Acute Exacerbations of COPD in Subjects Completing Pulmonary Rehabilitation

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1 Acute Exacerbations of COPD in Subjects Completing Pulmonary Rehabilitation S. Jocelyn Carr, Roger S. Goldstein and Dina Brooks Chest 2007;132; ; Prepublished online May 2, 2007; DOI /chest The online version of this article, along with updated information and services can be found online on the World Wide Web at: CHEST is the official journal of the American College of Chest Physicians. It has been published monthly since Copyright 2007 by the American College of Chest Physicians, 3300 Dundee Road, Northbrook IL All rights reserved. No part of this article or PDF may be reproduced or distributed without the prior written permission of the copyright holder ( ISSN:

2 CHEST Acute Exacerbations of COPD in Subjects Completing Pulmonary Rehabilitation* S. Jocelyn Carr, MSc, BSc (PT); Roger S. Goldstein, MB ChB, FCCP; and Dina Brooks, PhD, MSc, BSc (PT) Original Research COPD Background: Improvements in health status following pulmonary rehabilitation (PR) diminish with time. Acute exacerbations of COPD (AECOPDs) negatively impact adherence after PR and likely accelerate this diminution of benefit. This study was designed to characterize the pre-aecopd status of patients with moderate or severe COPD who had completed PR, and then to measure the impact of AECOPDs on health-related quality of life (HRQL) and functional exercise capacity. Methods: Sixty subjects who completed PR were enrolled in a 6-month observational study and were followed up until an AECOPD occurred. In the event of an AECOPD, primary outcome measures, the 6-min walk test (6MWT) and the chronic respiratory disease questionnaire (CRDQ), were repeated 2 weeks after the onset of symptoms. Between-group and repeated-measures analyses were performed. Results: The mean ( SD) age of the 53 subjects (49% female) completing the study was 68 9 years. Baseline airflow obstruction was moderate in 35 subjects (66%) and severe in 18 subjects (34%). Thirty-four subjects experienced a moderate or severe AECOPD. The mean distance walked on the baseline 6MWT in those subjects who experienced AECOPDs was m, compared to m walked in those subjects who did not (difference, 66 m; p < 0.02). The presence of an AECOPD was associated with significant reductions in 6MWT distance walked (difference, m; p < 0.01) and in the CRDQ domains of fatigue (difference, 1 1.3; p < 0.01), emotion (difference, ; p < 0.01), and mastery (difference, ; p < 0.05). Conclusions: Patients with lower functional exercise capacity are more likely to experience AECOPDs following PR. AECOPDs are associated with significant and clinically meaningful reductions in functional exercise capacity and HRQL. (CHEST 2007; 132: ) Key words: acute exacerbation; COPD; health-related quality of life; pulmonary rehabilitation; 6-min walk test Abbreviations: AECOPD acute exacerbation of COPD; CRDQ chronic respiratory disease questionnaire; FT feeling thermometer; HRQL health-related quality of life; LCADL London Chest Activity of Daily Living; MCID minimum clinically important difference; PR pulmonary rehabilitation; 6MWT 6-min walk test Pulmonary rehabilitation (PR) is the recommended standard of care for patients with COPD 1 4 as it has been shown to improve functional exercise capacity and health-related quality of life (HRQL). 5 7 The benefits *From the Graduate Department of Rehabilitation Science (Ms. Carr and Dr. Brooks), and the Department of Medicine and Physical Therapy (Dr. Goldstein), University of Toronto, Toronto, ON, Canada. Ms. Carr was awarded Fellowships from the Ontario Respiratory Care Society and the Canadian Respiratory Health Professionals of the Canadian Lung Association. Dr. Brooks held a New Investigator Award from the Canadian Institute for Health Research (CIHR). Financial support for this research was received from the Ontario Thoracic Society. gradually diminish over the subsequent 12 months, in part because of reduced program adherence. 8,9 Acute exacerbations of COPD (AECOPDs) are The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Manuscript received January 30, 2007; revision accepted March 26, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Dina Brooks, PhD, MSc, BSc (PT), Department of Physical Therapy, University Ave, Toronto, ON, M5G 1V7 Canada; dina.brooks@utoronto.ca DOI: /chest CHEST / 132 / 1/ JULY,

3 defined by changes in sputum volume, color, or consistency, accompanied by an increase in dyspnea. 10 They may also be classified as mild, moderate, or severe, based on their required management, which varies from minimal changes in bronchodilator medication to unscheduled emergency department visits or hospital admissions. 11 The frequency of AECOPDs varies, with many being unreported 12,13 despite patients being coached and provided with diary cards. Severe disease is associated with more frequent AECOPDs and, consequently, with increased unscheduled emergency department visits and hospital admissions. 14 Post-AECOPD, more physically active patients have a lower risk of repeat hospitalization, 15 whereas the converse is true for those with reduced physical activity. AECOPDs decrease exercise capacity and HRQL, which is the opposite of what is achieved by PR. 16,17 However, little is known regarding the impact of AECOPDs on patients subsequent to their completing PR. Reports of the impact of AECOPDs have not included pre-aecopd measurements, which were made when the patients were clinically stable. This study was designed to characterize the pre-aecopd status of patients with moderate or severe COPD who had completed PR, and then to measure the impact of AECOPDs on HRQL and functional exercise capacity. The subjects reported in this study became the subjects of a subsequent randomized controlled trial of PR. 21 Materials and Methods Approval was obtained from the appropriate ethics review boards. The design for this study was descriptive, with data collected prospectively. Subjects who met the criteria for the diagnosis of COPD 1 had moderate-to-severe airflow obstruction (moderate airflow obstruction, FEV 1 30% predicted and 70% predicted; severe airflow obstruction, FEV 1 30% predicted), were clinically stable, and could communicate clearly were considered to be eligible for the study. Subjects were ineligible if they had diagnoses unassociated with COPD, such as uncontrolled heart failure, severe lower limb arthritis, or symptomatic peripheral vascular disease, which affected the outcome measures of dyspnea or exercise tolerance more than COPD alone. Other comorbidities such as irritable bowel syndrome, glaucoma, or prostatic hyperplasia were included among those documented in Table 1. Subjects who met the inclusion criteria were recruited into the study on completion of their PR program. Baseline measurements were collected after obtaining informed consent. An AECOPD was defined based on symptoms according to the criteria described by Anthonisen and colleagues. 10 These symptoms were increased dyspnea with changes in sputum purulence or volume, lasting at least 2 consecutive days. We used intervention-based criteria for classifying the AECOPD as mild, moderate, or severe, depending on whether they were managed at home with no additional health-care provider contact (mild), at home with unscheduled health-care provider contact or the initiation of oral corticosteroids (moderate), or in the emergency Table 1 Baseline Characteristics of the 60 Participants* Characteristics Participants Who Completed Baseline Measures (n 60) Age, yr 69 8 (49 85) Height, cm ( ) Weight, kg (37 117) Gender 50% male Comorbidities (1 10) Disease severity, % Moderate 65 Severe 35 FEV 1 L ( ) % predicted (11 80) FVC actual ( ) FEV 1 /FVC ratio ( ) Supplemental oxygen, % 25 6MWT distance walked, m ( ) CRDQ, Av Sc/Q Dyspnea ( ) Fatigue ( ) Emotion ( ) Mastery ( ) *Values are as the mean SD (range), unless otherwise indicated. Av Sc/Q average score per question. Moderate disease severity, FEV 1 30% and 70% predicted; severe disease severity, FEV 1 30% predicted. department or hospital (severe). 11 Subjects were taught these definitions and were asked to call the research coordinator as soon as they had identified a moderate or severe AECOPD. They were also advised that they would be called on a monthly basis to verify the same. The treatment of the AECOPD was provided by the patient s physician. Details of the management and course of the AECOPD were recorded by the study coordinator. These details included the treatment received and any unscheduled physician or emergency department visits, or hospitalization. Outcomes were measured 2 to 4 weeks after the onset of symptoms, or as soon as the patient was well enough to attend. In the absence of an AECOPD, subjects were followed up for 6 months, with baseline measurements repeated at 3 and 6 months. Measures The primary outcomes were HRQL, using the chronic respiratory disease questionnaire (CRDQ), and functional exercise capacity, using the 6-min walk test (6MWT). The intervieweradministered version of the CRDQ that was used required 20 min for completion. The details have been described elsewhere, 21 but, in brief, the 20 questions are divided into the following four domains: dyspnea (five questions); fatigue (four questions); emotional function (seven questions); and mastery (four questions). Answers are scored on a 7-point scale, from maximum impairment (1 point) to no impairment (7 points). The results are expressed as the mean score per question for each domain and the mean overall score. The minimum clinically important difference (MCID) for the CRDQ is 0.5 U per question, with a moderate change being 1.0 U and a large change being 1.5 U. 22,23 The CRDQ is valid, reproducible, and responsive in patients with COPD The 6MWT was administered according to the American 128 Original Research

4 Thoracic Society guidelines 25 using standardized instructions 26 and the same quiet corridor for each measurement. Subjects were required to walk as far as they could in 6 min, and the distance walked was recorded. Subjects were familiar with this test, as they had recently completed a PR program in which it was administered on hospital admission and at hospital discharge. The properties of this test and its MCID have been published. 25,27,28 The results of the London Chest Activity of Daily Living (LCADL) questionnaire and the feeling thermometer (FT) were secondary outcomes. The LCADL, which is a 15-item questionnaire regarding routine home activities of daily living, was developed and validated for individuals with COPD. 29 A higher score reflects more breathlessness with each stated activity. The FT is a self-administered visual analog scale of well-being that ranges from best (100 points; full health) to worst (0 points; dead) and takes 3 min to complete. 30,31 It has been used in populations with chronic respiratory conditions and has an MCID of between five and seven. 32 Statistical Analysis The data were analyzed using between-group comparisons (t tests and 2 analyses) to compare those patients who experienced an AECOPD with those who did not. These comparisons were also made between those experiencing moderate and severe AECOPDs. Repeated-measures comparisons (paired sample t tests) were performed for the pre-aecopd to post-aecopd analyses. All analyses were completed with a statistical software package (SPSS, version 14.0; SPSS Inc; Chicago, IL). A p value of 0.05 was considered to be significant. Subjects Results Patients who participated in PR programs between September 2003 and January 2006 were screened consecutively for eligibility. Of the 364 patients screened, 94 met the inclusion criteria, and 64 were recruited and provided signed informed consent. The reasons for noneligibility, refusal, or drop out are summarized in Figure 1. Of those patients who were recruited, 60 completed baseline measurements, as 2 patients became ill prior to undergoing those measurements and 2 patients did not attend. The characteristics of the group are summarized in Table 1. Underlying airflow obstruc- Screened: 364 Did not Qualify: 272 Refused: 28 - Do not want to re-admit: 6 - Extended travel: 4 - Unwell: 4 - Excessive Driving: 4 - Unable to contact: 3 - Too busy: 3 - Family issues: 2 - Other: 2 Qualified: 92 Recruited: 64 - Not stable: 79 - Excessive comorbidities: 76 - Too far: 28 - In other study: 22 - Cognitive impairment: 19 - Poor compliance: 17 - Language barrier: 16 - Other: 15 Baselines not completed: 4-2 did not attend for measures -2 became ill prior to measures Baselines Completed: 60 Lost to follow-up and/or dropped out: 7-1 moved - 1 cardiac event - 1 attending other program - 2 diagnosed with cancer - 2 developed gastrointestinal illnesses. Participated in prospective data collection: 53 No AE in 26 wks = 19 Total # AE by 26 wks = 34 Moderate AE = 27 (79%) Severe AE = 7 (21%) Dropped out: 5 - Excessive Driving: 1 - Missed AEs: 3 - AE prior to D/C: 1 Completed measures: 22 Completed measures: 7 Figure 1. Study flow from initial screening to the identification of AECOPDs. AE acute exacerbation. CHEST / 132 / 1/ JULY,

5 tion was graded as moderate in 39 patients (65%) and severe in 21 patients (35%). There was no difference at baseline between the 7 patients who dropped out of the study vs the 53 patients who completed it, with the exception of the score for the mean emotional function domain of the CRDQ, which was lower in the group of patients who dropped out of the study ( vs , respectively; p 0.02). Pre-AECOPD Characteristics Of the 53 patients who were followed up after completing PR, a moderate or severe AECOPD occurred in 34 patients (64%), while 19 patients (36%) remained event-free (Fig 1). The mean time from obtaining the initial baseline measures at the end of PR to the AECOPD was weeks (range, 1 to 25 weeks). The baseline characteristics of those patients who experienced an AECOPD were compared with those of patients who remained event-free at 26 weeks. The groups differed significantly at baseline in terms of the 6MWT distance walked (difference, 66 m; p 0.018), their LCADL scores (difference, 0.28; p 0.03), and their FT scores (difference, 10.2; p 0.041), with those patients who remained event-free having the better scores (Table 2). AECOPDs were characterized as moderate in 27 patients (79%) and severe in 7 patients (21%) [Fig 1], with no differences in any baseline characteristics of lung function, exercise tolerance, or HRQL between these two groups. Of those in whom the event was classified as moderate, one patient used selfmanagement, while 26 patients made unscheduled visits to their physicians; of those in whom the event was classified as severe, three were managed in the emergency department and four required hospitalization. Impact of AECOPDs Subjects were measured a mean duration of weeks (range, 1.3 to 12.7 weeks) following their AECOPD, as soon as they were well enough to attend for study measurements. A reduction in mean 6MWT distance walked of m(p 0.001) was noted (Table 3, Fig 2, top, A). Three of four domains of the CRDQ also changed in a statistically and clinically meaningful way, as follows: fatigue (mean, ; p 0.001) [Fig 2, bottom, B]; emotional function (mean, ; p 0.003); and mastery (mean, ; p 0.04) [Table 3]. The FT was also significantly lower after AE- COPD (mean, ; p 0.04) [Table 3]. Despite the variability in the time from the onset of an AECOPD to presentation for measurement, the time interval was not related to the severity of the event (p 0.4), nor to the reductions in 6MWT distance walked (p 0.6) or CRDQ scores (dyspnea, p 0.6; fatigue, p 0.7; emotional function, p 0.6; mastery, p 0.3). Additionally, there was no association between the above time interval and either the degree of hyperinflation (p 0.9) or the inspiratory capacity (p 0.5). Those subjects who did not experience an AE- COPD were followed up for 6 months with measures repeated at 3 and 6 months. No differences were Table 2 Characteristics of Those Patients With AECOPDs and Those Who Remained Event-Free* Baseline Characteristics Patients With AECOPDs (n 34) Patients Who Were Event Free (n 19) Age, yr (53 84) (49 85) Height, cm ( ) ( ) Weight, kg (40 117) (37 114) Gender 47% male 58% male Comorbidities (1 10) (1 9) Severity of disease, % Moderate Severe FEV 1,L ( ) ( ) FEV 1 /FVC ratio ( ) ( ) IC, % predicted (40 156) (69 150) 6MWT distance walked, m ( ) ( ) LCADL, Av Sc/Q ( ) ( ) FT (25 90) (30 93) *Values are given as the mean SD (range), unless otherwise indicated. IC inspiratory capacity. See Table 1 for abbreviations not used in the text. p p p Original Research

6 Table 3 6MWT Walking Distance and HRQL Score Pre-AECOPD and Post-AECOPD* AECOPD by 26 Wk (n 29) Pre-AECOPD Closest Baseline Post-AECOPD Measures Mean Change p Value 6MWT (m) ( ) (10 501) CRDQ, Av Sc/Q Dyspnea ( ) ( ) Fatigue ( ) ( ) Emotion ( ) ( ) Mastery ( ) ( ) LCADL, Av Sc/Q (1 3) ( ) FT (30 90) (15 90) *Values are given as the mean SD (range), unless otherwise indicated. See Table 1 for abbreviations not used in the text. found between their initial baseline measures and the two subsequent sets of measures (Table 4). Compliance with telephone follow-up was good, with 92 of 114 conversations (81%) being completed on the first or second try. Analysis of the management of the 27 patients who had experienced a moderate AECOPD showed that 9 patients (33%) had been treated with both antibiotics and corticosteroids, while 16 patients (59%) had been treated only with antibiotics. Of the seven patients who experienced a severe AECOPD, six received both categories of medication, while only one patient was treated with antibiotics alone. Therefore, all those patients experiencing an AE- COPD received antibiotic therapy, while only 33% of those experiencing a moderate event and 86% of those experiencing a severe event also received corticosteroids. Discussion Although AECOPDs are associated with impairments of muscle function, 20 walking ability, 18,33,34 and HRQL, no reports to date have included baseline pre-aecopd measurements to allow comparison to measurements performed when subjects were stable. Therefore, we enrolled patients post-pr in order to capture outcome measures at the time of program completion and to use these as baseline measures for those patients experiencing an AE- COPD. In order to ensure that these baseline measures remained current, we repeated them at intervals of 3 months or until an AECOPD occurred. These baseline measures did not vary with time, reflecting the clinical stability of this population of patients with COPD, in the absence of an AECOPD. We observed differences in the 6MWT distances walked at baseline between those who subsequently experienced an AECOPD and those who did not (mean 6MWT distance walked in those who experienced a severe event, 335} 101 m; mean 6MWT distance walked in those who experienced a moderate event, m; mean 6MWT distance walked in those who experienced no event, m), as well as differences in the LCADL, a selfreport of breathlessness with activities, and in the FT, a measure of health utility. These observations are in keeping with the findings of Garcia-Aymerich and colleagues 15 and Kessler and colleagues, 38 highlighting the association between exercise capacity and the occurrence of an AECOPD. We did not find any differences in lung mechanics, exercise capacity, or HRQL between those patients who experienced moderate AECOPDs and those who experienced severe AECOPDs. The sample size was too small to evaluate the influence of gender on these results. Even though the majority of AECOPDs were classed as moderate, the marked changes in HRQL and 6MWT walk distance (mean, m) are important reminders that the pharmacologic management of AECOPDs alone may be insufficient. Whereas in some jurisdictions PR is only offered to patients who are clinically stable (ie, those with no recent AECOPD), there may be a strong case for enrolling post-aecopd patients directly into PR programs to try to offset the deleterious effects on exercise capacity and quality of life. 19 Given that PR improves functional capacity and HRQL 11,16,39,40 and that higher levels of physical activity have been associated with a reduced risk of hospital readmission, 15 it is possible that post-pr AECOPDs may be less frequent, or less likely to be severe, compared with patients who have not attended PR. Foglio and colleagues 41 reported between two and four AECOPDs per year in patients prior to PR, and zero to two AECOPDs per year post-pr; Murphy and colleagues 42 reported that only 2 of 16 patients in an exercise group, compared with 5 of 15 subjects in a control group, experienced an AECOPD at 6 months after undergoing PR. The influence of PR on AECOPDs will be important to establish with prospective studies that are powered to answer this question. Current estimates of the frequency of AECOPDs CHEST / 132 / 1/ JULY,

7 A B 6-Minute Walk Distance (m) CRQ Fatigue Closest Baseline Closest Baseline p < p < Post-AECOPD Post-AECOPD Figure 2. The effect of an AECOPD on (top, A) the 6MWT distance walked (p 0.001) and (bottom, B) the fatigue domain of the CRDQ (p 0.001). vary widely, although different methods for counting and analyzing the frequency can result in major discrepancies. Pharmaceutical studies have documented a rate of 1.75 to 1.9 per patient per year among those with moderate-to-severe COPD in placebo groups. Other studies 12,13,46 have described one to four AECOPDs per year among COPD patients not previously enrolled in a PR program. We did not use diary cards but chose to request that patients self-report any AECOPDs and supported this by calling them monthly, noting an 81% compliance with telephone follow-up. In 53 patients who were followed up for 6 months, we identified 34 AECOPDs, of which only 13% were severe (ie, had been managed in the emergency department or hospital). We noted a broad range of presentation times for outcome measures post-aecopd (mean presentation time, weeks; range, 1.3 to 12.7 weeks), but found no correlation between the time to presentation and the severity of baseline lung function or of the AECOPD. Seemungal and colleagues 12 have highlighted the wide range of recovery times following an AECOPD, with 75% of patients having returned to their pre-aecopd status at 35 days. Our finding that the change in dyspnea score 4 weeks post-aecopd did not reach significance is in keeping with the report of Wilkinson and colleagues, 36 who noted that most symptoms of an AECOPD, including dyspnea, had resolved by a median time of 11 days after the AECOPD (range, 7 to 14 days). Despite having completed PR, most of the 27 patients who had experienced moderate AECOPDs did not report self-management but made an unscheduled visit to their physician. We believe that this reflected the absence of education focused on self-management in the program and have modified it accordingly to include such components The strengths of the study include its prospective observational design, in which pre-aecopd baseline measures were collected and the subjects were tracked using valid, reproducible, interpretable outcome measures. The only other study to collect pre-aecopd baseline information 51 evaluated the influence of AECOPDs on a population of COPD patients who had not undergone PR. Our study was limited by a relatively small sample of 34 patients who had experienced AECOPDs, which precluded our being able to confidently identify predictive factors by multiple regression. Another limitation was the range of times required by the patients to return for post-aecopd measures. This report raises interesting issues, such as the need for a larger prospective study to establish whether PR influences the frequency or severity of AECOPDs. It also highlights design issues for conducting trials of PR in subjects post-aecopd, such as the need for the careful classification of the severity of the AECOPD as well as for the standardization of the time for measurement. We were also struck by the variability of treatment of an AECOPD by physicians, many of whom did not follow accepted evidence-based guidelines 1 4,11 with fewer than half the patients receiving a short course of therapy with oral corticosteroids. In conclusion, we have noted the negative impact of AECOPDs on the functional exercise capacity and HRQL of patients who have completed PR. Changes 132 Original Research

8 Table 4 Longitudinal Data for Those With No AECOPD* Outcomes Baseline 3 mo 6 mo p Value 6MWT distance walked, m ( ) ( ) ( ) 0.3 CRDQ, Av Sc/Q Dyspnea ( ) ( ) ( ) 0.3 Fatigue ( ) ( ) ( ) 0.9 Emotion ( ) ( ) ( ) 0.3 Mastery ( ) ( ) ( ) 0.4 *Values are given as the mean SD (range), unless otherwise indicated. See Table 1 for abbreviations not used in the text. By two-tailed repeated-measures analysis of variance. in these outcomes after an AECOPD, in comparison with measurements made soon after completing PR, highlight the need to combine pharmacologic and nonpharmacologic approaches to the post-aecopd patient. References 1 Celli BR, MacNee W, Agusti A, et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: Global Initiative for Chronic Obstructive Lung Disease. 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10 Acute Exacerbations of COPD in Subjects Completing Pulmonary Rehabilitation S. Jocelyn Carr, Roger S. Goldstein and Dina Brooks Chest 2007;132; ; Prepublished online May 2, 2007; DOI /chest This information is current as of April 11, 2008 Updated Information & Services References Permissions & Licensing Reprints alerting service Images in PowerPoint format Updated information and services, including high-resolution figures, can be found at: This article cites 46 articles, 32 of which you can access for free at: Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: Information about ordering reprints can be found online: Receive free alerts when new articles cite this article sign up in the box at the top right corner of the online article. Figures that appear in CHEST articles can be downloaded for teaching purposes in PowerPoint slide format. See any online article figure for directions.