exacerba2008

DOI 10.1378/chest.07-1207 2008;133;756-766Chest

Bradley S. Quon, Wen Qi Gan and Don D. Sin

*Exacerbations of COPDContemporary Management of Acute

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Contemporary Management of AcuteExacerbations of COPD*A Systematic Review and Metaanalysis

Bradley S. Quon, MD; Wen Qi Gan, MD; and Don D. Sin, MD, FCCP

Background: Systemic corticosteroids, antibiotics, and noninvasive positive pressure ventilation(NPPV) are recommended for patients with acute exacerbation of COPD. However, their clinicalbenefits in various settings are uncertain. We undertook a systematic review and metaanalysis tosystematically evaluate the effectiveness of these therapies.Methods: MEDLINE and EMBASE were searched to identify relevant randomized controlledclinical trials published from January 1968 to November 2006. We identified additional studies bysearching bibliographies of retrieved articles.Results: Compared with placebo, systemic corticosteroids reduced treatment failure by 46% (95%confidence interval [CI], 0.41 to 0.71), length of hospital stay by 1.4 days (95% CI, 0.7 to 2.2), andimproved FEV1 by 0.13 L after 3 days of therapy (95% CI, 0.04 to 0.21). Meanwhile, the risk ofhyperglycemia significantly increased (relative risk, 5.88; 95% CI, 2.40 to 14.41). Compared withplacebo, antibiotics reduced treatment failure by 46% (95% CI, 0.32 to 0.92) and in-hospitalmortality by 78% (95% CI, 0.08 to 0.62). Compared with standard therapy, NPPV reduced the riskof intubation by 65% (95% CI, 0.26 to 0.47), in-hospital mortality by 55% (95% CI, 0.30 to 0.66),and the length of hospitalization by 1.9 days (95% CI, 0.0 to 3.9).Conclusions: For acute COPD exacerbations, systemic corticosteroids are effective in reducingtreatment failures, while antibiotics reduce mortality and treatment failures in those requiringhospitalization and NPPV reduces the risk of intubation and in-hospital mortality, especially inthose who demonstrate respiratory acidosis. (CHEST 2008; 133:756–766)

Key words: controlled clinical trial; COPD; exacerbation; metaanalysis

Abbreviations: BPAP � bilevel positive airway pressure; CI � confidence interval; GOLD � Global Initiative forChronic Obstructive Lung Disease; LOS � length of hospital stay; NPPV � noninvasive positive pressure ventilation;RR � relative risk

A cute exacerbations of COPD are associated withsignificant morbidity, mortality, and health-care

expenditures. The in-hospital mortality rate for acuteCOPD exacerbations is approximately 10%,1 andapproximately 25% for those requiring admission toan ICU.2 Hospitalizations for COPD exacerbationshave increased significantly over the past 10 years.For instance, the number of hospitalizations forCOPD exacerbations in the United States was463,000 in 1990; whereas by 2000, it was 726,000,representing a 57% increase in just 10 years.3 Thetotal economic costs of COPD in the United Stateswere estimated at $32 billion in 2002, with $18billion representing direct medical expenditures re-lated largely to in-hospital care.4 The Global Initia-

tive for Chronic Obstructive Lung Disease (GOLD)committee5 defines COPD exacerbation as a changein a patient’s “baseline dyspnea, cough, and/or spu-tum that is beyond day-to-day variations, is acute inonset, and may warrant a change in regular medica-tion in a patient with underlying COPD.” Lunginflammation and infection appear to play prominentroles in the pathogenesis of COPD exacerbations,leading to worsening of symptoms and health statusand a decline in lung function.6 The most commonputative precipitants of exacerbations are bacterial orviral infections, and environmental pollution, al-though in many cases a clear precipitant is notapparent.7,8 As patients frequently experience wors-ening of lung function and health status, most clini-

CHEST Special Feature

756 Special Feature



cal guidelines recommend the use of bronchodilators(short-acting �2-agonists and anticholinergics) to re-duce dynamic hyperinflation, systemic corticoste-roids to reduce lung inflammation, antibiotics totreat potential bacterial pathogens, and occasionallynoninvasive positive pressure ventilation (NPPV) inselect cases to reduce the work of breathing. Despitethese widely promulgated recommendations, veryfew studies have systematically evaluated the clinicalbenefits of these interventions in comparison withplacebo or standard therapy. The objective of thisstudy was to systematically review and quantitativelysynthesize the impact of systemic corticosteroids,antibiotics, and NPPV on treatment failure, need forintubation, in-hospital mortality, and LOS duringCOPD exacerbations.

Methods and Materials

We decided a priori to examine the published evidence forsystemic corticosteroids, antibiotics, and NPPV in the treatmentof acute COPD exacerbations. For each of these therapies, weconducted a literature search by using MEDLINE andEMBASE. We limited the search to English-language articles

published from January 1968 to November 2006, conducted inadults (� 19 years of age) using a randomized, controlled trialdesign. To limit the studies to COPD, we used the followingterms: chronic obstructive lung disease, chronic obstructive air-way disease, COPD, emphysema, chronic bronchitis, or chronicairflow obstruction. Detailed search terms for each of thetherapies and search results are available in Table 1. To supple-ment this search, we examined the Cochrane Database ofSystematic Reviews as well as bibliographies of retrieved articles.

We included only studies that were conducted during acuteCOPD exacerbations, as defined by worsening cough or dyspneaor increased sputum production. Studies were excluded whenthere was clearly an alternative primary diagnosis such as asthma,pneumonia, or cardiogenic pulmonary edema. Most of theincluded studies had criteria excluding patients with an alterna-tive primary diagnosis based on clinical examination. In allincluded studies, the treatment group was compared with pla-cebo or with standard medical therapy. Standard medical therapyincluded supplemental oxygen (if the patients were hypoxemic),bronchodilators, antibiotics, corticosteroids, and diuretics butcould not include the treatment being studied. We used theJadad scale, which is composed of 5 questions about study design,to adjudicate the methodologic quality of the studies (the higherthe score, the better the quality of trial design).9 For systemiccorticosteroids and antibiotics, we restricted the analysis torandomized clinical trials that had a Jadad score � 3. For NPPV,we accepted studies with a score � 2 because study blinding wasnot possible for practical reasons. All included studies hadcomplete or near-complete follow-up data, and baseline charac-teristics that were well balanced between the treatment andcontrol groups. Studies in abstract form were included if themethods and results could be adequately analyzed to minimizepublication bias.

Data were abstracted from each trial by two authors (B.S.Q,W.Q.G.) independently using a prestandardized data abstractionform. Any discrepancies were resolved by iteration and consen-sus. Results were analyzed by intention to treat wheneverpossible. Treatment failures following treatment of COPD exac-erbations were defined variably between studies. In most cases,treatment failures were defined as unchanged or deterioratedsymptoms requiring additional treatment during the follow-upperiod. When possible, for each outcome we combined theresults from individual studies to produce summary effect esti-mates. For dichotomous outcomes, relative risks (RRs) and 95%confidence intervals (CIs) were calculated. For continuous vari-ables, weighted mean differences (and 95% CIs) were used to

*From the Department of Medicine, Respiratory Division, Uni-versity of British Columbia, and The James Hogg iCAPTURECenter for Cardiovascular and Pulmonary Research, St. Paul’sHospital, Vancouver, BC, Canada.This project is supported by the Canadian Institutes of HealthResearch. Dr. Sin is a Canada Research Chair in COPD and a seniorscholar with the Michael Smith Foundation for Health Research.The authors have no conflicts of interest to disclose.Manuscript received May 17, 2007; revision accepted July 16,2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Don D. Sin, MD, FCCP, James Hogg iCAP-TURE Center for Cardiovascular and Pulmonary Research, St.Paul’s Hospital, Room 368A, 1081 Burrard St, Vancouver, BC,V6Z 1Y6, Canada; e-mail: [email protected]: 10.1378/chest.07-1207

Table 1—Search Strategy and Terms

Intervention To Be Studied Search Terms Hits

Systemic corticosteroids (Antiinflammatory agents OR corticosteroids OR steroids OR prednisone OR methylprednisoloneOR prednisolone)

365

Antibiotics (Antimicrobial* OR antibiotic* OR penicillin OR ampicillin OR amoxicillin OR fluoroquinolone*OR *floxacin OR cephalosporin* OR cefalosporin* OR cefaclor OR cefalexine OR cephalotin ORcefazolin OR cefixime OR cefotaxime OR cefpodoxime OR cephradine OR ceftizoxime ORceftriaxone OR cefuroxime OR tetracyclin* OR demeclocycline OR doxycycline OR minocyclineOR oxytetracycline OR *cycline OR macrolide* OR *thromycin OR azithromycin ORclarithromycin OR dirithromycin OR erythromycin OR roxythromycin OR telithromycin ORtroleandomycin OR fluoroquinolone* OR ciprofloxacin OR gatifloxacin OR gemfloxacin ORgrepafloxacin OR levofloxacin OR lomefloxacin OR moxifloxacin OR ofloxacin OR sparfloxacinOR trovafloxacin OR *floxacin OR chloramphenicol OR clindamycin OR trimethoprim/sulfa* ORcotrimoxazole OR carbapenem* OR imipenem OR meropenem)

423

NPPV (NIPPV OR NPPV OR NIMV OR NIV OR BIPAP OR bi-level ventilat* OR noninvasive ventilat*OR noninvasive ventilat* OR positive-pressure ventilat* OR positive-pressure ventilat*)

316

www.chestjournal.org CHEST / 133 / 3 / MARCH, 2008 757



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pool the data. Heterogeneity of results across individual studieswas examined using the �2 test. If significant heterogeneity wasobserved (p � 0.10), the DerSimonian and Laird random-effectsmodel was used to pool the results together. In the absence ofsignificant heterogeneity (p � 0.10), a fixed-effects model wasused. All analyses were conducted using statistical software(RevMan version 4.2; Cochrane Collaboration; Oxford, England).

Results

Systemic Corticosteroids

A total of 10 studies10–19 involving 959 patients(Table 2) were identified that examined the effects ofsystemic corticosteroids during acute COPD exac-erbations. The mean age of patients of thesestudies was 67 years. The patients at the time ofpresentation to the hospital demonstrated an av-erage arterial pH of 7.40 and Paco2 of 42 mm Hg.Most of the patients were active smokers with amean smoking history of 63 pack-years. The treat-ment was initiated in hospital in eight of thestudies,11–17,19 while in two studies10,18 systemiccorticosteroids were administered in an outpatientsetting. In half of the studies,11,12,14,16,17 investiga-tors used parenteral methylprednisolone or hydro-cortisone, while in the other half of the stud-ies,10,13,15,18,19 oral prednisone or prednisolone wasused.

Six of the 10 studies10,12,13,15,16,18 (involving 742patients) examined the effects of systemic corticoste-roids on treatment failure defined as either clinicaldeterioration, withdrawal from the study due tounsatisfactory clinical improvement, or relapse ofexacerbation symptoms during the follow-up period.The follow-up period varied from 10 to 30 days.Overall, the treatment failure rate was reduced by46% with the use of systemic corticosteroids com-pared with placebo during acute exacerbations (RR,0.54; 95% CI, 0.41 to 0.71; p � 0.27 for heterogene-ity) [Fig 1]. The study by Emerman et al14 wasexcluded from the analysis because patients wereadministered just one dose of IV methylprednisoloneand were followed up for just 48 h. The method ofadministration (oral or parenteral) did not modifythe beneficial effects of systemic corticosteroids ontreatment failures.

Systemic corticosteroids also had beneficial effectsin reducing the length of hospitalization. Mean LOSwas reduced by a weighted mean of 1.42 days withsystemic corticosteroids (95% CI, 0.65 to 2.18;p � 0.40 for heterogeneity) [Fig 2].

Information on adverse drug effects includingheartburn, GI bleeding, hyperglycemia, infection, psy-chomotor disturbance, and weight gain was variably(and scarcely) reported. The only potential adverseeffect that was consistently reported in most of the

studies was hyperglycemia. The risk of hyperglycemiawas significantly increased with corticosteroid treat-ment (RR, 5.88; 95% CI, 2.40 to 14.41).13,15,16 Therewas insufficient information on the effect of corticoste-roids on mortality.

Antibiotics

There have been several placebo-controlled stud-ies20–30 that have examined the impact of antibioticson clinically important outcomes during COPD ex-acerbations (Table 3). Of the 11 eligible studies, only3 placebo-controlled studies23,24,27 have been per-formed since 1987, likely reflecting the acceptanceof antibiotics as standard of care in the managementof COPD exacerbations over the past 2 decades.Three of the studies20,22,24 were conducted in outpa-tients, seven studies21,23,25,26,28–30 were conducted inpatients in medical wards, and one study27 wasconducted in a medical ICU. The mean age of thepatients in these studies was 63 years. Minimum andmean durations of treatment were 7 days and 8.9

Wood-Baker et al,19 1998

Davies et al,13 1999

Niewoehner et al,16 1999

Maltais et al,15 2002

-4 -2 0 2 4

Pooled summary(WMD,-1.42; 95% CI, -2.18 to -0.65)

Favors PlaceboFavors Steroid

Weighted Mean Difference (95% Confidence Interval)

Figure 2. Effects of systemic corticosteroid therapy on LOS.WMD � weighted mean difference.

Bullard et al,12 1996

Thompson et al,18 1996

Davies et al,13 1999

Niewoehner et al,16 1999

Maltais et al,15 2002

Aaron et al,10 2003

0.1 0.2 0.5 1 2 5 10

Pooled summary(RR,0.54; 95% CI, 0.41-0.71)

Relative Risk (95% Confidence Interval)

Favors PlaceboFavors Steroid

Figure 1. Effects of systemic corticosteroid therapy on the riskof treatment failure.




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760 Special Feature



days, respectively. The antibiotics most commonlyused were oral �-lactams (43%) and tetracyclinederivatives (29%).

Compared with placebo, antibiotic use duringCOPD exacerbations (five studies20,21,24,27,30 involv-ing 557 patients) reduced treatment failures, definedas requiring additional antibiotics within the first 7days or unchanged or deteriorated symptoms within21 days, by 46% (RR, 0.54; 95% CI, 0.32 to 0.92)[Fig 3]. However, there was significant heterogene-ity of findings across the studies (p � 0.002). Strati-fication of studies according to patient type (in-hospital vs an outpatient setting) attenuated theheterogeneity. Antibiotics significantly reducedtreatment failures when they were administered topatients who were hospitalized (for three inpatientstudies21,27,30: RR, 0.34; 95% CI, 0.20 to 0.56;p � 0.48 for heterogeneity) but not when theywere used in ambulatory patients (for two outpa-tient studies20,24: RR, 0.88; 95% CI, 0.56 to 1.39;p � 0.06 for heterogeneity). Three clinical tri-als21,27,30 involving 181 patients demonstrated thatin-hospital mortality can be reduced by 78% withthe use of antibiotics during acute COPD hospi-talizations (RR, 0.22; 95% CI, 0.08 to 0.62;p � 0.92 for heterogeneity). Some studies25,27 re-ported the effect of antibiotics on short-term lungfunction, blood gas measurements, or length ofstay in hospital, but antibiotics did not materiallyaffect these outcomes compared with placebo.

Noninvasive Positive Pressure Ventilation

Fourteen studies compared the use of NPPV tostandard therapy in the management of acute COPDexacerbations (Table 4). All of the studies wereperformed since 1993.31–44 Mean age of the patientsin these studies was 67 years. Arterial blood gasmeasurements on study entry for included patients

revealed a mean pH of 7.31 and Paco2 of 68 mm Hg.In most cases, investigators used bilevel positiveairway pressure (BPAP) administered through aventilator via nasal or face mask. NPPV was initiatedas early as possible following hospitalization on ageneral medical or respiratory ward, or an ICU. Themean duration of NPPV use was 8.5 h/d, with a rangeof 6 to 14 h/d for a mean duration of 4.3 days (range,3 to 10 days). NPPV was continued as long asnecessary to avoid endotracheal intubation. Moststudies had prespecified clinical criteria for endotra-cheal intubation based on a set of clinical parametersand arterial blood gas measurements obtained seri-ally during follow-up.

The totality of randomized controlled trials dem-onstrates that NPPV reduced the need for intuba-tion, improved the risk of in-hospital mortality, andshortened hospital stays during acute COPD exacer-bations. In the 12 controlled randomized trials (959patients), NPPV reduced the need for intubation by65% (RR, 0.35; 95% CI, 0.26 to 0.47; p � 0.82 forheterogeneity) [Fig 4].31,32,34–44 The benefits weremodified by the average pH of the study participants.The beneficial effects of NPPV increased as thebaseline pH decreased (p � 0.047) [Fig 5].

We found 11 studies31,32,34–36,38–44 involving 940patients that evaluated the effects of NPPV onin-hospital mortality. Overall, compared with pla-cebo, the in-hospital mortality rate was reduced by55% (RR, 0.45; 95% CI, 0.30 to 0.66; p � 0.99 forheterogeneity) [Fig 6]. Although there was signifi-cant heterogeneity in the data (p � 0.005 for heter-ogeneity), the length of hospital stay was significantlyshortened by a weighted mean of 1.94 days with theuse of NPPV (95% CI, 0.01 to 3.87) [Fig 7].

Discussion

Acute exacerbations of COPD are an increasingcause of morbidity, mortality, and economic burdenin the United States and elsewhere. Despite thewidespread promulgation of clinical guidelines byvarious expert committees and professional societiesover the past decade, there continues to be consid-erable heterogeneity in the way in which acuteexacerbations are managed between physicians.31

For instance, a large survey31 found that � 3% ofpatients with acute COPD exacerbations weretreated with NPPV and � 85% were treated withantibiotics and systemic corticosteroids, which arethought to be cornerstones of inpatient manage-ment. The primary objective of this study31 was todetermine the strength of clinical data that supportthe use of these therapies on clinically relevant healthoutcomes such as treatment failures, the need for

Elmes et al,21 1965

Pines et al,30 1968

Anthonisen et al,20 1987

Jorgensen et al,24 1992

Nouira et al,27 2001

0.1 0.2 0.5 1 2 5 10


Favors PlaceboFavors Antibiotics


Figure 3. Effects of antibiotic therapy on the risk of treatmentfailure.




Tab

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762 Special Feature



intubation, in-hospital mortality, and LOS. The presentstudy builds on previous systematic reviews and meta-analysis by adding data from most recently publishedtrials by integrating the findings on these three thera-pies in one succinct report (as opposed to previouspublished analyses, which have evaluated these inter-ventions separately, which we believe will enhance thetranslation of these findings into clinical practice),32 andby presenting “new” analyses to address clinical issuesthat have not been previously evaluated.

GOLD guidelines recommend systemic cortico-steroids for in-hospital management of COPD exac-erbations, while antibiotics are recommended for

any exacerbations (regardless of severity) that lead toincreased dyspnea, sputum volume, and sputumpurulence. NPPV is believed to be beneficial only inexacerbations that are associated with moderate-to-severe respiratory acidosis.5 The findings of thisreview largely support these recommendations withsome notable exceptions. Firstly, we found thatsystemic corticosteroids reduced treatment failureby 46% during both inpatient and outpatient man-agement of COPD exacerbations, which are similarto the findings by Wood-Baker and colleagues.33

Secondly, we found that antibiotics reduced treat-ment failures by 46% and improved survival ofhospitalized patients. The survival effect was ob-

0

10

20

30

40

50

60

70

80

7.22 7.26 7.30 7.34 7.38 7.42

Baseline Average pH

Ris

k of

Intu

batio

n (%

)

Barbe491996

Dikensoy532002

Bott431993

Plant522000

CRC542005Celikel501998

Brochard461995

Martin512000

Angus481996

Kramer471995

Daskalopoulou441993

Keenan562005

Dhamija552005Daskalopoulou441993

Brochard461995

Martin512000

Celikel501998

Kramer471995

Angus481996

Plant522000

Barbe491996

CRC542005

Bott431993

Dhamija552005

Keenan562005

Standard Therapy

NPPV

Dikensoy532002

Figure 5. Relationship between arterial pH and the risk ofintubation in patients treated and not treated with NPPV duringCOPD exacerbations. For standard therapy group, R2 � 0.53,p � 0.005; for NPPV group, R2 � 0.36, p � 0.029; p � 0.047 forthe slope difference between two groups. See Figure 4 legend forexpansion of abbreviation.

Bott et al,43 1993

Servillo et al,45 1994

Brochard et al,46 1995

Kramer et al,47 1995

Angus et al,48 1996

Celikel et al,50 1998

Plant et al,52 2000

Dikensoy et al,53 2002

CRC et al,54 2005

Dhamija et al,55 2005

Keenan et al,56 2005

0.01 0.1 1 10 100

Favors Standard Therapy

Favors NPPV



Figure 6. Effects of NPPV on the risk of in-hospital mortalityduring COPD exacerbations. See Figure 4 legend for expansionof abbreviation.

Bott et al,43 993Daskalopoulou et al,44 1993Servillo et al,45 1994Brochard et al,46 1995Kramer et al,47 1995Barbe et al,49 1996Celikel et al,50 1998Plant et al,52 2000Dikensoy et al,53 2002CRC et al,54 2005Dhamija et al,55 2005Keenan et al,56 2005

-10 -5 0 5 10


Favors NPPV

Weighted Mean Difference (95% Confidence Interval)

Pooled summary(WMD,-1.94; 95% CI, -3.87 to -0.01)

Figure 7. Effects of NPPV on LOS during COPD exacerbations.See Figure 2, 4 legends for expansion of abbreviations.

Bott et al,43 1993

Daskalopoulou et al,44 1993

Servillo et al,45 1994

Brochard et al,46 1995

Kramer et al,47 1995

Angus et al,48 1996

Celikel et al,50 1998

Plant et al,52 2000

Dikensoy et al,53 2002

CRC et al,54 2005

Dhamija et al,55 2005

Keenan et al,56 2005

0.01 0.1 1 10 100


Favors NPPV



Figure 4. Effects of NPPV on the risk of intubation duringCOPD exacerbations. CRC � Collaborative Research Group ofNoninvasive Mechanical Ventilation for Chronic ObstructivePulmonary Disease.




served only among hospitalized patients. It should benoted, however, that although the combined analysisshowed a survival benefit, each individual study wasrelatively small in size and was underpowered toanswer this critical question. Even in the treatmentfailure data, there was significant heterogeneity inthe findings across the studies indicating lack ofconsistency and robustness in the results. In thefuture, large clinical trials are needed to clearlydetermine the role of antibiotics in the managementof COPD exacerbations. Until then, the currentevidence suggests that antibiotics might be a reason-able choice for severe exacerbations requiring hos-pitalization or exacerbations that fail to improvedespite systemic corticosteroid therapy.34 Thirdly,we found that NPPV reduced the need for endotra-cheal intubation in patients with severe exacerba-tions and demonstrated arterial (respiratory) acido-sis. The beneficial effect of NPPV was modified by thearterial pH of the study patients. At pH of 7.26, forinstance, the risk of intubation in the standard groupwas nearly 60%; whereas in the NPPV group, the riskwas only 20%. At higher pH values, the risk differ-ential was much smaller. Thus, our findings supportthe recommendations of the GOLD committee thatNPPV may be used for severe exacerbations whenthe pH is � 7.35. Our findings are also consistentwith three systematic reviews35–37 that evaluated therole of NPPV for acute exacerbations of COPD.

In view of the high mortality risk associated withCOPD exacerbations, mortality reduction is one ofthe major aims of hospital-based management ofacute COPD. We found that both antibiotics andNPPV reduced in-hospital mortality in a selectedgroup of patients but the mechanisms responsible fortheir survival benefits were uncertain. It is likely thatantibiotics reduced mortality by reducing treatmentfailure and by possibly preventing nosocomial infec-tions during hospitalizations especially in patientswho require endotracheal intubation. The risk of de-veloping ventilator-associated pneumonia can be ashigh as 30%, and the case fatality rate associated withsuch infections can be � 50%.38 A metaanalysis39 in-volving 36 trials and 6,922 patients demonstrated a 22%reduction in mortality with the administration of anti-biotic prophylaxis in patients receiving ventilation. Thesurvival benefit from NPPV, however, may be relatedin part to a 65% reduction in the need for endotrachealintubation and invasive mechanical ventilation and itsassociated morbidity and mortality.40 The impact ofsystemic corticosteroids on mortality is uncertain. Onlyfour small studies10–13 (involving 360 patients) reportedon mortality, and the event rates were too small (total of10 deaths) to draw any meaningful conclusions.

Both systemic corticosteroids and NPPV can re-duce LOS by a weighted mean of 1.42 days and 1.94

days, respectively. Only two studies25,27 analyzed theimpact of antibiotics on LOS, and the results wereconflicting. More studies on antibiotics are neededto determine their effect on LOS. Reducing LOS isan important goal of acute COPD managementbecause hospital stays are associated with morbidityand with increased costs. An average hospital daycosts the system approximately $600.41 Although wefound that antibiotics improved clinical outcomes inpatients who require hospital-based care, we didnot observe a significant difference in the clinicalbenefits among different classes of antibiotics. In thestudy by Anthonisen et al,20 for instance, there wereno material differences in clinical efficacy betweentrimethoprim-sulfamethoxazole, amoxicillin, or doxy-cycline. Several other studies42 comparing the variousantibiotic agents head-to-head have also failed to dem-onstrate clear superiority of newer agents over olderclasses of respiratory antibiotics. Antibiotic selectionshould therefore be guided by recent history of antibi-otic use and local microbial resistance patterns.

Another controversial area is the optimal dose andduration of systemic corticosteroid treatment. In thestudies10,12,13,15,16,18 showing clinical benefits, thecorticosteroid dose (expressed in oral prednisoneequivalents) varied from 0.5 to 1.0 mg/kg/d, and thetreatment duration varied from 8 to 15 days. Extend-ing the duration of therapy beyond 2 weeks does notappear to confer additional benefits. Niewoehner etal,16 for instance, failed to demonstrate additionalbenefits from extending systemic corticosteroid ther-apy from 2 to 8 weeks. Despite the numerousadverse drug effects associated with corticosteroiduse, the only short-term adverse effect reportedfrom the included studies was a sixfold increase inthe risk of hyperglycemia.

There were several important limitations to thissystematic review. Firstly, the definition of an acuteexacerbation was based on clinical criteria and notbased on more objective measures such as lungfunction, which may have resulted in some diagnos-tic misclassification. This may have in certain cir-cumstances (eg, misclassification with asthma) led toa slight overestimation of the benefit of systemiccorticosteroids. Secondly, not all studies included inthe analysis of NPPV had objective criteria forintubation. Since it was not possible to blind thetreating physicians and other health-care profession-als, patients in the standard medical therapy groupmay have been intubated sooner than the NPPVgroup, resulting in a higher “need for intubation”rate. However, the overall mortality benefit of NPPVwould unlikely to have been influenced by this bias.Thirdly, although antibiotics resulted in a largerreduction in treatment failure rates among hospital-ized compared with ambulatory patients, the exact

764 Special Feature



severity or clinical characteristics of patients whobenefited from antibiotic therapy is uncertain sincethere was a scarcity of reported data on lung functionand blood gases in these studies. Fourthly, althoughthere were many short-term clinical benefits ofsystemic corticosteroids, antibiotics and NPPV, thelong-term effects of these interventions remain un-certain. Fifthly, publication bias is of concern. Tomitigate this bias, we carefully searched the bibliog-raphies of salient articles and included studies thatwere published only in the abstract form. Finally,owing to a variety of metholdogic and clinical issuesincluding heterogeneity of trial design, definitions ofexacerbations and underlying clinical characteristicsof study patients, the risk estimates of the interven-tions are not directly comparable.

In summary, acute COPD exacerbations may betreated effectively with systemic corticosteroids, an-tibiotics, and NPPV. Systemic corticosteroids reducetreatment failures in both in-hospital and outpatientsettings, while antibiotics appear more effective inpatients requiring hospitalization. NPPV should beconsidered for carefully selected patients who dem-onstrate arterial respiratory acidosis.

References1 Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes

following acute exacerbation of severe chronic obstructivelung disease: the SUPPORT investigators (Study to Under-stand Prognoses and Preferences for Outcomes and Risks ofTreatments). Am J Respir Crit Care Med 1996; 154:959–967

2 Seneff MG, Wagner DP, Wagner RP, et al. Hospital and1-year survival of patients admitted to intensive care unitswith acute exacerbation of chronic obstructive pulmonarydisease. JAMA 1995; 274:1852–1857

3 Mannino DM, Homa DM, Akinbami LJ, et al. Chronicobstructive pulmonary disease surveillance–United States,1971–2000. MMWR Surveill Summ 2002; 51:1–16

4 Sullivan SD, Ramsey SD, Lee TA. The economic burden ofCOPD. Chest 2000; 117:5S–9S

5 Fabbri L, Pauwels RA, Hurd SS. Global strategy for thediagnosis, management, and prevention of chronic obstruc-tive pulmonary disease: GOLD executive summary updated2003. COPD 2004; 1:105–141

6 Seemungal TA, Donaldson GC, Paul EA, et al. Effect ofexacerbation on quality of life in patients with chronicobstructive pulmonary disease. Am J Respir Crit Care Med1998; 157:1418–1422

7 Sethi S, Evans N, Grant BJ, et al. New strains of bacteria andexacerbations of chronic obstructive pulmonary disease.N Engl J Med 2002; 347:465–471

8 Seemungal TA, Harper-Owen R, Bhowmik A, et al. Detec-tion of rhinovirus in induced sputum at exacerbation ofchronic obstructive pulmonary disease. Eur Respir J 2000;16:677–683

9 Jadad AR, Moore RA, Carroll D, et al. Assessing the qualityof reports of randomized clinical trials: is blinding necessary?Control Clin Trials 1996; 17:1–12

10 Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oralprednisone after emergency treatment of chronic obstructivepulmonary disease. N Engl J Med 2003; 348:2618–2625

11 Albert RK, Martin TR, Lewis SW. Controlled clinical trial ofmethylprednisolone in patients with chronic bronchitis andacute respiratory insufficiency. Ann Intern Med 1980; 92:753–758

12 Bullard MJ, Liaw SJ, Tsai YH, et al. Early corticosteroid usein acute exacerbations of chronic airflow obstruction. Am JEmerg Med 1996; 14:139–143

13 Davies L, Angus RM, Calverley PM. Oral corticosteroids inpatients admitted to hospital with exacerbations of chronicobstructive pulmonary disease: a prospective randomisedcontrolled trial. Lancet 1999; 354:456–460

14 Emerman CL, Connors AF, Lukens TW, et al. A randomizedcontrolled trial of methylprednisolone in the emergencytreatment of acute exacerbations of COPD. Chest 1989;95:563–567

15 Maltais F, Ostinelli J, Bourbeau J, et al. Comparison ofnebulized budesonide and oral prednisolone with placebo inthe treatment of acute exacerbations of chronic obstructivepulmonary disease: a randomized controlled trial. Am JRespir Crit Care Med 2002; 165:698–703

16 Niewoehner DE, Erbland ML, Deupree RH, et al. Effect ofsystemic glucocorticoids on exacerbations of chronic obstruc-tive pulmonary disease: department of Veterans Affairs Co-operative Study Group. N Engl J Med 1999; 340:1941–1947

17 Rostom R, Mink S, Hebert P, et al. The long term efficacy ofmethylprednisolone in the treatment of acute exacerbation ofCOPD [abstract]. Chest 1994; 106:161S

18 Thompson WH, Nielson CP, Carvalho P, et al. Controlledtrial of oral prednisone in outpatients with acute COPDexacerbation. Am J Respir Crit Care Med 1996; 154:407–412

19 Wood-Baker R, Wilkinson J, Pearce M, et al. A double-blind,randomised, placebo-controlled trial of corticosteroids foracute exacerbations of chronic obstructive pulmonary disease.Aust N Z J Med 1998; 28:262

20 Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotictherapy in exacerbations of chronic obstructive pulmonarydisease. Ann Intern Med 1987; 106:196–204

21 Elmes PC, King TK, Langlands JH, et al. Value of ampicillinin the hospital treatment of exacerbations of chronic bronchi-tis. BMJ 1965; 2:904–908

22 Fear EC, Edwards G. Antibiotic regimes in chronic bronchi-tis. Br J Dis Chest 1962; 56:153–162

23 Hansen M, Evald T, Balslov S, et al. A randomized double-blind trial between amoxycillin and placebo in the treatmentof acute exacerbations of chronic bronchitis [abstract]. EurRespir J 1990; 3(suppl 10):89

24 Jorgensen AF, Coolidge J, Pedersen PA, et al. Amoxicillin intreatment of acute uncomplicated exacerbations of chronicbronchitis: a double-blind, placebo-controlled multicentre studyin general practice. Scand J Prim Health Care 1992; 10:7–11

25 Manresa F, Blavia R, Martin R, et al. Antibiotics for exacer-bations of chronic bronchitis. Lancet 1987; 2:394–395

26 Nicotra MB, Rivera M, Awe RJ. Antibiotic therapy of acuteexacerbations of chronic bronchitis: a controlled study usingtetracycline. Ann Intern Med 1982; 97:18–21

27 Nouira S, Marghli S, Belghith M, et al. Once daily oralofloxacin in chronic obstructive pulmonary disease exacerba-tion requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet 2001; 358:2020–2025

28 Petersen ES, Esmann V, Honcke P, et al. A controlled studyof the effect of treatment on chronic bronchitis: an evaluationusing pulmonary function tests. Acta Med Scand 1967;182:293–305

29 Pines A, Raafat H, Greenfield JS, et al. Antibiotic regimens inmoderately ill patients with purulent exacerbations of chronicbronchitis. Br J Dis Chest 1972; 66:107–115

30 Pines A, Raafat H, Plucinski K, et al. Antibiotic regimens in




severe and acute purulent exacerbations of chronic bronchi-tis. BMJ 1968; 2:735–738

31 Lindenauer PK, Pekow P, Gao S, et al. Quality of care forpatients hospitalized for acute exacerbations of chronic obstruc-tive pulmonary disease. Ann Intern Med 2006; 144:894–903

32 Lenfant C. Shattuck lecture: clinical research to clinical practice;lost in translation? N Engl J Med 2003; 349:868–874

33 Wood-Baker RR, Gibson PG, Hannay M, et al. Systemic cortico-steroids for acute exacerbations of chronic obstructive pulmo-nary disease. Cochrane Database Syst Rev 2005; CD001288

34 Ram FS, Rodriguez-Roisin R, Granados-Navarrete A, et al.Antibiotics for exacerbations of chronic obstructive pulmo-nary disease. Cochrane Database Syst Rev 2006; CD004403

35 Keenan SP, Sinuff T, Cook DJ, et al. Which patients with acuteexacerbation of chronic obstructive pulmonary disease benefitfrom noninvasive positive-pressure ventilation? A systematicreview of the literature. Ann Intern Med 2003; 138:861–870

36 Lightowler JV, Wedzicha JA, Elliott MW, et al. Non-invasivepositive pressure ventilation to treat respiratory failure result-ing from exacerbations of chronic obstructive pulmonarydisease: Cochrane systematic review and meta-analysis. BMJ2003; 326:185

37 Ram FS, Picot J, Lightowler J, et al. Non-invasive positivepressure ventilation for treatment of respiratory failure due toexacerbations of chronic obstructive pulmonary disease. Co-chrane Database Syst Rev 2004:CD004104

38 Fagon JY, Chastre J, Domart Y, et al. Nosocomial pneumoniain patients receiving continuous mechanical ventilation: pro-spective analysis of 52 episodes with use of a protectedspecimen brush and quantitative culture techniques. Am RevRespir Dis 1989; 139:877–884

39 Liberati A, D’Amico R, Pifferi S, et al. Antibiotic prophylaxisto prevent nosocomial infections in patients in intensive careunits: evidence that struggle to convince practising clinicians.Intern Emerg Med 2006; 1:160–162

40 Tobin MJ. Mechanical ventilation. N Engl J Med 1994;330:1056–1061

41 Stanford RH, Shen Y, McLaughlin T. Cost of chronic ob-structive pulmonary disease in the emergency departmentand hospital: an analysis of administrative data from 218 UShospitals. Treat Respir Med 2006; 5:343–349

42 Dewan NA, Rafique S, Kanwar B, et al. Acute exacerbation ofCOPD: factors associated with poor treatment outcome.Chest 2000; 117:662–671

43 Bott J, Carroll MP, Conway JH, et al. Randomised controlledtrial of nasal ventilation in acute ventilatory failure due to chronicobstructive airways disease. Lancet 1993; 341:1555–1557

44 Daskalopoulou E, Tsara V, Fekete K, et al. Treatment of

acute respiratory failure in COPD patients with positivepressure via nasal mask. Chest 1993; 103:271S

45 Servillo G, Ughi L, Rossano F, et al. Non invasive maskpressure support ventilation in COPD patients [abstract].Intensive Care Med 1994; 20(suppl):S54

46 Brochard L, Mancebo J, Wysocki M, et al. Noninvasiveventilation for acute exacerbations of chronic obstructivepulmonary disease. N Engl J Med 1995; 333:817–822

47 Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospec-tive trial of noninvasive positive pressure ventilation in acuterespiratory failure. Am J Respir Crit Care Med 1995; 151:1799–1806

48 Angus RM, Ahmed AA, Fenwick LJ, et al. Comparison of theacute effects on gas exchange of nasal ventilation and doxa-pram in exacerbations of chronic obstructive pulmonarydisease. Thorax 1996; 51:1048–1050

49 Barbe F, Togores B, Rubi M, et al. Noninvasive ventilatorysupport does not facilitate recovery from acute respiratoryfailure in chronic obstructive pulmonary disease. Eur RespirJ 1996; 9:1240–1245

50 Celikel T, Sungur M, Ceyhan B, et al. Comparison ofnoninvasive positive pressure ventilation with standard med-ical therapy in hypercapnic acute respiratory failure. Chest1998; 114:1636–1642

51 Martin TJ, Hovis JD, Costantino JP, et al. A randomized,prospective evaluation of noninvasive ventilation for acute respi-ratory failure. Am J Respir Crit Care Med 2000; 161:807–813

52 Plant PK, Owen JL, Elliott MW. Early use of non-invasiveventilation for acute exacerbations of chronic obstructivepulmonary disease on general respiratory wards: a multicen-tre randomised controlled trial. Lancet 2000; 355:1931–1935

53 Dikensoy O, Ikidag B, Filiz A, et al. Comparison of non-invasiveventilation and standard medical therapy in acute hypercapnicrespiratory failure: a randomised controlled study at a tertiaryhealth centre in SE Turkey. Int J Clin Pract 2002; 56:85–88

54 Early use of non-invasive positive pressure ventilation foracute exacerbations of chronic obstructive pulmonary disease:a multicentre randomized controlled trial. Chin Med J (Engl)2005; 118:2034–2040

55 Dhamija A, Tyagi P, Caroli R, et al. Noninvasive ventilation inmild to moderate cases of respiratory failure due to acuteexacerbation of chronic obstructive pulmonary disease. SaudiMed J 2005; 26:887–890

56 Keenan SP, Powers CE, McCormack DG. Noninvasive positive-pressure ventilation in patients with milder chronic obstructivepulmonary disease exacerbations: a randomized controlled trial.Respir Care 2005; 50:610–616

766 Special Feature



DOI 10.1378/chest.07-1207 2008;133; 756-766Chest

Bradley S. Quon, Wen Qi Gan and Don D. Sin*Contemporary Management of Acute Exacerbations of COPD

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