- Email: [email protected]
Influence of inhaled procaterol on pulmonary rehabilitation in chronic obstructive pulmonary disease
respiratory investigation 50 (2012) 135–139
Contents lists available at SciVerse ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Influence of inhaled procaterol on pulmonary rehabilitation in chronic obstructive pulmonary disease Makoto Hasegawaa,n, Kunio Dobashib, Takeo Horiec, Naoki Wadaa, Kenji Shirakuraa a
Department of Rehabilitation, Gunma University Hospital, Japan Gunma University Graduate School of Health Sciences, Japan c Department of Respiratory Medicine, Maebashi Red Cross Hospital, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: Chronic obstructive pulmonary disease (COPD) is a progressive condition that
Received 17 February 2012
classically causes dyspnea during physical activity. Destruction of alveoli and bronchos-
Received in revised form
tenosis are thought to lead to shortness of breath and result in decreased physical activity.
6 August 2012
In this study, we examined the influence of inhaled procaterol on exercise therapy for
Accepted 8 August 2012
pulmonary rehabilitation.
Available online 13 September 2012
Methods: Patients with moderate to severe stable COPD were randomly divided into 2
Keywords:
groups those who inhaled procaterol before exercise (n ¼10) and those who did not (control
Chronic obstructive pulmonary
group) (n ¼11). For 12 weeks, all patients performed their pulmonary rehabilitation
disease
exercises at home. We measured the 6-minute walking distance (6MWD) to assess exercise
Short-acting beta2-agonist
tolerance and used St. George’s respiratory questionnaire (SGRQ) to assess health-related
Procaterol
quality of life (HRQOL) before and after the 12-week exercise program.
Assist use
Results: Compared to the control group, the group receiving inhaled procaterol showed
Pulmonary rehabilitation
significant improvement of 6MWD and SGRQ scores. Conclusion: Our data suggest that a pulmonary rehabilitation program combined with inhaled procaterol can improve both HRQOL and exercise tolerance in COPD patients. & 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is a chronic and progressive condition leading to alveolar destruction and bronchostenosis. The cardinal symptom of COPD is shortness of breath during physical activity. Severe dyspnea eventually leads to a decline in activity that results in loss of appetite, muscle weakness, decreased alertness, and deterioration of activities of daily living (ADLs) and quality of life (QOL). It is thought that pulmonary rehabilitation is useful for the treatment of COPD, with pharmacotherapy and exercise therapy
being the main treatments recommended for patients with stable COPD [1,2]. Long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), and short-acting beta2-agonists (SABA) are 3 classes of bronchodilators listed for pharmacotherapy in the guideline of The Japan Respiratory Society. LAMA and LABA are regularly prescribed for symptom control, while SABA are prescribed for relief of acute dyspnea. In the third edition of The Japan Respiratory Society COPD guidelines [2], it is stated that inhalation of a SABA just before exercise (assist use) is effective for prevention of dyspnea during exercise. In patients with
n
Corresponding author. Tel./fax: þ81 272 220 8532. E-mail address: [email protected] (M. Hasegawa).
2212-5345/$ - see front matter & 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2012.08.003
136
respiratory investigation 50 (2012) 135 –139
severe COPD, inhalation of SABA is also useful for preventing shortness of breath during ADLs such as bathing. Exercise therapy is focused on muscle training and endurance training, especially for the lower limb muscles, and is recommended to maintain ADLs and QOL. However, the need for increased ventilation produced by exercise leads to increased airway resistance in COPD patients. This increase of airway resistance induces air trapping and finally results in exacerbation of dyspnea that limits the performance of ADLs and decreases QOL. In the present study, we hypothesized that shortness of breath was a cause of exercise limitation and that both exercise tolerance and QOL would be improved by controlling dyspnea with inhalation of a bronchodilator before exercise therapy. Accordingly, we examined the influence of inhaled procaterol before exercise on the outcomes of pulmonary rehabilitation. Procaterol is a short-acting beta2-agonist with high intrinsic activity.
2.
Materials and methods
This study enrolled patients with COPD in stages II to IV according to The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. All patients inhaled tiotropium regularly and used procaterol for dyspnea, but none used a LABA, and no LABA was added during the study period. We excluded the following patients: (1) those who had received exercise therapy at the hospital during the previous year, (2) those who had suffered acute exacerbation within the previous 4 weeks, (3) those using oral bronchodilators, and (4) those with cardiovascular or orthopedic disorders that could influence rehabilitation.
2.1.
Groups and interventions
Patients were randomized to the SABA group or the control group. The patients performed prescribed exercise at home for 12 weeks. The SABA group inhaled 2 puffs of procaterol 30 min prior to home-based exercise, while the control group did not use a SABA before home-based exercise. If shortness of breath occurred during exercise, patients were instructed to rest without inhaling the SABA. The patients had received instructions about the home-based exercise after the first evaluation. All patients were advised to exercise at home for 30 min daily, and their exercise program included the followings components: (1) conditioning of the inspiratory muscles according to Honma’s method [3]. (2) Strength training for the quadriceps femoris and iliopsoas muscles, which are important for weight bearing, 1 set 10 times daily. (3) Endurance training featuring walking for at least 10 min daily at a perceived exertion level of 4 on a modified Borg scale. Patients were advised to rest if the perceived level of exertion exceeded 4. Exercise therapy was prescribed after evaluation of each patient at the start of the study. The patients were given exercise pamphlets and instructions by physical therapists about homebased exercise according to the pamphlets. Each patient was asked to keep a diary to record exercise sessions. Patients who could perform the exercises well after initial instruction were reevaluated to confirm that the home-based exercise was being done properly during their visits to the respiratory outpatient
department. Patients who initially could not perform the exercises adequately were given repeat instructions about the exercise program.
2.2.
Endpoints
The primary endpoint was exercise tolerance evaluated by the 6-minute walking distance (6MWD) without inhalation of the SABA before the test. The secondary endpoint was healthrelated QOL, which was evaluated with the Japanese version of the St. George’s Respiratory Questionnaire (SGRQ), translated by Nishimura. In addition, the Borg scale, SpO2, and heart rate were assessed at rest, and pulmonary function tests were performed. Patients were evaluated at the beginning and the end of the 12 week observation period.
2.3.
Statistical analysis
All values are expressed as the mean7standard deviation (SD). Results were compared by the Wilcoxon signed-rank test (for data shown in Figs. 1–2) or by the Mann–Whitney U test (for the data in Table 1). In all analyses, po0.05 was considered to be significant.
2.4.
Ethical considerations
The study protocol was approved by Gunma University Hospital Institutional Review Board. All subjects provided written informed consent before participation.
3.
Results
The clinical profiles of the 21 subjects (10 in the SABA group and 11 in the control group) are presented in Table 1. There were no significant differences between the 2 groups. During the study, we checked for side effects of SABA by reviewing the patient diaries and questioning each patient during visits to the clinic. No side effects of the SABA were reported. When the Borg scale, SpO2, heart rate, and lung function parameters
Fig. 1 – Comparison of 6-minute walking distance (6MWD) before and after rehabilitation.
137
respiratory investigation 50 (2012) 135 –139
Fig. 2 – St. George’s Respiratory Questionnaire (SGRQ) score before and after the 12-week exercise program. Table 1 – Character of the subjects.
GOLD (II/III/IV) MRC (2/3/4) Age (years) BMI FEV1/FVC (%) FEV1 % pred. (%) VC pred. (%) 6MWD (m) SGRQ
SABA (n¼ 10)
Control (n ¼11)
p-Value
6/4/0 5/2/3 73.775.8 21.872.2 43.3717.1 61.5723.9 102.6718.8 340.27106.1 40.579.2
7/2/2 7/3/1 67.979.0 22.572.8 45.8715.0 55.8720.4 97.4719.2 405.8790.3 40.8717.7
0.259 0.475 0.057 0.622 0.573 0.622 0.833 0.193 0.439
GOLD: Global Initiative for chronic obstructive lung disease; SABA: short-acting beta2-agonist; MRC: Medical Research Council; BMI: Body mass index; FEV1: forced expiratory volume in one second; FVC: forced expiratory capacity; FEV1 % pred.: percentage of predicted FEV1 value; VC pred.: percentage of predicted vital capacity value; 6MWD: six minutes walking distance; SGRQ: St George’s Respiratory Questionnaire.
Table 2 – .The Borg scale, SpO2, heart rate, and lung function parameters in the SABA and control groups before and after 12 weeks of home-based rehabilitation. SABA
Borg scale SpO2 (%) Heart rate (beats) FEV1/FVC (%) FEV1 % pred. (%) VC pred. (%)
CONTROL
Before rehab.
After rehab.
p Value
Before rehab.
After rehab.
p Value
0.570.7 96.372.0 82.579.9 43.3717.1 61.5724.0 102.6718.8
0.470.3 95.871.6 77.179.9 43.2716.3 69.5726.3 104.8722.2
0.686 0.0345 0.047 0.753 0.267 0.893
0.570.6 95.671.7 81.3714.6 45.8715.0 55.8720.4 97.4719.2
0.871.3 95.671.6 79.5713.2 44.5712.0 58.5719.8 100.7722.1
0.285 0.893 0.610 0.799 0.285 0.386
SpO2: percutaneous oxygen saturation; rehab.: rehabilitation.
were compared before and after the 12-week home-based exercise program, only the heart rate showed a significant change compared with baseline (Table 2). As shown in Fig. 1, exercise tolerance based on the 6MWD improved in both the SABA group (from 340.27106.1 m to 404.77102.4 m) and the Control group (from 405.8790.3 m to 427.67112.7 m) after 12 weeks of exercise at home, but only the SABA group showed significant improvement. The Borg scale, SpO2, and heart rate were compared before and after the 6MWD. In the SABA group, the heart rate and SpO2 showed a significant increase and decrease, respectively, after the 6MWD (Table 3). These results were consistent with the significant increase of the 6MWD seen in the SABA group after 12 weeks of home-based
rehabilitation compared with before exercise, as shown in Fig. 1. As shown in Fig. 2, all fields of the SGRQ index of healthrelated quality of life (HRQOL) improved significantly in the SABA group, including the SGRQ-symptom score (from 32.47 19.3 to 19.279.2), SGRQ-activity score (from 55.9712.0 to 42.7716.3), SGRQ-impact score (from 31.9711.4 to 24.5713.8), and SGRQ total score (from 40.679.2 to 30.1712.4). On the other hand, the SGRQ-symptom score (from 41.3722.1 to 28.6724.0), SGRQ-activity score (from 51.0721.8 to 47.1726.9), SGRQimpact score (from 31.4717.7 to 29.0729.1), and SGRQ-total score (from 40.8717.7 to 34.5723.5) showed no significant changes in the control group. It was difficult to compare the
138
respiratory investigation 50 (2012) 135 –139
Table 3 – The Borg scale, SpO2, and heart rate before and after the 6MWT in the SABA and control groups.
SABA
Borg scale SpO2 (%) Heart rate (beats/min)
CONTROL
Borg scale SpO2 (%) Heart rate (beats/min)
Before rehab. (Before/after 6MWT)
After rehab. (Before/after 6MWT)
p-Value
3.172.8 (0.570.7/3.772.8) 6.275.5 (96.372.0/90.176.7) 20.6710.6 (82.579.9/103.1712.5)
3.772.5 (0.470.3/4.172.4) 12.379.3 (95.871.6/83.579.5) 36.2715.9 (77.179.9/113.3715.9)
0.386
2.570.9 (0.570.6/3.071.0) 5.074.6 (95.671.7/90.676.0) 22.3711.0 (81.3714.6/103.5720.6)
2.271.5 (0.871.3/3.072.0) 6.976.6 (95.671.6/88.777.6) 25.3714.7 (79.5713.2/104.7718.8)
0.575
0.024 0.013
0.058 0.575
6MWT: six minutes walking test; rehab.: rehabilitation.
daily amount of exercise between the 2 groups correctly because many patients did not keep their diaries accurately.
4.
Discussion
In this study, we evaluated the influence of SABA inhalation before exercise on exercise tolerance in COPD patients. The cardinal symptom of COPD is shortness of breath during physical activity, which leads to inactivity and results in a progressive decline of ADLs and QOL. Pitta et al. [4] demonstrated an increase in the severity of exertional dyspnea induced inactivity in a study of patients who wore a pedometer with an acceleration sensor. In the present study, we showed that inhalation of procaterol led to greater improvement of exercise tolerance and health-related QOL than exercise without pre-treatment. The guidelines of The Japan Respiratory Society recommend inhalation of a LABA for COPD patients in stages II to IV. In this study, all subjects used tiotropium, but not a LABA. All patients were stable and no exacerbations were reported during the study period, so no patient received a LABA. This ensured consistency within the study groups when assessing the effects of the SABA. With regard to exercise tolerance, Casaburi et al. [5] have reported that patients who underwent pulmonary rehabilitation with bronchodilators achieved greater improvement of dyspnea and QOL than those who underwent rehabilitation without bronchodilators. Fujimoto et al. [6] reported that inhalation of a SABA just before an exercise tolerance test decreased shortness of breath and improved exercise tolerance in COPD patients. Kume [7] reported that a SABA with a higher intrinsic activity was more effective for improving the forced expiratory volume in 1 s and the inspiratory capacity of COPD patients. Therefore, we chose procaterol, which has a high intrinsic activity, for the present study. Sukisaki et al. [8] reported an immediate effect of inhaled procaterol on exercise tolerance. They reported that results of exercise tolerance tests were improved by inhalation of procaterol 4 h before testing. In addition, Satake et al. [9] suggested that inhalation of procaterol just before exercise could improve dyspnea and increase the effectiveness of exercise therapy.
Exercise-induced air trapping in COPD patients is referred to as dynamic hyperinflation, and Fujimoto et al. [10] reported that inhalation of procaterol before exercise led to improved exercise tolerance by reducing dynamic hyperinflation and dyspnea. Hospital-based exercise programs are performed under the supervision of physical therapists in rehabilitation units, so patients can continue the program easily with advice and encouragement. In contrast, a home-based exercise program is performed by the patient alone, so it is difficult for patients to maintain their motivation and to control anxiety related to exertional dyspnea. In this study, we tried to evaluate the frequency and level of exercise performed at home from patient diaries, but these generally did not contain enough details of the exercise session, which made it very difficult to compare the amount of exercise performed by the SABA and control groups. Therefore, we performed objective evaluations of the efficacy of the home-based rehabilitation programs by comparing improvements of 6MWD and SGRQ in the 2 groups. By these measures, we demonstrated significant improvement of exercise tolerance and health-related QOL in the SABA group. SABA inhalation before exercise at home relieved exertional dyspnea and allowed patients to continue their home-based exercise programs, resulting in significant improvement of ADLs and SGRQ-activity scores. This increase of activity also led to decreased anxiety about dyspnea and improved confidence in self-management. The SGRQ total score was also improved, although the SGRQ-symptom score was not improved. Satoh et al. [11] reported that use of a SABA relieved dyspnea and improved the QOL of COPD patients, but this group may have obtained somewhat different results because the SGRQ symptom score was improved by inhalation of a SABA before regular ADLs. In our study, patients only inhaled the SABA before home-based exercise. Thus, they noted a decrease in exertional dyspnea during exercise, but not with ADLs, because the SABA has a short duration of action. In COPD patients, shortness of breath tends to occur with exercise, and this leads to a decline in ADLs. It is important for COPD patients to maintain a certain level of activity in
respiratory investigation 50 (2012) 135 –139
daily life, however, particularly since Garcia-Aymerich et al. [12] have reported that a higher level of activity is associated with longer periods before hospitalization and death. It is important for COPD patients to continue their daily activities, but is difficult for them to do so without amelioration of exertional dyspnea. Accordingly, it is useful to reduce exertional dyspnea by SABA inhalation to allow the continuation of adequate exercise at home. Exercise therapy alone or pharmacotherapy alone is not enough to maintain patients on a home-based exercise program, but our data suggest that the combination of exercise therapy and SABA inhalation can increase the efficacy of home-based exercise. We considered it necessary to reduce dyspnea because dyspnea reduces activity and is a limiting factor in achieving successful rehabilitation at home. Sukisaki et al. [8] have reported that inhalation of procaterol before a 6MWD test improved exercise tolerance. However, their study only showed a temporary improvement in the 6MWD after inhalation of procaterol and before the test compared with no inhalation. In contrast, our study indicated that exercise tolerance and HRQOL were improved by regular use of SABA before home-based exercise over a period of 12 weeks. Thus, it appears that the combination of a SABA and exercise therapy can enhance the extent of rehabilitation. COPD patients may need to continue rehabilitation and the use of a SABA indefinitely. Therefore, it is important to watch for adverse effects of SABA inhalation. During this study, no adverse effects of SABA were observed. Although the resting heart rate was increased at the end of the study in the SABA group, it is not possible to attribute the increase to a direct effect of SABA inhalation because the SABA was not inhaled before evaluation of the heart rate. Shioya et al. [13] reported that there were no side effects after regular use of a SABA for 1 year. In our study, there were no serious side effects of the SABA observed in either group during the 12-week observation period. However, further investigation should be planned to identify any adverse effects of long-term SABA use.
5.
Conclusions
In this study, we found that inhalation of procaterol just before exercise at home reduced exertional dyspnea. In addition, home-based rehabilitation combined with inhalation of procaterol improved the 6MWD and the SGRQ score after the 12-week program. Accordingly, inhalation of procaterol just before exercise can improve exercise tolerance and QOL in patients performing home-based exercise.
139
Conflict of interest Authors have no potential conflict of interest.
r e f e r e nc e s
[1] From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2011. p. 19–38. Available from: /http://www.goldcopd.org/S. February 15, 2012. [2] The Japanese Respiratory Society. Guidelines for the diagnosis and treatment of COPD. 3rd edition [Pocket Guide]; 2009. p. 13–23. Available from: /http://www.jrs.or.jp/S. [3] Minehiko Y, Fujiyasu K, Masato S, et al. Clinical effects of four weeks of respiratory muscle stretch gymnastics in patients with chronic obstructive pulmonary disease. Nihon Kyobu Shikkan Gakkai Zasshi 1996;34:646–52. [4] Pitta F, Troosters T, Spruit MA, et al. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972–7. [5] Casaburi R, Kukafka D, Cooper CB, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127:809–17. [6] Fujimoto K, Ushiki A, Komatsu Y, et al. Additive efficacy of a short-acting beta-2-agonist on COPD treated with long-acting bronchodilators. J Jpn Soc Respir Care Rehabil 2009;1:64–70. [7] Kume H. Clinical use of b2-adrenergic receptor agonists based on their intrinsic efficacy. Allergol Int 2005;54:89–97. [8] Sukisaki T, Senjyu H, Oishi K, et al. Single dose of inhaled procaterol has a prolonged effect on exercise performance of patients with COPD. Physiother Theory Pract 2008;24:255–63. [9] Satake M, Takahashi H, Sugawara K, et al. Inhibitory effect of procaterol on exercise dynamic lung hyperinflation during the 6-min walk test in stable patients with chronic obstructive pulmonary disease. Arzneimittelforschung 2011;61:8–13. [10] Fujimoto K, Yashiike F, Yasuo M, et al. Effects of bronchodilators on dynamic hyperinflation following hyperventilation in patients with COPD. Respirology 2007;12:93–9. [11] Satoh H, Iwashima A, Endo Y, et al. Effect of proactive use of inhaled procaterol on dyspnea in daily activities and quality of life in patients with chronic obstructive pulmonary disease. Nihon Kokyuki Gakkai Zasshi 2009;47(9):772–80. [12] Garcia-Aymerich J, Lange P, Benet M, et al. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax 2006;61:772–8. [13] Shioya T, Satake M, Sato K, et al. Long-term effect of the beta2-receptor agonist procaterol on daily life performance and exercise capacity in patients with stable chronic obstructive pulmonary disease. Clinical study with special reference to health-related quality of life and activities of daily living. Arzneimittelforschung 2008;58:24–8.
Contents lists available at SciVerse ScienceDirect
Respiratory Investigation journal homepage: www.elsevier.com/locate/resinv
Original article
Influence of inhaled procaterol on pulmonary rehabilitation in chronic obstructive pulmonary disease Makoto Hasegawaa,n, Kunio Dobashib, Takeo Horiec, Naoki Wadaa, Kenji Shirakuraa a
Department of Rehabilitation, Gunma University Hospital, Japan Gunma University Graduate School of Health Sciences, Japan c Department of Respiratory Medicine, Maebashi Red Cross Hospital, Japan b
art i cle i nfo
ab st rac t
Article history:
Background: Chronic obstructive pulmonary disease (COPD) is a progressive condition that
Received 17 February 2012
classically causes dyspnea during physical activity. Destruction of alveoli and bronchos-
Received in revised form
tenosis are thought to lead to shortness of breath and result in decreased physical activity.
6 August 2012
In this study, we examined the influence of inhaled procaterol on exercise therapy for
Accepted 8 August 2012
pulmonary rehabilitation.
Available online 13 September 2012
Methods: Patients with moderate to severe stable COPD were randomly divided into 2
Keywords:
groups those who inhaled procaterol before exercise (n ¼10) and those who did not (control
Chronic obstructive pulmonary
group) (n ¼11). For 12 weeks, all patients performed their pulmonary rehabilitation
disease
exercises at home. We measured the 6-minute walking distance (6MWD) to assess exercise
Short-acting beta2-agonist
tolerance and used St. George’s respiratory questionnaire (SGRQ) to assess health-related
Procaterol
quality of life (HRQOL) before and after the 12-week exercise program.
Assist use
Results: Compared to the control group, the group receiving inhaled procaterol showed
Pulmonary rehabilitation
significant improvement of 6MWD and SGRQ scores. Conclusion: Our data suggest that a pulmonary rehabilitation program combined with inhaled procaterol can improve both HRQOL and exercise tolerance in COPD patients. & 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.
1.
Introduction
Chronic obstructive pulmonary disease (COPD) is a chronic and progressive condition leading to alveolar destruction and bronchostenosis. The cardinal symptom of COPD is shortness of breath during physical activity. Severe dyspnea eventually leads to a decline in activity that results in loss of appetite, muscle weakness, decreased alertness, and deterioration of activities of daily living (ADLs) and quality of life (QOL). It is thought that pulmonary rehabilitation is useful for the treatment of COPD, with pharmacotherapy and exercise therapy
being the main treatments recommended for patients with stable COPD [1,2]. Long-acting muscarinic antagonists (LAMA), long-acting beta2-agonists (LABA), and short-acting beta2-agonists (SABA) are 3 classes of bronchodilators listed for pharmacotherapy in the guideline of The Japan Respiratory Society. LAMA and LABA are regularly prescribed for symptom control, while SABA are prescribed for relief of acute dyspnea. In the third edition of The Japan Respiratory Society COPD guidelines [2], it is stated that inhalation of a SABA just before exercise (assist use) is effective for prevention of dyspnea during exercise. In patients with
n
Corresponding author. Tel./fax: þ81 272 220 8532. E-mail address: [email protected] (M. Hasegawa).
2212-5345/$ - see front matter & 2012 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resinv.2012.08.003
136
respiratory investigation 50 (2012) 135 –139
severe COPD, inhalation of SABA is also useful for preventing shortness of breath during ADLs such as bathing. Exercise therapy is focused on muscle training and endurance training, especially for the lower limb muscles, and is recommended to maintain ADLs and QOL. However, the need for increased ventilation produced by exercise leads to increased airway resistance in COPD patients. This increase of airway resistance induces air trapping and finally results in exacerbation of dyspnea that limits the performance of ADLs and decreases QOL. In the present study, we hypothesized that shortness of breath was a cause of exercise limitation and that both exercise tolerance and QOL would be improved by controlling dyspnea with inhalation of a bronchodilator before exercise therapy. Accordingly, we examined the influence of inhaled procaterol before exercise on the outcomes of pulmonary rehabilitation. Procaterol is a short-acting beta2-agonist with high intrinsic activity.
2.
Materials and methods
This study enrolled patients with COPD in stages II to IV according to The Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. All patients inhaled tiotropium regularly and used procaterol for dyspnea, but none used a LABA, and no LABA was added during the study period. We excluded the following patients: (1) those who had received exercise therapy at the hospital during the previous year, (2) those who had suffered acute exacerbation within the previous 4 weeks, (3) those using oral bronchodilators, and (4) those with cardiovascular or orthopedic disorders that could influence rehabilitation.
2.1.
Groups and interventions
Patients were randomized to the SABA group or the control group. The patients performed prescribed exercise at home for 12 weeks. The SABA group inhaled 2 puffs of procaterol 30 min prior to home-based exercise, while the control group did not use a SABA before home-based exercise. If shortness of breath occurred during exercise, patients were instructed to rest without inhaling the SABA. The patients had received instructions about the home-based exercise after the first evaluation. All patients were advised to exercise at home for 30 min daily, and their exercise program included the followings components: (1) conditioning of the inspiratory muscles according to Honma’s method [3]. (2) Strength training for the quadriceps femoris and iliopsoas muscles, which are important for weight bearing, 1 set 10 times daily. (3) Endurance training featuring walking for at least 10 min daily at a perceived exertion level of 4 on a modified Borg scale. Patients were advised to rest if the perceived level of exertion exceeded 4. Exercise therapy was prescribed after evaluation of each patient at the start of the study. The patients were given exercise pamphlets and instructions by physical therapists about homebased exercise according to the pamphlets. Each patient was asked to keep a diary to record exercise sessions. Patients who could perform the exercises well after initial instruction were reevaluated to confirm that the home-based exercise was being done properly during their visits to the respiratory outpatient
department. Patients who initially could not perform the exercises adequately were given repeat instructions about the exercise program.
2.2.
Endpoints
The primary endpoint was exercise tolerance evaluated by the 6-minute walking distance (6MWD) without inhalation of the SABA before the test. The secondary endpoint was healthrelated QOL, which was evaluated with the Japanese version of the St. George’s Respiratory Questionnaire (SGRQ), translated by Nishimura. In addition, the Borg scale, SpO2, and heart rate were assessed at rest, and pulmonary function tests were performed. Patients were evaluated at the beginning and the end of the 12 week observation period.
2.3.
Statistical analysis
All values are expressed as the mean7standard deviation (SD). Results were compared by the Wilcoxon signed-rank test (for data shown in Figs. 1–2) or by the Mann–Whitney U test (for the data in Table 1). In all analyses, po0.05 was considered to be significant.
2.4.
Ethical considerations
The study protocol was approved by Gunma University Hospital Institutional Review Board. All subjects provided written informed consent before participation.
3.
Results
The clinical profiles of the 21 subjects (10 in the SABA group and 11 in the control group) are presented in Table 1. There were no significant differences between the 2 groups. During the study, we checked for side effects of SABA by reviewing the patient diaries and questioning each patient during visits to the clinic. No side effects of the SABA were reported. When the Borg scale, SpO2, heart rate, and lung function parameters
Fig. 1 – Comparison of 6-minute walking distance (6MWD) before and after rehabilitation.
137
respiratory investigation 50 (2012) 135 –139
Fig. 2 – St. George’s Respiratory Questionnaire (SGRQ) score before and after the 12-week exercise program. Table 1 – Character of the subjects.
GOLD (II/III/IV) MRC (2/3/4) Age (years) BMI FEV1/FVC (%) FEV1 % pred. (%) VC pred. (%) 6MWD (m) SGRQ
SABA (n¼ 10)
Control (n ¼11)
p-Value
6/4/0 5/2/3 73.775.8 21.872.2 43.3717.1 61.5723.9 102.6718.8 340.27106.1 40.579.2
7/2/2 7/3/1 67.979.0 22.572.8 45.8715.0 55.8720.4 97.4719.2 405.8790.3 40.8717.7
0.259 0.475 0.057 0.622 0.573 0.622 0.833 0.193 0.439
GOLD: Global Initiative for chronic obstructive lung disease; SABA: short-acting beta2-agonist; MRC: Medical Research Council; BMI: Body mass index; FEV1: forced expiratory volume in one second; FVC: forced expiratory capacity; FEV1 % pred.: percentage of predicted FEV1 value; VC pred.: percentage of predicted vital capacity value; 6MWD: six minutes walking distance; SGRQ: St George’s Respiratory Questionnaire.
Table 2 – .The Borg scale, SpO2, heart rate, and lung function parameters in the SABA and control groups before and after 12 weeks of home-based rehabilitation. SABA
Borg scale SpO2 (%) Heart rate (beats) FEV1/FVC (%) FEV1 % pred. (%) VC pred. (%)
CONTROL
Before rehab.
After rehab.
p Value
Before rehab.
After rehab.
p Value
0.570.7 96.372.0 82.579.9 43.3717.1 61.5724.0 102.6718.8
0.470.3 95.871.6 77.179.9 43.2716.3 69.5726.3 104.8722.2
0.686 0.0345 0.047 0.753 0.267 0.893
0.570.6 95.671.7 81.3714.6 45.8715.0 55.8720.4 97.4719.2
0.871.3 95.671.6 79.5713.2 44.5712.0 58.5719.8 100.7722.1
0.285 0.893 0.610 0.799 0.285 0.386
SpO2: percutaneous oxygen saturation; rehab.: rehabilitation.
were compared before and after the 12-week home-based exercise program, only the heart rate showed a significant change compared with baseline (Table 2). As shown in Fig. 1, exercise tolerance based on the 6MWD improved in both the SABA group (from 340.27106.1 m to 404.77102.4 m) and the Control group (from 405.8790.3 m to 427.67112.7 m) after 12 weeks of exercise at home, but only the SABA group showed significant improvement. The Borg scale, SpO2, and heart rate were compared before and after the 6MWD. In the SABA group, the heart rate and SpO2 showed a significant increase and decrease, respectively, after the 6MWD (Table 3). These results were consistent with the significant increase of the 6MWD seen in the SABA group after 12 weeks of home-based
rehabilitation compared with before exercise, as shown in Fig. 1. As shown in Fig. 2, all fields of the SGRQ index of healthrelated quality of life (HRQOL) improved significantly in the SABA group, including the SGRQ-symptom score (from 32.47 19.3 to 19.279.2), SGRQ-activity score (from 55.9712.0 to 42.7716.3), SGRQ-impact score (from 31.9711.4 to 24.5713.8), and SGRQ total score (from 40.679.2 to 30.1712.4). On the other hand, the SGRQ-symptom score (from 41.3722.1 to 28.6724.0), SGRQ-activity score (from 51.0721.8 to 47.1726.9), SGRQimpact score (from 31.4717.7 to 29.0729.1), and SGRQ-total score (from 40.8717.7 to 34.5723.5) showed no significant changes in the control group. It was difficult to compare the
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Table 3 – The Borg scale, SpO2, and heart rate before and after the 6MWT in the SABA and control groups.
SABA
Borg scale SpO2 (%) Heart rate (beats/min)
CONTROL
Borg scale SpO2 (%) Heart rate (beats/min)
Before rehab. (Before/after 6MWT)
After rehab. (Before/after 6MWT)
p-Value
3.172.8 (0.570.7/3.772.8) 6.275.5 (96.372.0/90.176.7) 20.6710.6 (82.579.9/103.1712.5)
3.772.5 (0.470.3/4.172.4) 12.379.3 (95.871.6/83.579.5) 36.2715.9 (77.179.9/113.3715.9)
0.386
2.570.9 (0.570.6/3.071.0) 5.074.6 (95.671.7/90.676.0) 22.3711.0 (81.3714.6/103.5720.6)
2.271.5 (0.871.3/3.072.0) 6.976.6 (95.671.6/88.777.6) 25.3714.7 (79.5713.2/104.7718.8)
0.575
0.024 0.013
0.058 0.575
6MWT: six minutes walking test; rehab.: rehabilitation.
daily amount of exercise between the 2 groups correctly because many patients did not keep their diaries accurately.
4.
Discussion
In this study, we evaluated the influence of SABA inhalation before exercise on exercise tolerance in COPD patients. The cardinal symptom of COPD is shortness of breath during physical activity, which leads to inactivity and results in a progressive decline of ADLs and QOL. Pitta et al. [4] demonstrated an increase in the severity of exertional dyspnea induced inactivity in a study of patients who wore a pedometer with an acceleration sensor. In the present study, we showed that inhalation of procaterol led to greater improvement of exercise tolerance and health-related QOL than exercise without pre-treatment. The guidelines of The Japan Respiratory Society recommend inhalation of a LABA for COPD patients in stages II to IV. In this study, all subjects used tiotropium, but not a LABA. All patients were stable and no exacerbations were reported during the study period, so no patient received a LABA. This ensured consistency within the study groups when assessing the effects of the SABA. With regard to exercise tolerance, Casaburi et al. [5] have reported that patients who underwent pulmonary rehabilitation with bronchodilators achieved greater improvement of dyspnea and QOL than those who underwent rehabilitation without bronchodilators. Fujimoto et al. [6] reported that inhalation of a SABA just before an exercise tolerance test decreased shortness of breath and improved exercise tolerance in COPD patients. Kume [7] reported that a SABA with a higher intrinsic activity was more effective for improving the forced expiratory volume in 1 s and the inspiratory capacity of COPD patients. Therefore, we chose procaterol, which has a high intrinsic activity, for the present study. Sukisaki et al. [8] reported an immediate effect of inhaled procaterol on exercise tolerance. They reported that results of exercise tolerance tests were improved by inhalation of procaterol 4 h before testing. In addition, Satake et al. [9] suggested that inhalation of procaterol just before exercise could improve dyspnea and increase the effectiveness of exercise therapy.
Exercise-induced air trapping in COPD patients is referred to as dynamic hyperinflation, and Fujimoto et al. [10] reported that inhalation of procaterol before exercise led to improved exercise tolerance by reducing dynamic hyperinflation and dyspnea. Hospital-based exercise programs are performed under the supervision of physical therapists in rehabilitation units, so patients can continue the program easily with advice and encouragement. In contrast, a home-based exercise program is performed by the patient alone, so it is difficult for patients to maintain their motivation and to control anxiety related to exertional dyspnea. In this study, we tried to evaluate the frequency and level of exercise performed at home from patient diaries, but these generally did not contain enough details of the exercise session, which made it very difficult to compare the amount of exercise performed by the SABA and control groups. Therefore, we performed objective evaluations of the efficacy of the home-based rehabilitation programs by comparing improvements of 6MWD and SGRQ in the 2 groups. By these measures, we demonstrated significant improvement of exercise tolerance and health-related QOL in the SABA group. SABA inhalation before exercise at home relieved exertional dyspnea and allowed patients to continue their home-based exercise programs, resulting in significant improvement of ADLs and SGRQ-activity scores. This increase of activity also led to decreased anxiety about dyspnea and improved confidence in self-management. The SGRQ total score was also improved, although the SGRQ-symptom score was not improved. Satoh et al. [11] reported that use of a SABA relieved dyspnea and improved the QOL of COPD patients, but this group may have obtained somewhat different results because the SGRQ symptom score was improved by inhalation of a SABA before regular ADLs. In our study, patients only inhaled the SABA before home-based exercise. Thus, they noted a decrease in exertional dyspnea during exercise, but not with ADLs, because the SABA has a short duration of action. In COPD patients, shortness of breath tends to occur with exercise, and this leads to a decline in ADLs. It is important for COPD patients to maintain a certain level of activity in
respiratory investigation 50 (2012) 135 –139
daily life, however, particularly since Garcia-Aymerich et al. [12] have reported that a higher level of activity is associated with longer periods before hospitalization and death. It is important for COPD patients to continue their daily activities, but is difficult for them to do so without amelioration of exertional dyspnea. Accordingly, it is useful to reduce exertional dyspnea by SABA inhalation to allow the continuation of adequate exercise at home. Exercise therapy alone or pharmacotherapy alone is not enough to maintain patients on a home-based exercise program, but our data suggest that the combination of exercise therapy and SABA inhalation can increase the efficacy of home-based exercise. We considered it necessary to reduce dyspnea because dyspnea reduces activity and is a limiting factor in achieving successful rehabilitation at home. Sukisaki et al. [8] have reported that inhalation of procaterol before a 6MWD test improved exercise tolerance. However, their study only showed a temporary improvement in the 6MWD after inhalation of procaterol and before the test compared with no inhalation. In contrast, our study indicated that exercise tolerance and HRQOL were improved by regular use of SABA before home-based exercise over a period of 12 weeks. Thus, it appears that the combination of a SABA and exercise therapy can enhance the extent of rehabilitation. COPD patients may need to continue rehabilitation and the use of a SABA indefinitely. Therefore, it is important to watch for adverse effects of SABA inhalation. During this study, no adverse effects of SABA were observed. Although the resting heart rate was increased at the end of the study in the SABA group, it is not possible to attribute the increase to a direct effect of SABA inhalation because the SABA was not inhaled before evaluation of the heart rate. Shioya et al. [13] reported that there were no side effects after regular use of a SABA for 1 year. In our study, there were no serious side effects of the SABA observed in either group during the 12-week observation period. However, further investigation should be planned to identify any adverse effects of long-term SABA use.
5.
Conclusions
In this study, we found that inhalation of procaterol just before exercise at home reduced exertional dyspnea. In addition, home-based rehabilitation combined with inhalation of procaterol improved the 6MWD and the SGRQ score after the 12-week program. Accordingly, inhalation of procaterol just before exercise can improve exercise tolerance and QOL in patients performing home-based exercise.
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Conflict of interest Authors have no potential conflict of interest.
r e f e r e nc e s
[1] From the Global Strategy for the Diagnosis, Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD); 2011. p. 19–38. Available from: /http://www.goldcopd.org/S. February 15, 2012. [2] The Japanese Respiratory Society. Guidelines for the diagnosis and treatment of COPD. 3rd edition [Pocket Guide]; 2009. p. 13–23. Available from: /http://www.jrs.or.jp/S. [3] Minehiko Y, Fujiyasu K, Masato S, et al. Clinical effects of four weeks of respiratory muscle stretch gymnastics in patients with chronic obstructive pulmonary disease. Nihon Kyobu Shikkan Gakkai Zasshi 1996;34:646–52. [4] Pitta F, Troosters T, Spruit MA, et al. Characteristics of physical activities in daily life in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:972–7. [5] Casaburi R, Kukafka D, Cooper CB, et al. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127:809–17. [6] Fujimoto K, Ushiki A, Komatsu Y, et al. Additive efficacy of a short-acting beta-2-agonist on COPD treated with long-acting bronchodilators. J Jpn Soc Respir Care Rehabil 2009;1:64–70. [7] Kume H. Clinical use of b2-adrenergic receptor agonists based on their intrinsic efficacy. Allergol Int 2005;54:89–97. [8] Sukisaki T, Senjyu H, Oishi K, et al. Single dose of inhaled procaterol has a prolonged effect on exercise performance of patients with COPD. Physiother Theory Pract 2008;24:255–63. [9] Satake M, Takahashi H, Sugawara K, et al. Inhibitory effect of procaterol on exercise dynamic lung hyperinflation during the 6-min walk test in stable patients with chronic obstructive pulmonary disease. Arzneimittelforschung 2011;61:8–13. [10] Fujimoto K, Yashiike F, Yasuo M, et al. Effects of bronchodilators on dynamic hyperinflation following hyperventilation in patients with COPD. Respirology 2007;12:93–9. [11] Satoh H, Iwashima A, Endo Y, et al. Effect of proactive use of inhaled procaterol on dyspnea in daily activities and quality of life in patients with chronic obstructive pulmonary disease. Nihon Kokyuki Gakkai Zasshi 2009;47(9):772–80. [12] Garcia-Aymerich J, Lange P, Benet M, et al. Regular physical activity reduces hospital admission and mortality in chronic obstructive pulmonary disease: a population based cohort study. Thorax 2006;61:772–8. [13] Shioya T, Satake M, Sato K, et al. Long-term effect of the beta2-receptor agonist procaterol on daily life performance and exercise capacity in patients with stable chronic obstructive pulmonary disease. Clinical study with special reference to health-related quality of life and activities of daily living. Arzneimittelforschung 2008;58:24–8.