Effect of salmeterol on mucociliary and cough clearance in chronic bronchitis

doi:10.1016/j.pupt.2005.04.001

Pulmonary Pharmacology & Therapeutics

Volume 19, Issue 2, April 2006, Pages 96-100

https://doi.org/10.1016/j.pupt.2005.04.001 Get rights and content

Summary

The effect of long acting β₂-adrenergic bronchodilators on impaired mucociliary clearance in chronic bronchitis is unknown. Using a radiolabeled aerosol (technetium-99m-labeled sulfur colloid) and gamma camera analysis, we measured the acute effect of salmeterol vs. placebo on mucociliary and cough clearance in mild-moderate chronic bronchitics (n=14) over a 2 h period. During the 1–1(1/2) h period of observation patients performed 60 controlled coughs on each study day. Average whole lung clearance through 1 and 2 h after administration of salmeterol (42 μg) or placebo via metered dose inhaler (double-blinded, crossover design study) showed no significant difference between treatments. Similarly, for the specific period when cough was added to mucociliary clearance, there was no difference on whole lung clearance between treatments. However, when clearance from the peripheral region of the lung was assessed over the entire 2 h period of observation, salmeterol provided a 30% enhancement of airway clearance compared to placebo, average peripheral 2 h clearance (%)=22±9 vs. 17±10 for salmeterol vs. placebo (P=0.05 by paired analysis). Thus, in addition to its bronchodilating effects, salmeterol acutely enhances peripheral airway clearance of secretions in mild-moderate chronic bronchitis.

Introduction

Measurements of mucociliary clearance made by inhalation of radiolabeled particles to label airway surface liquid suggest that clearance of secretions is impaired in chronic smokers and patients with COPD [1], [2]. Salmeterol (a long acting β₂-adrenergic agonist) is widely used to treat bronchoconstriction in patients with COPD and asthma. A number of short acting β-agonists, e.g. salbutamol, isoproterenol, and albuterol have been shown to acutely enhance the rate of mucociliary clearance from the lung [3]. This enhancement is likely via increases in ciliary activity and increased water and/or mucus secretions onto the airway surface. Less is known about the effects of the new longer acting β-agonists (e.g. salmeterol and formoterol) on mucociliary clearance. Devalia et al. [4] found that salmeterol had a more potent, faster, and longer duration of action than salbutamol on stimulation of ciliary beat frequency (CBF) in cultured human bronchial epithelium. Yet both agonists produced only slight increases in CBF above baseline (<20% increase) [4]. A more recent study confirmed the ability of salmeterol to enhance CBF in both normal and COPD nasal epithelium [5] but again only to a modest degree. Piatti et al. [5] also found no changes in rheology for COPD sputum to which salmeterol had been added ex-vivo at a variety of concentrations [5]. But no reports have been made on the in-vivo effect of salmeterol pretreatment on either the quantity or quality of airway secretions in such patients. Hasani et al. [6] recently suggested that 2 week treatment of salmeterol in asthmatics mildly enhanced clearance of secretions from the airways. However, their findings were confounded by changes in the site of radiolabeled particle deposition following the 2-week treatment. There have been no assessments of the acute effect of salmeterol on mucociliary clearance in patients with airways disease.

Cough clearance is an important adjunct to mucociliary clearance in chronic bronchitic (CB) patients. We found previously that an anti-cholinergic bronchodilator, ipratropium bromide (IB), inhibited cough clearance in patients with severe COPD, the class of patients who rely most on cough to clear secretions from their airways [7]. It was not clear if the effect we observed with IB resulted from changes in flow dynamics induced by bronchodilation or changes in airway hydration and/or rheology of secretions. The effect of a β₂-adrenergic bronchodilator on cough clearance in CB patients has not been investigated in the same manner. If the effect of diminished cough clearance by IB therapy [7] were the result of changes in flow dynamics induced by bronchodilation per se, then it might be expected for salmeterol to have a similar effect.

In the present study we compared the acute effect of salmeterol to placebo on mucociliary and cough-enhanced clearance of secretions in patients with mild chronic bronchitis. To accomplish this, we used a radiolabelled aerosol (Tc99m sulfur colloid) and gamma camera analysis to determine rates of clearance on 2 study days (1) a placebo/control day and a (2) a salmeterol treatment day.

Section snippets

Subjects

Fifteen adult (age 39–70) (7F/8M) subjects with mild-moderate chronic bronchitis (current or ex-smokers with at least 10 pack-years) were studied. All subjects had a clinical diagnosis of chronic bronchitis based on the American Thoracic Society (ATS) definition, i.e. excess mucus production, occurring on most days for at least 3 months of the year for at least two successive years. All were current or ex-smokers (44±26 pack years) with FEV_1% pred ≥40% (mean 85±21 at time of screening).

Results

Table 1 shows the spirometric data (FEV1%pred and FEF 25–75 (L/s)) for the two treatment days, in each case pre, 1 and 2 h post-MDI treatment. For the salmeterol treatment day, FEV1%pred and FEF25–75 were significantly increased at both 1 and 2 h compared to pre-MDI measurements. A decrease in FEV1%pred between pre- and post-MDI was seen for the placebo treatment study day. The mean peak flow rates associated with the controlled coughs (i.e. during 1–1(1/2) h post-MDI treat) were increased from

Discussion

In the present study we found that in mild chronic bronchitics, there was no acute effect on whole lung mucociliary clearance with or without cough as a result of a single administration of salmeterol (a long acting β₂-adrenergic agonist). On the other hand, when region of interest analysis was employed we found that salmeterol significantly enhanced clearance from the peripheral lung region (Fig. 2). The fact that clearance during the cough period (1–2 h) was not different between salmeterol

Acknowledgements

Supported by Glaxo SmithKline Pharmaceuticals Dr Donohue has received honorarium from GlaxoSmithKline for Consulting, Advisory Boards, and Speaker Bureau.

References (20)

J.L. Devalia et al.
The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells in-vitro
Pulm Pharmacol
(1992)
A. Hasani et al.
Effect of salmeterol xinafoate on lung mucociliary clearance in patients with asthma
Respir Med
(2003)
W.D. Bennett et al.
The acute effect of ipratropium bromide bronchodilator therapy on cough clearance in COPD
Chest
(1993)
W.D. Bennett
Effect of β-Adrenergic agonists, on mucociliary clearance
J Allergy Clinical Immunol
(2002)
E. Vastag et al.
Mucociliary clearance and airways obstruction in smokers, ex-smokers and normal subjects who never smoked
Eur J Respir Dis
(1985)
R.M. Goodman et al.
Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis
Am Rev Respir Dis
(1978)
A. Wanner et al.
Mucociliary clearance in the airways (State of the Art)
Am J Respir Crit Care Med
(1996)
G. Piattia et al.
Effects of salmeterol on cilia and mucus in COPD and pneumonia patients
Pharm Res
(2005)
N.E. Alexis et al.
Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique
Am J Resp Crit Care Med
(2001)
F.A. Oldenburg et al.
Effect of postural drainage, exercise and cough on mucus clearance in chronic bronchitis
Am Rev Respir Dis
(1979)

There are more references available in the full text version of this article.

Cited by (34)

Ability of using different dry powder inhalers during COPD exacerbations
2018, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
Finally, AECOPD are usually characterized by increased mucus production. Since long acting bronchodilators are known to decrease mucus production [31,32] and to improve mucociliary clearance [33,34] in COPD patients they might possibly offer important release during AECOPD. Our study has several limitations.
Guidelines suggest that patients hospitalized for acute COPD exacerbations (AECOPD) are treated with short acting bronchodilators. Long acting bronchodilators, offer longer symptom relief but since they are usually administered via Dry Powder Inhalers (DPIs) it is considered that during AECOPD patients would not be able to achieve appropriate inspiratory flow (IF) to receive appropriate drug doses. The aim of the present study was to evaluate whether patients admitted to the hospital for AECOPD, are able to achieve the necessary IF using different DPIs.
IF was measured daily in patients admitted for AECOPD with a portable IF meter (In-Check Oral inhaler assessment kit), containing a series of adapters that simulate the resistance of 4 DPIs [Turbuhaler (T), Breezhaler/Aerolizer (B/F), Discus (A/A/D) and Handinhaler (HH)]. Dyspnea, spirometry and arterial blood gases were also recorded daily.
44 consecutive patients were included in the study. The majority of patients were able to achieve an IF over 30 L/min with all four device resistances. This minimum required IF was achieved in 90.9%, 100%, 95.5% and 81.8% of patients on admission and in 100%, 100%, 97.7%, and 95.5% of patients on discharge for T, B/F, A/A/D and HH respectively. No functional characteristic was able to predict the achievement of this minimum necessary IF.
Most patients hospitalized for AECOPD, are able to receive treatment with long acting bronchodilators administered via DPIs. The possible beneficial effects of such an intervention should be tested in further studies.
Bronchodilator therapy for chronic cough
2017, Pulmonary Pharmacology and Therapeutics
Experimental studies indicate that airway calibre increases the sensitivity of the afferents involved in the cough reflex but it has proved difficult to demonstrate that airway calibre increases the sensitivity of the afferents involved in the cough reflex. Therefore, bronchodilators might have a role, although rather minor, in the treatment of cough. However, although bronchodilators represent the standard of care in the treatment of airway obstruction associated with asthma or COPD, controversy persists regarding the mechanism(s) by which these agents alleviate cough. Furthermore, the available evidence indicates that the effects of bronchodilators on cough are rather inconsistent in humans and casts doubt on the appropriateness of the common practice of using bronchodilators in the treatment of patients with cough without any other evidence of airway obstruction. Regrettably, appropriate long-term trials specifically aimed at evaluating the clinical efficacy of bronchodilators in pathologic cough have not yet been performed. Therefore, properly executed clinical studies of bronchodilators in various types of acute and chronic pathologic cough are required.
Pharmacologic Agents for Mucus Clearance in Bronchiectasis
2012, Clinics in Chest Medicine
Citation Excerpt :
Mucokinetic agents such as β agonists and methylxanthene bronchodilators increase ciliary beat frequency and improve MCC. Both short-acting and long-acting β-adrenergic agonists have been shown to increase MCC acutely in patients with chronic bronchitis and asthma.36,37 Recently Meyer and colleagues38 reported an increased mucus clearance for up to 14 days in patients with mild to moderate COPD with inhaled formoterol (12 μg).
Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD
2011, Respiratory Medicine
Citation Excerpt :
Similarly, while 4 h retention after 14 days treatment with tiotropium was increased compared with that before treatment, this could be consistent with mucus clearance being unchanged. Mucus clearance occurs by both mucociliary and cough clearance mechanisms,6 and the clearances observed in this study may have resulted from a combination of both processes. Mucociliary clearance depends on both ciliary activity and the physical properties of mucus.
Lung mucociliary clearance is impaired in patients with chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend that patients with COPD receive maintenance therapy with long-acting beta-agonists and anticholinergic agents.
Twenty-four patients with mild to moderate COPD received formoterol (12 μg, twice daily from Turbuhaler^® dry powder inhaler (DPI)) or tiotropium (18 μg, once daily from Handihaler^® DPI) for 14 days. They also received single doses of formoterol, tiotropium, salbutamol (200 μg) and placebo. A radioaerosol technique was used to assess the effects on mucus clearance of 14 days treatment with formoterol or tiotropium, as well as single doses of these drugs.
The 4 h whole lung retention of radioaerosol was significantly higher after 14 days treatment with tiotropium (P = 0.016), but not after 14 days treatment with formoterol. However, patients bronchodilated after 14 days treatment with both drugs, so that the deposited radioaerosol may have had an increased distance to travel in order to be cleared by mucociliary action. A single dose of formoterol enhanced radioaerosol clearance significantly compared to other single dose treatments (P < 0.05).
Formoterol (12 μg) enhances mucus clearance in patients with mild to moderate COPD when given as a single dose, and may do so when given for 14 days. Studies of longer duration would be needed in order to assess the effects of the study drugs on mucus clearance when they are used for long-term maintenance therapy.
Pharmacological treatment of hyperinflation
2009, Revue des Maladies Respiratoires
P. Devillier, N. Roche
Lung hyperinflation leads to breathlessness, limitation in exercise capacity and tolerance, and impaired quality of life. Thus, it is important to target this key and characteristic feature of COPD.
Available pharmacological approaches rely mainly on bronchodilators, in particular beta2 agonists and anticholinergic agents. These treatments act through the reduction of expiratory airflow limitation. However, changes in classical indices of airflow obstruction do not accurately predict effects on hyperinflation and symptoms. The decrease in operating lung volumes (as reflected by inspiratory capacity or functional residual capacity) at rest and during exercise is one of the mechanisms by which these treatments improve quality of life and maybe also decrease the impact of exacerbations. The effect of beta2 agonists on hyperinflation might be amplified by concurrent treatment with inhaled corticosteroids.
The effect of new treatments targeting airways inflammation on hyperinflation remains to be explored.
Measuring the reduction in the degree of lung hyperinflation allows a better understanding of the symptomatic effect of COPD pharmacological treatments.
La distension est responsable de la dyspnée, de la limitation à l’exercice et de l’altération de qualité de vie dans la BPCO. Sa prise en charge est donc un des objectifs du traitement.
Les moyens pharmacologiques disponibles reposent principalement sur les bronchodilatateurs, beta2 agonistes et anticholinergiques au premier chef. L’effet de ces traitements passe par la réduction de la limitation des débits expiratoires. Les modifications obtenues sur les indices classiques d’obstruction bronchique ne sont toutefois pas prédictives de leur effet sur la distension et, donc les symptômes. La diminution du degré de distension (reflété par l’augmentation de capacité inspiratoire ou la réduction de capacité résiduelle fonctionnelle) au repos et à l’exercice, est un des biais par lesquels ces agents améliorent la qualité de vie et, peut-être, réduisent l’impact des exacerbations. L’effet des bêta-2 agonistes sur la distension pourrait être amplifié par l’association à une corticothérapie inhalée.
L’effet de nouveaux traitements, ciblant en particulier les phénomènes inflammatoires bronchiques, n’est pas encore connu.
La réduction, mesurable, de la distension permet de mieux comprendre l’effet symptomatique des traitements médicamenteux de la BPCO.
Update on the Pharmacologic Therapy for Chronic Obstructive Pulmonary Disease
2007, Clinics in Chest Medicine
Chronic obstructive pulmonary disease is a treatable disease characterized by progressive airflow limitation. Prevention of disease progression; improvement of symptoms, exercise tolerance, and health status; and decrease in exacerbations and mortality are the goals of management. Inhaled short-acting bronchodilators are recommended for symptoms in mild disease, whereas inhaled long-acting bronchodilators are recommended for maintenance therapy of daily symptoms. When symptoms are not controlled using one bronchodilator, combining bronchodilators may be more effective. Combining a long-acting β-agonist with an inhaled corticosteroid is more effective than either agent alone. Several novel therapies are in different stages of development.

View all citing articles on Scopus

View full text

Effect of salmeterol on mucociliary and cough clearance in chronic bronchitis

Summary

Introduction

Section snippets

Subjects

Results

Discussion

Acknowledgements

Pulm Pharmacol

Respir Med

Chest

J Allergy Clinical Immunol

Mucociliary clearance and airways obstruction in smokers, ex-smokers and normal subjects who never smoked

Eur J Respir Dis

Relationship of smoking history and pulmonary function tests to tracheal mucous velocity in nonsmokers, young smokers, ex-smokers, and patients with chronic bronchitis

Am Rev Respir Dis

Mucociliary clearance in the airways (State of the Art)

Am J Respir Crit Care Med

Effects of salmeterol on cilia and mucus in COPD and pneumonia patients

Pharm Res

Induced sputum derives from the central airways: confirmation using a radiolabeled aerosol bolus delivery technique

Am J Resp Crit Care Med

Effect of postural drainage, exercise and cough on mucus clearance in chronic bronchitis

Am Rev Respir Dis