPDexacerbations. The first is determining theappropriate setting to establish intervention(eg, outpatient, emergency department, hos-pital admission).10 Exacerbations are man-aged by improving airway obstruction byreducing inflammation and bronchocon-striction while promoting mucociliary clear-ance.11 Comorbid conditions or problemsthat may precipitate respiratory worseningor failure must also be addressed; if hypox-emia has manifested, it should be rectified.12

The severity of the exacerbation, treatmentfailures, comorbidities, and underlying dis-ease characteristics will determine treat-ment options and the setting in which it isadministered.13 Careful observation con-cerning underlying and evolving pulmonaryfunction, particularly in response to thera-py, is helpful in determining the need forhospital admission. Outpatient regimens mayinvolve bronchodilators, systemic cortico-steroids, and antibiotics; again, a stepwiseapproach is generally recommended.14-17

Guidelines for hospital care also consideroxygen therapy and potential mechanicalventilation.2 Establishing preventive meas-ures to decrease the likelihood of futureexacerbations is a final consideration.

Four aspects of COPD managementoffered by GOLD involve assessing andmonitoring COPD, reducing risk factors,managing stable COPD, and managing exac-erbations.2 The algorithm for treating acuteexacerbations of COPD in outpatient set-tings appears in Figure 1; the Table outlinesthe general considerations of inpatienttreatment.

Guidelines for Asthma. GINA recom-mends that asthma management involveestablishing and maintaining control ofsymptoms, preventing exacerbations andadverse effects of medications, maintaininglung function and normal activity levels, andpreventing irreversible airflow limitationsand mortality.6 The restoration of lung func-

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S140 THE AMERICAN JOURNAL OF MANAGED CARE JULY 2004

Figure 1. Global Initiative for Chronic Obstructive LungDisease (GOLD) Algorithm for the Management of anExacerbation of COPD at Home

Initiate or increase bronchodilator therapyConsider antibiotics

Reassess within hours

Resolution or improvementof symptoms

No resolution or improvement

Continue managementStep down when possible

Add oral corticosteroids

Review long-term managementReassess within hours

Worsening of signs/symptoms

Refer to hospital

Source: Reference 2.COPD indicates chronic obstructive pulmonary disease.

tion and the rapid improvement of both air-way obstruction and hypoxia are criticaltreatment goals for acute exacerbations.6

Treatment approaches for these acute casesacross guidelines follow stepwise approach-es that add additional therapeutic measureswhen considering the severity of exacerba-tion; outpatient management emphasizesincreasing short-acting β2-agonist use andmonitoring the response to initial treat-ment.18 According to the NAEPP, GINA, andother experts, the primary management ofexacerbations within inpatient settingsinvolves increasing the frequency of inhaledshort-acting β2-agonists, adding systemiccorticosteroids, and using oxygen supple-mentation.4-6,19-21 In instances when exacer-bations are resistant to initial treatment orare severe in nature, hospital- or emer-gency department–based monitoring andtreatment are recommended.6 NAEPPemphasizes the importance of early inter-vention in asthma exacerbations anddirecting special attention toward patientsat high risk for asthma-related mortality.4

Consideration is also placed on reducingthe probability of recurrent severe exacer-bations and developing written plans toaid in guiding the early management offuture exacerbations.

Although NAEPP and GINA generally coin-cide, clinicians should be aware that certainnuances exist between the 2 guidelines.Recommendations for outpatient manage-ment stipulate that the frequency of aninhaled short-acting β2-agonist be increasedand that continued intensive treatmentshould be carried out for several days basedon severity and response.5 Figure 2 presentsthe most recent guidelines from GINA on thehome management of asthma exacerbations,whereas Figure 3 focuses on hospital manage-ment. More important, development of specif-ic treatment algorithms in acute care settingshas been shown to improve patient outcomesand decrease resource consumption.22 Acaveat of care in acute asthma involves theuse of sedatives; use of these agents is gen-erally contraindicated because of potentialrespiratory depression and increased mor-tality.5,23,24 Clinicians treating severe casesthat require mechanical ventilation and theuse of sedatives are directed toward appro-

priate references for additional informationfor monitoring and intervention.5,6,25

Therapeutic Considerations inManagement and Treatment

Bronchodilators. The primary therapyfor overall COPD and related exacerbationsis inhaled bronchodilator therapy.2,14,15,26

Bronchodilators recommended specificallyfor COPD exacerbations include short-act-ing β2-agonists (eg, albuterol, levalbuterol,bitolterol, pirbuterol) and anticholinergics(eg, ipratropium bromide). Outpatient man-agement typically involves increasing thedose and/or frequency of agents prescribedto the patient, whereas inpatient therapyrelies on short-acting β-agonists by GOLDstandards.2 A meta-analysis indicated thatno significant differences in improvedforced expiratory volume in 1 second(FEV1) were noted in COPD exacerbationsbetween the β2-agonists and ipratropium,although the β2-agonists that were includedmay have worsened the arterial blood gasprofile in the hours immediately followinginitial patient presentation.27 Delivery via a

An Assessment of Therapeutic Regimens in the Treatment of Acute Exacerbations


Table. Global Initiative for Chronic Obstructive Lung Disease(GOLD) Management of Severe but Not Life-ThreateningExacerbations of COPD in the Emergency Department or theHospital*

Assess severity of symptoms, blood gases, chest X-ray

Administer controlled oxygen therapy and repeat arterial blood gasmeasurement after 30 minutes

Bronchodilators:Increase dose or frequencyCombine β2-agonists and anticholinergicsConsider adding intravenous aminophylline, if needed

Add oral or intravenous glucocorticosteroids

Consider antibiotics:When signs of bacterial infection, oral or occasionally intravenous

Consider noninvasive mechanical ventilation

At all times:Monitor fluid balance and nutritionConsider subcutaneous heparinIdentify and treat associated conditions (eg, heart failure, arrhythmias)Closely monitor condition of the patient

Source: Reference 2.COPD indicates chronic obstructive pulmonary disease.*Local resources need to be considered.

metered dose inhaler (MDI) and spacer hasbeen reported to produce similar effects asnebulization, although certain studies spe-cific to asthma have noted that MDIs with aspacer may provide a more rapid onset tolessen time spent in emergency depart-ments.28-30 The use of long-acting β2-agonists(eg, salmeterol, formoterol) is generallyreserved for maintenance treatment ofCOPD.2,31,32 Taken from Bach and col-leagues,33 the following was concluded intheir review of 14 randomized trials con-cerning bronchodilator use in COPD:

“Short-acting β-agonist–type and anti-cholinergic-type inhaled bronchodilatorshave similar effects on spirometry and agreater effect than all parenterally admin-istered bronchodilators (ie, parenteralmethylxanthines and sympathomimet-ics); the toxicity profile of the methylxan-thine agents makes them potentiallyharmful; and some patients may experi-ence additional benefits when a second

bronchodilating agent is administered afterthe maximal dose of the initial inhaledbronchodilator is reached.”33

Tiotropium bromide, a long-acting mus-carinic receptor M1- and M3-selective anti-cholinergic agent, has demonstrated ininternational clinical trials improved effica-cy relative to ipratropium as well as salme-terol in the treatment of stable COPD.34-37

Decreases in exacerbations in COPD havebeen observed with the once-daily dosedmedication.38,39 Given the long-acting natureof tiotropium, however, its use in the emer-gent care of acute exacerbations of eitherCOPD or asthma has yet to be established.Currently, no newer short-acting anti-cholinergic agents are in an advanced devel-opment phase.40

According to NAEPP and GINA, inpatientcare of exacerbations in asthma emphasizesthe use of inhaled short-acting β2-agonists,whereas systemic β2-agonists (eg, epine-phrine, terbutaline) should only be con-

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Figure 2. Guidelines for the Home Management of Acute Exacerbations in Asthma Offered by GlobalInitiative for Asthma (GINA)*

Assess severity

Persistent PEF <80% personal best or predicted (on 2 successive days)or >70% if no response to bronchodilator

Clinical features: cough, breathlessness, wheeze, chest tightness, use ofaccessory muscles and supraternal retractions

Initial treatment

Inhaled rapid-acting β2-agonists up to 3 treatments in 1 hour

Good responseMild episode

If PEF >80% predicted or personal best: Response to β2-agonists sustained for 4 hours May continue β2-agonist every 3-4 hours for 24-48 hours

If PEF <60% predicted or personal best: Add oral glucocorticosteroid 3-4 hours for 24-48 hours Repeat β2-agonist immediately Add inhaled anticholinergic Immediate transport to hospital emergency department, consider ambulance

Contact clinician for follow-up instructions To emergency department

Incomplete responseModerate episode

Poor responseSevere episode

If PEF 60%-80% predicted or personal best: Add oral glucocorticosteroid Add inhaled anticholinergic Continue β2-agonist Consult clinician

Contact clinician urgently (this day) for instructions

Source: Reference 6.PEF indicates peak expiratory flow.*Patients at risk for asthma-related death should contact clinician promptly after initial treatment. Additional therapy may be required.



Figure 3. Guidelines for the Hospital Management of Acute Exacerbations in Asthma Offered by the GlobalInitiative for Asthma (GINA)*

Initial assessment

History, physical examination (auscultation, use of accessory muscles,heart rate, respiratory rate, PEF or FEV1-O2 saturation, arterialblood gas of patients in extremis, and other tests as indicated)

Initial treatment

Inhaled rapid-acting β2-agonist, usually by nebulization, 1 dose every 20 minutes for 1 hourOxygen to achieve O2 saturation ≥90% (95% in children)Systemic glucocorticosteroid if no immediate response, if patient recently took oral glucocorticosteroid, or if episode is severeSedation is contraindicated in the treatment of exacerbations

Good response

Response sustained 60 minutes after last treatmentPhysical exam: normalPEF >70%No distressO2 saturation >90% (95% in children)

Incomplete response within 1-2 hours

History: high-risk patientPhysical exam: mild-to-moderate symptomsPEF <70%O2 saturation not improving

Poor response within 1 hour

History: high-risk patientPhysical exam: symptoms severe, drowsiness, confusionPEF <30%PaCO2 ≥45 mm HgPaO2 <60 mm Hg

Discharge home

Continue with inhaled β2-agonistConsider, in most cases, oral glucocorticosteroidPatient education: Take medication correctly Review action plan Close medical follow-up

Discharge home

If PEF >60% predicted/personal best and sustained on oral/inhaled medication

Admit to intensive care

If no improvement within 6-12 hours

Admit to hospital

Improve Not Improve

Inhaled β2-agonist ± inhaled anticholinergicSystemic glucocorticosteroidOxygenConsider intravenous methylxanthineMonitor PEF, O2 saturation, pulse, theophylline

Admit to intensive care

Inhaled β2-agonist hourly or continuously plus inhaled anticholinergicIntravenous corticosteroidOxygenPossible intubation and mechanical ventilation

Repeat assessment

Physical examination, PEF, O2 saturation, other tests as needed

Moderate episode

PEF 60%-80% predicted/personal bestPhysical exam: moderate symptoms, accessory muscle useInhaled short-acting β2-agonist and inhaled anticholinergic every 60 minutesConsider glucocorticosteroidContinue treatment 1-3 hours, provided there is improvement

Severe episode

PEF <60% predicted/personal bestPhysical exam: severe symptoms at rest, chest retractionHistory: high-risk patientNo improvement after initial treatmentInhaled β2-agonist, hourly and inhaled anticholinergicOxygenSystemic glucocorticosteroidConsider subcutaneous, intramuscular, or intravenous β2-agonistConsider intravenous methylxanthinesConsider intravenous magnesium

Source: Reference 6.FEV1 indicates forced expiratory volume in 1 second; PEF, peak expiratory flow; PaO2, arterial pressure of oxygen; PaCO2, arterial pres-sure of carbon dioxide.*Preferred treatments are inhaled β2-agonists in high doses and systemic glucocorticosteroids. If inhaled β2-agonists are not available, con-sider intravenous aminophylline.

sidered in very severe or nonresponsivecases.5,6,20,21 Research has found either equalor improved efficacy with aerosolized β2-agonists versus systemic agents in acuteasthma, also noting an improved safety pro-file and lower potential for toxicity.41 Com-bined treatment with both intravenous andnebulized β2-agonists is not warranted.42

The routine use of continuous nebulization,although commonplace, has not been empir-ically established as a preferred manage-ment strategy relative to intermittenttreatment.43 The long-acting β2-agonists (eg,salmeterol, formoterol) are generally notrecommended for emergent care of acuteasthma.25,44

Opinion and research have indicated thatthe use of ipratropium in an adjunctive rolewith β2-agonist regimens for acute exacerba-tions in asthma may improve airflow, partic-ularly in more severe cases.21,45 NAEPP andGINA consider the addition of ipratropiumto β2-agonists for emergency departmentand hospital-based care of asthma exacerba-tions, and GINA guidelines state that the useof ipratropium with β2-agonist treatmentshould be considered before methylxan-thines because of potentially lower hospital-ization rates and improvement in peakexpiratory flow and FEV1.

4-6 However, uni-form support does not yet exist concerningthe routine addition of ipratropium with β2-agonists in acute asthma, although someexperts state that the concomitant approachmay appear to be a beneficial first-line strat-egy in severe adult asthma.25,46-50 Thus, thetherapeutic placement of the agent is gener-ally recommended only as an adjunctiveapproach in patients who are not responsiveto β2-agonist therapy alone.4,48,51,52 In chil-dren, research has noted that all individualsreceiving intensive emergency departmenttreatment did not receive benefit when ipra-tropium was added to β2-agonist and corti-costeroid therapy; however, other literaturesuggest that ipratropium offers clinicalimprovements, particularly in more severecases.6,21,53-57

The side-effect profile of ipratropium hasbeen purported to be milder than β-agonists,with fewer number and frequency of sideeffects being reported.33,46,58 Within the classof short-acting β-agonists, albuterol is the

most commonly used agent, and side effectsare dose-dependent.25,44,59 Recent evidencesuggests that levalbuterol (R-albuterol) maybe associated with lower toxicity, higher effi-cacy, and decreased length of hospital stayswhen compared with racemic albuterol, andthe single isomer may have potential use inCOPD, asthma, and related exacerbations;its use has also been noted in children.59-65

Although evidence presented primarily frompreclinical models found that S-albuterol isassociated with pharmacologic effects andmay enhance smooth muscle contractionand airway hyperresponsiveness, clinical tri-als have suggested that the S-isomer may beclinically inert.66-68 Other clinical findingsmay be indicative of negative effects associ-ated with the S-isomer; additional study iswarranted to establish more robust conclu-sions.59,63,64,69 If high-dose β2-agonist therapyis used with albuterol in acute asthma,appropriate delivery and administrationmethods should be selected to minimize sideeffects and toxicity.22,25

The methylxanthines (eg, aminophylline,theophylline) are considered efficaciousbronchodilators, although the narrow thera-peutic window and side-effect profile limittheir use in exacerbations of COPD andasthma.2,4-6 Recent meta-analyses for bothCOPD and asthma exacerbations found noconsistent benefit from methylxanthines,yet an increase in adverse events wasobserved.70,71 Of all the guidelines discussingCOPD exacerbations, only older guidelinesrecommended the use of methylxanthines inCOPD exacerbations when inhaled bron-chodilators provide inadequate therapy.15 Inacute asthma, GINA guidelines suggest thatthe use of these agents be considered onlyduring severe exacerbations and remain analterative therapy.6,71 NAEPP does not rec-ommend methylxanthine use in emergencydepartments or hospital settings, and the useof these agents was controversial for adultswhile offering little benefit but increased riskto children.4,5,72

Systemic Corticosteroids. Systemic cor-ticosteroids (eg, prednisone, prednisolone,methylprednisolone) are considered effec-tive in both inpatient and outpatient settingsfor the treatment of COPD exacerbations by

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accelerating recovery time and lung functionwhile decreasing relapse rates; meta-analyseshave found the therapies to offer short-termimprovement for exacerbations, althoughthe analyses also addressed increased risksfor adverse drug reactions associated withthe class.73-77 GOLD suggests the addition ofsystemic corticosteroids to bronchodilatorsif moderate-to-severe COPD is present andas a general recommendation for inpatientcare.2 These guidelines also state that nebu-lized budesonide may offer an alterative tooral agents in outpatient management in theabsence of respiratory acidosis.2,78 Contin-ued study is warranted concerning the use ofcorticosteroids in outpatient venues, partic-ularly with optimum dosing and duration.33

For long-term treatment in COPD, a meta-analysis found inhaled corticosteroids toslow the progression of pulmonary functiondecline dramatically, although others hadconsidered the class to offer minimal clinicalbenefit in COPD.79,80

Although they are not recommended rou-tinely in acute asthma treatment, cortico-steroids (eg, beclomethasone, budesonide,flunisolide, fluticasone, triamcinolone) mayeither be initiated or the frequencyincreased under certain circumstances foroutpatient management of exacerbations.4

The GINA guidelines address the role ofinhaled corticosteroids in already-developedexacerbations, and reviews of clinical stud-ies have reported improved bronchodilationand decreased relapse rates with early use inmilder cases.6,81-83 Conflicting results fromclinical trials exist concerning the use ofinhaled corticosteroids in acute asthma,however, some clinicians strongly cautionagainst routine use, particularly in chil-dren.81,84-86 Less debatable is the use of sys-temic administration of corticosteroids inmore moderate or severe exacerbationsin home management. GINA, NAEPP, andother experts place systemic corticosteroidsadministered via oral or intravenous routesas an integral component of inpatient carefor all but mild exacerbations. A meta-analysis found the early use of systemiccorticosteroids to significantly decrease hos-pital admissions from emergency depart-ments.4,6,87,88 The choice of intravenousversus oral dosage forms does not appear to

offer a difference in efficacy, which is animportant consideration in their use bychildren.89,90 Precise dosing and scheduleshave not been established, yet high dosesdo not appear to provide added clinicalbenefit.79

Antibiotics. Although approximately onethird of COPD exacerbations are either viralin nature or have no identifiable etiology,antibiotics are generally recommended ifworsening dyspnea is accompanied byincreased sputum production and/or changein sputum purulence.91,92 Evidence has alsosuggested that more severe cases of COPDexacerbations are afforded the greatestimprovement in clinical outcomes withantibiotic therapy.93 GOLD recommendsthat the spectrum of activity should echolocal patterns of sensitivity concerningStreptococcus pneumoniae, Haemophilusinfluenzae, and Moraxella catarrhalis.2

Concerns addressing drug resistance andrelapse rates, especially in patients withsevere COPD, have been investigated andaddressed in the literature.13

Similar to COPD recommendations byGOLD, both NAEPP and GINA do not sum-marily recommend antibiotic use for asthmaexacerbations except in instances for whichcomorbid conditions or the presence of fever,sputum changes, or suspected pneumonia orbacterial sinusitis warrant their use.4,6 Ameta-analysis of the role of antibiotics inacute asthma noted many challenges in inter-preting results from disparate literature andindicated that established consensus recom-mendations would likely remain until morerobust empirical assessments are made.94 Therole of bacterial infections in acute asthma isbelieved to be small, although atypical bacte-ria including Mycoplasma pneumoniae orChlamydia pneumoniae have been found insome exacerbations.95 Viral respiratory infec-tions, particularly from rhinovirus, have beenreported to play a major role in precipitatingasthma exacerbations, with virus-inducedacute asthma potentially warranting specialmanagement considerations.96-98

Oxygen. In moderate-to-severe exacerba-tions of COPD, hypoxemia is considered aprimary concern in regard to morbidity.



When patients present to an inpatient settingor emergency department with exacerba-tions, their initial therapy should be con-trolled oxygen as recommended by GOLD.Oximetry is helpful for determining the needand success of oxygen therapy. Oxygen ther-apy has been associated with increases in sur-vival.2,51 Although oxygen therapy has beenfound to worsen hypercapnia and can resultin pulmonary failure, the beneficial effects ofthe therapy on respiratory and cardiovascularfunction are often considered to outweigh therisks.33 Because of clinical concerns, howev-er, identification of patients at highest risk forhypercapnia has been suggested.33 In thetreatment of asthma exacerbations, especial-ly in more moderate-to-severe cases, oxygentherapy is an important supportive caremeasure in emergency department or hospi-tal settings and is generally recommended formost patients.5,6,21,25

Magnesium Sulfate. Intravenous mag-nesium sulfate, which relaxes smooth mus-cle causing bronchodilation, is consideredadjunctive therapy for acute severe asthma,with collective assessments of clinical trialsnot necessarily demonstrating a clear bene-fit for routine use in emergency departmentsettings.6,21,99,100 In certain patients withpoor response to β2-agonists or with adultswhose FEV1 on presentation is from 20% to30% predicted, some benefit has beendemonstrated. GINA guidelines confirm theuse of intravenous magnesium sulfate forthe hospital management of severe episodesof asthma exacerbation.6,101

Noninvasive Positive Pressure Ventila-tion. Noninvasive positive pressure ventila-tion (NIPPV) has demonstrated efficacy inrespiratory failure among a wide range ofdiseases.102 In cases of respiratory failurerelated to COPD exacerbations, NIPPV hasbeen found to shorten hospital stays andimprove survival rates and offers an impor-tant alternative to intubation or mechanicalventilation.103 Overall, the treatment may beused in intensive care or hospital settingswith appropriate training of personnel.104

The use of NIPPV in acute exacerbations ofasthma is less clear than in COPD, althoughsome research indicates decreased hospital-

ization rates and improved pulmonary func-tion.105,106 Expert panels have recommendedthat a more comprehensive evaluation ofNIPPV is needed from clinical trials.107 It hasbeen suggested that NIPPV use be limited tocases of impending respiratory failure or asan alternative to intubating patients withacute asthma.25

Mucolytics and Expectorants. The useof mucolytic agents in COPD exacerbationsis an area warranting additional research byGOLD.2 Although a meta-analysis has indi-cated potential benefits based on reductionin exacerbations and in disability days instable COPD, the agents are generally notconsidered in the routine management ofacute exacerbations.108 NAEPP and GINAguidelines coincide with older recommenda-tions on the use of inhaled mucolytic agentsfor asthma exacerbations. Furthermore,they do not recommend the regimensbecause of a lack of consistently demon-strated benefit and concerns of the risk asso-ciated with worsened airway obstructionand cough, particularly in more severecases.4,6,21

Heliox. Small trials of combined heliumand oxygen (heliox) in COPD exacerbationshave shown some improvement in respira-tory function in inpatient settings.109 Helioxis not addressed in the GOLD guidelines forCOPD exacerbations.2 For asthma, clinicalstudies have generally indicated that thecombination does not necessarily improvelung function in mild or moderate asthmaexacerbations relative to standard thera-py, a finding that was also offered frombroad meta-analyses concerning the thera-py.110,111 GINA guidelines for asthma statethat the mixture may be best reserved forpatients presenting with more severe dis-ease, and that routine use in other cases isunwarranted.6

Leukotriene Antagonists. Leukotrieneantagonists (eg, montelukast, zafirlukast,zileuton) are used primarily for the long-term management of asthma.112 Initial find-ings and opinions from clinical trials inacute asthma, however, may provide evi-dence for a potential role in their use based

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on improvements in symptoms and pul-monary function; the overall cost effective-ness in acute asthma, however, has beenquestioned.113-115 No consensus currentlyexists concerning the use of these agents inacute asthma, and additional investigation iswarranted concerning their role in the treat-ment of exacerbations.116

Prevention

A strategy encompassing continuous,long-term, comprehensive care with appro-priate clinician follow-up should be soughtto prevent or reduce future exacerbations inboth COPD and asthma. No therapy existsthat substantially modifies the long-termprogression of COPD.2 As such, risk-factormodification, particularly smoking cessa-tion, is pertinent to ease the progression ofthe disease, although patient education,influenza vaccination, and potential pul-monary rehabilitation are also impor-tant.2,117,118 GOLD generally recommendsthat the treatment of stable COPD follows astepwise approach based on severity andoften involves bronchodilators, exercise,and, occasionally, corticosteroids.2 Methodsto both increase patient adherence to thecomplex therapies in COPD and selectingappropriate interventions have also beenemphasized.119 Hospital discharge recom-mendations often involve monitoring oftherapeutic interventions and lung function,increased patient education, risk modifica-tion, discussion of barriers to care or disabil-ities, and follow-up care.2

Overall recommendations concerning theprevention of future exacerbations in asth-ma include developing management part-nerships between clinicians and patients,education, appropriate assessment andmonitoring, establishing plans for medica-tion use and for treating exacerbations, min-imizing risk factors, and routine follow-upcare.5,6

Discharge from emergency department orhospital settings should involve detailedinformation concerning appropriate medica-tion use, management, monitoring, and fol-low-up care.6 Discharge use of oralcorticosteroids has been shown to reducethe frequency of relapses (NAEPP). Inhaledsteroids have been specifically shown to

reduce subsequent exacerbations after anacute asthmatic episode.120-122 Long-termcontrol of asthma may also include agentssuch as long-acting inhaled β2-agonists (eg,salmeterol, fomoterol), leukotriene receptorantagonists, cromolyn, nedocromil, or com-bination products (eg, fluticasone/salme-terol).5 Management by allergy specialistshas also been shown to reduce the likelihoodof asthma exacerbations.123-129

Future Treatment Options

Statements of future areas of research inCOPD have addressed the need for a moredetailed understanding of the specific surro-gate markers and mechanisms involved inthe inflammatory component of the diseaseto aid in the identification of at-risk patientsand in the development of new treatments.2

Ultimately, methods to potentially reverseCOPD and promote alveolar regrowthrequire advances in numerous areas. Therole of inflammatory processes in both theprevention and treatment of exacerbationsin COPD has been discussed elsewhere.130-133

Based on recent advances in the under-standing of the pathogenesis of inflamma-tion in COPD, numerous agents that may beused to treat COPD are being studied,including those that may offer disease-mod-ifying properties. Specifically related toresearch with new agents for COPD, mixedfindings have been observed involvingleukotriene inhibitors, protease inhibitors(ie, α1-antitrypsin, neutrophil elastase), andmatrix metalloproteinase inhibitors.130-133

Although cytokine inhibitors targeting medi-ators of inflammation (eg, interleukin [IL]-8,IL-10, tumor necrosis factor [TNF]-α) havegenerated considerable interest with appli-cation to COPD, concerns of cost and safetyhave also accompanied the agents.130-133

Additional study is warranted concerningphosphodiesterase-4 inhibitors (eg, cilomi-last), retinoids, antioxidants, and mucousregulators (ie, P2Y2 purinergic-receptor ago-nists, tachykinin antagonists).131-133

In asthma, research has also been direct-ed toward identifying at-risk patients, inunderstanding inflammatory mechanismsof the disease, and in developing new treat-ment options.6,134,135 Cytokine and chemo-kine inhibition or modulation has been

investigated to target interleukins (eg, IL-4,IL-5, IL-13), TNF-α, interferons (eg, interfer-on [INF]-γ, INF-α), and eosinophils.134-137

Mediator antagonists (eg, mast cell tryptase,platelet activating factor, tachykinins,thromboxane) may offer treatment options,although limited potential has beenobserved in asthma for some of theagents.6,134,138 Phosphodiesterase-4 inhibitors(eg, cilomilast, roflumilast) and α4 integrinantagonists are also potential targets fortherapy.134,135,139,140 Studies with ozalizumab,an immunoglobulin E–specific monoclonalantibody for use in moderate-to-severe per-sistent asthma, have indicated thatdecreased asthma exacerbations and reduc-tions in corticosteroids accompanied thetreatment.141

Conclusion

Acute exacerbations in COPD and asthmarepresent potentially life-threatening clini-cal events that require appropriate diagno-sis, treatment, and monitoring in bothinpatient and outpatient settings. Guidelinesfor the management of exacerbations inCOPD and asthma are built on consensusand consider therapies as a function of theresponse to initial treatment, exacerbationseverity, treatment setting, and underlyingpatient characteristics and risk factors.Although standard agents used in exacerba-tions of both conditions involve bron-chodilators, systemic corticosteroids, andoxygen, there are several novel agentsbeing investigated that address the inflam-matory mechanisms of the conditions.Future research is required in several areasto offer improved patient care and to mini-mize associated morbidity and mortality.However, more consistent use of currentlyavailable modalities for persistent asthma,such as inhaled corticosteroids, should beconsidered.120-122,129,142-148

REFERENCES

1. Skrepnek GH, Skrepnek SV. Epidemiology, clinicaland economic burden, and natural history of chronicobstructive pulmonary disease and asthma. Am J ManagCare. 2004;10:S129-S138.

2. Global Initiative for Chronic Obstructive Lung Disease(GOLD). Global Strategy for the Diagnosis, Management,and Prevention of Chronic Obstructive Pulmonary

Disease, Updated 2003. National Heart, Lung, and BloodInstitute, World Health Organization; 2003.3. Snow V, Lascher S, Mottur-Pilson C. Evidence basefor management of acute exacerbations of chronicobstructive pulmonary disease. Ann Intern Med. 2001;134:595-599.4. National Heart, Lung, and Blood Institute. NationalAsthma Education and Prevention Program (NAEPP).Expert Panel Report 2: Guidelines for the Diagnosis andManagement of Asthma. National Institutes of HealthPublication 97-4051. Bethesda, Md: US Department ofHealth and Human Services; 1997.5. National Heart, Lung, and Blood Institute. NationalAsthma Education and Prevention Program (NAEPP).Expert Panel Report: Guidelines for the Diagnosis andManagement of Asthma. National Institutes of HealthPublication 03-5074. Bethesda, Md: US Department ofHealth and Human Services; 2003.6. Global Initiative for Asthma (GINA). Global Strategyfor Asthma Management and Prevention, Updated 2003.National Institutes of Health Publication 02-3659.Bethesda, Md: US Department of Health and HumanServices; 2002.7. Guidelines on the management of asthma. Statementby the British Thoracic Society, the British PaediatricAssociation, the Research Unit of the Royal College ofPhysicians of London, the King’s Fund Centre, theNational Asthma Campaign, the Royal College ofGeneral Practitioners, the General Practitioners inAsthma Group, the British Association of Accident andEmergency Medicine, and the British PaediatricRespirator Group. Thorax. 1993;48:S1-S24.8. British Thoracic Society, National AsthmaCampaign, Research Unit of the Royal College ofPhysicians of London, King’s Fund Centre. Guidelineson the management of asthma in adults II—acute severeasthma. Thorax. 1990;301:767-800.9. National Heart, Lung, and Blood Institute. Inter-national consensus report on the diagnosis and manage-ment of asthma. Clin Ex Allergy. 1992;22(suppl):1s-72s.10. MacNee W, Calverley PMA. Management of COPD.Thorax. 2003;58:261-265.11. Blanchard AR. Treatment of acute exacerbations ofCOPD. Clin Cornerstone. 2003;5:28-36.12. MacNee W. Acute exacerbations of COPD. SwissMed Wkly. 2003;133:247-257.13. Sciurba FC. Medical management of chronicobstructive pulmonary disease. Chest Surg Clin N Am.2003;13:615-629.14. Siafakas NM, Vermeire P, Pride NB, et al. Optimalassessment and management of chronic obstructive pul-monary disease (COPD). The European RespiratorySociety Task Force. Eur Respir J. 1995;8:1398-1420.15. American Thoracic Society. Standards for the diag-nosis and care of patients with chronic obstructive pul-monary disease. Am J Respir Crit Care Med. 1995;152(suppl):77s-121s.16. Sachs FL. Chronic bronchitis. Clin Chest Med.1981;2:79-89.17. Celli BR. Current thoughts regarding treatment ofchronic obstructive pulmonary disease. Med Clin NorthAm. 1996;80:589-609.18. Roy SR, Milgrom H. Managing outpatient asthmaexacerbations. Curr Allergy Asthma Rep. 2003;3:179-189.19. FitzGerald JM, Grunfeld A. Status asthmaticus. In:Lichenstein LM, Fauci, eds. Current Therapy in Allergy,

REPORTS


Immunology, and Rheumatology. 5th ed. St Louis, Mo:Mosby; 1996.20. Papiris S, Kotanidou A, Malagari K, Roussos C.Clinical review: severe asthma. Crit Care. 2002;6:30-44.21. Volovitz B, Nussinovitch M. Management of chil-dren with severe asthma exacerbation in the emergencydepartment. Paediatr Drugs. 2002;4:141-148.22. McFadden ER, Elsanadi N, Dixon L, et al. Protocoltherapy for acute asthma: therapeutic benefits and costsavings. Am J Med. 1995;99:651-661.23. FitzGerald JM, Macklern P. Fatal asthma. Annu RevMed. 1996;47:161-168.24. Joseph KS, Blais L, Ernst P, et al. Increased morbidi-ty and mortality related to asthma among asthmatic pa-tients who use major tranquilizers. BMJ. 1996;312:79-82.25. Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma inadults: a review. Chest. 2004;125:1081-1102.26. McCrory D, Brown C, Gelfand S, et al.Management of acute exacerbations of COPD: a sum-mary and appraisal of published evidence. Chest.2001;119:1190-1209.27. Brown CD, McCrory D, White J. Inhaled short-act-ing beta2-agonists versus ipratropium for acute exacerba-tions of COPD. Cochrane Database Syst Rev. 2003.28. Turner MO, Patel A, Ginsberg S, et al. Broncho-dilator delivery in acute airflow obstruction. A meta-analysis. Arch Intern Med. 1997;157:1736-1744.29. Cates CJ, Rowe BH, Bara A. Holding chambers ver-sus nebulizers for β-agonist treatment of acute asthma.Cochrane Database Syst Rev. 2002.30. Newman KB, Milne S, Hamilton C, et al. A compar-ison of albuterol administered by metered dose inhalerand spacer with albuterol by nebulizer in adult patientspresenting to an urban emergency department withacute asthma. Chest. 2002;121:1036-1041.31. Mahler DA. The effect of inhaled β2-agonists onclinical outcomes in chronic obstructive pulmonary dis-ease. J Allergy Clin Immunol. 2001;110(suppl):298S-303S.32. Cazzola M, Matera MG. Long-acting β2-agonists asa potential option in the treatment of acute exacerbationsof COPD. Pulm Pharmacol Ther. 2003;16:197-201.33. Bach PB, Brown C, Gelfand SE, McCrory DC.Management of acute exacerbations of chronic obstruc-tive pulmonary disease: a summary and appraisal of pub-lished evidence. Ann Intern Med. 2001;134:600-620.34. Littner MR, Ilowite JS, Tashkin DP, et al. Long-act-ing bronchodilation with once-daily dosing of tiotropium(Spiriva) in stable chronic obstructive disease. Am JRespir Crit Care Med. 2000;161:1136-1142.35. van Noord JA, Bantje T, Eland M, et al. A random-ized controlled comparison of tiotropium and ipratropi-um in the treatment of chronic obstructive pulmonarydisease. The Dutch Tiotropium Study Group. Thorax.2000;55:289-294.36. Maesen F, Smeets J, Sledsens F, et al. Tiotropiumbromide, a new long-acting antimuscarinic bronchodila-tor: a pharmacodynamic study in patients with chronicobstructive pulmonary disease (COPD). Eur J Respir Dis.1995;8:1506-1513.37. Brusasco V, Hodder R, Miravitlles M, et al. Healthoutcomes following treatment for six months with oncedaily tiotropium compared with twice daily salmeterol inpatients with COPD. Thorax. 2003;58:399-404.38. Vincken W, Can Noord JA, Greefhorst AP, et al.Improved health outcomes in patients with COPD dur-

ing 1 year’s treatment with tiotropium. Eur Respir J.2002;19:209-216.39. Casaburi R, Mahler DA, Jones PW, et al. A long-term evaluation of once-daily inhaled tiotropium inchronic obstructive pulmonary disease. Eur Respir J.2002;19:217-224.40. Barnes PJ. New treatments for COPD. Nat Rev DrugDiscovery. 2002;1:437-446.41. Kelly HW, Murphy S. β-adrenergic agonists foracute, severe asthma. Ann Pharmacother. 1992;26:81-91.42. Travers A, Jones AP, Kelly K, Barker SJ, CamargoCA, Rowe BH. Intravenous beta2-agonists for acute asth-ma in the emergency department. Cochrane DatabaseSyst Rev. 2001.43. Rodrigo GJ, Rodrigo C. Continuous versus intermit-tent β-agonists in the treatment of acute adult asthma: asystematic review with meta-analysis. Chest. 2002;122:160-165.44. Kercsmar CM. Current trends in management ofpediatric asthma. Respir Care. 2003;48:194-205.45. Rodrigo G, Rodrigo C, Burschtin O. Ipratropiumbromide in adults with acute asthma: a meta-analysis ofrandomized controlled trials. Am J Med. 1999;107:363-370.46. Karpel JP, Schacter EN, Fanta C, et al. A comparisonof ipratropium and albuterol versus albuterol alone forthe treatment of acute asthma. Chest. 1996;10:611-616.47. Lanes SF, Garrett JE, Wentworth CE III, FitzGeraldJM, Karpel JP. Effect of adding ipratropium bromide tosalbutamol in the treatment of acute asthma: a pooledanalysis of three trials. Chest. 1998;114:65-72.48. Plotnick LH, Ducharme FM. Should inhaled anti-cholinergics be added to beta2 agonists for treating acutechildhood and adolescent asthma? A systematic review.BMJ. 1998;317:971-977.49. Rodrigo GJ, Rodrigo C. First-line therapy for adultpatients with acute asthma receiving multiple-dose pro-tocol of ipratropium bromide plus albuterol in the emer-gency department. Am J Respir Crit Care Med. 2000;161:1862-1868.50. Rodrigo GJ, Rodrigo C. The role of anticholinergicsin acute asthma treatment: an evidence-based evalua-tion. Chest. 2002;121:1977-1987.51. Kelly HW, Sorkness CA. Asthma. In: DiPiro JT,Talbert RL, Yee GC, et al, eds. Pharmacotherapy: APathophysiologic Approach. New York, NY: McGraw-Hill; 2002.52. Plotnick LH, Ducharme FM. Combined inhaledanticholinergics and beta2-agonists for initial treatment ofacute asthma in children. Cochrane Database Syst Rev.2000.53. Schuh S, Johnson DW, Callaha S, Canny G, LevisonH. Efficacy of frequent nebulized ipratropium added tohigh dose albuterol therapy in severe childhood asthma.J Pediatr. 1995;126:639-645.54. Qureshi F, Pestian J, Davis P, Zaritsky A. Effect ofnebulized ipratropium on the hospitalization rates ofchildren with asthma. N Engl J Med. 1998;339:1030-1035.55. Goggin N, Macarthur C, Parkin PC. Randomizedtrial of the addition of ipratropium bromide to albuteroland corticosteroid therapy in children hospitalizedbecause of an acute asthma exacerbation. Arch PediatrAdolesc Med. 2001;155:1329-1334.56. Craven D, Kercsmar CM, Myers RT, et al.Ipratropium bromide plus nebulized albuterol for the



treatment of hospitalized children with acute asthma. J Pediatr. 2001;138:51-58.57. Streetman DD, Bhatt-Mehta V, Johnson CE.Management of acute, severe asthma in children. AnnPharmacother. 2002;36:1249-1260.58. Rebuck A, Chapman K, Abboud R, et al. Nebulizedanticholinergic and sympathomimetic treatment of asth-ma and chronic obstructive airways disease in the emer-gency room. Am J Med. 1987;82:59-64.59. Handley DA, Tinkelman D, Noonan M, et al. Dose-response evaluation of levalbuterol versus racemicalbuterol in patients with asthma. J Asthma. 2000;37:319-327.60. Milgrom H, Skoner DP, Bensch G, et al. Low-doselevalbuterol in children with asthma: safety and efficacyin comparison with placebo and racemic albuterol. J Allergy Clin Immunol. 2001;108:938-945.61. Handley DA. Single-isomer beta-agonists.Pharmacotherapy. 2001;21(suppl):21S-27S.62. Carl JC, Myers TR, Kirchner HL, Kercsmar CM.Comparison of racemic albuterol and levalbuterol fortreatment of acute asthma. J Pediatr. 2003;143:731-736.63. Truitt T, Witko J, Halpern M. Levalbuterol com-pared to racemic albuterol: efficacy and outcomes inpatients hospitalized with COPD or asthma. Chest.2003;123:128-135.64. Nowak RM, Emerman CL, Schaefer K, et al. Leval-buterol compared with racemic albuterol in the treat-ment of acute asthma: results of a pilot study. Am JEmerg Med. 2004;22:29-36.65. Pleasants RA. Focus on inhaled β2-agonists: efficacy,safety, and patient preference. Pharmacotherapy. 2004;24(suppl):S44-S54.66. Page CP, Morley J. Contrasting properties of albuterolstereoisomers. J Allergy Clin Immunol. 1999;104(suppl):S31-S41.67. Templeton A, Chapman I, Chilvers E, et al. Effectsof S-salbutamol on isolated human bronchus. PulmPharmacol Ther. 1998;11:1-6.68. Lotvall J, Palmqvist M, Arvidsson P, et al. The ther-apeutic ratio of R-albuterol is comparable with that ofRS-albuterol in asthmatic patients. J Allergy ClinImmunol. 2001;108:726-731.69. Nelson H, Bensch G, Pleskow WW, et al. Improvedbronchodilation with levalbuterol compared withracemic albuterol in patients with asthma. J Allergy ClinImmunol. 1998;102:943-952.70. Barr RG, Rowe BH, Camargo CA Jr. Methyl-xanthines for exacerbations of chronic obstructive pul-monary disease. Cochrane Database Syst Rev. 2001.71. Parameswaran K, Belda J, Rowe BH. Addition ofintravenous aminophylline to beta2-agonists in adultswith acute asthma. Cochrane Database Syst Rev. 2000.72. Kelly HW, Murphy SJ. The management of acutesevere asthma in children. In: Busse WW, Holgate ST,eds. Asthma and Rhinitis. Boston, Mass: BlackwellScience; 2001.73. Thompson WH, Nielson CP, Carvalho P, CharanNB, Crowley JJ. Controlled trial of oral prednisone inoutpatients with acute COPD exacerbation. Am J RespirCrit Care Med. 1996;154:407-412.74. Davies L, Angus RM, Calverly PM. Oral cortico-steroids in patients admitted to hospital with exacerbationsof chronic obstructive pulmonary disease: a prospectiverandomized controlled trial. Lancet. 1999;354:456-460.

75. Niewoehner DE, Erbland ML, Deupree RH, et al.Effect of systemic glucocorticoids on exacerbations inchronic obstructive pulmonary disease. Department ofVeterans Affairs Cooperative Study Group. N Engl JMed. 1996;154:407-412.76. Wood-Baker R, Walters EH, Gibson P. Oral corti-costeroids for acute exacerbations of chronic obstructivepulmonary disease. Cochrane Database Syst Rev. 2003.77. Singh JM, Palda VA, Stanbrook MB, Chapman KR.Corticosteroid therapy for patients with acute exacerba-tions of chronic obstructive pulmonary disease: a sys-tematic review. Arch Intern Med. 2002;162:2527-2536.78. Maltais F, Ostinelli J, Bourbeau J, et al. Comparisonof nebulized budesonide and oral prednisolone withplacebo in the treatment of acute exacerbations ofchronic obstructive pulmonary disease: a randomizedcontrolled trial. Am J Respir Crit Care Med. 2002;165:698-703.79. Sutherland ER, Allmers H, Ayas NT, Venn AJ,Martin RJ. Inhaled corticosteroids reduce the progres-sion of airflow limitation in chronic obstructive pul-monary disease: a meta-analysis. Thorax. 2003;58:937-941.80. Adcock IM, Chung KF. Why are corticosteroids inef-fective in COPD? Curr Opin Investig Drugs. 2002;3:58-60.81. Rodrigo G, Rodrigo C. Inhaled flunisolide for acutesevere asthma. Am J Respir Crit Care Med. 1998;157:2201-2203.82. FitzGerald JM, Shragge D, Haddon J, et al. A ran-domized controlled trial of high dose, inhaled budes-onide versus oral prednisone in patients discharged fromthe emergency department following an acute asthmaexacerbation. Can Respir J. 2000;7:61-67.83. Chipps BE, Chipps DR. A review of the role ofinhaled corticosteroids in the treatment of acute asthma.Clin Pediatr. 2001;40:185-189.84. Edmonds ML, Camargo CA Jr, Pollack CV Jr, RoweBH. Early use of inhaled corticosteroids in the emer-gency department treatment of acute asthma. CochraneDatabase Syst Rev. 2003.85. Schuh S, Reisman J, Alshehri M, et al. A comparisonof inhaled fluticasone and oral prednisone for children withsevere acute asthma. N Engl J Med. 2000;343:689-694.86. Hendeles L, Sherman J. Are inhaled corticosteroidseffective for acute exacerbations of asthma in children? J Pediatr. 2003;142(suppl):26S-33S.87. Rachelefsky G. Treating exacerbations of asthma inchildren: the role of systemic corticosteroids. Pediatrics.2003;112:382-397.88. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA,Bota GW. Early emergency department treatment ofacute asthma with systemic corticosteroids. CochraneDatabase Syst Rev. 2001.89. Kelly HW, Murphy S. Corticosteroids for acutesevere asthma. DICP. 1991;25:72-79.90. Hendeles L. Selecting a systemic corticosteroid foracute asthma in young children. J Pediatr. 2003;142(suppl):40S-44S.91. Patel IS, Seemungal TA, Wilks M, et al. Relationshipbetween bacterial colonization and the frequency, char-acter, and severity of COPD exacerbations. Thorax.2002;57:759-764.92. Saint S, Bent S, Vittinghoff E, Grady G. Antibioticsin chronic obstructive pulmonary disease. A meta analy-sis. JAMA. 1995;273:957-960.

REPORTS


93. MacFarlane JT, Colville A, Guion A, MacFarlaneRM, Rose DH. Prospective study of aetiology and out-come of adult lower respiratory tract infections in thecommunity. Lancet. 1993;341:511-514.94. Graham V, Lasserson T, Rowe BH. Antibiotics foracute asthma. Cochrane Database Syst Rev. 2001.95. Freymuth F, Vabert A, Brouard J, et al. Detection ofviral, Chlamydia pneumoniae and Mycoplasma pneumo-niae infections in exacerbations of asthma in children.J Clin Virol. 1999;13:131-139.96. Nicholson K, Kent J, Ireland D. Respiratory virusesand exacerbations of asthma in adults. BMJ. 1993;307:982-986.97. Johnston SL, Pattermore PK, Sanderson G, et al.Community study of the role of viral infections in exac-erbations of asthma in 9-11 year old children. BMJ.1995;310:1225-1229.98. Weinberger M. Treatment strategies for viral respira-tory infection-induced asthma. J Pediatr. 2003;142(suppl):S34-S39.99. Rowe BH, Bretzlaff JA, Bourdon C, et al.Intravenous magnesium sulfate treatment for acute asth-ma in the emergency department: a systematic review ofthe literature. Ann Emerg Med. 2000;36:181-190.100. Rodrigo GJ, Rodrigo C, Burschtin O. Intravenousmagnesium as an adjuvant in acute bronchospasm: a meta-analysis of randomized trials. Am J Emerg Med.2000;18:216-221.101. Silverman RA, Osborn H, Runge J, et al. IV mag-nesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest.2002;122:489-497.102. Brochard L. Noninvasive ventilation for acute res-piratory failure. JAMA. 2002;288:932-935.103. Lightowler JV, Wedzicha JA, Elliot MW, Ram FS.Non-invasive positive pressure ventilation to treat respi-ratory failure from exacerbations of chronic obstructivepulmonary disease: Cochrane systematic review andmeta analysis. BMJ. 2003;326:185-189.104. Plant PK, Owen JL, Elliot MW. Early use of non-invasive ventilation for acute exacerbations of chronicobstructive pulmonary disease on general respiratorywards: a multicentre randomized controlled trial. Lancet.2000;355:1931-1935.105. Fernandez MM, Villagral A, Blanchl L, et al. Non-invasive mechanical ventilation in status asthmaticus.Intensive Care Med. 2001;27:486-492.106. Soroksky A, Stav D, Shpirer I. A pilot prospective,randomized, placebo-controlled trial of bilevel positiveairway pressure in acute asthmatic attack. Chest.2003;123:1018-1025.107. British Thoracic Society Standards of CareCommittee. Non-invasive ventilation in acute respiratoryfailure. Thorax. 2002;57:192-211.108. Poole PJ, Black PN. Mucolytic agents for chronicbronchitis or chronic obstructive pulmonary disease.Cochrane Database Syst Rev. 2003.109. Tassaux D, Jolliet P, Roeseler J. Effects of helium-oxygen on intrinsic positive end-expiratory pressure inintubated and mechanically ventilated patients withsevere chronic obstructive pulmonary disease. Crit CareMed. 2000;28:2721-2728.110. Ho AMH, Lee A, Karmakar MK, et al. Heliox ver-sus air-oxygen mixtures for the treatment of patients withacute asthma: a systematic review. Chest. 2003;123:882-890.

111. Rodrigo GJ, Rodrigo C, Pollack CV, Rowe B. Useof helium-oxygen mixtures in the treatment of acuteasthma: a systematic review. Chest. 2003;123:891-896.112. Ducharme FM. Anti-leukotrienes as add-on therapyto inhaled glucocorticoids in patients with asthma: sys-tematic review of current evidence. BMJ. 2002;324:1-7.113. Foresi A, Paggiaro P. Inhaled corticosteroids andleukotriene modifiers in the acute treatment of asthmaexacerbations. Curr Opin Pulm Med. 2003;9:52-56.114. Camargo CA, Smithline MA, Malice MP, et al. Arandomized controlled trial of intravenous montelukastin acute asthma. Am J Respir Crit Care Med. 2003;166:528-533.115. Dempsey OJ, Lipworth BJ. Intravenous mon-telukast in acute asthma: expensive aminophylline?Thorax. 2000;55:808-809.116. Rowe BH, Edmonds ML, Spooner CH, CamargoCA. Evidence-based treatments for acute asthma. RespirCare. 2001;46:1380-1390.117. Anthonisen NR, Connett JE, Kiley JP, et al. Effectsof smoking intervention and the use of an inhaled anti-cholinergic bronchodilator on the rate of decline ofFEV1. The Lung Health Study. JAMA. 1994;272:1497-1505.118. Nichol KL, Margolis KL, Wuorenma J, VonSternberg T. The efficacy and cost effectiveness of vacci-nation against influenza among elderly persons living inthe community. N Engl J Med. 1994;331:778-784.119. Ramsey SD. Suboptimal medical care in COPD:exploring the causes and consequences. Chest. 2000;117(suppl):S33-S37.120. Rowe BH, Bota GW, Fabris L, Therrien SA, MilnerRA, Jacono J. Inhaled budesonide in addition to oralcorticosteroids to prevent asthma relapse following dis-charge from the emergency department: a randomizedcontrolled trial. JAMA. 1999;281:2119-2126.121. Sin DD, Man SF. Low-dose inhaled corticosteroidtherapy and risk of emergency department visits for asth-ma. Arch Intern Med. 2003;162:1591-1595.122. Smith MJ, Rascati KL, McWilliams BC. Inhaledanti-inflammatory pharmacotherapy and subsequenthospitalizations and emergency department visits amongpatients with asthma in the Texas Medicaid program.Ann Allergy Asthma Immunol. 2004;92:40-46.123. Freund DA, Stein J, Hurley R, Engel W, WoomertA, Lee B. Specialty differences in the treatment of asth-ma. J Allergy Clin Immunol. 1989;84:401-406.124. Zeiger RS, Heller S, Mellon MH, Wald J, FalkoffR, Schatz M. Facilitated referral to asthma specialistreduces relapses in asthma emergency room visits. J Allergy Clin Immunol. 1991;87:1160-1168.125. Mahr TA, Evans R 3rd. Allergist influence on asth-ma care. Ann Allergy. 1993;71:115-120.126. Westley CR, Spiecher B, Starr L, et al. Cost effec-tiveness of an allergy consultation in the management ofasthma. Allergy Asthma Proc. 1997;18:15-18.127. Vollmer WM, O’Hollaren M, Ettinger KM, et al.Specialty differences in the management of asthma. Across-sectional assessment of allergists’ patients and gen-eralists’ patients in a large HMO. Arch Intern Med.1997;157:1201-1208.128. Kelly CS, Morrow AL, Shults J, Nakas N, StropeGL, Adelman RD. Outcomes evaluation of a compre-hensive intervention program for asthmatic childrenenrolled in Medicaid. Pediatrics. 2000;105:1029-1035.



129. Schatz M, Cook EF, Nakahiro R, Petitti D. Inhaledcorticosteroids and allergy specialty care reduce emer-gency hospital use for asthma. J Allergy Clin Immunol.2003;111:503-508.130. Ziedalski TM, Sankaranarayanan V, Chitkara RK.Advances in the management of chronic obstructive pul-monary disease. Expert Opin Pharmacother. 2003;4:1063-1082.131. Barnes PJ. New treatments for COPD. Nat RevDrug Discovery. 2002;1:437-446.132. Di Maria G, Spicuzza L, Mazzarella G. Futuretreatment of chronic obstructive pulmonary disease.Monaldi Arch Chest Dis. 2002;57:200-205.133. Friedman M. Future treatment strategies for COPD.Clin Cornerstone. 2003;5:45-51.134. DeKorte CJ. Current and emerging therapies for themanagement of chronic inflammation in asthma. Am JHealth-Syst Pharm. 2003;60:1949-1959.135. Sullivan SD, Meltzer EO. Emerging therapeuticstrategies for asthma management. J Manag Care Pharm.2003;9(suppl):S14-S21.136. Kips JC. Cytokines in asthma. Eur Respir J.2001;18(suppl):S24-S33.137. Kips JC, Tournoy KG, Pauwels RA. New anti-asth-ma therapies: suppression of the effect of interleukin (IL)-4 and IL-5. Eur Respir J. 2001;17:499-506.138. Peccini F, Dottorini ML, Casucci G, et al.Ineffectiveness of a four-week treatment with the throm-boxane synthetase inhibitor, imidazole salycilate, inreducing airway hyperresponsiveness to methacholine inasthmatics. Monaldi Arch Chest Dis. 1997;52:130-137.139. Giembycz MA. Cilomilast. A second generationphosphodiesterase 4 inhibitor for asthma and chronic

obstructive pulmonary disease. Expert Opin InvestDrugs. 2001;10:1361-1379.140. Jackson DY. Alpha 4 integrin antagonists. CurrPharm Des. 2002;8:1229-1253.141. Walker S, Monteil M, Phelan K, Lasserson TJ,Walters EH. Anti-IgE for chronic asthma. CochraneDatabase Syst Rev. 2004.142. Donahue JG, Weiss ST, Livingston JM, GoetschMA, Greineder DK, Platt R. Inhaled steroids and the riskof hospitalization for asthma. JAMA. 1997;277:887-891.143. Blais L, Ernst P, Boivin JF, Suissa S. Inhaled corti-costeroids and the prevention of readmission to hospitalfor asthma. Am J Respir Crit Care Med. 1998;158:126-132.144. Suissa S, Ernst P, Kezouh A. Regular use of inhaledcorticosteroids and the long term prevention of hospitali-sation for asthma. Thorax. 2002;57:880-884.145. Lieu TA, Quesenberry CP Jr, Capra AM, Sorel ME,Martin KE, Mendoza GR. Outpatient management prac-tices associated with reduced risk of pediatric asthmahospitalization and emergency department visits.Pediatrics. 1997;100(3 pt 1):334-341.146. Cowie RL, Revitt SG, Underwood MF, Field SK.The effect of a peak flow-based action plan in the pre-vention of exacerbations of asthma. Chest. 1997;112:1534-1538.147. Adams RJ, Smith BJ, Ruffin RE. Factors associatedwith hospital admissions and repeat emergency depart-ment visits for adults with asthma. Thorax. 2000;55:566-573.148. Abramson MJ, Bailey MJ, Couper FJ, et al. Are asth-ma medications and management related to deaths fromasthma? Am J Respir Crit Care Med. 2001;163:12-18.

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