Assessment of acute bronchodilator effects from specific airway resistance changes in stable COPD patients

https://doi.org/10.1016/j.resp.2014.03.012Get rights and content

Highlights

  • In COPD patients, acute bronchodilator response is currently assessed in terms of FEV1 and FVC changes, according to ATS/ERS criteria.

  • These changes are poorly associated to beneficial effects of bronchodilation, such as reduction of hyperinflation, gas trapping, and dyspnea.

  • In COPD patients, bronchodilator induced changes of total airway resistance were closely related to improvements of lung mechanics and dyspnea.

  • In contrast, concomitant changes of FEV1 correlated with those of FVC only.

  • Changes of total specific airway resistance better identify the beneficial impact of bronchodilators.

Abstract

Background

In COPD patients, reversibility is currently evaluated from the changes of forced expiratory volume at 1 s (ΔFEV1) and forced vital capacity (ΔFVC). By lowering peripheral airway smooth muscle tone, bronchodilators should decrease dynamic hyperinflation, gas trapping, and possibly dyspnea at rest. Hence, we hypothesize that specific airway resistance changes (ΔsRAW) should better characterize the acute response to bronchodilators.

Methods

On two days, 60 COPD patients underwent dyspnea evaluation (VAS score) and pulmonary function testing at baseline and one hour after placebo or 300 μg indacaterol administration.

Results

Spirographic and ΔsRAW-based criteria identified as responders 24 and 45 patients, respectively. ΔsRAW correlated with changes of intrathoracic gas volume (ΔITGV) (r = 0.61; p < 0.001), residual volume (ΔRV) (r = 0.60; p < 0.001), ΔFVC (r = 0.44; p = 0.001), and ΔVAS (r = 0.73; p < 0.001), while ΔFEV1 correlated only with ΔFVC (r = 0.34; p = 0.008). Significant differences in terms of ΔITGV (p = 0.002), ΔRV (p = 0.023), and ΔVAS (p < 0.001) occurred only if patients were stratified according to ΔsRAW.

Conclusions

In assessing the acute functional effect of bronchodilators, ΔsRAW-based criterion is preferable to FEV1-FVC-based criteria, being more closely related to bronchodilator-induced improvements of lung mechanics and dyspnea at rest.

Introduction

Studies concerned with the evaluation of the efficacy of bronchodilator therapy in patients with chronic obstructive pulmonary disease (COPD) have used the forced expired volume in one second (FEV1) as the end point measure. A significant increase of the group mean value of FEV1 is taken as an indicator of the bronchodilating properties, and its amount used to assess the effectiveness of the drug. Furthermore, FEV1 is commonly used as a tool for the evaluation and classification of COPD severity (Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD), 2013).

On the other hand, ATS/ERS guidelines (Pellegrino et al., 2005) recommend that changes in FEV1 should also be used to evaluate the acute response to bronchodilators of single COPD patients, i.e. to assess reversibility, although it has been recognized that this variable reflects intrapulmonary airway resistance poorly (Pride, 1971, Skinner and Palmer, 1974). Furthermore, FEV1 measurements are obtained with a maneuver which by itself can affect the airway caliber, besides being often poorly performed. Indeed, after bronchodilator administration flow increases less if forced expirations start from total lung capacity rather than near the end of a normal inspiration, and this leads to an underestimation of FEV1, flow at any given absolute lung volume, and forced vital capacity (FVC) (Barnes et al., 1981, Berry and Fairshter, 1985, Pellegrino et al., 1998), the other variable the changes of which concur in assessing reversibility according to ATS/ERS criteria (Pellegrino et al., 2005). Although some investigations have reported a substantial increase of reversibility based on FVC changes, at least in very severe COPD patients (Newton et al., 2002, Taskin et al., 2008), other studies have suggested that this additional criterion has a minor impact, because FEV1 and FVC are strongly related (Sourk and Nugent, 1983, Schermer et al., 2007, Deesomchok et al., 2010). Finally, a further limitation of ATS/ERS reversibility criteria is represented by the dependency of the acute changes of FEV1 and FVC on the severity of the disease: in fact, the percentage of severe COPD patients who meet these criteria can be very small (Newton et al., 2002, Deesomchok et al., 2010). While the need for the evaluation of novel procedures for acute bronchodilator reversibility testing has been stressed in the most recent review article on reversibility in COPD (Hanania et al., 2011), no alternatives to current criteria seem to have been taken into consideration, although there are indications that plethysmography and/or impulse oscillometry might better reflect bronchodilation in COPD patients (Borrill et al., 2004).

In COPD patients, bronchodilators should significantly improve lung function and relieve respiratory symptoms to the extent that they decrease airway resistance during tidal breathing, thus preventing or reducing dynamic hyperinflation and increasing inspiratory capacity (IC) (Barnes et al., 1981, Berry and Fairshter, 1985, Pellegrino et al., 1998). Because in these patients the disease affects more the small than the large airways, another favorable effect of reducing bronchomotor tone could be the decrease of airway closing pressure, leading to a fall in the residual volume (RV) and increase in the vital capacity (VC). Surprisingly, few studies in COPD patients have evaluated the effects of acute bronchodilation on specific total airway resistance (sRAW), a variable that accurately reflects peripheral airway resistance (Bassiri et al., 1997, Borrill et al., 2004, Mahut et al., 2012), although its relative changes were found systematically greater than those of FEV1 and FVC (Ramsdell and Tisi, 1979, Smith et al., 1992, Taube et al., 2000, Borrill et al., 2004, Deesomchok et al., 2010). Furthermore, sRAW changes with bronchodilator administration have never been related to those of the variables commonly used to evaluate the improvement of lung function.

This investigation was undertaken to assess whether changes of sRAW during quiet breathing occur beyond their short term variability in response to acute bronchodilation even in COPD patients who do not meet the current criteria for reversibility (Pellegrino et al., 2005), and to determine whether sRAW changes adequately predict those of commonly used pulmonary function parameters. In addition, we have investigated the relationships between the changes in dyspnea scores at rest and those of sRAW, static and dynamic lung volumes.

Section snippets

Patient population

Sixty consecutive COPD patients were recruited from a Lung Rehabilitation and Academic Medical Center. Inclusion criteria were: >50 years of age; FEV1/FVC < 0.7 and FEV1 < 80% of predicted value; current or former smokers with a smoking history of more than 20 pack years; stable conditions at time of inclusion and absence of respiratory tract infections or exacerbations for at least 2 months; no change of inhalation therapy for at least 4 weeks. Exclusion criteria were: known unstable or

Results

The effects of indacaterol or placebo on pulmonary function and dyspnea at rest are shown in Table 2, together with measures of short term variability. No difference in any variable occurred at baseline between the two test days, nor did placebo cause significant changes. In contrast, indacaterol caused significant changes in all variables both relative to baseline and placebo, except FEV1/FVC, total lung capacity (TLC) and expiratory reserve volume (ERV) which never changed, and shall be,

Discussion

Indacaterol caused acute bronchodilation, reduced lung hyperinflation, and alleviated dyspnea perception at rest (Table 2). The changes in static and dynamic lung volumes were consistent with those observed with indacaterol in previous studies (Rennard et al., 2008, Beier et al., 2009, Rossi et al., 2012), as well as with salbutamol in very large samples of COPD patients (Newton et al., 2002, Deesomchok et al., 2010). In fact, both the severity of the disease evaluated by MRC score or GOLD

Conclusions

The present results support the notion that the effects of bronchodilators should be evaluated from the changes of airway resistance in the resting tidal volume range rather than FEV1 and/or FVC, especially in connection with the dependent improvement of dyspnea. In contrast, both FEV1 and sRAW are equally good evaluators of the severity of bronchoconstriction at baseline. It is also shown that the decrease of RV and ITGV is mainly due to changes in the mechanical properties of the peripheral

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