COPD Anno 2011: Emphasis on Bronch(iol)odilation

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of disability and death worldwide. Although COPD is considered to be a preventable and treatable disease, there are concerns that COPD remains substantially underdiagnosed and undertreated. Even in mild disease, patients suffer from significant impairments in health status, which places a considerable burden on patients as well as society. Symptomatic patients are likely to progress to more advanced disease. To avoid breathlessness, they adapt and gradually reduce their activities, which, inevitably, leads to further deconditioning. As a consequence, a progressive deterioration in physical activity with increasing severity of COPD can be observed. Because physical activity is closely related to exacerbation rate, hospitalization, and mortality in patients with COPD, it is important to recognize the role of pharmaceutical interventions in enabling patients to stay physically active. Bronch(iol)odilation not only has important direct effects (symptom relief), but also exerts indirect effects on exercise capacity, exacerbation rate, health status, and mortality. In patients with COPD, the latter effects may be even more important than the direct effects. In this review the current view on causes and consequences of activity limitation in COPD is summarized. From this perspective, the rationale behind bronch(iol)odilator therapy as the cornerstone of treatment for patients with COPD will be discussed.

Introduction

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death worldwide, with population prevalence rates of ∼10%.⁽¹⁾ By 2030, COPD will be the third leading cause of death in middle-income countries.⁽²⁾ In addition, COPD accounts for a significant proportion of healthcare budgets, with the majority of costs being attributed to hospitalizations for exacerbations. COPD is characterized by airflow limitation and inflammation, resulting in progressive decline in respiratory function and quality of life (QoL). Patients with COPD face a significantly increased risk for premature death. Patients may suffer from exacerbations that can be life threatening, and are associated with worsening outcomes, including increased mortality risk. In addition, comorbid conditions such as cardiovascular disease, diabetes mellitus, and depression, as well as associated systemic consequences, including weight loss and muscle dysfunction, add considerably to the overall burden of disease.

COPD is considered to be preventable and treatable. However, despite its high prevalence and significant burden, it remains substantially underdiagnosed and undertreated.⁽³⁾ Most of the patients with COPD have mild or moderate disease.⁽³⁾ Undiagnosed early-stage patients, especially if they are symptomatic,^(4,5) are more likely to progress to a more severe form of COPD that impacts further on QoL and increases healthcare costs. In fact, when offering free community spirometry testing for the early detection of COPD in smokers, about 50% of the patients with newly detected COPD fell in stage II according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) definition versus about 40% in GOLD stage I.⁽⁶⁾ Recent studies increased awareness that even in mild disease patients suffer from significant impairments in health status.⁽⁷⁾ Already in the early stages of COPD, patients not only experience limitations in maximal exercise capacity,⁽⁸⁾ but also become less physically active in daily life.^(9,10) The progressive decrease in physical activity observed in patients with COPD is likely to play a role in the progression of the disease and in the occurrence of systemic effects and comorbidities.

In this review we will summarize the current view on causes and consequences of activity limitation in COPD. From this perspective, we will then elucidate the rationale behind bronch(iol)odilator therapy as the cornerstone of treatment for patients with COPD.

Physical Activity in COPD

Physical activity in patients with COPD is reduced compared to healthy elderly subjects⁽¹¹⁾ and deteriorates already early in the course of the disease.^(9,10) The importance of physical activity is shown by its close relation to exacerbation rate, hospitalization, and mortality in patients with COPD.^(12–15) Also, an association was shown between physical activity and clinical status of patients in terms of exercise capacity, diffusion capacity of the lung for carbon monoxide, maximal expiratory pressure, and level of systemic inflammation.⁽¹⁶⁾ Physical activity even appeared to be a better predictor of (all-cause) mortality in COPD than clinical status.⁽¹⁵⁾ A lack of physical activity and also the presence of metabolic syndrome in patients with COPD have been linked to higher levels of systemic inflammation.^(10,17) Systemic inflammation is associated with higher morbidity⁽¹⁸⁾ and mortality, even in patients with milder COPD.⁽¹⁹⁾ Skeletal muscle wasting, cachexia, osteoporosis, cardiovascular diseases, diabetes, and depression are seen as both systemic manifestations of COPD and as comorbidities.⁽²⁰⁾ The presence of such comorbidities also raises the risk of hospitalization and mortality in patients with COPD.⁽²¹⁾

This suggests that there is a complex interplay between the severity of COPD, level of physical activity, and the presence of systemic inflammation and comorbidities in patients with COPD.⁽²²⁾

Dyspnea

The most prominent symptom of COPD is dyspnea,⁽⁷⁾ a major cause of disability and anxiety associated with the disease. Dyspnea has been defined as “a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses.”⁽²³⁾ It is comprehensible that patients adapt and reduce their activities,⁽²⁴⁾ leading to a vicious circle of deconditioning and further limitation of exercise capacity.⁽²⁵⁾ Indeed, exercise capacity deteriorates over time and is, especially in more advanced disease, predominantly limited by exertional dyspnea.⁽²⁶⁾ Although knowledge about limitations during activities of daily life (ADL) in mild COPD is scarce, it is likely that the onset of dyspnea during ADL plays a role in adapting and reducing such activities to avoid respiratory discomfort. Therefore, reducing dyspnea, at rest and during activity, is of great importance to prevent deterioration in physical activity.

Pathophysiology of Dyspnea in COPD

Changes at rest

Together with the pathological changes in the airway walls and lung parenchyma the physiological consequences of these changes develop slowly over time. Because of this slow progression, patients usually do not seek medical attention until dyspnea starts to have repercussions on their daily functioning. However, breathing discomfort may also exist while patients are at rest. Due to ventilation–perfusion abnormalities,⁽²⁷⁾ physiological dead space is often increased in patients with COPD. As a consequence, elimination of carbon dioxide is less efficient and results in an increased activation of the ventilatory pump. Together with increased airway resistance this adds to afferent sensory information transferred from the respiratory system to the cortex. In addition, hyperinflation of the lung slowly develops as a result of decreased airway patency and increasing lung compliance. This results in shortening of the inspiratory muscles and may reduce their force-generating capacity, thereby contributing to symptoms of dyspnea.⁽²⁸⁾

Changes during exercise

Although dyspnea is multifactorial in origin, dynamic hyperinflation has been shown to be the main determinant of dyspnea complaints during exercise in COPD.⁽²⁹⁾ Dynamic hyperinflation can be defined as the increase in end-expiratory lung volume that occurs when breathing frequency increases. A decrease in elastic recoil of the lung and increased airway resistance, which are a consequence of the structural changes of the lung, increase the time constant for lung emptying.⁽³⁰⁾ Together with a higher breathing rate, and consequent shorter exhalation time during exercise, the lung cannot empty to its relaxation volume. This results in an increase in end-expiratory lung volume. To maintain tidal volume, patients have to recruit their inspiratory reserve volume (IRV). This, however, has adverse mechanical consequences.⁽³¹⁾ On the one hand, the load on the inspiratory muscles increases as a result of airflow obstruction, static, and dynamic hyperinflation (adding elastic load, because the lung is stiffer at higher volumes) and intrinsic positive end-expiratory pressure.⁽³²⁾ As a result, more inspiratory muscle contraction is needed to achieve a negative intrathoracic pressure, thus requiring a higher neural respiratory drive (NRD).⁽³³⁾ On the other hand, the hyperinflation of the lung puts the inspiratory muscles in an unfavorable position, leading to functional respiratory muscle weakness.⁽²⁸⁾ Together, this imbalance between load and capacity of the respiratory muscles leads to what is referred to as neuromechanical uncoupling. The increased NRD no longer matches increased output, which contributes to breathlessness.⁽³³⁾ When the end-inspiratory lung volume approaches total lung capacity (decreasing IRV to 500 mL or less) and neuromechanical uncoupling develops, a sharp increase in dyspnea has been shown together with termination of exercise.⁽³⁴⁾

Changes during ADL

Several studies have shown that dynamic hyperinflation also occurs during ADL in patients with COPD.^(35,36) Compared to healthy controls, patients use a higher proportion of their peak aerobic capacity and have a higher ventilatory demand with similar activities.^(36,37) As a consequence of dynamic hyperinflation, patients have higher operating lung volumes and experience more dyspnea. This results in shorter ADL time.⁽³⁶⁾ In patients with moderate to very severe COPD the amount of dynamic hyperinflation during ADL is not related to their forced-expiratory volume in 1 sec (FEV₁).⁽³⁵⁾ However, because progression of COPD is associated with increasing (static) hyperinflation,⁽³⁸⁾ dynamic hyperinflation results in high end-inspiratory lung volumes in patients with lower FEV₁.⁽³⁵⁾ In very severe patients a critically low IRV (<500 mL), with consequent neuromechanical uncoupling, can already be attained with little dynamic hyperinflation. Others have shown that the amount of dynamic hyperinflation is associated with resting inspiratory capacity (IC),⁽³⁹⁾ also suggesting that “room to hyperinflate” plays a role. Because dynamic hyperinflation has been shown to occur in patients with mild disease^(8,40) during maximal cardiopulmonary exercise testing, one may presume that this also occurs during ADL. Although in mild patients dynamic hyperinflation not necessarily results in neuromechanical uncoupling, it is understandable that any increase in operating lung volumes changes afferent information from the respiratory system to the cortex and may result in dyspnea.

Morphological Basis for Obstruction of Small Airways

Limitation of expiratory airflow in patients with COPD mainly occurs in the small airways as a result of increased resistance. Different phenomena lie on the basis of an increased resistance to airflow. On the one hand, there is small airway remodeling due to inflammatory processes. Accumulating macrophages, neutrophils, and lymphocytes in bronchioles and alveoli induce airway wall thickening (fibrosis), narrowing of the bronchiolar lumen or destruction of terminal bronchioles (obliteration).⁽⁴¹⁾ On the other hand, there is loss of elasticity and destruction of lung parenchyma (emphysema), reducing lung elastic recoil and thereby causing small airway closure. Both phenomena lead to fixed airflow limitation and can occur separately or in combination.^(30,42) In addition, airflow limitation is also caused by edema, mucus overproduction, and/or mucus accumulation and airway smooth muscle (ASM) hyperresponsiveness and/or hypertrophy. Because ASM is present in the bronchiolar compartment, its influence on airway patency is considerable.

Pathological changes in the small airways have been demonstrated in patients with mild or moderate disease⁽⁴³⁾ and might explain the increases in residual volume (RV), functional residual capacity, and specific airways resistance that have been observed in patients with mild disease.⁽⁴⁴⁾ The above-mentioned alterations in lung tissue may have different underlying mechanisms,^(45,46) contributing furthermore to the fact that COPD is a clinically heterogeneous disease.

Pharmacotherapeutical Interventions

According to current guidelines,⁽⁴⁷⁾ all patients who are symptomatic merit a trial of drug treatment. Currently available medications can not only reduce or abolish symptoms, but also may improve exercise capacity, reduce the number and severity of exacerbations, and have a positive effect on health status. The most important consequence of bronchodilator therapy appears to be ASM relaxation and improved lung emptying during tidal breathing.⁽⁴⁷⁾ By relaxing ASM airway radius increases and thus airway resistance decreases. Several classes of bronchodilators are available now, targeting different mechanisms that regulate ASM tone. In the group of anticholinergics (parasympathicolytics), both ipratropium bromide and long-acting tiotropium bromide are nonselective muscarinic antagonists, but act predominantly on M₃ receptors. They block the muscarinic receptors for the neurotransmitter acetylcholine (ACh), which is released from cholinergic nerve endings in the airways. When ACh no longer can act on muscarinic receptors, the main facilitator for contraction of ASM is inhibited, inducing relaxation of ASM and thereby bronchodilation. Anticholinergics have some side effects, including dry mouth, glaucoma, and urinary retention, which are all mediated by M₃ receptors as well.⁽⁴⁸⁾

The other class of bronchodilators are the β₂-agonists (sympathicomimetics). Their action on adrenergic receptors is not completely understood, but they are thought to stabilize receptors in their activated state. The activated β₂ adrenoceptor couples to adenylate cyclase through the α-subunit of a trimeric G_s protein. This catalyses the formation of cyclic adenosine 3′,5′-monophosphate (cAMP) and activates protein kinase A (PKA), which is involved in regulating ASM tone. cAMP also influences the intracellular concentration of Ca²⁺ by inhibiting Ca²⁺ release, decreasing Ca²⁺ entry into cells and inducing sequestration of intracellular Ca²⁺, thereby contributing to relaxation of ASM.⁽⁴⁹⁾ Both short-acting salbutamol and fenoterol and long-acting formoterol, salmeterol and (ultra long-acting) indacaterol are in use. Side effects of sympathicomimetics may be changes in blood pressure, peripheral edema, and arrhythmia, especially in patients who are already at risk. Therefore, the choice and dose of bronchodilator(s) depend on the response as well as (possible) side effects in an individual patient. Also, it is of importance to match the inhaler device to the individual patient. Most drugs are available in dry powder inhalers (DPI), pressurized metered dose inhalers (pMDI), and soft mist inhalers.

In addition to improving expiratory flow, bronchodilators can also positively change lung volumes such as RV, vital capacity, and IC. Although this is most evident in the GOLD III/IV group, a large proportion of patients with mild or moderate COPD also show a positive volume response.⁽⁴⁴⁾ Different bronchodilators have varied effects on IC. Compared to placebo, once-daily indacaterol and twice-daily formoterol both increased FEV₁ and IC. At 8 h and 24 h postdose, indacaterol had a greater effect than formoterol on FEV₁, although peak effects on FEV₁ were similar. On peak IC, however, indacaterol had a greater effect.⁽⁵⁰⁾ Both formoterol and salmeterol increase IC in patients with COPD, with formoterol showing a greater increase in IC over the first hour postdose than salmeterol, consistent with a more rapid onset of action.⁽⁵¹⁾ With tiotropium, peak IC increased by 0.35 L after 4 weeks of use.⁽⁵²⁾ Adding formoterol once or twice daily to tiotropium resulted in additional improvements in terms of airflow obstruction, and resting hyperinflation.⁽⁵³⁾ This implies that for some patients the combined use of anticholinergics and β₂-agonists should be considered to reach an optimal response.

It may be postulated that particle size of a bronchodilator determines its effect on small airways patency and thus IC. However, because the disaggregation of the particles inside an inhaler depends on the interaction between the inhalation flow and the inhaler's resistance,⁽⁵⁴⁾ particle size of a specific bronchodilator may vary between inhaler devices. Formoterol in the budesonide/formoterol DPI has a mass median aerodynamic diameter (MMAD) of 3.3 μm,⁽⁵⁵⁾ but can be 2.1 μm in a single inhaler.⁽⁵⁶⁾ The MMAD values of salmeterol in combination with fluticasone, administered via DPI, can vary between 3.1 μm⁽⁵⁷⁾ and 3.5 μm,⁽⁵⁵⁾ depending also on administered dose. The MMAD of tiotropium, administered via DPI is 4.1 μm,⁽⁵⁸⁾ whereas administration via a soft mist inhaler can result in a MMAD of 2.0 μm. Considering the influence of conspiratory flow rate on particle size, educating and instructing patients how to use their device to optimize efficacy of treatment should be emphasized.⁽⁵⁹⁾

Besides the direct effects on pulmonary function, long-acting bronchodilators may have even more important indirect effects. A recent long-term trial with long-acting bronchodilators, the UPLIFT^® study showed statistical improvements in health-related QoL and possibly survival.⁽⁶⁰⁾ A possible explanation may be that optimal bronch(iol)odilation reduces exacerbation rate and improves exercise capacity and thereby leads to improvements in health-related QoL and survival.

Importance of Bronch(iol)odilation for Exercise Capacity

Exercise capacity in patients with COPD can be limited by several factors. Initially, expiratory flow limitation and increasing hyperinflation will restrict ventilatory capacity. In due course, however, this may also contribute to reduced cardiac output and reduced energy supply to the working muscles.^(26,61,62) Exercise capacity can be improved by increase of ventilatory capacity, reduction of operating lung volumes, and/or reduction of ventilatory demand at a given level of work load.⁽⁶³⁾ Pharmacotherapy can play an important role in achieving these goals. As we discussed before, ASM are the primary target in pharmacotherapy. The reduction in ASM tone leads to bronch(iol)odilation and results in less airflow resistance. This results not only in higher expiratory flow, but also resets the relaxation volume of the lung, thereby improving static and dynamic hyperinflation of the lung. This volume response (decrease in hyperinflation) has direct mechanical advantages (in rest as well as) during exercise. Belman et al.⁽⁶⁴⁾ showed that in patients with moderate to severe COPD, inhalation of salbutamol lowered operating lung volumes during exercise and improved inspiratory pressure reserve and neuromechanical coupling. Operating lung volumes, neuromechanical coupling, and breathlessness were interrelated, with lower end-inspiratory lung volume as the main determinant of reduced breathlessness.

Increases in both predose and postdose IC were shown in patients with COPD after 6 weeks treatment with tiotropium. Together with this, their exercise time improved and IC was higher and dyspnea scores lower at standardized time during exercise.⁽⁶⁵⁾ Also the ultra long-acting indacaterol has been shown to improve exercise capacity together with increases in both resting and end-exercise IC.⁽⁶⁶⁾ In symptomatic patients with mild COPD, lower RV (−19%) was associated with reduced dyspnea at equal minute ventilation during exercise with ipratropium bromide.⁽⁶⁷⁾ This also implies that patients with relatively preserved lung function at rest are likely to benefit from bronchodilation.

Because the mechanical advantage that is gained by decreasing hyperinflation lowers dyspnea intensity, higher training intensities are enabled.⁽⁶⁸⁾ This could increase the effect of a training program. Effects such as improved aerobic capacity and muscle strength lower the ventilatory demand at a given work load. This not only preserves ventilatory capacity, but also reduces the adverse effects of dynamic hyperinflation.⁽⁶⁸⁾

Concluding Remarks

As we discussed, bronch(iol)odilation has important direct (less dyspnea) and indirect effects (better exercise capacity, less exacerbations, better health status, lower mortality) in patients with COPD. Heterogeneity in COPD and presence of comorbidities require individual pharmacotherapeutical therapy. To achieve maximal bronchodilation with minimal adverse effects, extensive patient assessment is necessary to determine which molecule at which dose is optimal for an individual patient. Small-particle drugs that target smaller airways can improve efficacy. With current knowledge about the structural basis for obstruction and pathophysiology of dyspnea in COPD there seems to be a rationale for early interventions, especially in patients where static lung volumes start to increase and/or dyspnea complaints during daily activities are already present. Improving expiratory airflow and reducing hyperinflation of the lung by targeting the bronchioles not only reduces dyspnea complaints, but also improves a patient's ability to exercise. Ultimately, this could prevent or slow down the vicious circle of deconditioning that patients with COPD are known to go through, because patients are enabled to remain physically active. There is a paucity in longitudinal studies investigating the relation between exercise capacity, ADL physiology, physical activity, and the subsequent development of systemic effects and/or comorbidities. Further research and especially early intervention studies are warranted to clarify whether early interventions will have a significant effect on the complex relations between physical activity and the presence of systemic inflammation and comorbidities in patients with COPD and ultimately on outcomes such as hospitalization and mortality.

Footnotes

Acknowledgments

This review was funded by The Netherlands Asthma Foundation and the Radboud University Nijmegen Medical Centre. There are no other funding sources.

Author Disclosure Statement

The authors declare that there are no conflicts of interest.

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