copyright of the original publisher. and distribution prohibited.

Transcription

1 Dis Manage Health Outcomes 2007; 15 (2): LEADING ARTLE /07/ /$44.95/ Adis Data Information BV. All rights reserved. The Role of Spirometry in Evaluating Therapeutic Responses in Advanced COPD Pierantonio Laveneziana 1 and Denis E. O Donnell 2 1 Respiratory Investigation Unit, Department of Medicine, Queen s University, Kingston, Ontario, Canada 2 Division of Respirology & Critical Care Medicine, Department of Medicine, Queen s University, Kingston, Ontario, Canada Abstract Traditional This spirometry, while material of unquestionable diagnostic utility, provides is imprecise information about the nature and extent of physiological impairment or the resultant clinical consequences in any given patient with chronic obstructive pulmonary disease (COPD). The corollary is that exclusive reliance on spirometric forced expiratory flow rates as the primary outcome measure for the evaluation of therapeutic efficacy can lead to significant underestimation of clinical benefit. Recognition of the limitations of routinely used physiological parameters has prompted a search for additional simple and reliable tests for use in clinical trials. Among these, copyright of the the spirometric inspiratory capacity () shows early promise as a useful, clinically relevant outcome measure that complements traditional expiratory flow measurements. Consistent improvements in after bronchodilator therapy signify reduction in lung hyperinflation and can occur in the setting of minimal or no change in maximal expiratory flow rates, particularly in patients with more severe disease. Moreover, improved has been shown to correlate well with improvement in important clinical outcomes such as dyspnea and exercise endurance in patients with moderate to severe COPD. This review charts the evolving experience with this novel parameter in the clinical trial setting. Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world and has significant economic COPD, desirable therapeutic goals include improvement of ventiis prohibited. bronchodilator therapy is the first step in achieving these therapeutic goals. impact. [1] Therefore, COPD is often targeted in disease manage- Studies designed to evaluate the efficacy of bronchodilator ment programs. Significant opportunities are available to improve therapy increasingly incorporate these important clinical outthe care for the COPD population. In patients with symptomatic comes. [2-7] Improvement in airway function in response to bronchodilator therapy is generally confirmed by simple spiromelatory mechanics, alleviation of dyspnea, increased activity levels, try. The forced expiratory volume in 1 second (FEV1) is the most and improved quality of life. Health education, including smoking common test of physiological impairment in COPD and has stood cessation, is effective in accomplishing these goals. Prescription of the test of time. However, changes in the FEV1 following inhaled corticosteroids in COPD is still a controversial issue and is bronchodilator therapy have been shown to correlate weakly with currently recommended only for those patients with advanced important patient-centered outcomes such as reduced exertional disease and frequent exacerbations. All patients benefit from exer- dyspnea and activity limitation. [2,8,9] Recent studies have suggestcise training programs, which improve both exercise tolerance and ed that attendant reductions in the end-expiratory lung volume symptoms of dyspnea and fatigue, with consequent favorable (EELV), as a result of bronchodilator-induced improvements in effects on activity levels and quality of life. Long-term administra- lung emptying, may be more closely associated with symptom tion of oxygen to patients with chronic respiratory failure has been relief and increased exercise capacity than traditional spirometric shown to increase survival. However, it is noteworthy that indices. [2,5,6,10-16]

2 92 Laveneziana & O Donnell This review briefly examines the basic pathophysiology of tion (mucosal edema, airway remodeling, and mucous impaction) COPD in order to better understand how this can be manipulated and possibly increased cholinergic airway smooth muscle tone by pharmacotherapy for the patients benefit. Current concepts of (figure 1). Emphysema results in reduced lung elastic recoil presairway reversibility in advanced COPD are reviewed by examin- sure, which leads to reduced driving pressure for expiratory flow ing the contribution of spirometric indices, such as the FEV 1, through narrowed and poorly supported airways in which airflow forced vital capacity (FVC), forced expiratory volume in 6 resistance is significantly increased. Expiratory flow limitation is seconds (FEV6), and maximal mid-expiratory flow (FEF25 75%), said to be present when the expiratory flows generated during in the evaluation of therapeutic responses. The review discusses spontaneous tidal breathing represent the maximal possible flow the role of other spirometric indices, such as inspiratory capacity rates that can be generated at that operating lung volume. [17] (), EELV, residual volume, and total lung capacity, in the In COPD, the increased compliance of the lung leads to a evaluation of therapeutic responses to modern inhaled bronchodiresetting of the respiratory system s relaxation volume to a higher lators. level than in age-matched healthy individuals. [18] This has been termed static lung hyperinflation. The volume of air remaining in 1. Literature Search We did not conduct a full systematic review on the topic, and functional residual capacity. While the EELV during relaxed searched to identify relevant articles. Key words used for the lished in English, with adult participants who had a diagnosis of blind studies with either a crossover or parallel-group design, and who had undergone pulmonary function testing and cardiopulmois prohibited. therefore did not apply the methods of the Cochrane Collaboration. The search strategy for this review was based on the MED- LINE/PubMed database and used MeSH descriptors. Reference lists from pertinent articles were searched, personal contact was made with authors, and books and targeted journals were manually literature search included COPD, spirometry, inspiratory capacity, bronchodilators, lung volume, respiratory mechanics, dyspnea, exercise capacity, and quality of life. Studies pub- stable COPD were included. With regard to the methodology of bronchodilator studies reported in table I and in the text, we included randomized, double- with either a placebo or comparator drug as a control. Most studies were prospective; however, we did include a large retrospective study [13] with participants obtained from a database of patients nary exercise testing in our own laboratory. 2. Basic Pathophysiology of Chronic Obstructive Pulmonary Disease (COPD) COPD is characterized by heterogeneous pathophysiologic derangements of the small and large airways, lung parenchyma, and capillary bed in highly variable combinations, and these combined structural abnormalities are unlikely to be reflected in any simple spirometric test. Expiratory flow limitation is the pathophysiologi- cal hallmark of COPD and arises because of the dual effects of permanent parenchymal destruction (emphysema) and airway dysfunction. The latter reflects the effects of small airway inflamma- the lung at the end of spontaneous expiration (i.e. EELV) is increased in patients with COPD compared with healthy individu- als. [2,18] EELV is synonymous with the more conventional term resting breathing in healthy individuals corresponds with the actual equilibrium position of the respiratory system, this is often not the case in patients with COPD. [18] During spontaneous resting breathing in patients with expiratory flow limitation, the EELV is dynamically determined and is maintained at a level above the statically determined relaxation volume of the respiratory system. In flow-limited patients, the mechanical time-constant for lung emptying (i.e. the product of compliance and resistance, τ ) is increased in many alveolar units, but the expiratory time available (as dictated by the respiratory control centers) is often insufficient to allow the EELV to decline to its normal relaxation volume, and gas accumulation and retention (often termed air trapping ) re- sults. In other words, lung emptying during expiration becomes incomplete because it is interrupted by the next inspiration, and the EELV therefore exceeds the natural relaxation volume of the respiratory system. The EELV in COPD is a continuous dynamic variable that varies with the extent of expiratory flow limitation, the net timeconstant abnormalities of the lungs, and the prevailing ventilatory demand. [19] In patients with diffuse bronchoconstriction and expiratory flow limitation, severe lung hyperinflation is best explained by dynamic rather than static mechanisms. [20-23] There is increas- ing evidence that lung hyperinflation, which becomes acutely amplified under conditions of increased ventilatory demand (i.e. exercise, hypoxemia, voluntary hyperventilation, anxiety) or worsening expiratory flow limitation (i.e. acute exacerbation), results in immediate negative mechanical and sensory consequences for patients with COPD. [24-30] For this reason, lung hyper-

3 Table I. Bronchodilator-induced changes in spirometric variables and resting lung volumes in patients with chronic obstructive pulmonary disease (COPD) Study Bronchodilator Dosage and frequency of Mean baseline Mean baseline Mean change Mean change Mean Mean change administration FEV1, L, L in FEV1 from in FVC from change in in from (% of (% of baseline, baseline, FEV1/FVC baseline, predicted) predicted) L (%) L (%) from L (%) baseline, % O Donnell et al. [11] Salmeterol 50µg bid for 8 weeks 1.21 (39.5) 2.26 (NS) (14) (9.9) (11.9) Salmeterol + 250/50µg bid for 8 weeks 1.32 (42.5) 2.14 (NS) (18) (9.5) (15.4) fluticasone Peters et al. [10] Ipratropium + 0.5mg + 2.5mg (1 dose) 1.16 (43) 2.01 (72) (28) (15.3) (16.3) salbutamol van Noord et al. [12] Tiotropium 18µg od for 2 weeks 1.05 (38) 2.18 (NS) (10) (22.5) (18) Tiotropium + 18µg od + 12µg od for 2 weeks 1.05 (38) 2.18 (NS) (36.4) (30.7) (24.3) formoterol Tiotropium + 18µg od + 12µg bid for 2 weeks 1.05 (38) 2.18 (NS) (37) (30.3) (25.3) formoterol Maltais et al. [7] Tiotropium 18µg od for 6 weeks 1.20 (43.1) 2.1 (NS) (14) (13) (10.5) O Donnell et al. [6] Tiotropium 18µg od for 6 weeks 1.25 (42) 2.19 (NS) (17.6) (15.7) (11) O Donnell et al. [14] Salmeterol 50µg bid for 2 weeks 1.08 (42) 1.81 (65) (14.8) (14.6) (18.8) Di Marco et al. [16] Salbutamol 200µg (1 dose) NS (52) NS (74) (16) (9.1) NC (11.4) Formoterol 12µg (1 dose) NS (52) NS (74) (18.4) (10.3) NC (16.5) Salmeterol 50µg (1 dose) NS (52) NS (74) (13.3) (8) NC (9) Oxitropium 200µg (1 dose) NS (52) NS (74) (6.7) (4.1) NC (6.5) Celli et al. [15] Tiotropium 18µg od for 4 weeks 1.23 (46) 2.1 (NS) (19.6) (19.5) (16) Newton et al. [13] Salbutamol in 200µg (1 dose) NS (52.4) NS (87.1) (14.9) (15.6) (11.5) patients with severe hyperinflated COPD Salbutamol in 200µg (1 dose) NS (78) NS (94.9) (11) (9.1) (5.7) patients with moderate hyperinflated COPD O Donnell et al. [2] Ipratropium 500µg tid for 3 weeks 1.05 (40) 1.83 (NS) (16) (14.3) (18) bid = twice daily; FEV 1 = forced expiratory volume in 1 second; FVC = forced vital capacity; = inspiratory capacity; NC = no significant change; NS = not stated; od = once daily; tid = three times daily. Spirometry in Evaluating Therapeutic Responses in COPD 93

4 94 Laveneziana & O Donnell inflation has become an important therapeutic target in this population. 3. Bronchodilator Reversibility in COPD value as a single cross-sectional test, it is an important measure for disease management when repeated over time. The FEV 1 is a simple, reproducible test of unquestionable diagnostic utility; it allows an objective assessment of disease progression and is a recognized prognostic indicator. However, spirometric FEV1 is prone to measurement artifact related to volume history. Moreover, forced maneuvers initiated from total lung capacity introduce gas and airway compression effects, and result in an altered pattern of lung emptying compared with that which occurs during normal tidal breathing over a range of operat- ing lung volumes. Spirometric FEV1 gives no information about the extent of prevailing expiratory flow limitation, the shape of the Bronchodilator reversibility criteria have traditionally been based on changes in the FEV1. Acceptable minimum spirometric improvements according to the American Thoracic Society and European Respiratory Society criteria (i.e. an increase in FEV1 and/or FVC by 12% and 200mL compared with baseline during a single testing session) [31] are more likely to indicate actual revers- ible airway obstruction than random variation of the measurement. maximal expiratory flow-volume curve over the range of operating tidal volume, or the extent of resting and dynamic hyperinfla- tion of the lung required to maximize expiratory flow rates (figure 2). This measurement, therefore, does not provide an assessment of the dynamic expiratory flow reserves available under condi- tions of increased ventilatory demand such as exercise. The magnitude of bronchodilator response in any given patient will vary with time and will depend on the type and dosage of the bronchodilator used. [32] Patients can derive significant symptomatic relief from bronchodilator therapy in the presence of little or no increase in the FEV1. On the other hand, a recent study has shown In several research studies, the FEV1 has been shown repeated- ly to correlate poorly with measures of disability such as dyspnea and exercise capacity. [33-36] In addition, the change in the FEV1 surprisingly large improvements in the FEV1 after combined short-acting β 2 -adrenoceptor agonist and anticholinergic inhalers, even in patients with more advanced COPD. [10] A single spirometric assessment in the clinic or laboratory will not reliably predict (on an individual basis) a long-term symptomatic response, and therefore this test should not be used in isolation to guide treatment following bronchodilator therapy is poorly predictive of improve- choices. However, even though the FEV1 may not have significant P L P L Healthy COPD V. ment in symptoms and exercise endurance in advanced COPD. [2,8,9] This poor statistical correlation is borne out by com- mon clinical observation. Thus, patients with the same measured FEV1 (expressed as a percentage of predicted FEV1) may vary greatly in their level of disability; patients may deteriorate clinically, either acutely (e.g. during exacerbations) or chronically, while preserving the spirometric FEV 1. Moreover, patients may achieve considerable improvements in symptoms and exercise endurance as a result of interventions such as bronchodilators, oxygen ther- apy, or exercise training, with little or no change in the FEV1. [2-4] Fig. 1. Schematic representations of alveolar units in healthy individuals and in patients with chronic obstructive pulmonary disease (COPD). Airway narrowing in COPD can result from increased airway wall thickness and increased collapsibility due to reduced tethering. Expiratory flow limitation in COPD occurs because of the combined effects of increased airway resistance and reduced lung recoil: alveolar emptying is therefore critically dependent on expiratory time, which, if insufficiently long, results in lung overinflation. PL = lung recoil pressure; V = flow; X = vagus nerve. All classes of bronchodilator act by relaxing airway smooth muscle tone. Post-bronchodilator improvements in the FEV1 signify reduced resistance in the larger airways, as well as in alveolar V. X X units, with rapid time-constants for lung emptying. In more advanced COPD (in contrast to asthma), post-bronchodilator increases in the FEV1 mainly occur as a result of lung volume recruitment; the FEV1 : FVC ratio is unaltered or even decreases in response to bronchodilator therapy. [2,5-7,13,37] Improvements in FVC reflect reductions in residual volume. Due to the prolonged expiration with relatively low expiratory flow rates in COPD, the FVC is critically dependent on the motivation and breath-holding capacity of the patient. Measurements of timed vital capacity or FEV6 appear to be more sensitive than the FVC in detecting enhanced lung emptying after pharmacotherapy. [38-40]

5 Spirometry in Evaluating Therapeutic Responses in COPD 95 a 8 6 Healthy COPD Predicted Measured 4 Flow (L/second) 2 0 TLC 1 second RV 1 second Lung volume (L) Lung volume (L) b Lung volume (% of predicted TLC) Unauthorised 20 copying Fig. 2. (a) Maximal expiratory (large outer loops lines) and tidal (small inner loops) flow-volume loops in a healthy individual and in a patient with chronic obstructive pulmonary disease (COPD). and The patient exhibits distribution a markedly reduced forced expiratory volume in 1 second, expiratory flow limitation, and lung hyperinflation, i.e. reduced inspiratory capacity (). (b) Lung volume compartments in the same healthy individual and COPD patient in (a). Note the The FEF25 75% is a highly variable is spirometric prohibited. test, in part TLC EILV EELV Healthy individual COPD patient marked lung hyperinflation, with reduced compared with results from the healthy individual. EELV = end-expiratory lung volume; EILV = end-inspiratory lung volume; IRV = inspiratory reserve volume; RV = residual volume; TLC = total lung capacity; VT = tidal volume. and indicate that higher maximal (and, by extrapolation, tidal) expiratory flows could now be achieved at lower operating lung volumes. Improvement in these effort-independent flows correlat- ed well with reductions in residual volume and EELV after bronchodilators. because it depends on the FVC, which increases with expiratory time in subjects with airflow obstruction. It should be noted that, if the FVC changes, the post-bronchodilator FEF25 75% is not com- Improvement in small airway function is more difficult to measure accurately, but reduced lung volumes (residual volume and EELV) as a consequence of reduced airway closure and enhanced gas emptying in alveolar units with slower time-con- stants provide indirect evidence of a positive effect. Recent studies parable with that measured before the bronchodilator. At least two studies have assessed the utility of FEF25 75%, but the results were disappointing. [41,42] In order to solve this problem, it becomes necessary to undertake a volume adjustment of FEF25 75%. In this regard, O Donnell and colleagues showed in two clinical trials that bronchodilators consistently increased volume-corrected maximal mid-expiratory flow rates. [5,14] Improvements in individual volume-corrected mid-expiratory flow rates are probably important IRV V T EELV 4. Lung Deflation Following Bronchodilators

6 96 Laveneziana & O Donnell sure technique) and those with more severe resting lung hyperinflation have demonstrated the greatest lung volume reduction with bronchodilators. [13,43,44] have shown that substantial reductions (i.e. >0.5L) in lung hyperinflation can occur after acute short- and long-acting bronchodilator treatment in the presence of only modest improvements in the FEV1. [5-7,13,15,37,43,44] Bronchodilator therapy does not necessarily abolish resting expiratory flow limitation (especially in more severe disease) but changes the conditions under which it occurs (figure 3). [43] Thus, patients may remain flow limited but can now accomplish the required alveolar ventilation at a lower operating lung volume and, therefore, at a reduced oxygen cost of breathing. Patients who show expiratory flow limitation during spontaneous resting breathing (as determined by the negative expiratory pres- breathing was unaffected. Lung deflation, therefore, primarily reflected improvements in the mechanical time-constants for lung emptying, i.e. reduced airway resistance. In contrast to the situa- tion following lung volume reduction surgery, [46] acute bronchodilator administration was not associated with increased elastic lung recoil pressure and is not, therefore, likely to affect the statically determined relaxation volume of the respiratory system. The main impact is, therefore, on the dynamically determined resting EELV through pharmacological manipulation of airway resistance. These important bronchodilator-induced improvements in ventilatory mechanics are indirectly reflected by increases in the spirometric resting. 5. Implications of Improvement in Resting Inspiratory Capacity for Exercise Performance A recent mechanical study on the mechanisms of dyspnea relief tone was associated with improved airway conductance at all lung following tiotropium therapy showed that release of cholinergic Inspiratory capacity is defined as the maximal volume of air that can be inspired after a quiet expiration to EELV. Improve- ments in resting have been shown to occur as a result of treatment with all classes of bronchodilator and this indirectly signifies reduced EELV. [3-5,14] A bronchodilator-induced increase in the resting (indicating reduced lung hyperinflation) in the order of 0.3L or 10 15% of predicted (or 15 17% of baseline volumes from total lung capacity to residual volume. [45] Static elastic recoil of the lung was unchanged after acutely administered tiotropium, and expiratory timing during spontaneous resting Flow (L/second) value) appears to be clinically meaningful and corresponds with important improvements in exertional dyspnea and exercise endurance in flow-limited COPD patients with moderate-to-severe disease (table I). [2,5-7,10-16] The resting represents the operating limits for tidal volume expansion during the increased ventilation of exercise in COPD, and the increased in response to a bronchodilator means that flow-limited patients could achieve the same, or greater, ventilation while breathing at lower lung volumes, thus positioning tidal volume on the steeper and more placebo bronchodilator Bronchodilator Placebo favorable portion of the respiratory system s pressure-volume curve. Dynamic hyperinflation refers to the temporary and variable increase in EELV above the resting value that occurs during Lung volume (L) Fig. 3. Maximal expiratory (large outer loops) and tidal (small inner loops) flow-volume loops in a typical chronic obstructive pulmonary disease patient receiving placebo or a bronchodilator. Maximal expiratory flows increase from placebo after a bronchodilator in association with a decrease in end-expiratory lung volume, as reflected by an increase in inspiratory capacity (). Tidal volume was positioned at a lower operating lung volume, and inspiratory reserve volume was increased after bronchodilator compared with placebo. The results for this patient are representative of those presented in the reviewed clinical trials evaluating both short- and long-acting bronchodilators in moderate to severe chronic obstructive pulmonary disease. [6,7] increases in ventilatory demand. Dynamic hyperinflation can be tracked during exercise by serial measurements: since the total lung capacity does not change with exercise, the change in reflects the inverse change in EELV. Several studies have shown that bronchodilator therapy does not alter the magnitude of dynamic hyperinflation (or air trapping) during the increased ventilation of exercise. [2-7,10,11,14] In fact, the rest-to-peak exercise reduction in may actually increase as a result of the higher levels of ventilation permitted by bronchodilator therapy. [2-7,10,11,14] However, because of recruitment of the at rest, the dynamic EELV at

7 Spirometry in Evaluating Therapeutic Responses in COPD 97 Lung volume (% predicted TLC) Healthy IRV V T EELV Pre-dose COPD Post-dose V T TLC EELV Ventilation (L/min) Ventilation (L/min) Ventilation (L/min) Fig. 4. The effect of increases in ventilation during exercise on operating lung volumes in age-matched, healthy individuals and in patients with chronic obstructive pulmonary disease (COPD) before (pre-dose) and after (post-dose) administration of inhaled bronchodilator. Bronchodilators reduce endexpiratory lung volume (EELV) and increase inspiratory capacity (), thereby, resulting in less mechanical restriction on tidal volume (V T) expansion during exercise. These mechanical improvements translate into improved dyspnea and exercise capacity. The dashed line shows pre-dose resting EELV. Reproduced from O Donnell and Mahler, the with permission. IRV = inspiratory reserve volume; TLC = total lung capacity. copyright of the peak exercise is lower, in absolute terms, than the value obtained at the breakpoint of exercise during the placebo arm of the treat- ment. [2-7,10,11,14] In other words, bronchodilator treatment is associated with a parallel, downward shift in the EELV over the course of the exercise test (figure 4). recruitment of resting : in these patients, total lung capacity and 6. Combined Bronchodilator Therapy ments in this variable should be linked to improved exercise The resting (standardized as a percentage of the predicted normal value) has been shown to correlate well with peak symp- performance. Several studies, which used various bronchodilators, have now shown that increased both at rest and during exercise is associated with increased tidal volume and ventilatory capaci- ty. [2-7,10,11,14] By increasing sarcomere fiber length in the dia- phragm, lung volume deflation may also favorably affect this muscle s force-generating capacity, which again would contribute to reduced effort requirements (and central neural drive) for a given tidal volume displacement. [49] Thus, avoidance of high end mechanics (where the respiratory system s pressure-volume rela- tionship is relatively flat), as a result of bronchodilator-induced reductions in EELV and increases in inspiratory reserve volume, should contribute importantly to exertional dyspnea alleviation and improved exercise performance (figure 5). [6,13,15,18,24,37,44] Improvements in post-bronchodilator therapy are not anticipated in patients with a preserved resting baseline who do not have expiratory flow limitation during spontaneous quiet breath- ing. In a minority of patients with severe resting hyperinflation, acute bronchodilator administration may not be associated with EELV may decline in parallel, thus preserving. tom-limited oxygen uptake during incremental exercise testing in demonstrably flow-limited patients. [25,48] It follows that improve- Although maximal bronchodilation can be achieved with a high dose of a single agent, combining two classes of bronchodilators allows the use of lower doses, with similar efficacy results and fewer adverse effects. [50] In this regard, recent studies in patients with moderate to severe COPD have indicated that combined long-acting anticholinergic and β2-adrenoceptor agonist bronchodilators have additive effects on airway function and on lung deflation. [51,52] A recent study by van Noord et al. [12] showed that tiotropium (once daily) combined with formoterol (twice daily) was associated with sustained lung volume reduction as assessed by serial measurements over a 24-hour period. The average increase in (0 24 hours) after this bronchodilator combination was 0.215L, with an impressive peak effect within 2 hours of administration of 0.55L during waking hours. Improve- ments of this magnitude are arguably clinically important and should translate into an important reduction in activity-related dyspnea and increased exercise endurance. The question arises as to whether this peak effect could be sustained throughout the 24 hours by the addition of further bronchodilator therapy or possibly by adding inhaled corticoste-

8 98 Laveneziana & O Donnell Intensity of dyspnea a Maximal 10 Very, very severe 9 8 Very severe 7 6 Severe 5 Somewhat severe 4 Moderate 3 Slight 2 Very slight 1 Nothing at all 0 Maximal Very, very severe Very severe Severe Somewhat severe Moderate Slight Very slight Nothing at all b Fig. 5. Effect of tiotropium on the intensity of dyspnea (Borg scale) during constant work-rate cycle ergometry to symptom limitation at 75% of peak work capacity and the first 5 the minutes of recovery copyright in patients with chronic obstructive pulmonary disease of after 42 days the of treatment with either once-daily tiotropium (n = 131) or placebo (n = 117): (a) 2.25 hours after administration; (b) 8 hours after administration. Reproduced from Maltais et al., [7] with permission. * p = 0.05, p < 0.01 vs placebo. roid therapy. It is noteworthy that prescription of inhaled corticooriginal publisher. individual basis. To the extent that bronchodilators are adminis- trial setting. Formal spirometric reversibility testing is time-con- steroids in COPD is still a controversial issue and is currently recommended only for patients with advanced disease and frequent exacerbations. However, a recent study confirmed that a fluticasone propionate/salmeterol combination (250/50µg twice daily) was associated with reduced lung hyperinflation, improved, and increased cycle exercise endurance time when compared with placebo. [11] Improvements in exercise endurance time during constant work rate cycle exercise (at 75% of each patient s peak 7. Office Evaluation of Bronchodilator Efficacy Currently, there is no consensus as to the best way to evaluate therapeutic responses to newly introduced bronchodilator treat- * * Exercise time (minutes) Placebo during exercise Placebo during recovery Tiotropium during exercise Tiotropium during recovery ments in the office or ambulatory clinic, i.e. outside the clinical suming and, as we have seen, has little predictive value on an tered primarily for the purpose of reducing dyspnea and activity limitation, direct inquiry into the patient s perception of the impact of the medication on these specific patient-centered outcomes is appropriate. The care provider will deduce that the medication is beneficial if the patient reports that he/she can now undertake a particular daily task or activity with less respiratory discomfort and/or for a longer duration. If no subjective improvement is work rate) averaged just over 2 minutes and were seen after first administration. [11] In this study, preliminary comparisons between fluticasone propionate/salmeterol 250µg/50µg twice daily and salmeterol alone suggested superiority of the combination prod- uct. [11] Based on the results of studies that have examined the effects of combining long-acting bronchodilators, there is every indication that the combination of tiotropium and fluticasone propionate/salmeterol will have additive clinical benefits, with a greater impact on impairment, disability, and handicap than either treatment alone. evident to a patient (on optimal drug dosage) whose adherence and inhaler technique are not in question, then it can be argued that there is little justification for continuing to prescribe the medica- tion in the absence of evidence for long-term benefits such as a survival advantage. However, we must recognize that several factors can obscure a bronchodilator effect, such as inadequate assessment, interference induced by nutritional status, cardiopulmonary fitness, peripheral muscle strength, comorbidities, and depression. All may influence dyspnea sensation and exercise capacity, limiting the ability of the patient to judge the subjective effect of bronchodilator treatment.

9 Spirometry in Evaluating Therapeutic Responses in COPD Conclusions 9. Leitch AG, Hopkin JM, Ellis DA, et al. The effect of aerosol ipratropium bromide and salbutamol on exercise tolerance in chronic bronchitis. Thorax 1978; 33: Peters MM, Webb KA, O Donnell DE. Combined physiological effects of bronchodilators and hyperoxia on exertional dyspnoea in normoxic COPD. Thorax 2006; 61: O Donnell DE, Sciurba F, Celli B, et al. Effect of fluticasone propionate/salmeterol Traditionally, the airway obstruction of more advanced COPD is thought to be largely irreversible, and this may have contributed to a pervasive therapeutic nihilism. This view has recently changed, and there is an emerging consensus that airway obstruc- on lung hyperinflation and exercise endurance in COPD. Chest 2006; 130: tion, even in the later stages of the disease, is indeed partially O Donnell DE, Voduc N, Fitzpatrick M, et al. Effect of salmeterol on the ventilato- ry response to exercise in chronic obstructive pulmonary disease. Eur Respir J 2004; 24: Celli B, ZuWallack R, Wang S, et al. Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003; 124 (5): Di Marco F, Milic-Emili J, Boveri B, et al. Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in COPD. Eur Respir J 2003; 2: responsive to bronchodilator therapy. Exclusive reliance on the change in FEV1 as the primary outcome measure in assessing therapeutic efficacy in clinical trials as well as in clinical practice can lead to underestimation of a true clinical benefit in some 2002; 121: patients with advanced COPD. Additional consideration of bronchodilator-induced changes in spirometric lung volumes (or 12. van Noord JA, Aumann JL, Janssens E, et al. Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006; 129: Newton M, O Donnell DE, Forkert L. Response of lung volumes to inhaled salbutamol in a large population of patients with severe hyperinflation. Chest capacities) can provide clinically useful and complementary infor- 17. Hyatt RE. Expiratory flow limitation. J Appl Physiol 1983; 55: 1-8 mation. In this regard, the spirometric resting, which is a simple reproducible measurement, is an acceptable surrogate for direct measurements of resting lung hyperinflation. Improved resting following bronchodilator therapy has been shown to correlate significantly with improved exercise tolerance and dyspnea alleviation, and thus provides a solid physiological rationale for these benefits. Advocators of disease management programs should be 18. Pride NB, Macklem PT. Lung mechanics in disease. In: Fishman AP, editor. Handbook of physiology. Section 3, Vol. III, Pt 2: the respiratory system. Bethesda (MD): American Physiological Society, 1986: Vinegar A, Sinnett EE, Leith DE. Dynamic mechanisms determine functional residual capacity in mice, mus musculus. J Appl Physiol 1979; 46: aware of these issues when designing or implementing a program for COPD to ensure suitable tests of therapeutic efficacy are utilized in order to achieve appropriate and realistic outcomes. Acknowledgments 20. Sharp JT. The respiratory muscles in chronic obstructive pulmonary disease. Am Rev Respir Dis 1986; 134: Demedts M. Mechanisms and consequences of hyperinflation. Eur Respir J 1990; 3: Macklem PT. Hyperinflation [editorial]. Am Rev Respir Dis 1984; 129: Leith DE, Brown R. Human lung volumes and the mechanisms that set them. Eur ance in COPD. Am J Respir Crit Care Med 2001; 164: O Donnell DE, D Arsigny C, Webb KA. Effects of hyperoxia on ventilatory and Blood Institute, 2006 Nov. Available from URL: No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review. Respir J 1999; 13: O Donnell DE. Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006; 3: O Donnell DE, Revill S, Webb KA. Dynamic hyperinflation and exercise intoler- limitation during exercise in advanced chronic obstructive pulmonary disease. References Am J Respir Crit Care Med 2001; 163: National Heart Lung and Blood Institute. Global strategy for diagnosis, manage- 27. Gelb AF, Guitierrez CA, Weisman IM, et al. Simplified detection of dynamic ment and prevention of COPD [online]. Bethesda (MD): National Heart Lung hyperinflation. Chest 2004; 126: O Donnell DE, Parker CM. COPD exacerbations. 3: pathophysiology. Thorax 2. O Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinfla- 2006; 61: tion and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 158: Parker CM, Voduc N, Aaron SD, et al. Physiological changes during symptom 3. Chrystyn H, Mulley BA, Peake MD. Dose-response relation to oral theophylline in recovery from moderate exacerbations of COPD. Eur Respir J 2005; 26: severe chronic obstructive airways disease. BMJ 1988; 297: Stevenson NJ, Walker PP, Costello RW, et al. Lung mechanics and dyspnea during 4. Belman MJ, Botnick WC, Shin JW. Inhaled bronchodilators reduce dynamic exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care hyperinflation during exercise in patients with chronic obstructive pulmonary Med 2005; 172: disease. Am J Respir Crit Care Med 1996; 153: Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function 5. O Donnell DE, Lam M, Webb KA. Spirometric correlates of improvement in tests. Eur Respir J 2005; 26: exercise performance after anticholinergic therapy in COPD. Am J Respir Crit 32. Anthonisen NR, Lindgren PG, Tashkin DP, et al. Bronchodilator response in the Care Med 1999; 160: lung health study over 11 yrs. Eur Respir J 2005; 26: O Donnell D, Fluge T, Gerken F, et al. Effects of tiotropium on lung hyperinflafunction 33. Wolkove N, Dajczman E, Colacone A, et al. The relationship between pulmonary tion, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004; 23: and dyspnea in obstructive lung disease. Chest 1989; 96: Maltais F, Hamilton A, Marciniuk D, et al. Improvements in symptom-limited 34. Hay JG, Stone P, Carter J, et al. Bronchodilator reversibility, exercise performance exercise performance over 8h with once-daily tiotropium in patients with and breathlessness in stable chronic obstructive pulmonary disease. Eur Respir COPD. Chest 2005; 128: J 1992; 5: Tobin MJ, Hughes JA, Hutchison DCG. Effects of ipratropium bromide and 35. Bauerle O, Chrusch CA, Younes M. Mechanisms by which COPD affects exercise fenoterol aerosols on exercise tolerance. Eur J Respir Dis 1984; 65: tolerance. Am J Respir Crit Care Med 1998; 157: 57-68

10 100 Laveneziana & O Donnell 36. Carlson DJ, Ries AL, Kaplan RM. Predictors of maximum exercise tolerance in 48. Diaz O, Villafranca C, Ghezzo H, et al. Role of inspiratory capacity on exercise patients with COPD. Chest 1991; 100: tolerance in COPD patients with and without tidal expiratory flow limitations at 37. O Donnell DE. Assessment of bronchodilator efficacy in symptomatic COPD: is rest. Eur Respir J 2000; 16: spirometry useful? Chest 2000; 117: 42-7S 49. Man WDC, Mustfa N, Nikoletou D, et al. Effect of salmeterol on respiratory 38. Rabe KF, Bateman ED, O Donnell D, et al. Roflumilast: an oral anti-inflammatory muscle activity during exercise in poorly reversible COPD. Thorax 2004; 59: treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 2005; 366: Swanney MP, Jensen RL, Crichton DA, et al. FEV6 is an acceptable surrogate for 50. Serra C, Giacopelli A, Luciani G. Acute controlled study of the dose-response FVC in the spirometric diagnosis of airway obstruction and restriction. Am J relationship of fenoterol, ipratropium bromide and their combination. Respira- Respir Crit Care Med 2000; 162: tion 1986; 50: Enright RL. The FEV1/FEV6 predicts lung function decline in adult smokers. 51. van Noord JA, Aumann JL, Janssens E, et al. Comparison of tiotropium once daily, Respir Med 2002; 96: formoterol twice daily and both combined once daily in patients with COPD. 41. Olsen CR, Hale FC. A method for interpreting acute response to bronchodilators Eur Respir J 2005; 26: from the spirogram. Am Rev Respir Dis 1968; 98: Donohue JF. Combination therapy for chronic obstructive pulmonary disease: 42. Boggs PB, Bhat KD, Velovius WA, et al. The clinical significance of volume clinical aspects. Proc Am Thorac Soc 2005; 2: adjusted maximal mid expiratory flow (iso-volume FEF25 75%) in assessing airway responsiveness to inhaled bronchodilator in asthmatics. Ann Allergy 1982; 48: (Rome) and Specialty Qualification in Respirology (Florence). He joined 43. Tantucci C, Duguet A, Similowski T, et al. Effect of salbutamol on dynamic hyperinflation in chronic obstructive pulmonary disease patients. Eur Respir J 1998; 12: O Donnell s Laboratory (Respiratory Investigation Unit) at Queen s Uni- 44. O Donnell DE, Forkert L, Webb KA. Evaluation of bronchodilator responses in patients with irreversible emphysema. Eur Respir J 2001; 18: O Donnell DE, Hamilton AL, Webb KA. Sensory-mechanical relationships during high-intensity, constant-work-rate exercise in COPD. J Appl Physiol 2006; 101: conducting a number of clinical studies in the broad area of exercise 46. Sciurba FC, Rogers RM, Keenan RJ, et al. Improvement in pulmonary function and elastic recoil after lung-reduction surgery for diffuse emphysema. N Engl J Med 1996; 334: O Donnell DE, Mahler DA. Effect of bronchodilators and inhaled corticosteroids on dyspnea in COPD. In: Mahler DA, O Donnell DE, editors. Dyspnea: mechanisms, measurement, and management. 2nd ed. Boca Raton (FL): Taylor & Francis Group, 2005: About the Author: Dr Pierantonio Laveneziana is a graduate of the Univer- sities of Rome and of Florence, where he obtained his basic MD degree versity (Kingston, Ontario, Canada) in September 2005 and has been work- ing in the capacity of clinical research fellow since then. He has been pathophysiology, specifically looking at the mechanisms of dyspnea and exercise limitation in patients with COPD. Correspondence: Dr Denis E. O Donnell, Stuart Street, Kingston, Ontario K7L 2V6, Canada. odonnell@post.queensu.ca