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Improvements in exercise capacity and dyspnoea by inhaled anticholinergic drug in elderly patients with chronic obstructive pulmonary disease.

Introduction

With the growth in the aged population, increasing numbers of patients with chronic obstructive pulmonary disease (COPD) are elderly. COPD is a slowly progressive disease, and the main objectives of treatment are prevention of exacerbations, production of bronchodilation to maintain lung function, and achievement of an acceptable quality of life (QOL) [1]. At present, [[beta].sub.2]-adrenergic agonists are usually the first-line bronchodilators for treatment of COPD [2]. Inhaled anticholinergic drugs are also effective for COPD patients, since the pathogenesis of COPD is closely related to bronchomotor tone, which reflects sympathetic and parasympathetic balance [3, 4]. The main benefit of inhaled anticholinergics is as additional bronchodilator therapy, either in addition to [[beta].sub.2]-adrenergic agonists or in place of them in subjects who are more sensitive to anticholinergics than [[beta].sub.2]-agonists [5, 6]. Because, [beta]-adrenergic receptors decrease with age [7], the response to anticholinergic agents in elderly subjects may be greater than that in young adults. However, older patients with airway obstruction, that has some reversibility to the drugs, may not always be treated. This may result from lack of information regarding effectiveness of the drugs for symptomatic relief.

In the present study, we tested the effects of the anticholinergic drug, oxitropium bromide (OTB), on lung function, exercise capacity, and exertional dyspnoea in elderly COPD patients (more than 75 years old) using a double-blind placebo-controlled study, in comparison with middle-aged patients (less than 65 years of age).

Methods

Patients: We studied 24 men with mild to moderate chronic obstructive pulmonary disease (COPD). The demographic and anthropometric data of the patients are shown in Table I. Our sample was defined by history and supporting radiological and pulmonary function criteria. All patients were smokers or ex-smokers. No patients had a forced expiratory volume in one second ([FEV.sub.1]) of more than 60% of that predicted, and no patient had more than 15% reversibility on a 6-adrenergic inhalation test. In addition, no patient had a diffusing capacity of the lung for CO (Dco) of more than 60% predicted. Predicted values for vital capacity and Dco were recalculated using the equation of Baldwin et al. [8] and Burrows et al. [9]. Prior to the beginning of this study, all patients gave informed consent to participate in the study, and all treatment was withheld for 4 weeks. Subjects were divided into two groups based on age: an elderly group of 75 years and older and a middle-aged group, 50-65 years old.
Table I. Clinical and physiological data
                                  Elderly            Middle-aged
                                  group              group
                                  (n = 12)           (n = 12)
Age (years)                       78.7 (1.1)          66.1 (1.0)
range                             75-86               55-64
Height (cm)                      162.2 (1.1)         163.7 (1.0)
Weight (kg)                       51.7 (1.6)          53.6 (2.1)
FVC (1)                            2.37 (0.06)         2.54 (0.09)
%VC (%)                           81.9 (1.8)          74.0 (2.5)
[FEV.sub.1] (1)                    1.25 (0.06)         1.33 (0.08)
[FEV.sub.1%] (%)                  41.3 (1.6)          38.9 (2.0)
DLco(ml/min/mmHg)                  5.08 (0.61)         7.64 (0.69)
DLco% (%)                         44.1 (4.4)           45.2 (3.1)
Presented as mean (SE).
FVC: forced vital capacity, %VC: FVC percentage of
predicted VC, [FEV.sub.1]: forced expiratory volume in  1s,
[FEV.sub.1%]: [FEV.sub.1] as a percentage of predicted VC, DLco:
diffusion capacity of the lung for carbon monoxide, DLco%:
DLco percentage of the predicted value.


Study design: Spirometry and exercise testing were performed twice a day on the 24 patients before and after inhalation of OTB 300 [mu]g or placebo 300 [mu]g (Figure 1). On-the next day, the same protocol was repeated using alternate inhalation. Each study started between 09 h 00 and 10 h 00. Spirometric indices were obtained for each patient from the best three maximal flow-volume curves using a dry-sealed-type box spirometer (ST-460, Fukuda Sangyo, Japan) immediately before (`Pre') and 30 minutes after (`Post') inhalation of OTB 300 [mu]g. Measurements were made on forced vital capacity (FVC) and [FEV.sub.1]. The OTB was administered by three puffs from identical metered-dose inhalers (MDI), delivered successively and without delay. The progressive 10 watt incremental exercise testing was repeated to a symptom-limited maximum on a bicycle ergometer (220 Wood RD, Collins Corp.) before and 45 minutes after inhalation of OTB or placebo (Figure 1). After 1 minute of cycling, the work-load was increased by 10 watt each minute until the patient was unable to continue. Patients stopped the exercise test mainly because of dyspnoea. Measurements were made of minute ventilation (VE), oxygen uptake ([Vo.sub.2]) and respiratory frequency (Rf) by mass spectrometer (WSMR-1400, Westron Corp., Japan)-pneumotachometer-computer (PC-9801, NEC Corp., Japan) system (WLCS-5100) [10]. Prior to each test, the spirometer was calibrated with a 2-1 calibration syringe, and the mass spectrometer was calibrated against gas mixtures of known concentrations ([O.sub.2] 20.9%, Ar 9.5%, C02 5.00%, [C.sub.2][H.sub.2] 0.650%, [N.sub.2] balance) [10]. Arterial oxygen saturation ([Sao.sub.2]) was continuously monitored from before to after exercise using a pulse oximeter (502-P, Criticare System Inc. . Rest [Sao.sub.2] was determined by the stable [Sao.sub.2] in the resting ventilation immediately before exercise. Nadir [Sao.sub.2] was determined as the minimum value which was observed during the exercise test.

Assessment of dyspnoea during exercise: Dyspnoea during exercise was evaluated using the index based on the linear relationship between the Borg scale (BS) and oxygen uptake ([Vo.sub.2]) as described elsewhere [11]. Briefly, we assessed the sensation of difficult breathing in these patients using BS in each load of exercise testing. In all patients, there was a significant positive correlation between the dyspnoea expressed on BS and [Vo.sub.2] during exercise. From this correlation, we determine Borg scale slope (BSS) as the slope of the regression line (the slope of [delta]BS/[delta][Vo.sub.2]) for the quantitative assessment of dyspnoea. The BSS was compared before and after inhalation of the OTB or placebo.

Statistical analysis: Statistical analyses were performed using Student's paired t test for paired data. Data were analysed with Student's unpaired t test between oxitropium and placebo group. The analyses were performed by a software package using Stat View 4.0 (Abacus Concepts, Inc.). Data are presented as mean with SE; p<0.05 was defined as statistical significance.

Results

The mean (SE) age of the 12 elderly patients with COPD and the mean age of the 12 middle-aged patients was 78.7 (1.1) years and 60.1 (1.0) years, respectively. Measurements of spirometric indices before and after OTB or placebo are summarized in Table II. Mean pretreatment [FEV.sub.1] in the elderly group was 1.25 (0.06) litres, which was 41.3 (2.0)% of that predicted, and was not different from the mean value of the middle-aged [1.33 (Q.08)), being 38.9 (2.4)% of predicted. The FVC and [FEV.sub.1] following the inhalation of OTB were significantly greater than those before administration, but not following placebo. The mean increase in [FEV.sub.1] after OTB in the elderly group was 14.5 (1.7)% of baseline value, and the increase in the middle-aged was 15.7 (1.8)%.

[TABULAR DATA II OMITTED]

The rest [Sao.sub.2] and nadir [Sao.sub.2] during exercise after OTB or placebo-inhalation were not different from those values before inhalation, irrespective of the agents (Table III).

[TABULAR DATA III OMITTED]

In the exercise testing, there were significant relationships between dyspnoea sensation expressed on BS and [Vo.sub.2] during exercise (p < 0.05, r = 0.865-0.999) in all patients. From these correlations, BSS was calculated for the assessment of dyspnoea as previously described. The BSS after OTB inhalation was significantly decreased as compared with that before inhalation in both the elderly and middle-aged groups (Figure 2). The magnitude of the decrease in BSS of the elderly group did not differ from that of the middle-aged patients.

The maximum oxygen uptake ([Vo.sub.2] Max) in the exercise test was slightly, but significantly increased by OTB inhalation in the elderly patients (Table III). The same level of increase in [Vo.sub.2] was also observed in the middle-aged group. Ventilatory indices during exercise testing in the COPD patients are presented in Table III. The minute ventilation and pulse rate following the inhalation of OTB did not differ from those before the inhalation. At the peak exercise, the respiratory frequency was slightly decreased after OTB inhalation, but not significantly so. The ventilatory equivalency for oxygen uptake (VE/[Vo.sub.2]) during exercise was significantly decreased after the OTB inhalation, compared with that before the inhalation.

In this study, untoward effects following administration of OTB or placebo were not observed in the elderly or middle-aged patients.

Discussion

The effectiveness of various bronchodilators including anticholinergic drugs have been reported in patients with COPD [1-6, 12-14]. While the effects of anticholinergic drugs on conventional spirometric indices have been extensively examined in COPD patients [12-14], little information is available about the effects of anticholinergics on the symptoms of patients [15, 16]. Dyspnoea on exertion is a common symptom in COPD and exertional dyspnoea may impair activities of daily living (ADL) in many COPD patients and aged persons [1, 17]. Although opiates and sedatives are effective in decreasing the sensation of dyspnoea in COPD [18, 19], these drugs suppress the warning signs and normal ventilatory responses in the patients with COPD, and such drugs are not recommended for elderly patients. We have reported that the inhaled anticholinergic drug, OTB, produces the reduced sensation of dyspnoea with exercise [15]. This reduction in the sensation of exertional dyspnoea which is expressed as the decreased slope of [delta]BS/[delta][Vo.sub.2] (BSS) is a favourable effect for COPD patients. Whether anticholinergic drugs have similar effects in elderly COPD patients is not known, and so this study was conducted to test the effects of OTB on dyspnoea during exercise and an exercise capacity in elderly COPD patients.

In the present study, there was no difference in the bronchodilating response to OTB as indexed by changes in [FEV.sub.1] between elderly and middle-aged COPD patients. A significant improvement in airway obstruction following OTB was achieved in both elderly and middle-aged groups. The dyspnoeic sensation with exercise as indicated by BSS was decreased after OTB inhalation, but not after placebo inhalation, in both the elderly and middle-aged patients. Exercise capacity measured as [Vo.sub.2] max was augmented by inhalation of OTB, in the elderly as in the middle-aged group. Many patients interrupted the exercise testing owing to their sensation of dyspnoea at peak exercise levels, and so a reduced sensation of dyspnoea may improve patients' exercise performance. The degree of improvements in spirometric indices, dyspnoea, and exercise performance following OTB inhalation as compared with placebo inhalation did not differ between elderly and middle-aged groups. Although an age-associated decrease in number and sensitivity of [beta]-receptors has been reported [7, 20], the anticholinergic action of OTB in the respiratory system may be little affected by age. This study indicates that inhaled anticholinergic drugs are effective for symptomatic relief in elderly as well as in middle-aged subjects with COPD. Many elderly patients with COPD may be untreated in spite of some reversibility of airways obstruction but our findings indicate that the older patients with chronic airflow limitation are likely to benefit from inhaled anticholinergic drugs. As the use of inhalation is not always easy for elderly patients, they must be instructed carefully [21] and observation of inhaler technique is essential to ensure correct procedure.

The mechanism of the decrease in dyspnoea sensation during exercise following OTB is not clear. A possible explanation is that the decreased work of breathing both from the increase of the ventilatory reserve (1 - [VE.sub.max]/maximum voluntary ventilation),and the increase of ventilatory efficiency (lowered VE/[Vo.sub.2]) may reduce the sense of effort in breathing, because the dyspnoeic sensation is closely related to sense of effort of breathing [22].

We conclude that the inhaled anticholinergic drug, oxitropium bromide, produces useful improvements in dyspnoea and exercise capacity in both elderly and middle-aged patients with COPD. These favourable effects of inhaled anticholinergic drug may contribute to improvement of some aspects of QOL in elderly patients with COPD.

[Figures 1 & 2 ILLUSTRATION OMITTED]

References

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Authors' address Department of Geriatrics, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Address correspondence to Shinji Teramoto, MD, Department of Geriatrics, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan, 113

Received in revised form 16 November 1994
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Author:Teramoto, Shinji; Fukuchi, Yoshinosuke
Publication:Age and Ageing
Date:Jul 1, 1995
Words:2686
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