AE of COPD

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DOI 10.1378/chest.119.4.11902001;119;1190-1209Chest

Douglas C. McCrory, Cynthia Brown, Sarah E. Gelfand and Peter B. BachSummary and Appraisal of Published Evidence

: A*Management of Acute Exacerbations of COPD

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) ISSN:0012-3692http://chestjournal.chestpubs.org/site/misc/reprints.xhtml(written permission of the copyright holder.No part of this article or PDF may be reproduced or distributed without the priorChest Physicians, 3300 Dundee Road, Northbrook, IL 60062. All rights reserved.been published monthly since 1935. Copyright2001by the American College of

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Management of Acute Exacerbations ofCOPD*

A Summary and Appraisal of Published Evidence

Douglas C. McCrory, MD, MHSc; Cynthia Brown, MD; Sarah E. Gelfand, BA;and Peter B. Bach, MD

Study objectives: To critically review the available data on the diagnostic evaluation, risk stratifica-tion, and therapeutic management of patients with acute exacerbations of COPD.

Design, setting, and participants: English-language articles were identified from the followingdatabases: MEDLINE (from 1966 to week 5, 2000), EMBASE (from 1974 to week 18, 2000),HealthStar (from 1975 to June 2000), and the Cochrane Controlled Trials Register (2000, issue 1).The best available evidence on each subtopic then was selected for analysis. Randomized trials,

sometimes buttressed by cohort studies, were used to evaluate therapeutic interventions. Cohortstudies were used to evaluate diagnostic tests and risk stratification. Study design and results weresummarized in evidence tables. Individual studies were rated as to their internal validity, externalvalidity, and quality of study design. Statistical analyses of combined data were not performed.

Measurement and results: Limited data exist regarding the utility of most diagnostic tests. However,chest radiography and arterial blood gas sampling appear to be useful, while short-term spirometrymeasurements do not. In terms of the risk of relapse and the risk of death after hospitalization for anacute exacerbation, there are identifiable clinical variables that are associated with these outcomes.Therapies for which there is evidence of efficacy include bronchodilators, corticosteroids, andnoninvasive positive-pressure ventilation. There is also support for the use of antibiotics in patientswith more severe exacerbations. Based on limited data, mucolytics and chest physiotherapy do notappear to be of benefit, and oxygen supplementation appears to increase the risk of respiratoryfailure in an identifiable subgroup of patients.Conclusions: Although suggestions for appropriate management can be made based on availableevidence, the supporting literature is spotty. Further high-quality research is needed and will requirean improved, generally acceptable, and transportable definition of the syndrome acute exacerbationof COPD and improved methods for observing and measuring outcomes.

(CHEST 2001; 119:11901209)

Abbreviations: ACCPAmerican College of Chest Physicians; ACPAmericanCollege of Physicians; APACHE acutephysiology and chronic health evaluation; ASIM American College of Physicians-American Society for Internal Medicine;CI confidence interval; CXR chest radiograph; EV external validity; Exp experimental; MDImetered-doseinhaler; NPPV noninvasive positive-pressure ventilation; Obs observational; PEFR peak expiratory flow rate;RCT randomized controlled trial; SCCOPE trial Systemic Corticosteroids in COPD Exacerbations trial

*From the Center for Clinical Health Policy Research (Drs.McCrory and Brown), Duke Evidence-Based Practice Centerand Duke University Medical Center, Durham, NC; and theDepartment of Epidemiology and Biostatistics (Ms. Gelfand andDr. Bach), Health Outcomes Research Group, Memorial Sloan-Kettering Cancer Center, New York, NY. This paper also ap-peared in Annals of Internal Medicine 2001; 134:600 620.This article is based on research conducted by investigators atMemorial Sloan-Kettering Cancer Center, New York, NY, undercontract with the ACPASIM and the ACCP, and by investigators atDuke University, Durham, NC, under contract with the Agency for

Healthcare Research and Quality (contract No. 29097-0014).The authors of this article are responsible for its contents,including any clinical or treatment recommendations. No state-ment in this article should be construed as an official position ofthe Agency for Healthcare Research and Quality of the USDepartment of Health and Human Services.Manuscript received August 1, 2000; revision accepted Decem-ber 8, 2000.Correspondence to: Peter B. Bach, MD, MAPP, Health Out-comes Research Group, Memorial Sloan-Kettering CancerCenter, 1275 York Ave, Box 221, New York, NY 10021.

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This article describes the background evidence forthe clinical practice guidelines entitled The

Evidence Base for Management of Acute Exacerba-tions of COPD. A joint panel from the AmericanCollege of Physicians (ACP)-American Society for

For related article see page 1185

Internal Medicine (ASIM) and the American Col-lege of Chest Physicians (ACCP) assisted in thedesign, conduct, and development of this summary,

which is based in large part on the evidence reportproduced by the Evidence-Based Practice center atDuke University, Durham, NC.1

The primary aims of this article are to summarizeand evaluate the published data addressing the careof patients with acute exacerbations of COPD and toimprove the care that these patients receive byidentifying efficacious and inefficacious treatmentstrategies. We first review the health impact of

COPD. We then define the entityacute exacerbationand describe the methods that we used to identifyand grade the available data on the care of patients

with this condition. In the Results section, weassess studies that evaluate diagnostic techniques,prognostic and risk stratification models, and anarray of therapies and interventions. In the conclud-ing sections, we review important elements of pos-texacerbation management, with special attention tofollow-up care, and gradual titration of therapeuticagents such as oxygen and corticosteroids. Last, wecomment on domains of management for patients

with acute exacerbations that would most benefitfrom further research.

COPD

In the United States at present, 16 millionadults are afflicted with COPD, a slowly progressivecondition that typically becomes symptomatic in thefifth and sixth decade of life. As the US populationages, the prevalence of this disease is expected toclimb.2 COPD currently accounts for approximately110,000 deaths per year, making it, after heartdisease, cancer, and stroke, the fourth leading causeof death. Nonasthma COPD in the United States

annually accounts for 16,367,000 office visits,500,000 hospitalizations, and direct health-care costsof $18 billion.3,4

The term COPD is used to describe a range ofpathophysiologic entities that are characterized byairflow obstruction, including chronic bronchitis,emphysema, asthma, and bronchiectasis. In this ar-ticle, and in our guidelines, we focus our attention onthe care of patients with the chronic bronchitis and

emphysema, an approach consistent with the Na-tional Heart, Lung, and Blood Institute definition ofCOPD as an umbrella term used to encompassseveral more specific respiratory conditions includ-ing chronic (obstructive) bronchitis and emphyse-ma.5 In fact, separating these entities is difficult both

when evaluating clinical studies and when practicingclinical medicine.

Causes of COPD include smoking (85 to 90% ofall cases), genetic factors (including 1-antitrypsindeficiency), passive smoking, occupational expo-sures, air pollution, and possibly hyperresponsiveairways. Although the precise distinctions betweenchronic bronchitis and emphysema are a subject ofdebate, tradition holds that chronic bronchitis isresponsible for 85% of COPD. Patients with chronicbronchitis experience intermittent airway inflamma-tion that leads to frequent, prolonged episodes ofproductive cough. In contrast, 15% of patients withCOPD suffer primarily from emphysema, a diseasein which destruction of the infrastructure of alveoli

and distal airspaces, and thus the portion of the lungthat provides elastic recoil, occurs. Both conditionspredispose patients to a common constellation ofsymptoms and signs, and to a collection of derange-ments in respiratory function.

Spirometric testing is used to confirm the diag-nosis of COPD. Typical abnormalities include adecrease in FEV1 and a decrease in the ratio ofFEV1 to FVC. Other abnormalities include anincreased residual volume and total lung capacity,and a limited and incomplete response in FEV1 tobronchodilators (incomplete reversibility). A di-minished diffusing capacity of the lung for carbon

monoxide is often seen in patients with emphy-sema, and a response to bronchodilators can beseen in patients with concomitant asthma. Severalstaging systems are available for patients withstable COPD. Both the European RespiratorySociety and the American Thoracic Society sys-tems use FEV1, which correlates most closely withmortality and frequency of acute exacerbation, asthe sole staging characteristic. The British Tho-racic Society staging definition also includes clin-ical features of a patients cough, sputum, dyspnea,and lung sounds (Table 1).

What Is an Acute Exacerbation of COPD?

In evaluating the published literature, and indeveloping practice guidelines, we have attempted toadhere to a generally accepted and useful concept ofan acute exacerbation or flare of COPD. Unfortu-nately, many definitions exist, many authors employsubstantively different criteria, and many studies

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poorly describe their inclusion criteria. As a gener-alization, however, most published definitions em-brace some combination of the following three clin-ical findings: worsening of dyspnea; increase insputum purulence; and increase in sputum volume.Unlike the staging systems for stable COPD, thereare no standardized, validated grading systems forthe severity of an acute exacerbation. Probably the

most commonly used system was developed byAnthonisen and colleagues6 and is based on theseand other symptoms. Patients with type 1 (severe)exacerbations have all three of the above symptoms,and those with type 2 (moderate) exacerbations havetwo of three of the symptoms. Patients with type 3(mild) exacerbations have at least one of thesesymptoms, as well as one of the following clinicalcriteria: an upper respiratory tract infection in thepast 5 days; fever without another apparent cause;increased wheezing; increased cough; or increase inrespiratory rate or heart rate by 20% above baseline(Table 1).6 Clinicians should be aware that other

conditions such as heart failure and pulmonary em-bolism can mimic an acute exacerbation.Tracheobronchial infections are believed to be a

common inciting cause of acute exacerbations ofCOPD; however, controversy exists regarding thenature of the infectious agent, as well as its exactrole. Sputum obtained from patients with mild tomoderately severe chronic bronchitis routinely growa variety of bacteria in cultures, including Haemophi-

lus influenzae (22%), Pseudomonas aeruginosa(15%), Streptococcus pneumoniae (10%), andMoraxella catarrhalis (9%).7 Nonpathogenic bacte-ria, such as Haemophilus parainfluenzae, account forup to one third of all isolates. Also, the followingcertain groups of patients are more likely to becolonized with resistant organisms such as Pseudo-monas: patients from nursing homes; patients re-

cently treated with antibiotics; and patients admittedto ICUs. The role of these colonizers in the patho-genesis of acute exacerbation remains unclear, andtheir presence makes the interpretation of any spu-tum culture difficult. Some investigators810 alsohave proposed that Mycoplasma pneumoniae orChlamydia pneumoniae may precipitate between 1%and 10% of exacerbations, and others11,12 havepointed out that the presence of eosinophilic inflam-mation in bronchial biopsy specimens of patients

with exacerbations is consistent with viruses (notablyrhinovirus) playing an important role.

Acute exacerbations are clearly associated with

environmental exposures as well, as significant cor-relations between levels of respirable particles (di-ameter, 10 m) and ozone have been linked tohospital admission rates.13 Finally, severe exacerba-tions may be precipitated by other serious clinicalconditions, such as heart failure, nonpulmonary in-fections, pulmonary embolism, and pneumothorax.14

The outcomes of COPD exacerbations are simi-larly heterogeneous. While nearly 50% of exacerba-

Table 1Available Staging Systems for COPD*

Staging Systems

Staging Systems for Stable COPD

Mild Moderate Severe

Stable COPDERS guidelines109

FEV1 70% 5069% 50%ATS 1995 guidelines110

FEV1

50% 3549% 35%BTS Guidelines111

FEV1 6079% predicted 4059% predicted 40% predictedCough Smokers cough Cough ( sputum) ProminentDyspnea Minimal On exertion On exertion or at restLung examination findings N1 wheeze Hyperinflation, wheezeOther examination findings N1 N1 Cyanosis, edema

Acute exacerbations of COPDType 3 1 of 3 symptoms as well as 1 of the

following: upper respiratory tractinfection in past 5 d, fever withoutother apparent cause, 1 wheezing,1 cough, and 1 respiratory rate orheart rate by 20% above baseline

Type 2 2 of 3 symptomsType 1 All 3 symptoms

*N1 normal;1 increase;2 decrease; ERS European Respiratory Society; ATS American Thoracic Society; BTS British ThoracicSociety.

Cardinal symptoms of acute exacerbations of COPD: worsening of dyspnea; increase in sputum purulence; and increase in sputum volume.6

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tions are not reported to physicians,15,16 exacerba-tions requiring hospitalization are associated with aninpatient mortality of 3 to 4%.17 For those patientsrequiring treatment in an ICU for an acute exacer-bation, mortality rates are substantially higher (inhospital, 11 to 24%; by 1 year, 43 to 46%). 14,1821

After an acute exacerbation, most patients are ex-pected to experience at least a temporary decrementin functional status and quality of life,16,22,23 and halfof those patients who are hospitalized are expectedto be readmitted at least once in the ensuing 6months.14,24

Materials and Methods

Identification of Topics for Literature Search

Topics to be covered in this article and in the practice guidelinewere determined through a consensus process that involved boththe ACP-ASIM/ACCP expert panel and the technical advisorypanel of the Evidence-Based Practice Center at Duke University

(Durham, NC). The topic list was generated to address thefollowing three questions: (1) what information is available to aidclinicians in predicting the clinical course of a patient with anacute exacerbation?; (2) what information is available about theutility of diagnostic tests used to evaluate patients with symptomsof acute exacerbation?; and (3) what information is available tohelp guide clinicians in using available therapies and interven-tions? In this article, we do not consider the care of patients instable condition with chronic COPD, experimental (Exp) thera-pies that are not widely available, or the provision of invasivemechanical ventilation.

Search Strategy

The information presented in this report was gathered through

systematic searches and ongoing surveillance of the MEDLINE(from 1966 to week 5, 2000), EMBASE (from 1974 to week 18,2000), and HealthStar (from 1975 to June 2000) databases and ofthe Cochrane Controlled Trials Register (2000, issue 1). Searchstrategies included index terms and text words for COPD andacute exacerbation and specific terms relating to the interven-tions and outcomes discussed in ensuing sections. Variations onseveral search strategies were tested in order to locate thegreatest number of relevant articles. The abstracts of relevantarticles were reviewed against predetermined criteria, appropri-ate articles were retrieved, and the reference lists of those wereexamined. Seven hundred seven full-text articles were obtainedthrough this process, and those that were eligible for analysis

were summarized in evidence tables. The data, study methods,and evidence available in each article then were evaluated in themanner described below.

Assessment of the Quality of Available Evidence

Each retrieved study was evaluated along the following twodimensions: to what extent did the study enroll the patients in

whom we were interested (external validity [EV])?; and to whatextent did the study follow the optimal design (internal validity)?Our criteria for EV hinged on the following two questions: didthe study enroll patients who had COPD by a conventionaldefinition (Table 1)?; and did the study enroll patients with acute

exacerbations of COPD, as documented both by a description ofthe cohort symptomatology and by a description of the diagnostictesting that was used to exclude other etiologies? We generateda scoring system for EV (Table 2) that ranged from 0 (poorestquality) to 5 (highest quality) based on the adequacy of thedocumentation of each study for these two concerns. Sample size

was not taken into consideration, and all comments about thesignificance of results reflect that the authors reported statisti-cal significance at the p 0.05 level.

Our criteria for internal validity differed when we evaluatedExp vs observational (Obs) studies. To evaluate Exp studies, weemployed the scoring system described by Jadad and colleagues25

that assigns scores based on the quality of design of randomizedcontrolled trials (RCTs) (Table 3). Specifically, scores range from0 to 5, and points are earned for adequate randomization,blinding, and assessment of withdrawals and dropouts. To eval-uate Obs studies, we used the hierarchy of evidence proposed byBall et al26 (Table 4). Unlike the Jadad scale for Exp designs,lower scores for the internal validity of Obs studies denote ahigher level of evidence. For studies that presented prognosticmodels, clinical prediction rules, or severity-of-illness algorithms,

we assessed the extent of model validation reported using thesystem proposed by Justice and colleagues27 (Table 5). Thisscoring system ranges from 0 to 5; higher scores reflect that theprediction model presented in the article has been more exten-

sively evaluated on independent populations of patients.For studies that appear in the tables, these scores are recorded

in those tables. For studies that are referenced only in the text,these assessments are recorded in parentheses the first time thestudy is mentioned in the following manner. EV is documented asa ratio of the total number of points earned to the number ofpoints possible (eg, 3:5 [Table 2]). For internal validity, the typeof study (Exp or Obs) is documented, followed by the score onthe relevant scale (see Tables 3 and 4). The degree of validationof prognostic models is relevant only to the studies presented inTables 7 and 8, and are reported there.

Choice of Inclusion of Studies for Reporting and Analysis

The minimum threshold for inclusion of studies of differentdesign types was driven by the relative availability of studies ineach category. Randomized, placebo-controlled studies are con-sidered to produce the highest level of evidence, but for some

Table 2EV Scale*

Scale Criteria

1 Validity of the underlying COPD diagnosisA. COPD diagnosis based on spirometry109

B. Baseline stable ventilatory status (eg, FEV1) ofstudy population described

2 Validity of diagnosis of acute exacerbation of COPD.Definition of acute exacerbation includes at least 2 ofthe following: increased sputum purulence; increased

sputum volume; increased dyspnea3 Characterization of severity of acute exacerbation of

COPD. Study describes the severity at enrollmentbased on at least 2 of the following: mental statuschange; work of breathing (ie, respiratory rate or useof accessory muscles); ventilatory status (ie, FEV1 orPEFR; Pco2 and either O2 saturation or Po2)

4 Duration of follow-up (treatment articles only);outcomes assessed at 24 h

*For each set of criterion: Yes 1, No 0.

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treatment and diagnostic modalities, information from thesetypes of studies was either scanty or lacking. Ultimately, we chosea different threshold of inclusion for each topic based on theavailability of relevant data (Table 6). The varying quality of theassessed studies is taken into account in the evaluation.

Approach to the Patient With an Acute

Exacerbation of COPD

In the following section, we discuss our recom-mendations and findings for the following threedomains of care for patients with acute exacerbations

of COPD: risk stratification of patients (specifically,data on predictors of outpatient relapse) and predic-tors of inpatient mortality; choice of diagnostic tests;and benefits and risks of therapeutic interventions,including mucus clearance strategies, bronchodilat-ing agents, corticosteroids, antibiotics, oxygen, andnoninvasive mechanical ventilation. Three method-ological problems hindered our analysis. First, thecare of patients with acute exacerbations of COPD issometimes characterized as shotgun therapy; thatis, most patients receive most available therapies. Assuch, many studies designed to evaluate one inter-

vention include patients receiving other interven-

tions, and these cointerventions make analysis of theeffects of single therapies more difficult, especiallywhen cointerventions are not standardized. Second,many studies evaluate changes in FEV1 as theprimary outcome of interest because it can be safelyand easily measured. This measure of respiratoryfunction, although a reliable predictor of other clin-ical outcomes, is relatively insensitive to changes inclinical condition when compared both to other

quantitative measures (such as arterial blood gasvalues) and to qualitative evaluations of symp-toms.15,28 Last, the majority of studies that we foundaddress the care of patients in emergency depart-ments or inpatient settings, while many patients withmilder acute exacerbations do not receive care inthese settings. As such, our conclusions are morefocused on the care of patients with more severeexacerbations.

Risk Stratification

Prediction of Outpatient Relapse

Based on 10 studies that evaluated patients withacute exacerbations of COPD in emergency depart-ments (7 studies) and in the outpatient setting (3studies), we concluded that certain characteristicsare associated with patients returning for more treat-ment rather than with those experiencing gradualimprovement (Table 7). The ability to identify pa-tients at high risk for relapse should improve deci-sions about hospital admissions and follow-up ap-pointments. Several investigators have confirmedthat patients who have lower pretreatment or post-treatment FEV1 levels, who receive more broncho-dilator treatments or corticosteroids during their visitor have higher rates of prior relapse, are more likelyto return (ie, relapse) than are patients with morefavorable values of these characteristics. At present,the available prediction models can provide clinicalguidance based on these identified predictors, andthose patients with these characteristics are at higherrisk of relapse. It should be noted that these models,

however, show only moderately good discriminatorypower. For example, the best model derived topredict relapse (defined as a return to the emergencydepartment within 14 days of initial presentation)had a sensitivity of 0.57 and a specificity of 0.72. 29

Prediction of Inpatient Mortality

Based on 11 studies, we concluded that certainphysiologic characteristics are associated with ahigher likelihood of inpatient mortality. Predictionmodels containing these characteristics are poten-tially useful for risk stratification in the context of

population-based and randomized studies. To theextent that these characteristics are used to influencedecisions about instituting, continuing, or withdraw-ing life-sustaining therapies, caution should be exer-cised. We identified no prediction models that wereable to identify patients who were virtually certain todie (for example, those with a likelihood of death of 90%) during their inpatient stay. It should benoted also that in these studies, there is substantial

Table 3Internal Validity Scale (Exp Studies)*

1. Was the study described as randomized?1 Yes0 No

2. Was the method of randomization well described and adequate?0 not described1 described and adequate1 described, but not adequate

3. Was the study described as double-blind?1 Yes0 No

4. Was the method of double-blinding well described andadequate?

0 not described1 described and adequate1 described, but not adequate

5. Was there a description of withdrawals and dropouts sufficientto determine the number of patients in each treatment groupentering and completing the trial?

1 Yes0 No

*Adapted from Jadad et al.25

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variability in the inclusion criteria, raising concernsabout the EV of some of these results. Of the 11studies, 8 (Table 8) documented an association be-tween specific clinical predictors and mortality,

while the other 3 studies did not report significant

Table 4 Internal Validity Scale (Obs Studies)*

Grade ofRecommendation

Level ofEvidence Prognosis Diagnosis

A 1a SR (with homogeneity) of inception cohort studies; or aCPG validated on a test set.

SR (with homogeneity) of level 1 diagnosticstudies; or a CPG validated on a test set

1b Individual inception cohort study with 80% follow-up

Independent blind comparison of anappropriate spectrum of consecutive

patients, all of whom have undergone boththe diagnostic test and the referencestandard

1c All or none case-series Absolute SpPins and SnNoutsB 2a SR (with homogeneity) of either

retrospective cohort studies oruntreated control groups inRCTs

SR (with homogeneity) of level 2diagnostic studies

2b Retrospective cohort study orfollow-up of untreated controlpatients in an RCT; or CPGnot validated in a test set.

Independent blind comparison but either innonconsecutive patients or confined to anarrow spectrum of study individuals (orboth), all of whom have undergone boththe diagnostic test and the referencestandard; or a diagnostic CPG not

validated in a test set2c Outcomes research3 Independent blind comparison of an

appropriate spectrum, but the referencestandard was not applied to all studypatients

C 4 Case-series (and poor quality prognostic cohort studies)

Reference standard was not appliedindependently or not applied blindly

D 5 Expert opinion without explicitcritical appraisal, or based onphysiology, bench research, orfirst principles

Expert opinion without explicit criticalappraisal, or based on physiology, benchresearch, or first principles

*Adapted from Centre for Evidence-Based Medicine.26 SR systematic review; CPG clinical practice guidelines; SpPin diagnostic findingthe specificity of which is so high that a positive result rules in the diagnosis; SnOut diagnostic finding the sensitivity of which is so high thata negative result rules out the diagnosis.

Homogeneity means free of worrisome variations in the directions and degrees of results between individual studies.Well-designed prospective studies were included in this category.

Inception cohort studies with 80% follow-up and retrospective studies were included in this category.Poor quality prognostic cohort studies include ones in which sampling was biased in favor of patients who already had the target outcome, or inwhich the measurement of outcomes was accomplished in 80% of study patients, or in which outcomes were determined in an unblinded,nonobjective way, or in which there was no correction for confounding factors.

Table 5Degree of Validation of Predictive Models

Level Description

0 Internal validation1 Prospective validation2 Independent validation3 Multisite validation4 Multiple independent validations5 Multiple independent validations with life-table analyses

Table 6 Inclusion Thresholds by Topic

TopicMinimum Study Design

Included

Diagnosis/prognosis Cohort designMucus clearance

strategiesRandomized, placebo-controlled

Bronchodilating agents Randomized, agent-to-agentcomparisons

Corticosteroids Randomized, placebo-controlledAntibiotics Randomized, placebo-controlledOxygen therapy Obs cohortNPPV Randomized, controlled; Obs

cohort

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Table7PredictorsofRelapseAnalyzedinMoreThanOneStudy*

Predictors

Fedulloetal112/

1986

(n

24)

Murataetal113/

1989

(n

268)

E

mermanetal114/

1991

(n

83)

Murataetal115/

1991

(n

352)

Murataetal29/

1992

(n

289)

Murataetal29/

1992

(n

213)

Balletal116/

1995

(n

471)

Parshall117/

1999

(n

239)

Adamsetal118/

2000

(n

173)

Dewanetal119/

2000

(n

107)

Patientdemographics

Olderage

Femalesex

Smokinghistory

Clinicalcharacteristics

1

Bodytemperature

1

Heartrate

1

Respiratoryrate

1

WBCcount

Hypertension

Diabetes

Liverdisease

Chronicrenalfailure

Heartdisease/heartfailure

Pulmonaryfunctiontests

%RecoveryofFEV1

Paco2

1

Pao2

2

pH2

PosttreatmentFEV1

2

PretreatmentFEV1

2

Severityofexacerbation

Abnormalfindingsonauscultation

EDtimingandvisits

Admissionrateofprevious

visits1

Previousvisitwithin7d

Relapserateofpreviousvisits1

Nighttimeadmission

Treatment

Useofhomeoxygen

Weekendvisit

Shorterdurationofdyspnea

Aminophyllinetreatment

Noantibioticsondischarge

Lengthoftreatment

Numberofbronchodilatortreatments1

Oralprednisoneatentry

Nooralprednisoneatdisch

arge

SteroidtreatmentinED

INTV

2b

2b

1b

2b

2b

2b

1b

1b

4

2b

EV

1

2

2

4

2

2

1

0

3

2

*ED

emergencydepartmen

t;INTV

internalvalidity;

statisticallysig

nificantlyassociatedwithrelapse;

notstatis

ticallysignificantlyassociatedwithrelapse.SeeTable1forabbreviationsnot

usedintext.Degreeofvalid

ationofmodeliszeroinallcases.

Murataetal29

andMurataetal115

containpartiallyoverlappingstudypopulations.

Threehundredsixty-twopat

ientvisitswereanalyzedfromasampleof173

patients.

Twohundredthirty-twoexacerbationswereanalyzedfromasampleof107

patients.

Indicatesscoreoutofapossibletotalof4points.

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predictors.17,30,31 The two largest studies examiningthis outcome are summarized below.

The Study to Understand Prognoses and Prefer-ences for Outcomes and Risks of Treatments en-

rolled 1,016 patients with acute exacerbations ofCOPD on hospital admission.14 The patients hada variety of etiologies for exacerbation, includingrespiratory tract infection (including pneumonia)(48%), congestive heart failure (26%), lung cancer(3.3%), pulmonary embolus (1.4%), and pneumotho-rax (1%). The outcome of interest was mortality by180 days, which was 33% (2-year mortality, 49%).Significant predictors were worse acute physiology

score from the acute physiology and chronic healthevaluation (APACHE) III algorithm,32 lower bodymass index, older age, worse functional status 2

weeks before hospital admission, lower Po2/fraction

of inspired oxygen ratio, history of congestive heartfailure, lower serum albumin level, presence of corpulmonale, lower activities of daily living scores, andlower Duke activity status index score. Predictionsfrom the model that included these variables showedgood calibration (calibration index, 0.0016) and fairdiscrimination (area under receiver operating char-acteristics curve, 0.731) in a validation cohort.

Another large prospective cohort study enrolled

Table 8 Statistically Significant Predictors of Inpatient Mortality*

Study/yr Setting Analysis N

Validity

Significant Predictors of MortalityExt IntDegree ofValidation

Connors et al21/1981 ICU Multi 1,016 1 1b 3 1 APS2 BMI1 Age

2 ADL2 Pao2/Fio2 ratioAbsence of comorbid CHF2 Serum albuminAbsence of comorbid cor pulmonale

Seneff et al20/1995 ICU Multi 362 1 1b 0 1 Nonrespiratory APS score1 No. of pre-ICU hospital days

Burk and George18/1973

Hospital ward/ICU Uni 74 1 2b 0 Use of mechanical venti lation (vs conservative care)

General medical ward care (vs ICU care)CHF as etiology of ARF (vs respiratory infection)

Warren et al120/1980 Hospital ward Uni 135 2 2b 0 1 AgeHighest level of arterial Paco2 during controlled

oxygen therapyLowest pH 7.26 (p 0.025)

Jeffrey et al121/1992 Hospital Uni 95 2 1b 2 Measured at admission

1 blood urea concentration2 systolic BP2 arterial pH

Measured throughout hospital stayLowest pH 7.26Lowest pH 7.28

Heuser et al122/1992 ICU Multi 3,050 0 2b 0 1 AgePrimary diagnosis pneumonia (vs asthmatic bronchitis)MedisGroups Admitting severity group 3 or 4

Portier et al19/1992 ICU Multi 322 1 1b 0 Presence of cachexia2 Serum sodiumRequired mechanical ventilation in first 24 hNot COPD as underlying chronic respiratory

insufficiencyPrevious confinement to homePresence of edema

Fuso et al123/1995 Hospital Multi 590 3 2b 0 1 AgeP(A-a)O2 41 mm HgPresence of atrial fibrillationPresence of ventricular arrhythmias

*Ext external; Int internal; Multi multivariate; Uni univariate; P(A-a)O2 alveolar-arterial oxygen pressure difference; BMI bodymass index; ADL activities of daily living; CHF chronic heart failure; APS acute physiology score; ARF acute respiratory failure.

Presence of predictor in noted direction is associated with an increased risk of mortality.

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362 patients who were admitted to ICUs with respira-tory failure because of COPD. Patients with pneumo-nia, pulmonary edema, or pulmonary embolus wereexcluded. The in-hospital mortality of 23.8% was pre-dicted by the number of pre-ICU hospital days and the

nonrespiratory component of the APACHE III score.A separate analysis identified the following three pre-dictors of 180-day mortality: acute physiology score; oldage; and a higher number of pre-ICU hospital days.Activities of daily living were also a significant predictoron univariable analysis.20

Diagnostic Testing

General Approach

Many assessment techniques frequently are usedin evaluating patients with acute exacerbations ofCOPD. These include measuring routine laboratory

values, performing a physical examination, obtainingan ECG, assessing cardiac function, and institutingan empiric trial of diuretics. We found no publishedevidence that could help us to determine the utilityof these approaches. For another commonly usedassessment (arterial blood gas sampling), we foundindirect evidence in a number of studies supportingits clinical utility. These studies, which are covered indetail in other parts of this report, demonstrate thatarterial blood gas analysis is helpful both in terms ofgauging the severity of an exacerbation, and inidentifying those patients currently in need of oxygentherapy and those potentially requiring mechanical

ventilatory support. Two other diagnostic modalities,chest roentgenography and spirometric testing, havebeen assessed and are discussed below.

Chest Roentgenography in Establishing Causes/Coexisting Illnesses in Acute Exacerbation ofCOPD

Based on three Obs studies, we concluded that forpatients treated in emergency departments or hos-pitals, a chest radiograph (CXR) is a useful diagnostictest. A substantial rate of CXR abnormalities wasdocumented in the following two retrospective stud-ies: 16% abnormality rate from a study of 685episodes occurring in a single urban emergency

department (EV, 0/4; internal validity, Obs 2b)33

;and 16% (7% judged as clinically significant) oc-curring in 107 patients admitted to a single hospital(EV, 0/4; internal validity, Obs 2b).34 In a prospec-tive cohort study of 128 hospital admissions forasthma or COPD, 21% of patients had a change inmanagement that was prompted by their CXR result(the majority of these patients had new pulmonaryinfiltrates or evidence of congestive heart failure)

(EV, 14; internal validity, Obs 1b).35 Models pre-sented by these authors for predicting CXR abnor-malities were not sufficiently reliable to be clinicallyuseful.

Spirometric Testing

Although several studies have shown that FEV1 is

loosely correlated with relapse rate, based on threeObs studies, we concluded that spirometric assess-ment at the time of presentation or during the courseof treatment is of limited usefulness in the care ofpatients with acute exacerbations of COPD. Changesin clinical status do not correlate well, in general,

with changes in spirometric measures in patientswith this disease. A study performed in one urbanemergency department (EV, 3:4; internal validity,Obs 1b) enrolling 70 patients demonstrated thatFEV1 at the time of presentation was weakly, butstatistically significantly, correlated with both Pco2(r0.46; p 0.001) and pH (r 0.33; p 0.01)

but was uncorrelated with arterial Po2. These resultsare different from those seen in studies of patients

with asthma presenting to the emergency depart-ment, in which spirometry and arterial blood gaslevels are highly correlated.36 Another study enroll-ing 199 patients presenting with acute exacerbationof COPD in an urban emergency department dem-onstrated that peak expiratory flow rate (PEFR) andFEV1 are correlated (r 0.84; p 0.001); the clin-ical implication of this finding, however, is unclear(EV, 1:4; internal validity, Obs 1b).37 This latter studyalso noted that for a minority of patients, the absolutedifference between the percent predicted values basedon FEV1 and those based on PEFR was 10%.

Therapeutic Interventions

Bronchodilating Agents

Based on 14 randomized studies, we concludedthe following: that short-acting -agonist-type andanticholinergic-type inhaled bronchodilators havecomparable effects on spirometry and a greatereffect than all parenterally administered bronchodi-lators (ie, parenteral methylxanthines and sympatho-mimetics); that the toxicity profile of the methylxan-thine agents makes them potentially harmful; and

that there may be an additional benefit in somepatients when a second bronchodilating agent isadministered once the maximal dose of the initialinhaled bronchodilator is reached. These generaliza-tions are limited by the small number of analyzabletrials38,39 that have been published, the substantialdifferences in inclusion and exclusion criteria be-tween them, and the variability in drug dosages that

were studied.

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Efficacy of Bronchodilators: There were fiveRCTs that compared individual bronchodilatingagents. Two RCTs39,40 compared the efficacy ofinhaled ipratropium bromide to that of short-acting-agonists (EV, 2:5; internal validity, Exp 3:539; EV,3:5; internal validity, Exp 5:540). The first studyenrolled 40 patients and observed that FEV1 amongthose receiving ipratropium showed statistically sig-nificant improvement from day 1 to day 7 at 15 and30 min after administration, while no significantdifferences were seen at 0, 5, 10, 60, 120, and 240min after administration. Similarly, the only signifi-cant improvement observed in patients receivingfenoterol was at 60 min after treatment on day 7(p 0.05).39 The second study involved 32 patientsin a crossover design comparing ipratropium andmetaproterenol. At 30 min after administration, pa-tients receiving ipratropium had a significant rise inPao2, while those receiving metaproterenol had asignificant fall in Pao2. At 90 min, these differenceshad disappeared, and both patient groups showed a

significant improvement in FEV1. However, no ad-ditional improvement was seen after the patients

were crossed over to treatment with the seconddrug.40 In a study of 90 patients with asthma and/orCOPD during transport to an emergency depart-ment, treatment with nebulized albuterol was com-pared to treatment with subcutaneous terbutaline.Patient-perceived improvement, respiratory rate,and dyspnea rating showed significant improvementsonly in the group receiving albuterol (p 0.05) (EV,0:5; internal validity, Exp 5:5).41 In a dosing study42

involving 86 patients, there were no significant dif-ferences in FEV1 at 2 h between patients receiving

nebulized albuterol, 2.5 mg, given every 20 min andthose receiving nebulized albuterol, 2.5 mg, givenevery hour, although there was a suggestion thatpatients with lower FEV1 benefited from the formerregimen (EV, 1:5; internal validity, Exp 4:5).

Incremental Benefit of a Second Bronchodilator:The addition of a methylxanthine to inhaled bron-chodilators was examined in three randomized stud-ies. One study43 involving 143 patients with asthmaand COPD receiving care in an emergency depart-ment reported a trend toward lower hospitalizationrates for patients given aminophylline in addition to

short-acting -agonists and corticosteroids (EV, 1:5;internal validity, Exp 3:5). Two studies44,45 found nosignificant differences in measured changes in FEV1between patients receiving standard therapy (includ-ing short-acting -agonists) and those who also re-ceived aminophylline (EV, 4:5; internal validity, Exp5:544; EV, 1:5; internal validity, Exp 4:545). Theeffect of adding a second class of bronchodilator (ie,anticholinergic or short-acting -agonists) to a full-

dose regimen of the other agent has been examinedin seven randomized studies. Six of these stud-ies38,4650 specifically examined the impact of ananticholinergic added to a short-acting -agonist fortreatment of acute exacerbations of COPD. In astudy46 of 57 emergency department patients, theaddition of glycopyrrolate to albuterol resulted in aproportionally larger increase in FEV1 than thatexperienced by patients treated with albuterol alone.(EV, 2:5; internal validity, Exp 4:5). A study47 of 68emergency department patients found that the ad-dition of ipratropium to isoetharine resulted in sig-nificantly lower lengths of stay but that admissionrates to the hospital were similar (EV, 1:5; internal

validity, Exp 5:5). Three other studies38,48,49 wereunable to detect a difference in spirometry (FEV1and/or FVC) in patients treated with short-acting-agonists alone when compared to those who also

were given anticholinergic agents (EV, 3:5; internalvalidity, Exp 4:548; EV, 1:5; internal validity, Exp2:538; and EV, 1:5; internal validity, Exp 4:549). A

three-armed study50 examined 52 emergency depart-ment patients receiving a short-acting -agonistalone (fenoterol), an anticholinergic alone (ipratro-pium), or both agents. At 90 min, patients in all threegroups experienced similar improvements in FEV1.Patients receiving ipratropium alone had the lowestrate of reported side effects (EV, 2:5; internal valid-ity, Exp 5:5).

Adverse Effects: The adverse effects of broncho-dilators are varied. The side effects of ipratropiumbromide are generally fewer and milder. ThreeRCTs39,47,49 did not report any adverse effects withipratropium bromide. Other effects include in-creased incidence of tremors and dry mouth,40,50 andurinary retention when used in combination withalbuterol.48 The adverse effects of albuterol includetremors, headache, nausea, vomiting, and palpita-tions. Adverse cardiovascular effects such as changesin heart rate, BP, and ECG tracings are also possiblebut rare.51 Adverse effects associated with theophyl-line include nausea, vomiting, headache, arrhyth-mias, and seizures.44,52 The effects are more signifi-cant among those patients with higher levels oftheophylline.

Bronchodilating Agent Delivery Devices

Based on eight RCTs5360 comparing metered-dose inhalers (MDIs) and nebulizers in patients withacute exacerbations of COPD, we concluded thatthere is insufficient evidence to support the conclu-sion that one delivery modality is superior to theother. Of the eight studies, six5355,57,59,60 describedusing spacer devices with the MDIs, one56 specifi-

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Table9

RandomizedTrialsofCorticosteroidAgents*

Study/yr

Sa

mple

Size

CorticosteroidAgent

EquivalentDay1Dosageof

Methylprednisolone,mg

EndPoint

Steroidvs

Placebo

Steroid

OverTime

Validity

Bullardetal63/1996

138

Hydrocortisone(100mgIVonce)

20

1

FEV

1

from06h

External1:5

Internal4:5

Daviesetal66/1999

56

Prednisolone(30mgpodailyfor14d)

37.5

1

Mea

n%predictedprebronchodilator

FEV1

External4:5

Internal5:5

1

Mea

n%predicted

postb

ronchodilatorFEV1

2

Lengthofstay

Thompsonetal65/1996

27

Prednisone(60mgpodailyfor3d,

thentapered)

75

1

Mea

nslopeofFEV1

External5:5

%ChangeinFEV1

fromday1today

10

Internal3:5

Emermanetal64/1989

100

Methylprednisolone(100mgIVonce)

100

2

Lengthofstay

External3:5

1

FEV

1

(%improvement)

NR

Internal4:5

Hospita

ladmissionrate

Albertetal62/1980

44

Methylprednisolone(35mg[basedon

0.5mg/kg]IVevery6hfor3d)

140

1

FEV

1

(%changeprebronchodilator)

External4:5

Internal5:5

1

FEV

1

(%changepostbronchodilator)

Niewoehneretal67/1999

271

Methylprednisolone(125mgIVevery

6hfor3d,followedbypo

prednisonetaper)

500

2

Lengthofstay

External2:5

1

FEV

1

atdays1,2,and3

Internal4:5

*NR

notreported;

beneficialeffectofcorticosteroid;

beneficial

effectofplacebo.

Significanceatp

0.05leve

l.

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cally mentioned using an MDI without a spacer, andone (an abstract)58 did not describe whether or not aspacer was used. The percentage improvement inthe FEV1 was significantly larger after treatment

with the nebulizer than with the MDI in two stud-ies57,58 but was not significantly different in the othersix.5355,56,59,60 A meta-analysis61 of bronchodilatordelivery devices in acute airflow obstruction in-cluded these studies of COPD and additional studiesof patients with asthma. The meta-analysis found anegligible effect of nebulizers vs MDI that is neitherclinically nor statistically significant. The doses of thebronchodilator administered by MDIs in these stud-ies were lower than those delivered by nebulizer and

were lower than those often used in clinical practice,and, thus, the few positive results may reflect differ-ences in the dose of the bronchodilator actuallyreceived. Furthermore, the studies were all rathersmall, resulting in imprecise estimates of the efficacyof MDI vs nebulizer delivery.

Corticosteroid Drugs

Based on six randomized, placebo-controlled stud-ies, we concluded that a short course of systemiccorticosteroid therapy given to patients with acuteexacerbations of COPD improves spirometry anddecreases the relapse rate (Table 9). However, theoptimal dose and duration of treatment remainuncertain, and few data exist documenting the effi-cacy of corticosteroids for patients cared for inoutpatient settings. There was a great deal of vari-ability in the dosage, length of treatment, adminis-tration, and setting among the studies evaluated.6267

In the largest study, the Systemic Corticosteroids inCOPD Exacerbations (SCCOPE) trial, 271 patientsadmitted for acute exacerbations of COPD at one of25 Veterans Administration hospitals were assignedto receive placebo or 3 days of IV methylpred-nisolone followed by a course of oral prednisone.67

For the combined glucocorticoid group, the risk oftreatment failure was reduced by 10% (33% vs 23%),and FEV1 showed an improvement averaging ap-proximately 0.1 L in the first 3 days of treatment.The change in FEV1 is similar to the magnitude ofbenefit reported in smaller trials. The SCCOPE trialdemonstrated equivalence between an 8-week regi-

men and a 2-week regimen, the latter consisting ofthe following: methylprednisolone, 125 mg IV every6 h (on days 1 to 3); oral prednisone, 60 mg each day(on days 4 to 7); oral prednisone, 40 mg each day (ondays 8 to 11); and oral prednisone, 20 mg each day(on days 12 to 15).

Several trials have examined the time course ofimprovement in FEV1 during treatment with sys-temic corticosteroids. The difference in FEV1 be-

tween glucocorticoid-treated and placebo-treatedpatients in the SCCOPE trial was highest after thefirst day of treatment, remained statistically signifi-cant after the second and third days, and was nolonger significant at 2 weeks. Of two trials63,64 thatconsidered short-term outcomes of emergency de-partment treatment, one64 observed similar improve-ments in FEV1 in patients receiving corticosteroidsand placebo, and the other63 demonstrated a signif-icant improvement in FEV1 over time for patientsreceiving corticosteroids but did not compare thesepatients to those receiving placebo. Those trials thatmeasured FEV1 changes over longer periods of time,in contrast, have shown more conclusive results.

The most common adverse effect associated withsystemic corticosteroids for acute exacerbation ofCOPD was hyperglycemia.66,67 In the SCCOPE trial,two thirds of the episodes of hyperglycemia requir-ing treatment occurred in patients who were knownto have diabetes mellitus. Nearly all episodes oc-curred in the first 30 days, and whether hyperglyce-

mia was more frequent or severe in the 8-week orthe 2-week course of therapy was not described.67

Antibiotics

Based on 11 randomized, placebo-controlled stud-ies of antibiotic treatment, we concluded that anti-biotics are beneficial in the treatment of patients

with acute exacerbations of COPD (Table 10).6,6877

Patients with more severe exacerbations are morelikely to experience benefit than those who are lessill. These conclusions are consistent with those of arecent meta-analysis that included many of the trials

reviewed herein.78 It should be noted that many ofthe studies that do show benefit were performedbefore the emergence of respiratory pathogens thatare resistant to multiple antibiotics.

In their meta-analysis, Saint and colleagues78 in-cluded nine RCTs of antibiotics. These trials usedthe following variety of outcome measures: PEFR;duration of exacerbation; Pao2; symptom score; andoverall severity score as determined by a physician.Three of nine studies6,6875 found a statisticallysignificant benefit for antibiotics, three found a trendfavoring antibiotics, and three failed to show anydifference from placebo. The most consistently mea-

sured end point across studies, improvement inPEFR, was estimated to improve a mean of 10.75L/min more in patients treated with antibiotics thanin patients treated with placebo (95% confidenceinterval [CI], 4.96 to 16.54).

Three of these studies6,68,75 analyzed the efficacyof antibiotics within subgroups defined either byevidence of bacterial infection or by severity ofillness. One trial6 found that an a priori selection of

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Table10CharacteristicsofRCTsofAntibioticsinAcuteExa

cerbationsofCOPD*

Study/yr

Patients,No.

Medication

MeanPEFR

atEntry,

L/min

Patient

s

With

Purulen

t

Sputum,

%

Level

ofCare

Glucocorticoid

Use

Resu

lts

Validity

TreatmentGroup

Control

Group

Jrgensenetal71/1992

268

Amoxicillin

Placebo

295

33

Opt

Prohibited

Overallclin

ical

assessment

External2:5

Symptoms(MD)

Internal3:5

PEFR

Sachsetal77/1995

71

Amoxicillinorcotrimoxazole

Placebo

233

27

Opt

Prescribed

Symptoms(pt)

External4:5

PEFR

Internal4:5

Petersenetal73/1967

19

Chloramphenicol

Placebo

214

74

Inpt

N/S

PEFR

External2:5

Internal5:5

Anthonisenetal6/1987

173

Trimethoprim-sulfamethoxazole

,

amoxicillin,ordoxycycline

Placebo

190

60

Opt

Permitted

(42%all)

Overallclin

ical

assessment

External5:5

PEFR

Internal4:5

Nicotraetal72/1982

40

Tetracycline

Placebo

160

N/S

Inpt

Permitted

(75%abx;

65%pbo)

Symptoms(pt)

External4:5

Symptoms(MD)

Internal4:5

FEV1,PEF

R,FVC

Pinesetal74/1972

259

Tetracyclineorchloramphenico

l

Placebo

146

100

Inpt

N/S

Overallclin

ical

assessment

External3:5

Symptoms(MD)

Internal4:5

PEFR

Pinesetal76/1968

30

Penicillinandstreptomycin,

penicillinalone

Placebo

88

100

Inpt

N/S

Overallclin

ical

assessment

External2:5

Internal5:5

Elmesetal75/1965

58

Ampicillin

Placebo

79

78

Inpt

Prohibited

Overallclin

ical

assessment

External2:5

PEFR

Internal5:5

Lengthofs

tay

Berryetal68/1960

53

Oxytetracycline

Placebo

N/S

60

Opt

N/S

Symptoms(MD),pts

withmodera

tetosevere

exacerbation

s

External2:5

Internal3:5

Elmesetal69/1957

59

Oxytetracycline

Placeboorno

treatment

N/S

N/S

Opt

N/S

Durationofsymptoms

External2:5

Workdayslost

Internal5:5

FearandEdwards70/1962

62

Oxytetracycline

Placebo

N/S

N/S

Opt

N/S

Symptoms(MD)

External2:5

Durationofsymptoms

Internal5:5

*abx

antibiotics;inpt

inpatient;N/S

notspecified;opt

outpatient;pbo

placebo;pt

patient-assessed;MDphysician-assessed;

benefitforantibiotic-treatedpatientsoverplacebo-

treatedpatients;

norep

ortedbenefitofantibiotic-treatedpatientsoverplacebo-treatedpatients.

Estimatedfrom.

Sputumcolor:yellowvsnon

e,clear,orwhite.

WeightedaverageofmensmedianPEFRandwomensmedianPEFRinc

ontrolgroup(n

10);valueforactive-treatme

ntgroupcouldnotbesimilarlyestimated.

Significanceatp

0.05level.

Moderatelypurulentorpurulent.

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patients with more severe exacerbations (using theabove-mentioned grading system [Table 1]) identi-fied those more likely to benefit from antibiotictreatment. Patients with type 1 exacerbations (se-

vere) experienced a benefit (antibiotic-treated pa-tients, 63%; placebo-treated patients, 43%). Thebenefit of antibiotic treatment was less apparent in

less severe exacerbations (type 1 vs type 2 exacerba-tions, 70% vs 60%; type 1 vs type 3 exacerbations,74% vs 70%). Another study68 demonstrated thatphysician-assigned severity was correlated with alikelihood of benefit from antibiotics. Among pa-tients with mild attacks, there were no significantdifferences between patients treated with antibioticsand those treated with placebo. Among patients withmoderate or severe attacks, patients treated withantibiotics had significantly fewer severe symptomson days 2 and 7. A third study75 demonstrated asimilar relationship between the severity of theexacerbation and the benefit from antibiotics. How-

ever, this study included patients with clinical evi-dence of pneumonia among those with severe exa-cerbations.

There is little evidence regarding the appropriateduration of administration of antibiotics. Typicaladministration periods range from 3 to 14 days inboth placebo-controlled and head-to-head compari-sons of antibiotics for this condition. A single retro-spective study of patients receiving amoxicillin foracute exacerbations of COPD found a clinicallyfavorable response in 70% of patients who receivedbetween 6 and 10 days of treatment. No follow-upassessment was performed.79

Oxygen Therapy

Oxygen therapy provides enormous benefits topatients with acute exacerbations of COPD who arehypoxemic (ie, the Po2 level in arterial blood isreduced). Oxygen relieves pulmonary vasoconstric-tion and right heart strain, and lessens myocardialischemia, thereby improving cardiac output andoxygen delivery to the CNS and to other criticalorgans. There is also a substantial amount of evi-dence supporting the hypothesis that improved oxy-

gen delivery to the lung enhances pulmonary de-fenses and augments mucociliary transport. Themajor concern for most clinicians administering ox-

ygen to patients with acute exacerbations of COPD isthe risk that oxygen supplementation will lead tohypercarbia and subsequent respiratory failure. Var-ious mechanisms have been advanced to explain thisobservation, including depression of respiratorydrive, alteration in ventilation/perfusion matching,

and the Haldane effect (ie, oxygenated erythrocyteshave lower capacity for CO2 than deoxygenatederythrocytes).

Based on four Obs studies,8083we concluded thatoxygen administration in patients with acute exacer-bations of COPD may result in hypercarbia but thatthere are methods for identifying the patients athighest risk for developing respiratory failure associ-ated with oxygen administration.

A study80 of 23 patients with respiratory failureaccompanying COPD (EV, 3:4; internal validity, Obs1b) who were given 28% oxygen demonstrated thatarterial Pco2 increased in 17 patients, with a meanrise of 4 mm Hg (range, 2 to 11 mm Hg). Theauthors stated that in no patient was serious CO2retention encountered. A study83 of seven patients(EV, 3:4; internal validity, Obs 4) with acute exacer-bations given both 24.5% and 28% oxygen demon-strated that Pco2 increased in six of the sevenpatients. A study82 of 53 patients (EV, 1:4; internal

validity, Obs 2b) with acute exacerbations who were

given graded oxygen therapy to raise oxygen satura-tion had similar findings. All but three patients hadelevations in Pco2, and the greatest rise was ob-served in patients who presented with the lowestPao2 levels. The largest study81 (EV, 2:4; internal

validity, Obs 1b) to address this issue enrolled 50patients with acute exacerbations of COPD andpatients received 24% oxygen, followed by 28%oxygen if hypoxemia persisted. Thirteen of the pa-

Figure 1. The discriminant function, pH 7.660.00919 (Pao2),

helpsto identify patients at risk for carbondioxide retention after theadministration of supplemental oxygen. Whenthe patientsobservedPao2 is entered into the equation, the pH that has been calculatedcan be compared with the measured pH to distinguish betweenhigh-risk and low-risk patients. If a patient is at high risk, the valuecalculated will be greater than that observedin thearterialblood gas.The symbols represent Pao2 and pH values on hospital admission ofpatients who were eventually intubated (triangles) or not nonintu-bated (circles) in a study evaluating this predictive model. Thediagonal line reflects values of the discriminant function and sepa-rates high-risk and low-risk patients. Adapted with permission from

Wysocki et al.98

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tients (26%) developed hypercarbia and subse-quently required mechanical ventilation. These 13patients did not differ from the 37 who did notrequire mechanical ventilation in terms of age, base-line pulmonary function test results, or initial re-sponse to therapy. Notably, the relationship betweenarterial pH and Pao2 at the time of presentation waspredictive of respiratory failure but resting Pco2

was not. The authors derived a discriminant function(Fig 1) for predicting respiratory failure (pH 7.660.00910 Pao2) that had a sensitivity of 77%. Theauthors then validated this predictive function in acohort of 76 subsequent patients, 16 of whom (21%)required mechanical ventilation. Of these 16 pa-tients, 13 had values of pH and Pao2 that intersectedbelow the discriminant line (sensitivity, 81%). Al-though, to our knowledge, this predictive modeldoes not currently see heavy use, it does empha-size that patients with simultaneous hypercarbiaand hypoxemia are at the greatest risk of develop-ing respiratory failure.

To our knowledge, there are no available datadirectly addressing the titration of oxygen after anacute exacerbation of COPD. Perhaps the best datacan be extrapolated from the Nocturnal OxygenTherapy Trial, which found that 20% of the 800patients studied no longer required oxygen 3 weeksafter hospital discharge after acute exacerbations ofCOPD.84

Mucus Clearance Strategies

Expectorants, Mucolytics, and Mucokinetics:Based on five RCTs73,8588 involving five different

drugs, we concluded that pharmacologic mucusclearance strategies have not been demonstrated toshorten the course of treatment for patients withacute exacerbations of COPD, although there is apossibility that these agents improve symptoms.There were no statistically significant differencesreported in mean FEV1 between treatments in anystudy. Comparisons tested included domiodol vscontrol (EV, 1:5; internal validity, Exp 1:5),85 brom-hexine vs placebo (EV, 2:5; internal validity, Exp5:5),86 ambroxol vs control (EV, 2:5; internal validity,Exp 3:5),87 S-carboxymethylcysteine vs bromhexine(EV, 3:5; internal validity, Exp 4:5),88 and potassium

iodide vs chloramphenicol, physiotherapy, and pla-cebo (EV, 2:5; internal validity, Exp 1:5).73 Of thefive trials measuring subjective symptom scores ondifficulty with expectoration, only two85,87 reportedsignificant differences (p 0.01) favoring the muco-lytic drug over the control.

Physical and Respiratory Therapies: Based onthree RCTs73,89,90 of chest physiotherapy and one

Obs study,91 we conclude that mechanical percus-sion of the chest as applied by physical/respiratorytherapists is ineffective and perhaps even detrimen-tal in the treatment of patients with acute exacerba-tions of COPD. None of the randomized trials (EV,3:5, internal validity, Exp 3:589; EV, 2:5; internal

validity, Exp 1:573; and EV, 2:5; internal validity, Exp1:590) reported any improvement in ventilatory func-tion (either FEV1 or FVC). One RCT90 described asignificantly lower FEV1 in patients who receivedchest percussion therapy compared with controlsubjects. A similar transient decrease in FEV1 afterchest percussion was previously described in anuncontrolled study.91 No other adverse effects werereported.

Noninvasive Positive-Pressure Ventilation

Based on five RCTs9296 and five Obs studies,99103

we concluded that noninvasive positive-pressureventilation (NPPV) is a beneficial support strategy

that, in selected hospitalized patients with respira-tory failure, decreases the likelihood of requiringinvasive mechanical ventilation and, possibly, im-proves survival time (Table 11). In some of thesestudies, the exclusion criteria were omitted from thereports, while in others, exclusion criteria includedsignificant cardiovascular disease, lack of mentalcapacity, presence of pneumonia, and concern aboutupper airway narrowing or obstruction. As such, theselection criteria for this therapy remain unclear.

Among the four RCTs9295 that compared NPPVto a standard therapy control, a significant differencein need for intubation was found in two trials,94,95

with reduced need for intubation in the NPPVgroups (26% vs 74% in a study involving 85 pa-tients94; 9% vs 67% in a study involving 23 pa-tients95). A fifth trial, comparing NPPV to a respira-tory stimulant medication (doxapram) demonstrateda mortality benefit associated with NPPV that wasnot statistically significant.96 A meta-analysis97 pub-lished in 1996 that included three of the above trials,as well as three published abstracts97a,97b,97c and oneother published study,98 concluded that the risk ofdeath was lower in patients who were randomized toreceive NPPV (odds ratio, 0.29; 95% CI, 0.15 to0.59), as was the risk of requiring invasive mechan-

ical ventilation (odds ratio, 0.20; 95% CI, 0.11 to0.36). The results from four prospective case se-ries99102 were similar to those from the RCTs whenNPPV-treated patients were compared to historicalcontrol subjects. One Obs study103 found no in-creased effectiveness of NPPV over more conven-tional treatment and observed a large number ofadverse effects associated with the use of NPPV.

Additional questions addressed in the literature

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include comparisons between NPPV and invasiveventilation, optimal NPPV delivery methods, andpredictors of the successful application of NPPV.Four prospective controlled studies compared typesof NPPV delivery methods (EV, 3:5; internal validity,Exp 0:5104; EV, 1:5; internal validity, Exp 1:5105; EV,1:5; internal validity, Exp 1:5106; and EV, 4:5; internal

validity, Exp 2:5107). Outcomes of interest were theeffect on gas exchange, the need for intubation,mortality, adverse effects/side effects, and the com-fort with which the devices may be used. No signif-icant differences in these parameters were seenamong the various modes of ventilation. A retrospec-tive study attempting to identify parameters thatcould predict a successful outcome with the use ofNPPV looked at anthropometric and demographiccharacteristics, nutritional status, spirometry, bloodgas levels, and causes of acute exacerbation ofCOPD. Factors that predicted success includedhigher pH, lower Paco2, and higher FVC (p 0.05).Poor outcomes were associated with a diagnosis of

pneumonia, poor nutritional status, and decreasedcompliance with the apparatus.108,124,125

Research Priorities

In a disease held responsible for 5% of all deathsin the United States, enormous disability, and $18billion dollars in annual health-care costs, the paucityof primary data on therapeutics is startling. Wefound that in more than 40 years of research, fewerthan 1,100 patients had been enrolled in random-ized, placebo-controlled trials of antibiotics, fewer

than 650 patients had been enrolled in studies ofcorticosteroids vs placebo (before the 1999 SCOPPEtrial, the count was less than 400), and virtually nocontrolled trials (to our knowledge) have enrolledpatients with milder (outpatient) exacerbations. Cer-tainly, more in-depth research into therapeutics andmanagement would greatly benefit patients with thisdisease.

To be maximally beneficial, however, moregroundwork is required. At present, we lack a repro-ducible, transportable definition of acute exacerba-tion, and we also lack an objective rating system forseverity. Equally important, there is no consensus on

the outcomes that should be measured and reportedin clinical studies, although there is an emergingrecognition that nonphysiologic outcomes such assymptomatology, quality of life, and interval beforesubsequent relapse are all important to patients.Given these opportunities, our first research objec-tives must include untangling the questions sur-rounding the selection of patients for antibiotic andcorticosteroid treatment, identifying optimal dosing

Table11RandomizedStudiesCo

mparingPatientsReceivingNPPVvsN

onventilatoryControlSubjects*

Study/yr

Patients,No.

Intervention

NeedforIntubation

Mo

rtality

BloodGasImprovement

StudyValidity

NP

PV

Control

Type

Duration

NPPV

Control

NPPV

Control

NPPV

Contro

l

External

Internal

Angusetal96/1996

9

8

N,PS

4honce

NR

NR

0

3(38)

Yes

NR

No

3:5

1:5

Barbeetal92/1996

1

0

10

N,BV

3h,twice/d

0

0

NR

NR

Yes

Yes

3:5

2:5

Bottetal93/1993

3

0

30

N,VC

16h/d

0/30(0)

2/30(7)

3/30(10)

9/30(30)

YesNR

NoNR

2:5

2:5

Brochardetal94/1995

4

3

42

FM,PS

6h/d

11/43(26)

31/42(74)

4/43(9)

12/42(29)

Yes

NR

No

2:5

3:5

Krameretal95/1995

1

1

12

N,BV

8h/d

1/11(9)

8/12(67)

1/16(6)

2/15(13)

NR

NR

2:5

2:5

*BV

bilevelventilation;N

nasal;FM

facemask;PS

pressuresupport;VC

volumecycled;Yes

within-groupimprovementpretreatmentvsposttreatment;N

o

noimprovementwithin

group;

nosignificantdifferencebetweengroups;

statisticallysignificantdifferenceinimprovementbetweengroups.SeeTable9forotherabbreviationsnotused

intext.ValuesgivenasNo.

ofpersons/No.ingroup(%),unlessotherwiseindicated.

Improvementsinbloodgaslevelsweredefineddifferentlyindifferentstud

ies.Resultsreportedhereinarebasedonthed

efinitionsofeachstudy.

Significanceatp

0.05leve

l.

CHEST / 119 / 4 / APRIL, 2001 1205



18/22

and durations for these agents, and determining towhat degree broad-spectrum and narrow-spectrumantibiotics have similar efficacy.

There are a number of potentially promising newresearch directions as well, including the following:(1) the components of mucus formation, content,release, and transport; (2) strategies for improvingmuscle strength and reducing muscle fatigue; (3)therapies aimed at aborting the exacerbation cycle,including arrest of the inflammatory cascade; (4)strategies aimed at preventing infectious exacerba-tions, perhaps through reducing bacterial adherenceor limiting cellular damage in the presence of micro-organisms; and (5) the determination of biologicalmarkers of infection and inflammation (eg, antielas-tase, antioxidant, and cytokine release or action) inthe blood and/or sputum.

ACKNOWLEDGMENTS: We gratefully acknowledge the assis-tance of the combined ACP-ASIM and ACCP expert panel, theEvidence-Based Center peer review and technical advisory pan-els, and the efforts of Ruth E. Goslin, MAT, and Rebecca N.

Gray, DPhil.

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