Bronchodilator reversibility in Australian adults with chronic obstructive pulmonary disease

Abstract Background and aims: Bronchodilator reversibility (BDR) and inhaled corticosteroid (ICS) use were assessed for volunteers who responded to an advertisement requesting current or ex‐smokers who were experiencing breathlessness to attend for lung function testing. Methods: One hundred and fifty‐four volunteers responded. Forced expiratory volume (FEV₁) was measured before and after 400 µg of salbutamol. Significant BDR was assessed according to guidelines of: (i) the American Thoracic Society (≥12% plus 200 mL of baseline FEV₁ or forced vital capacity), (ii) the British ­Thoracic Society (BTS) (≥15% plus 200 mL of baseline FEV₁), (iii) the European Thoracic Society (≥10% predicted FEV₁), and (iv) the most commonly used criteria in Australia and New Zealand (≥15% of baseline FEV₁). Results: One hundred and twenty‐three subjects (33 female; 40 current smokers; median pack years 48 (range 5?144)) were suitable for analysis (i.e. had no history of asthma, demonstrable airflow limitation and a forced expiratory ratio (FER) of <70%). Twenty (16%) patients had an FEV₁ within the normal range but FER of <70%, 24 (20%) patients had mild disease (FEV₁ 60?80% predicted), 31 (24%) patients had moderate disease (FEV₁ 40?59% predicted), and 48 (39%) patients had severe disease (FEV₁ <40% predicted), according to BTS criteria. Significant BDR was evident in: (i) 58 (47%) subjects by American criteria, (ii) 26 (21%) subjects by British criteria, (iii) 19 (15%) subjects by European criteria and (iv) 36 (29%) subjects by Australasian criteria. ICS use was reported by 71 (58%) subjects overall and was weakly, but significantly, related to poorer FEV₁ (r = ?0.2; P < 0.01), and greater BDR (r = 0.3; P < 0.005). Conclusion: Chronic obstructive pulmonary disease in Australian volunteers with no history of asthma encompasses many individuals with significant BDR. Interestingly, most volunteers reported ICS use and this was related to poorer spirometry and greater BDR. However, until the underlying immuno­pathology has been determined they cannot be assumed to have ‘asthma’ or even an ‘asthmatic element’. (Intern Med J 2003; 33: 572?577)     

Bronchodilator response in chronic obstructive pulmonary disease

We measured response to 250 micrograms isoproterenol in 985 patients with COPD who were carefully studied and followed closely for nearly 3 yr. Response was quantitated in relative (% increase in FEV1) and absolute (change in FEV1 as a % predicted normal) terms. Patients were told to abstain from bronchodilator for 6 h before testing, and responses were larger in those who said they had done this. Responses were not related to blood theophylline concentrations. In patients who had abstained for 6 h, response averaged 15% of the baseline FEV1 or 5% of the predicted normal FEV1. Relative response was inversely proportional to baseline FEV1, whereas absolute response was directly related to baseline FEV1. Responses were positively related to symptomatic wheezing and exercise capacity, and negatively to smoking history, but these features accounted for little of the observed variation in response. Patients with large relative and absolute responses demonstrated increased variability of FEV1 with time and a decreased annual rate of decline of FEV1. There was little change in response with time, and the change observed could probably be explained by a gradual decrease in FEV1. However, time-related interindividual and intraindividual variations of response were large and impossible to separate from random variations of FEV1.     

Bronchodilator therapy in chronic obstructive pulmonary disease

This paper reviews new developments in bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Most patients with COPD respond to bronchodilators, but we have no reliable way to predict which patients will respond. When responsiveness is assessed, changes in lung volume as well as improvements in FEV1 should be considered. The combination of a beta-agonist and an anticholinergic agent produces greater improvement than either agent alone. Anticholinergic agents have few adverse side effects in patients with COPD, but concern remains about the possible cardiac side effects of beta-agonists. No clear answer exists about whether new, long-acting beta-agonists, such as salmeterol, should supplant anticholinergic agents as "first-line" therapy in COPD.     

Bronchodilator therapy for chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of diseases characterized by cough, sputum production, dyspnoea, airflow limitation and bronchial hyperreactivity. The airflow limitation declines progressively and is irreversible or partially reversible. Bronchodilator therapy is prescribed to relieve the symptoms, reverse airway obstruction and hopefully slow the rate of disease progression and decelerate the decline in pulmonary function. During acute exacerbation, inhalation of β2-agonists remain the therapy of choice. The usefulness of anticholinergic inhalation in acute attacks is investigated in order to determine if a higher dose and more frequent administration have same benefit as β2-agonists inhalation. Theophylline is usually given orally as a sustained release formulation for chronic maintenance therapy. Some patients may benefit from theophylline infusion during an acute phase when appropriately used; however, sympathomimetic agents fail to produce adequate bronchodilation. During interim periods of stability, inhalation of ipratropium bromide has increased in popularity as a regular long-term bronchodilator therapy. Although ipratropium and β2-agonists are equally efficacious when the dosage is adequate enough, a combination of both provides a rapid onset of action of the adrenergic agents and a prolonged action of the anticholinergic. Furthermore, this combination can be given in a reduced dose, thereby avoiding side-effects. Inhalation techniques can influence the efficacy of bronchodilator therapy. For severe dyspnoeic patients or patients with poor technique of co-ordination with metered-dose inhaler (MDI), attachment of a spacer to the MDI or using a nebulizer will overcome these difficulties. Bronchodilator therapy can not prevent the development of COPD or slow down the decline of pulmonary function, other interventions should be included in a comprehensive management programme.     

Inspiratory capacity, dynamic hyperinflation, breathlessness, and exercise performance during the 6-minute-walk test in chronic obstructive pulmonary disease

Patients with severe chronic obstructive pulmonary disease (COPD) develop dynamic lung hyperinflation (DH) during symptom-limited incremental and constant work exercise with cycle ergometer and treadmill. The increase in end-expiratory lung volume seems to be the best predictor of dyspnea. Quantification of DH is based on the relatively complex use of on-line measurement of inspiratory capacity (IC) from flow volume loops. We reasoned that DH could occur during daily activities such as walking, and that it could be simply measured using the spirometrically determined IC. We studied 72 men with COPD (FEV(1) = 45 +/- 13.3% predicted). IC was measured at rest and after a 6-min walk test. Exertional dyspnea was evaluated using the Borg scale and dyspnea during daily activities with the modified Medical Research Council (MRC) scale. IC decreased significantly from 28.9 +/- 6.7% TLC at rest to 24.1 +/- 6.8% TLC after exercise (p < 0.001). Exertional dyspnea correlated with DeltaIC (r = -0.49, p < 0.00001) and baseline MRC (r = 0.59, p < 0.00001). In many patients with COPD, walking leads to DH that can be easily determined with simple spirometric testing. DH helps explain exercise capacity limitation and breathlessness during simple daily activities.     

Effects of beta-agonists on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease

In a single-blind placebo-controlled trial in 12 patients with advanced chronic obstructive pulmonary disease (COPD) we compared the effects of nebulized salbutamol (1 mg), clenbuterol (30 micrograms) and placebo (4 ml of normal saline) on spirometric indices (FVC, FEV1), maximal expiratory flows (Vmax50 and Vmax25), the distance walked in 6 min (6MD), assessment of breathlessness by visual analogue scale (VAS), and estimates by the patients of perceived exertion (RPE). Both clenbuterol and salbutamol produced significant increases in FEV1, FVC, Vmax50 and Vmax25. With both drugs, 6MD increased significantly (p less than 0.01) and breathlessness decreased significantly without an appreciable increase in RPE after exercise despite the extra distance covered. The absolute improvements in FEV1 and 6MD after clenbuterol were correlated (r = 0.763, p less than 0.01), but these indices were not correlated after salbutamol (r = 0.121, p greater than 0.1). The lack of correlation between the changes in 6MD and FEV1 after salbutamol might indicate that relief of airways obstruction is not the only explanation for the effects on distance walked, at least with salbutamol.     

Lack of effect of dextromethorphan on breathlessness and exercise performance in patients with chronic obstructive pulmonary disease (COPD)

We have previously shown that the exercise performance of patients with severe chronic obstructive pulmonary disease (COPD) can be increased with the administration of oral morphine (0.8 mg.kg-1). The purpose of this study was to determine whether the administration of dextromethorphan (DXT), an antitussive structurally similar to codeine, would result in increased exercise performance and decreased dyspnoea in patients with COPD, without the side-effects of opiates. Six eucapnic patients (mean age = 66 +/- 3.8 yrs) with COPD (mean forced expiratory volume in one second (FEV1) = 1.01 +/- 0.07 l) underwent two incremental cycle ergometer tests to exhaustion (Emax) and assessment of their hypercapnic and hypoxic ventilatory responses and mouth occlusion pressure responses following first the oral administration of placebo (P) and then dextromethorphan (60 mg) in a single-blind fashion. There was no statistically significant difference in the maximal exercise performance, perceived dyspnoea (modified Borg scale), breathing pattern or expired gases after the two different treatments. In addition, the ventilatory response to CO2 production during exercise (delta VE/VCO2) and the ventilatory and mouth occlusion pressure responses to hypoxia and hypercapnia did not differ significantly after DXT as compared with after P. Indeed the exercise performance was poorer and the ventilatory responses were brisker after DXT. We conclude from this study that the administration of this opiate analogue does not improve the exercise capacity or decrease the ventilatory response of patients with COPD.     

Effects of oral morphine on breathlessness and exercise tolerance in patients with chronic obstructive pulmonary disease

Previous studies have shown that opiates increase the maximal external work performed at exhaustion in patients with chronic obstructive pulmonary disease (COPD). The mechanism responsible for this improvement in exercise tolerance is unknown. The purpose of this study was to determine the effects of an oral morphine solution (0.8 mg/kg) on the exercise tolerance, perception of dyspnea, and arterial blood gases of patients with COPD. Thirteen eucapnic patients with stable COPD (FEV1 = 0.99 +/- 0.48) underwent duplicate incremental cycle ergometer tests to exhaustion (Emax) after the ingestion of placebo and after the ingestion of morphine. After the ingestion of morphine, the maximal workload increased by 18% (p less than 0.001) and the VO2 increased by 19.3% (p less than 0.001). Ten of the 13 patients had a higher ventilation at Emax after morphine ingestion. Despite the higher ventilation at Emax after morphine, the mean Borg score was not significantly higher. At Emax after morphine ingestion, the PaO2 (65.8 +/- 11.6 mm Hg) was significantly lower and the PaCO2 (43.5 +/- 8.3 mm Hg) was significantly higher than at Emax after placebo (71.9 +/- 15.5 and 38.3 +/- 8.5, respectively). When data at the highest equivalent workload were analyzed, the ventilation and the Borg scores were significantly lower, whereas the VO2 and VCO2 were comparable. From this study, we conclude that the administration of opiates can substantially increase the exercise capacity of patients with COPD. The improved exercise tolerance appears to be related to both a higher PaCO2 resulting in lowered ventilation requirements for a given workload and also to a reduced perception of breathlessness for a given level of ventilation.     

Corticosteroids in stable chronic obstructive pulmonary disease

Although systemic corticosteroids are widely used in treating stable chronic obstructive pulmonary disease (COPD), the evidence for their efficacy is still disputed. To reappraise this evidence, the authors used a new analytic strategy in which the 14 available randomized clinical trials were evaluated according to a methodologic "review of systems" and an examination of the statistical precision of the outcome results. Although none of the trials satisfied all of the methodologic criteria for both validity and clinical pertinence, the trials finding steroids efficacious were generally better designed and more statistically precise than trials failing to show efficacy. The authors propose a set of five main methodologic guidelines that require a stable baseline state, a crossover design with suitable washout, adequate doses of corticosteroids, pragmatic designs, and comprehensive choices of outcome events. Attention to these guidelines can help improve both design and evaluation for future trials of systemic steroids for stable COPD.     

Bronchodilator effect of zafirlukast in subjects with chronic obstructive pulmonary disease

Cysteinyl leukotrienes (LT) are involved in airway inflammation and mucus hypersecretion, characteristically present in asthma and chronic obstructive pulmonary disease (COPD). Zafirlukast is an LT receptor antagonist that improves airway function within 1-3 h after oral administration in subjects with chronic persistent asthma. Through a randomised, double-blind, crossover and placebo-controlled study, we assessed the short-term effects of zafirlukast in patients with severe COPD. We enrolled 23 subjects (seven women) aged 59.4 (1.67) yr [mean (SEM)] with a smoking history of 60.7 (5.2) pack-yr. At screening day the mean FEV(1)was 0.876 (0.72) l; FEV(1) % predicted=35 (3)% and 107 (14) ml increment post-salbutamol. They came two different days, apart from each other at least 72 h. After baseline spirometry, a single oral dose of 40 mg zafirlukast or the corresponding placebo was administered. FVC and FEV(1) was measured every 30 min until 2 hrs. On zafirlukast day, the mean FEV(1) at 90 min [0.813 (0.64) l] and the mean FVC at 90 min [1.76 (0.1) l] were significantly higher than the respective means at placebo day (mean FEV(1)=0.747 (0.55) l; mean FVC=1.63 (0.1) l; p<0.05 Tukey Kramer multiple comparisons test). The maximum mean increase in FEV(1) was 75 (19) ml. A positive correlation was found between absolute response to salbutamol in FEV(1) and the response to zafirlukast (r=0.41; p<0.04). In conclusion, these findings suggest that zafirlukast has a bronchodilator or antibronchoconstrictor effect in COPD patients with severe airflow limitation.     

Variability of breathlessness measurement in patients with chronic obstructive pulmonary disease

The purpose of our study was to evaluate the reproducibility of a Borg rating of dyspnea in patients with COPD. We examined nine patients with COPD who performed a SST on four separate days within a ten-day period. The patients walked on a treadmill for 6 min. At the end of each minute, patients matched a Borg rating to the intensity of their breathlessness. We measured the HR, VE, VO2, VT and f at the end of each minute. While the mean VO2, VE, HR, VT and f stabilized after one or two attempts, the Borg ratings decreased with successive tests. We conclude that the Borg scale for measuring breathlessness shows progressive decreases with repetition whereas VO2, VE, HR, VT and f stabilize after one or two practice attempts. This suggests that desensitization to dyspnea may play a role in the improvement of patients after exercise.     

肺康复对稳定期慢性阻塞性肺疾病的疗效分析

目的探讨肺康复锻炼对稳定期慢性阻塞性肺疾病患者的临床疗效及意义。方法 300例稳定期慢阻肺患者,采用前瞻性随机对照法分为两组:康复组(n=149)给予门诊慢阻肺健康宣教,包括饮食干预,戒烟教育,用药指导;肺康复锻炼(呼吸运动训练联合步行运动训练)。对照组(n=151)仅给予门诊慢阻肺健康宣教。比较6个月后两组患者的血气分析、肺功能、6MWD(6分钟步行距离)及慢阻肺急性加重期住院的次数等。结果 6个月后共234例完成试验,康复组(n=121)较对照组(n=113)的6MWD,血气分析等指标有明显改善,具有统计学意义(P0.05),而两组间肺功能FEV_1/FVC、FEV_1%和慢阻肺急性加重期住院的次数无统计差异(P0.05)。结论肺康复锻炼(呼吸运动训练联合步行运动训练)能有效提高PaO_2及降低PaCO_2,提高6MWD,适度改善运动耐力,是一种简便易行的康复锻炼方法,值得临床应用及推广。     

Proportional assist ventilation may improve exercise performance in severe chronic obstructive pulmonary disease.

PURPOSE: Exercise tolerance is impaired in chronic obstructive pulmonary disease (COPD), in part because of a reduction in ventilatory capacity and excessive dyspnea experienced. The authors reasoned that proportional assist ventilation (PAV), a ventilator mode in which the level of support varies proportionately with patient effort, could be used during exercise to assist ventilation. The purpose of this study was to evaluate the efficacy of PAV to improve exercise endurance and related physiologic parameters in COPD. METHODS: In 8 patients (age = 62.8 years mean, +/- 6.9 standard deviation) with severe COPD (forced expiratory volume in 1 second = 0.70 +/- 0.21 L) flow, volume, dyspnea, leg fatigue, arterial blood gases, and gas exchange were measured during constant workrate exercise (37 +/- 18 watts; i.e., 80% previously determined maximum oxygen consumption). Crossover exercise trials were performed in random order: while spontaneously breathing through the experimental circuit without assistance (control trial) and with PAV (using 9.8 +/- 2.1 cm H2O/L and 3.3 +/- 1.0 cm H2O/L/sec of volume assist and flow assist, respectively). RESULTS: The application of PAV during exercise was well tolerated by each subject. Compared with the control measurement at equivalent time during exercise, PAV improved breathing pattern and arterial blood gases while dyspnea was reduced. Consequently, there was a significant increase in exercise duration with PAV (323 +/- 245 seconds during the control trial compared with 507 +/- 334 seconds with PAV, P = 0.02). CONCLUSIONS: Proportional assist ventilation can improve performance during constant workrate exercise in severe COPD.     

Treatment of stable chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a readily diagnosable disorder that responds to treatment. Smoking cessation can reduce symptoms and prevent progression of disease. Bronchodilator therapy is key in improvement of lung function. Three classes of bronchodilators-beta agonists, anticholinergics, and theophylline-are available and can be used individually or in combination. Inhaled glucocorticoids can also improve airflow and can be combined with bronchodilators. Inhaled glucocorticoids, in addition, might reduce exacerbation frequency and severity as might some bronchodilators. Effective use of pharmacotherapy in COPD needs integration with a rehabilitation programme and successful treatment of co-morbidities, including depression and anxiety. Treatment for stable COPD can improve the function and quality of life of many patients, could reduce admissions to hospital, and has been suggested to improve survival.     

Cerebral bioenergetics in stable chronic obstructive pulmonary disease

Cerebral intracellular energy production (cerebral bioenergetics) via oxidative phosphorylation and the production of adenosine triphosphate (ATP) is critical to cerebral function. To test the hypothesis that patients with chronic stable hypoxia also generate neuronal ATP via an anaerobic metabolism, we studied the changes in cerebral (31)P magnetic resonance spectra ((31)P MRS) in patients with stable chronic obstructive pulmonary disease (COPD), and compared the results with MR spectra from similar areas of the brain in control subjects. Ten patients with stable COPD (age: 65 +/- 9 yr [mean +/- SD]; Pa(O(2)): 8.8 +/- 1.2 kPa; Pa(CO(2)): 6.1 +/- 0.8 kPa; pH 7.42 +/- 0.03, and FEV(1): 41 +/- 20% predicted) and five healthy volunteers underwent cerebral (31)P MRS (TR-5,000 ms) at 1.5 T. When COPD patients were compared with controls, the percentage MR signal with respect to total MR-detectable phosphorus-containing metabolites was increased from inorganic phosphate (Pi) (7.1 +/- 1. 3% versus 3.9 +/- 0.7%, p = 0.0001) and phosphomonoesters (PMEs) (9. 4 +/- 1.2% versus 6.9 +/- 0.3%, p = 0.0001), whereas the signal from phosphodiesters was reduced (34.8 +/- 3.2 versus 40.4 +/- 3.3%, p = 0.015). The ratios of Pi to betaATP (0.8 +/- 0.2 versus 0.4 +/- 0.1, p = 0.001) and of PME to betaATP (1.0 +/- 0.2 versus 0.7 +/- 0.1, p = 0.015) were increased, but the phosphocreatine-to-Pi ratio (2.1 +/- 0.6 versus 3.2 +/- 0.6, p = 0.01) was reduced in patients as compared with controls. This alteration in phosphorus-containing metabolites within cerebral cells provides evidence of extensive use of anaerobic metabolism in hypoxic COPD patients.     

Effect of carbon monoxide on exercise performance in chronic obstructive pulmonary disease

We evaluated the effect of breathing 100 ppm of carbon monoxide versus compressed, purified air for 1 hour on exercise performance in 10 patients with chronic obstructive pulmonary disease in a double-blind, randomized, crossover study. The mean arterial carboxyhemoglobin was 1.48 per cent in the carbon monoxide control period and increased from 1.43 to 4.08 per cent after breathing carbon monoxide (P less than 0.001). The mean arterial carboxyhemoglobin level was 1.52 percent in the air control period and decreased from 1.47 to 1.34 per cent after purified air (P less than 0.001). The mean exercise time until marked dyspnea decreased from 218.5 seconds in the carbon monoxide control period to 146.6 seconds after breathing carbon monoxide (P less than 0.001). The mean exercise time was 219.9 seconds in the air control period and 221.3 seconds after purified air (P not significant). Breathing 100 ppm of carbon monoxide for 1 hour caused a significant reduction in exercise performance in patients with chronic obstructive pulmonary disease.     

改良运动处方对慢性阻塞性肺疾病稳定期患者的康复疗效

目的 以联合缩唇-腹式呼吸法和六字诀训练为改良的运动处方,探讨其对慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)稳定期患者的康复疗效.方法 将100例患者随机分为四组:对照组、缩唇-腹式呼吸组、六字诀组、运动处方组,每组25例,各组分别于锻炼前和坚持锻炼半年后测定肺功能、6分钟步行距离(6MWD)和动脉血气分析.结果 运动处方组较对照组、缩唇-腹式呼吸组、六字诀组的肺功能指标FEV1、FEV1占预计值百分比和6MWD及血气分析等有明显改善,差异有统计学意义.结论 改良运动处方能有效改善COPD稳定期患者的肺功能、提高运动耐力、提高动脉血氧分压(PaO2)及降低动脉二氧化碳分压(PaCO2),且在改善肺功能、提高运动耐力及降低PaCO2等方面的疗效明显优于单独的缩唇-腹式呼吸操和六字诀训练.     

Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease

We investigated the mechanism of hyperoxic-induced hypercapnia in 17 stable patients with moderate to severe chronic obstructive pulmonary disease (mean FEV1 = 0.95 L and FVC = 2.43 L). Ventilatory and mouth occlusion pressure (P0.1) responses to hypercapnia and hypoxia were measured with standard rebreathing techniques. In a randomized, single-blind fashion, we studied the effect of 15 min of hyperoxia or air on transcutaneous carbon dioxide (PtcCO2), CO2 production (VCO2), total minute ventilation (VE), and calculated dead space to tidal volume ratio (VD/VT). With O2, the PtcCO2 (p less than 0.01) and VD/VT (p less than 0.02) increased. The change in PtcCO2 with O2 was not significantly related to the indices of respiratory drive, nor to the baseline PtcCO2 or SaO2, but was related to the FEV1 (p less than 0.05). The O2 caused a slight decrease in mean VE and mean VCO2, but the effects in individual patients were variable. Both substantial increases or decreases in VE (delta VE) occurred, but these were accompanied by changes in VCO2 (delta VCO2) in the same direction. The effect of changes in VE on PaCO2 is shown to be almost completely cancelled by the concomitant changes in VCO2. Thus, the major portion of the change in PaCO2 was due to changes in VD/VT. We conclude that hyperoxic-induced hypercapnia is primarily due to impairment in gas exchange rather than to depression of ventilation. A reduced FEV1 appears to be a significant risk factor, whereas indices of respiratory drive are not likely to play a major role.