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Review

Exercise dyspnea in patients with COPD

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Pages 429-439 | Published online: 20 Oct 2022

Abstract

Dyspnea, a symptom limiting exercise capacity in patients with COPD, is associated with central perception of an overall increase in central respiratory motor output directed preferentially to the rib cage muscles. On the other hand, disparity between respiratory motor output, mechanical and ventilatory response of the system is also thought to play an important role on the increased perception of exercise in these patients. Both inspiratory and expiratory muscles and operational lung volumes are important contributors to exercise dyspnea. However, the potential link between dyspnea, abnormal mechanics of breathing and impaired exercise performance via the circulation rather than a malfunctioning ventilatory pump per se should not be disregarded. Change in arterial blood gas content may affect dyspnea via direct or indirect effects. An increase in carbon dioxide arterial tension seems to be the most important stimulus overriding all other inputs from dyspnea in hypercapnic COPD patients. Hypoxia may act indirectly by increasing ventilation and indirectly independent of changes in ventilation. A greater treatment effect is often achieved after the addition of pulmonary rehabilitation with pharmacological treatment.

No natural phenomenon can be adequately studied in itself alone, but to be understood must be considered as it stands connected with all nature.

(Sir Francis Bacon 1561–1626)

Preface

Contribution to our understanding of the nature and the mechanisms of dyspnea evolved in the last two centuries. Although the relationship was never formally specified discomfort was assumed to accompany respiratory muscle activity. Hypothesis and theories of dyspnea thus becomes synonymous with the factors controlling the extremes of respiratory muscle activity with expiratory muscle activity and discomfort now being controlled by the same factors. In his introduction to the “Breathlessness symposium” held in Manchester (1995), Julius H Comroe predicted that none of the speakers would deal directly with dyspnea: instead they would present only what they understood-the control of breathing, circumstance in which dyspnea may occur. In the event Comroe was largely right. Few contributors dealt with sensory aspects of the subjects, and what sensory physiology there was naïve (J.B. Howell 1992).

In the quarter of the last century since that symposium, things changed greatly as the contributions to the Moran Campbell Symposium held in Hamilton (1991) testified. Both investigators and clinicians have adopted the attitude of sensory physiology and the methods of psychophysics. Also, the main related topic concerned the respiratory muscles rather than the control of breathing. In both of these changes the influence on Moran Campbell was central.

Introduction

Dyspnea is the major reason for referral to pharmacological treatment and respiratory rehabilitation programs in patients with chronic obstructive pulmonary disease (COPD) (CitationATS 1999; CitationTrooster et al 2005). Dyspnea characterizes 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 (CitationATS 1999). This definition underlines the importance of the different qualities covered by the term dyspnea, the involvement of integration of multiple source of neural information about breathing, and the physiological consequences.

In the following paragraphs we will try to answer the following questions: (i) Which is the role of the respiratory muscles, operational lung volumes, vascular factors, arterial blood gases in dyspnea? (ii) Does competition between ventilatory and locomotor muscles for the available energy supplies increase with increasing work of breathing and, if any, does this affect dyspnea on exercise in COPD patients? (iii) What is the link between the language of exercise dyspnea and the underlying neurophysiological mechanisms? (iv) On what basis do bronchodilators reduce dyspnea intensity on exercise? and (v) How can rehabilitation program modulate exercise dyspnea?

Methods

A Medline search of articles published between 1960 and 2006 was undertaken. A large body of scientific information on exercise dyspnea has been published since the last 1960 (CitationHowell and Campbell 1966; CitationJones and Killian 1992). Starting from those miliar stones on origin and pathophysiology of dyspnea we present the accumulate knowledge with particular emphasis on researches published in the last 16 years. We restricted our presentation to COPD a disease state that compromises the energy supply, increases the work of breathing and decreases the respiratory muscle efficiency and increase dyspnea during exercise.

Pathophysiology

Given the complexity of disturbances in respiratory mechanics it is difficult to be sure which alterations contribute most strongly to the sensation of dyspnea. This section is an attempt to identify the pathophysiological basis of dyspnea in patients with COPD. We shall consider the contribution of the respiratory muscles, operational lung volumes, vascular factors, and arterial blood gases to dyspnea.

The respiratory muscles

Respiratory effort

The intensity of the outgoing central motor command activating the muscular receptors and the copy of the increased motor command to the sensory cortex are consciously appreciated as effort (CitationEl-Manshawi et al 1986; CitationLeblanc et al 1988; CitationO’Donnell et al 1997). Emphasis has been put on the importance of the relationships between demands placed on the inspiratory muscles and their capacity to generate pressure in understanding the perception of dyspnea experienced by patients with respiratory disorders (CitationLeblanc et al 1988). The pressure per breath to maximal inspiratory pressure-generating capacity ratio increases during progressive exercise in proportion to the sense of effort in patients with COPD in whom expiratory flow limitation enhances the recruitment of expiratory muscles (CitationPotter et al 1971; CitationGrimby et al 1976; CitationBabcock et al 1995).When expiratory flow is limited, the enforced slowing of expiratory muscle velocity of shortening may increase expiratory pressure which may affect dyspnea (CitationKaiser et al 1997).

Respiratory muscle recruitment

Dyspnea may be the signal that rib cage inspiratory muscles are being recruited to assist the diaphragm (CitationBabcock et al 1995). With increased disease severity patients with COPD exhibit a shift in ventilatory muscle recruitment from the diaphragm to the rib cage, and the experienced degree of dyspnea may relate in part to this shift (CitationWard et al 1988, CitationMartinez et al 1990). During unsupported arm exercise the respiratory muscles of the rib cage actively help maintain the position of the upper torso and extend arms. Hence, by decreasing their participation in respiration (CitationCriner and Celli 1988) contribute to the sensation of dyspnea (CitationCelli et al 1986; CitationGigliotti et al 2005).

Respiratory muscle weakness

The intensity of dyspnea is greater in patients with cardiorespiratory disorders and weak respiratory muscles because it takes more effort to drive a weak muscle than it does to drive a strong muscle. During exercise, for a given work load the weaker the inspiratory muscles the greater the dyspnea; a two-fold increase in their power output results in about 30% decrease in dyspnea (CitationHamilton et al 1995).

Inspiratory muscle fatigue

Fatigue is defined as a loss of the capability to generate skeletal muscle force and/or velocity which is accompanied by recovery during rest (CitationNHLB 1990). High intensity exercise does not cause diaphragmatic fatigue (CitationMador et al 2000) in most patients with COPD of moderate severity. Central inhibitory fatigue of the diaphragm, that is, a low level of activation of the muscle, does not take place in patients while exercising to exhaustion; dynamic hyperinflation during exhaustive exercise reduces diaphragm pressure-generating capacity, while promoting a high level of diaphragm activation (CitationSinderby et al 2001) contributing to dyspnea (CitationEl-Manshawi et al 1986).

Operational lung volumes

The disparity between respiratory motor output and the mechanical response of the system is thought to play a major role in the increased perception of dyspnea in patients with COPD (CitationO’Donnell and Webb 1993). Decrease in inspiratory capacity, a mirror of increase in dynamic hyperinflation, along with a change in tidal volume and respiratory frequency account for 61% of the variance in rating of breathing difficulty in exercising patients with COPD (CitationO’Donnell and Webb 1993). Even though hyperinflation maximizes tidal expiratory flow rates (CitationKoulouris et al 1997) breathing at high lung volumes has serious mechanical and sensory consequences: (i) tidal volume becomes positioned closer to total lung capacity where there is a significant elastic loading to the inspiratory muscles (CitationO’Donnell and Webb 1993; CitationO’Donnell, Revill et al 2001); (ii) shortening of the operating length of the inspiratory muscles, compromises their ability to generate pressure; (iii) inspiratory muscles are forced to use a large fraction of their maximal force generating capacity during tidal volume (CitationLeblanc et al 1988; CitationO’Donnell and Webb 1993; CitationGorini et al 1996; CitationO’Donnell, Revill et al 2001); and (iv) effort production without an adequate concurrent volume or flow reflects the neuro-ventilatory dissociation of the respiratory pump (CitationO’Donnell and Webb 1993; CitationO’Donnell, Revill et al 2001).

Although there is much evidence for an increase in end-expiratory-lung-volume (EELV) during exercise in many patients with COPD several more recent studies also indicate that this is not always the case (CitationCalverley 2006): This is in keeping with earlier data suggesting that patients with COPD could also be limited by fatigue of their leg muscles when they exercised rather than simply by ventilatory factors (CitationHamilton et al 1995). CitationAliverti et al (2004) by measuring the total chest wall volume non-invasively using opto electronic pletismography have shown that exercise limitation and its attendant dyspnea is not necessarily associated with dynamic pulmonary hyperinflation in COPD. Unlike patients who hyperinflate, a significant number of patients (euvolumics) reduces abdominal volume preventing dynamic hyperinflation. The most likely explanation was a difference between groups in their resting tidal expiratory flow limitation associated with hyperinflation. Moreover, despite their better flow reserve, euvolumics reduced end-expiratory-thoracic-volume (EETV) largely by reduction in the volume of their abdominal compartment. To do that they developed high intra-abdominal pressure rather than permitting EETV to rise as in the hyperinflators. Subsequent data during endurance exercise (CitationVogiatzis et al 2005) have shown two significant patterns of change in EETV in patients who hyperinflate during exercise: most patients exhibited a progressive significant increase in EETV (early hyperinflators) while in the remaining patients EETV remained unchanged up to 66% peak of work rate (Wpeak) and increased significantly at Wpeak (late hyperinflators). Note that in the two studies (CitationAliverti et al 2004; CitationVogiatzis et al 2005) the patterns of response – euvolumics vs hyperinflators, and early vs late hyperinflators – were associated with similar intensity of breathlessness. Prof PT CitationMacklem (2005a) has recently focused on physiological differences between euvolumics and hyperinflators:

“expiratory muscle recruitment, work of breathing, and competition between respiratory and locomotor muscles are all considerably less in hyperinflators than in euvolumics: they have learned to bypass the normal control of the respiratory muscles and hence their expiratory pressure remains low. [....] Without respiratory muscle recruitment dynamic hyperinflation is inevitable if patients are sufficient flow limited”

More recently, CitationO’Donnell et al (2006) have demonstrated that dynamic hyperinflation early in exercise allowed expiratory flow limited patients to increase ventilation while minimizing respiratory discomfort; an advantage negated later – with EELV remaining constant – when tidal volume expanded to reach a critical low respiratory reserve volume of approximately 0.5 L below total lung capacity. After reaching this minimal inspiratory reserve volume dyspnea rose to intolerable level and reflected the disparity between inspiratory effort (near maximal central respiratory drive) and the concurrent fixed tidal volume response. CitationProf PT Macklem (2005) has recently focused on physiological differences between euvolumics and hyperinflators.

Although “there can be no doubt that dynamic hyperinflation is a common and potent mechanism limiting exercise in COPD, a greater deal of research has show that patients are crippled as a result: recruit your respiratory muscles or not, patients with COPD are damned if they do and damned if they don’t” (CitationMacklem 2005a).

Vascular factors and ventilatory-locomotor muscle competition

Given the complexity of disturbances in respiratory mechanics during exercise, it is difficult to be sure which alterations contribute most strongly to the sensation of dyspnea. Severe respiratory mechanical changes can be responsible for hemodynamic abnormalities and diminished exercise performance in patients with severe COPD. The implication is a potential link between abnormal mechanics of breathing, impaired exercise performance, and dyspnea via the circulation rather than a malfunctioning ventilatory pump per se (CitationMontes de Oca et al 1996).The consequence of the positive pressure swings during strenuous exercise is that mean intra-thoracic pressure during exercise could impede venous return and could impose a limitation to cardiovascular response to exercise in patients, producing a situation similar to a Valsalva maneuver (CitationAliverti and Macklem 2001; CitationAliverti, Dellaca, et al 2005).

Locomotor and ventilatory muscles compete for available energy supplies with increase work of breathing in healthy subjects (CitationHarms et al 2000). COPD could deprive the locomotor muscles of considerably more energy than in health because of the high cost of breathing at given level of ventilation (CitationLevison and Cherniack 1968; CitationOelberg et al 1998). This can establish ventilatory-locomotor muscle competition for the available oxygen supply even at low exercise work loads (CitationAliverti and Macklem 2001; CitationSimon et al 2001; CitationMacklem 2005b). The conclusion is that the major limitation to exercise performance in patients with COPD who exercise beyond lactate threshold is an inadequate oxygen supply. This suggests that the relative ischemia of the respiratory muscles may contribute to the sensation of dyspnea (CitationAliverti and Macklem 2001).

Effects of interaction between ventilatory and circulatory mechanics on dyspnea during exercise

The mechanisms that couple ventilation to cardiac output during exercise are not well understood. Increased right ventricular after-load led CitationMorrison et al (1987) to speculate that exercise limitation in COPD occurs as a result of the dynamic interaction between disordered right heart function and ventilation. High expiratory pleural pressure in COPD were reported indeed by CitationPotter et al (1971), confirmed by CitationDodd et al (1984), CitationMontes de Oca et al (1996) and more recently by CitationAliverti et al (2004). The high expiratory pleural pressure interferes with venous return to right heart; and a high alveolar pressure increases pulmonary vascular resistance and decreases both left heart filling and cardiac output (CitationAliverti and Macklem 2001). In presence of tidal expiratory flow the expiratory muscles might develop excessive pressure in the vain attempt to increase flow; above the anaerobic threshold the perfusion of locomotor and respiratory muscles provides insufficient oxygen to meet the demands (CitationAliverti and Macklem 2001). It seems that combination of high ventilatory demands and limitation of cardiac output (CitationAliverti, Dellaca et al 2005) – both caused by excessive expiratory pressure – can be potent factor limiting exercise performance in COPD.

Arterial blood gases

Hypercapnia and hypoxia drive breathing and, therefore, must influence the perception of the motor events. Recent evidence indicates that hypercapnia makes an independent contribution to dyspnea. CitationBanzett et al (1989) showed the effect of increasing hypercapnia in mechanically ventilated quadriplegics in whom air hunger, as the dyspnea descriptor, increased when end-tidal CO2 fraction (PetCO2) was surreptitiously raised by 7–11 mmHg. Similar results were obtained in ventilated healthy subjects (CitationBanzett et al 1990). These studies contrast sharply with previous studies of CitationCampbell et al (1967, Citation1969). They showed in two conscious volunteer physicians paralyzed with curare that the distressing sensation normally associated with breath holding was completely absent when ventilation was suspended for over 4 min and PaCO2 was allowed to rise. The observation that the less you breathe at given PCO2 the more breathless you fill argues against the Campbell’s criticism about a subject reporting the extreme air hunger at PacO2 of (only) 45 mmHg (CitationCampbell 1992). Indeed, if arterial PCO2 is increased and breathing is not allowed to increase the subject experiences air hunger; likewise if PCO2 is held constant and tidal volume is decreased the subject experiences air hunger (Banzett 2006).

CitationMarin et al (1999) found that central chemoresponsiveness can explain a part of the variance in peak dyspnea in exercising COPD. As reported later by the same group central chemoresponsiveness explained about 28% of the variance in peak dyspnea, whereas no mechanical factors appeared to be involved (Montes de Oca et al 1998). CitationCloosterman et al (1998) found in patients with a wide range of obstructive pulmonary disease performing an incremental cycle ergometer test that ventilatory muscle could be one of the important factors that correlated with the sensation of dyspnea in the group without CO2 retention; in contrast in the group with CO2 retention an increase in PaCO2 appeared to be the most important stimulus overriding all other inputs for dyspnea.

Dyspnea may be generated by hypoxia but it is a much weaker stimulus of dyspnea. Nonetheless, more effort is required to generate any given muscle power as arterial oxygen content declines (eg, altitude or anemia). Change in oxygen content may affect dyspnea directly or indirectly. Hypoxia may act indirectly by increasing ventilation, and directly independent of change in ventilation in patients with COPD (CitationLane et al 1987). CitationSwimburn et al (1984) showed similar relationship of ventilation with dyspnea whether COPD patients breathed air or 60% oxygen. The data suggested to the authors that hypoxia had no dyspnogenic effect, and that it caused dyspnea by stimulating ventilation.

How can we measure exercise dyspnea?

Quantitative assessment

Multidimensional instruments such as baseline dyspnea index (BDI) and transitional dyspnea index (TDI) and dyspnea components of chronic respiratory questionnaires provide comprehensive measurement of dyspnea as related to activities of daily living (CitationAmbrosino and Scano 2004) .

BDI ad TDI questionnaires and chronic respiratory questionnaire (CRDQ) are valid, reliable and responsive instruments (CitationMahler et al 1991). The BDI exhibits consistently high correlations with Medical Research Council (MRC) questionnaire, 6 min walking distance test (6 mWD), and quality of well being score (CitationMahler and Harver 1992). BDI and TDI adequately reflects the beneficial effects of pulmonary rehabilitation programs (CitationMahler et al 1995).

Category ratio scale (CR-10) developed by CitationBorg (1982) and visual analogue scale (VAS) could reproducibly measure symptoms during incremental and steady state exercise, and could detect the effect of drug intervention. During cycle ergometry, power production or work performed are used as a stimulus (independent variable) for examining the dyspnea response (dependent variable) (CitationMahler et al 1991) assessed as Borg score. Continuous rating of dyspnea on response to a stimulus (ie, B2 agonist, work rate) during both incremental and constant work exercise offers some advantages to discrete rating of the symptom (CitationMahler et al 2005).

Qualitative assessment

In general the language of dyspnea complements physiological measurements, both being essential to a comprehensive understanding of exercise tolerance and dyspnea. When requested to qualitatively assess their dyspnea on the base of the language of dyspnea (CitationSimon et al 1990; CitationMahler et al 1996; CitationScano et al 2005) COPD patients describe the symptom as an increased respiratory work/effort at rest and unrewarded inspiration and/or inspiratory difficulty during exercise (CitationO’Donnell et al 1997). The following, however, requires consideration: (1) cultural, socio-economic, linguistic and educational backgrounds may influence the use of the language of dyspnea; and (2) whether improvement of the physiological derangements modifies the language of dyspnea has yet to be defined.

Clinics

Physical examination

A male with a long history of heavy cigarette smoking, long been complaining of dyspnea during walking on the level. Patient sits forward while bracing their hands or elbows against a table or their knees. He manifests excessive inward motion of intercostal spaces during inspiration (Hoover sign) (CitationHoover 1920) and adopts a pursed lip breathing pattern (CitationCasciari et al 1981; CitationBreslin 1992; CitationBianchi et al 2004). During daily activity requiring the use of arms such as combing, dressing, washing, brushing and so on, he feels arm fatigue and greater dyspnea (CitationCelli et al 1986; CitationCriner and Celli 1988; CitationGigliotti et al 2005). Speaking, limited to a few words, increases dyspnea. On the other hand when requested to qualitatively assess their dyspnea on the basis of its language he describes increases of respiratory effort at rest, and denies chest tightness (CitationMahler et al 1996). If one acknowledges that asthma and COPD involve different pathophysiological derangements, one can also conceivably accept the possibility of different descriptors for the two conditions. Preliminary evidence has been provided that chests tightness characterizes asthma more that COPD. The reported sensitivity of chest tightness was 0.86 for asthma and 0.07 for COPD: the specificity was 0.69 and 0.64, respectively. The data indicate that over 86% of the patients who report chest tightness have asthma not COPD, and about 69% of patients who do not report chest tightness do not have asthma. Another descriptor, I feel I cannot get a deep breath has high specificity for COPD and fairly less for asthma and low sensitivity for both (CitationHarver et al 2000).

Lung function test

The scenario is one of a typical fixed obstructive pattern with severe decrease in FEV1 with hyperinflation (increased functional residual capacity). Flow limitation is evident on the flow volume curve. Muscle weakness is coupled with an increased requirement of inspiratory pressure generation. Diffusion lung properties are remarkably reduced. Mild hypoxia and mild carbon dioxide retention are also found. Measurement of dyspnea complements the clinical evaluation of patients in who administration of standard dose of B2 short acting agonist does not result in any significant change in baseline pulmonary function despite less dyspnea.

Submaximal and maximal exertional testing

Patients walk a less than predicted timed distance and during incremental cycling exercise are less than predicted peak work rate, ventilation, and oxygen uptake; they also exhibit a decreased inspiratory capacity (ie, dynamically hyperinflate), stop cardiopulmonary exercise test complaining either dyspnea or leg effort, or both (CitationHamilton et al 1995, Citation1996). The presence of high heart rate reserve and the absence of ventilatory reserve support the conclusion that they have ventilatory limitation. The clinical findings, abnormal baseline normal function, and chest Xr pattern clearly differentiate these patients from subjects who complain of difficult breathing with activities, but actually report higher rating for leg effort than dyspnea at submaximal and maximal exercise intensity (CitationMahler and Harver 1998). These findings combined with a reduced peak oxygen uptake, and a normal breathing reserve (>30%) strongly single out individuals actually limited by deconditioning or musculoskeletal factors, rather than respiratory disease (CitationMahler and Horowitz 1994).

There is strong evidence that either dyspnea or leg effort, or both limit exercise performance (CitationO’Donnell and Webb 1993; CitationHamilton et al 1996; CitationO’Donnell et al 1997; CitationGigliotti, Coli et al 2003; CitationStendardi et al 2005). Leg fatigue appears to be more important in those with less COPD (CitationHamilton et al 1995).This is consistent with the belief that perception of effort to drive both respiratory and peripheral muscles plays an important role in limiting muscular performance (CitationHamilton et al 1996; Jones and Killian 2000; CitationScano et al 2006). In this connection it has been postulated that in conditions of moderate intensity of submaximal exercise when cardiac output is abnormally low and ventilatory work is high the effect of respiratory muscle load on maximal exercise performance might be due to the associated reduction in leg blood flow which increases both leg effort and intensity with which leg effort and dyspnea are perceived (CitationHarms et al 2000). During prolonged submaximal exercise with a constant load both the perceived effort of breathing and the perceived effort of exercising the skeletal muscles gradually increase with time, eventually reaching the subject’s tolerable limit (CitationKearon et at 1991). During progressively increasing exercise both the perceived effort of exercising and the perceived effort to breathing begin to increase at threshold of about 25% of maximal capacity and most subjects stop when they reach 4–7 on the Borg scale (CitationKillian et al 1992). Patients’ data showing that after exercise rehabilitation programs a similar decrease in exertional dyspnea as in leg effort is associated with unchanged inspiratory effort and maximal oxygen pulse (ie, the ratio of oxygen consumption to maximal heart rate) indicate other reasons for decreased perception being in play. On the other hand, the sedentary lifestyle of the patients with COPD contributes to peripheral muscle deconditioning, and there is evidence that peripheral muscle function is impaired in moderately severe COPD (CitationBernard et al 1998). Specific muscle weakness has been attributed to a possible COPD peripheral myopathy (CitationPalange and Wagner 1999). This has been proposed on the basis of biochemical and istological changes in the quadriceps muscle of the patients. However, there is debate about the adequacy of oxygen delivery during exercise in these circumstance and whether this rather than any intrinsic abnormality explains the poor performance (Cuillard et al 1999; CitationRichardson et al 1999). In this connection, strong evidence has been provided that exercise performance is limited by inadequate energy supply in COPD (CitationRichardson et al 1999). These data suggested to the authors that reduced whole body exercise capacity in patients is the result of central restraints rather than peripheral skeletal muscle dysfunction and that the respiratory system is not the sole constraint to oxygen consumption.

It follows that treatment of airflow resistance alone may not improve the exercise capacity of patients whose muscles are weak or produce excess lactate, unless muscle strength and aerobic capacity are concurrent improved (CitationMaltais et al 1996).

Treating exercising dyspnea

Pharmacological treatment

Optimal bronchodilatation can be seen as a first step in improving exercise endurance and exertional dyspnea intensity in patients with COPD (CitationBelman et al 1996; CitationO’Donnell et al 1999; CitationMahler et al 2002; CitationO’Donnell, Fluge et al 2004; CitationO’Donnell Voduc 2004). Despite apparent non reversibility in spirometric parameter, long term administration of once-daily inhaled anticholinergic demonstrates sustained improvement in inspiratory capacity, reduction in thoracic gas volume, and health outcomes (CitationCelli et al 2003; CitationO’Donnell, Fluge et al 2004; CitationMaltais et al 2005). Although the precise neurophysiopathological mechanisms of dyspnea relief remains speculative the ability of bronchodilators to increase tidal volume represents the basis for reducing dyspnea intensity, or for alteration of its quality (CitationO’Donnell, Voduc et al 2004). A number of bronchodilator studies have shown that the reduced dyspnea score on exercise at isotime correlates well with reduced operational lung volumes (ie, reduced end expiratory lung volume and increased inspiratory reserve volume) and improved breathing pattern (CitationCelli et al 2003; CitationO’Donnell et al 2000). The evidence supports the idea that the beneficial effect of bronchodilators on respiratory sensation of COPD patients potentially relates to increase in neuromechanical coupling of the ventilatory pump as a result of improved dynamic ventilatory mechanics (CitationBelman et al 1996; CitationO’Donnell et al 1999).

On the other hand, CitationAliverti, Rodger et al (2005) have recently shown that patients who increased their end expiratory abdominal compartmental volume during exercise after treatment with short acting B2 agonist were able to exercise for longer. In contrast, less hyperinflated patients after the active drug reduced the abdominal compartmental volume in a fashion analogous to the euvolumic patients with COPD studied during incremental exercise (CitationAliverti et al 2004), and this paradoxically reduced their exercise capacity with higher isotime levels of dyspnea. The kinematic difference between improvers and worseners was the degree of expiratory muscle recruitment. The worseners were using the abdomen to pump the lung much more than the improvers. This requires coordinated activity of the abdominal muscles and the diaphragm. As stated above excessive expiratory pleural pressure during flow-limited exercise acts as a Valsalva maneuver decreasing cardiac output and producing the blood shift from trunk to extremities (CitationAliverti et al 2002, Citation2005; CitationIandelli et al 2002). It seems that a combination of high ventilatory demands and limitation of cardiac output (CitationLevison and Cherniack 1968) both caused by excessive expiratory pressures can be a potent factor limiting exercise performance in COPD (CitationMacklem 2005b).

There is no consensus regarding which exercise test to use to evaluate the functional impact of exercise dyspnea in patients with COPD (CitationPalange et al 2000; Mann et al 2003). In particular, recent data indicate that endurance shuttled walking is a sensitive test to detect changes in exercise tolerance following bronchodilation. Difference in the occurrence of quadriceps muscle fatigue may explain in part the different responsiveness to change between cycling and walking (CitationPepin et al 2005). Nonetheless, greater treatment effects (eg, improvement in exercise performance, symptoms, health-related quality of life) are often achieved only after the addition of pulmonary rehabilitation (CitationTroosters et al 2005).

Pulmonary rehabilitation program

A six week outpatient pulmonary rehabilitation program includes education, breathing retraining and limb exercise training. Let first consider how quantitatively and qualitatively does a patient modulate dyspnea at baseline by breathing retraining (CitationGigliotti, Romagnoli et al 2003). He/she spontaneously adopts a pursed lip breathing pattern (PLB). Despite improvement in gas exchange and efficient ventilation, the efficacy of PLB in relieving dyspnea varies greatly among patients (CitationTroosters et al 2005) and is still a matter of debate (CitationSpahija et al 2005). It has been recently shown that whatever the level of baseline hyperinflation the effect of PLB on dyspnea relies upon its deflationary effect on the chest wall abdominal compartment by an increased expiratory time (CitationBianchi et al 2004). Leaning forward (LF) attenuated patient’s dyspnea sensation. While standing position increases activation of the diaphragm and its force production, LF decreases both (CitationSharp et al 1980). The reason for the association of LF with less dyspnea lies in the common belief that dyspnea is linked to increased central motor command to the respiratory muscles (CitationEl-Manshawi et al 1986; CitationLeblanc et al 1988; CitationO’Donnell et al 1997); hence, a decreased respiratory muscle activation lowers dyspnea in this patient with partial restoration. During daily activities requiring the use of the arms patient exhibits increased sensations of arm effort and dyspnea. Bracing their arms partially restores the increased sensation of arm effort and dyspnea, whereas arm training program increases arm endurance at 7% maximal work rate, modulates dynamic hyperinflation and lowers the Borg score of arm effort and dyspnea (CitationGigliotti et al 2005).

Let now consider how does exercise training modulate exercise dyspnea in patients with COPD. Although the physiologic mechanisms involved in the reduction of dyspnea after training are likely to be complex the following seems to play a major role: (i) cardiovascular factors, (ii) decreased ventilatory demand, (iii) decreased impedance to ventilatory muscle action, and (iv) non physiologic factors.

Cardiovascular factors

Ventricular dysfunction in addition to respiratory impairment may limit exercise performance in some patients with COPD (CitationMahler et al 1984). Inadequate 02 delivery is important in the impairment of exercise performance (CitationMontes de Oca et al 1996). Should these factors play a role in increasing exercise performance with exercise training we would observe an increased ratio of oxygen consumption to maximal heart rate (V02/HR), a non invasive estimate of stroke volume.

Decreased ventilatory demand

The decrease in both ventilation and carbon dioxide production at standardized work rate indicates a decreased ventilatory demand. An increased aerobic capacity with exercise training is in line with a decrease in lactate production reported in older severely obstructed patients (CitationMahler and Horowitz 1994).

Decreasing impedance

Despite an unaltered ventilatory equivalent for carbon dioxide there is less Borg per unit change in ventilation after training. This would suggest an improved mechanical efficiency which is usually accomplished by a decrease in dynamic elastance in association with decrease in dynamic hyperinflation. Change in inspiratory capacity is a mirror of changes in dynamic end-expiratory-lung-volume. The role of dynamic hyperinflation on dyspnea and that of increased respiratory muscle effort on the perception of inspiratory effort have been elucidated in the section of Pathophysiology. According to this scenario, exercise training reduced dyspnea by reducing the inspiratory effort, end-expiratory-lung-volume and respiratory rate. In turn it reduces the neuromuscular discoupling (ie, the ratio of respiratory effort to concurrent volume, or flow).

Non-physiologic factors

An increased tolerance to dyspnea may play an important role in the referred reduction of dyspnea at equivalent ventilation. Moreover, breathing retraining may actually improve the breathing pattern slowing respiratory rate, and indirectly contributing to modifying dyspnea (CitationHamilton et al 1996).

During leg exercise patients may also be given supplemental oxygen to improve exercise tolerance (CitationScano et al 1982) and reduce exertional dyspnea (CitationO’Donnell, D’Arsigny et al 2001). Most importantly, Borg score and ventilation fall proportionally; the slope in air and oxygen are superimposed indicating that the decrease in Borg is associated with reduced ventilatory demand. As a consequence of the improved aerobic metabolism, dyspnea decreases at iso-work load. Oxygen can also modify the strategy of respiratory muscle recruitment in these patients by increasing exercise performance of the diaphragm and unloading the accessory and abdominal muscles, with dyspnea being less (CitationCriner and Celli 1987). This pattern was thought to prevent overloading of other respiratory muscles (accessory inspiratory and abdominal muscles), with this resulting in less dyspnea. The results of a recent study in non hypoxemic COPD patients have shown that supplemental oxygen given during high-intensity endurance training adds to the benefit of training: endurance capacity, and dyspnea improves significantly (CitationEmtner et al 2003).

Finally, based on the findings that unloading the respiratory muscles by pressure support produces a substantial reduction in inspiratory effort and dyspnea (CitationMaltais et al 1995; CitationDolmage et al 1997; CitationPolkey et al 2000), and that a more pronounced improvement is obtained in patients with respiratory muscle weakness the possibility has been considered for the application of inspiratory support to enhance training intensity. Further studies, however, are needed to evaluate the effects of long term non invasive ventilation on change in daily dyspnea in these patients (CitationRossi and Hill 2000).

Lung volume reduction surgery (LVRS)

Surgical intervention for patients with severe bullous emphysema who remain incapacitated by dyspnea despite optimal pharmacological therapy and pulmonary rehabilitation has emerged as a useful therapeutic option. LVRS has shown to improve pulmonary function and elastic recoil (CitationSciurba et al 1996), neuromechanical coupling of the diaphragm (CitationLaghi et al 1998), exercise tolerance and quality of life, with reduction in the degree of airflow obstruction and dynamic hyperinflation (CitationMartinez et al 1997). Much of the success of LVRS depends on patients selection criteria. Preoperative screening assessment and pulmonary rehabilitation should be used to select those patients most likely to benefit from surgery.

In summary

The mechanisms contributing to dyspnea must be approached in an integrative manner. Respiratory muscle function and its relationship to metabolic and cardio–pulmonary variables during exercise identify some of the factors that limit exercise performance in patients with COPD. The identification of other factors that contribute to variability in dyspnea during exercise could result in improvement in patient’s exercise capacity. Regardless of the relationships between respiratory and cardiovascular factors, a consistent amount of the variability of dyspnea remains unexplained. This is probably due to the fact that dyspnea is a subjective sensation which is dependent on the stimulus involved, the central processing, integration of many sensory inputs, the situational context in which it occurs, behavioral influences, and patient’s ability to describe sensations.

References

  • AlivertiADellacaRLottiP2005Influence of expiratory flow-limitation during exercise on systemic oxygen delivery in humansEur J Appl Physiol952294216086145
  • AlivertiAMacklemPT2001How and why exercise is impaired in COPDRespiration6922939
  • AlivertiARodgerKDellacaR2005Effect of salbutamol on lung function and chest wall volumes at rest and during exercise in COPDThorax609162415994253
  • AlivertiAStivensonNDellacaR2004Regional chest wall volumes during exercise in chronic obstructive pulmonary diseaseThorax592101614985554
  • AmbrosinoNScanoG2004Dyspnoea and its measurementBreathe11017
  • [ATS] American Thoracic Society1999Dyspnea: mechanisms, assessment, and management: A consensus statement.Am J Respir Crit Care Med159321409872857
  • BanzettRBLansingRWReidMB1989“Air hunger” arising from increased PC02 in mechanically ventilated quadriplegic patientsRespir Physiol7653672499025
  • BanzettRBLansingRWBrownR1990“Air hunger” from increased PC02 persists after complete neuromuscular block in humansRespir Physiol811172120757
  • BanzettR2005Hunger for air: from afferent input to cerebral cortex. Dyspnea: mechanisms and management329th–30th2005San Diego, CA
  • BabcockMAPegelowDFMcLaranSR1995Contribution of diaphragmatic power output to exercise-induced diaphragm fatigueJ Appl Physiol781710197649904
  • BelmanMJBotnickWCShinJN1996Inhaled bronchodilators reduced dynamic hyperinflation during exercise in patients with COPDAm J Respir Crit Care Med153967758630581
  • BernardSLeBlancPWhittomF1998Peripheral muscle weakness in a patients with COPDAm J Respir Crit Care Med158629349700144
  • BianchiRGigliottiFRomagnoliI2004Chest wall kinematics and breathlessness during pursed-lip breathing in patients with COPDChest1254596514769725
  • BorgGAV1982Psychophysical basis of perceived exertionMed Sci Sport Exerc1437787
  • BreslinHE1992The pattern of respiratory muscle recruitment during pursed lip breathing COPDChest1017581729114
  • CampbellEJM1992Breathlessness: The Campbell SymposiumJonesNLKillianKJHamilton Ontario122
  • CampbellEJMFreedmanSClarkTJH1967The effect of muscular paralysis induced by tubocurarine on the duration and sensation of breathing-holdingCli Sci3242532
  • CampbellEJMGodfrySClarkTJH1969The effect of muscular paralysis on the duration and sensation of breathing-holding during hypercapniaClin Sci3632385772108
  • CalverleyMA2006Dynamic hyperinflation: it is worth measuringProc Am Thorac Soc32394416636092
  • CasciariRJFairshterRDHarrisonA1981Effects of breathing retraining in patients with COPDChest7939387226902
  • CelliBRassuloJMakeBJ1986Dyssynchronous breathing during arm but not leg exercise in patients with chronic airflow obstructionN Engl J Med3141485903702963
  • CelliBZu WallackRWsangS2003Improvement in resting inspiratory capacity and hyperinflation with Tiotropium in COPD patients with increased static lung volumesChest1241743814605043
  • CloostermanSGHoflandIDvan SchayckCP1998Exertional dyspnoea in patients with airway obstruction, with and without CO2 retentionThorax537687410319059
  • ComroeJHJr1966Some theories of the mechanisms of dyspnoeaHowellJBLCampbellEJMBreathlessnessOxfordBlackwell15
  • CouillardAMaltaisFSaeyD2003Exercise-induce quadriceps oxidative stress and peripheral muscle dysfunction in patients with chronic obstructive pulmonary diseaseAm J Respi Crit Care Med16716649
  • CrinerGJCelliBR1988Effect of unsupported arm exercise on ventilatory muscle recruitment in patients with severe chronic airflow obstructionAm Rev Respir Dis3885661
  • CrinerGJCelliBR1987Ventilatory muscle recruitment in exercise with oxygen in obstructed patients with mild hypoxemiaJ Appl Physiol6195200
  • DoddDSBrancatisanoTEngelLA1984Chest wall mechanics during exercise in patients with severe chronic air-flow obstructionAm Rev Respir Dis1293386230971
  • DolmageTEGoldsteinRS1997Proportional assist ventilation and exercise tolerance in subjects with COPDChest1114227
  • El-ManshawiAKillianKJSummersE1986Breathlessness during exercise with and without resistive loadingJ Appl Physiol618969053759774
  • EmtnerMPorszaszJBurnsM2003Benefits of supplemental oxygen in exercise training in nonspecific chronic obstructive pulmonary disease patientsAm J Respir Crit Care Med16810344212869359
  • GigliottiFColiCBianchiR2005Arm exercise and hyper-inflation, in patients with COPD. Effect of arm trainingChest12812253216162710
  • GigliottiFColiCBianchiR2003Exercise training improves exertional dyspnea in patients with COPD: evidence of role of mechanical factorsChest231794802
  • GigliottiFRomagnoliIScanoG2003Breathing retraining and exercise conditioning in patients with chronic obstructive pulmonary disease (COPD): a physiological approachRespir Med9719720412645825
  • GoriniMMisuriGCorradoA1996Breathing pattern and carbon dioxide retention in severe chronic obstructive pulmonary diseaseThorax51677838882072
  • GrimbyAGoldmanMMeadJ1976Respiratory muscle action inferred from rib cage and abdominal V-P partitioningJ Appl Physiol4173951993162
  • HamiltonALKillianKJSummersE1995Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disordersAm J Respir Crit Care Med1522021318520771
  • HamiltonALKillianKJSummersE1996Symptom intensity and subjective limitation to exercise in patients with cardio respiratory disordersChest1101255638915230
  • HarmsCAWetterTJSt CroixCM2000Effects of respiratory muscle work on exercise performanceJ Appl Physiol89131810904044
  • HarverAMahlerDASchwartzsteinRM2000Use of a descriptor model for prospective diagnosis of chronic dyspneaAm J Respir Crit Care Med161A705
  • HooverCF1920The diagnostic significance of inspiratory movements of the costal marginAm J Med Sci15963346
  • HowellJBLCampbellEJM1966BreathlessnessManchester, BlackwellOxford
  • KaiserBSliwinskiPYanS1997Respiratory effort sensation during exercise with induced expiratory flow limitation ion in healthy humansJ Appl Physiol83936479292483
  • IandelliIAlivertiAKaiserB2002Determinants of exercise performance in normal men with externally imposed expiratory flow limitationJ Appl Physiol9219435211960944
  • JonesNKillianK1992Breathlessness: The Campbell SymposiumHamiltonBoehringer Ingelheim
  • KearonMCSummerEJonesNL1991Effort and dyspnea during effort of varying intensity and durationEur Respir J4917251783081
  • KillianKJSummerEJonesNL1992Dyspnea and leg effort during incremental cycle ergometryAm Rev Respir Dis1451339451596000
  • KoulourisNGDimopoulouIValtaP1997Detection of expiratory flow limitation during exercise in COPD patientsJ Appl Physiol82723319074955
  • LaghiFJubranATopeliA1998Effects of lung volume reduction surgery on neuromechanical coupling of the diaphragmAm J Respir Crit Care Med157475839476861
  • LaneRCockcroftAAdamsL1987Arterial oxygen saturation and breathlessness in patients with chronic obstructive airway diseaseClin Sci7269383595075
  • LeblancPSummersEInmanMD1988Inspiratory muscles during exercise: a problem of supply and demandJ Appl Physiol64248293403432
  • LevisonHCherniackRM1968Ventilatory const of exercise in chronic obstructive pulmonary diseaseJ Appl Physiol252175661150
  • MacklemPT2005aExercise in COPD. Damned if you do and if you don’tThorax60887816263942
  • MacklemPT2005bCompetition between respiratory and locomotor muscles for available energy supplies during exercise in COPDProc Am Thorac Soc2A304
  • MadorMJKufelTJPinedaLA2000Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med1611182310619807
  • MahlerDA2002The effects of inhaled B2 agonists on clinical outcomes in chronic obstructive pulmonary diseaseJ All Clin Immunol1106 Suppl298303
  • MahlerDABrentBNLokeJ1984Right ventricular performance and central circulatory hemodynamics during upright exercise in patients with chronic obstructive pulmonary diseaseAm Rev Respir Dis13072296388444
  • MahlerDAFaryniarzKLentineT1991Measurement of breathlessness during exercise in asthmatics: predictor variables, reliability, and responsivenessAm Rev Respir Dis14439442064139
  • MahlerDAFierro-CarrionGMejia-AlfaroR2005Responsiveness of continuous rating of dyspnea during exercise in patients with COPDMed Sci Sports Exerc375293515809548
  • MahlerDAHarverA1992A factor analysis on dyspnea ratios, respiratory muscle strength, and lung function in patients with chronic obstructive pulmonary diseaseAm Rev Respir Dis145467701736759
  • MahlerDAHarverA1998Prediction of peak oxygen consumption in obstructive airway diseaseMed Sci Sports Exerc205748
  • MahlerDAHarverALentineT1996Descriptors of breathlessness in cardiorespiratory diseasesAm J Respir Crit Care Med1541357638912748
  • MahlerDAHorowitzMB1994Clinical evaluation of exercise dyspneaClin Chest Med15259698088092
  • MahlerDATomlinsonDOlmsteadEM1995Changes in dyspnea, health status and lung function in chronic airway diseaseAm J Respir Crit Care Med1516157812573
  • MaltaisFLeBlancPSimardC1996Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med15444278756820
  • MaltaisFHamiltonAMarciniukD2005Improvements in symptom-limited exercise performance over 8 h with once daily tiotropium in patients with COPDChest121104250
  • MaltaisFReissmannHGottfriedSB1995Pressure support reduces inspiratory effort and dyspnea during exercise in chronic airflow obstructionAm J Respir Crit Care Med1511027337697226
  • ManWDCSolimanMGGGearingJ2003Symptoms and quadriceps fatigability after walking and cycling in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med16855762
  • MarinJMMontes de OcaMRassuloJ1999Ventilatory drive at rest and perception of exertional dyspnea in severe COPDChest115129330010334142
  • MartinezFJCouserJICelliBR1990Factors influencing ventilatory muscle recruitment in patients with chronic airflow obstructionAm Rev Respir Dis142276822382890
  • MartinezFJMontes de OcaMWhyteRTI1997Lung-volume reduction surgery improves dyspnea, dynamic hyperinflation, and respiratory muscle functionAm J Respir Crit Care Med1551984909196106
  • Montes de OcaMRassuloJCelliBR1996Respiratory muscle and cardiopulmonary function during exercise in very severe COPDAm J Respir Crit Care Med154128498912737
  • MorrisonDAAdcockKCollinsCM1987Right ventricular dysfunction and exercise limitation in chronic obstructive pulmonary diseaseJ Am Coll Cardiol91219293584714
  • NHLB Workshop1990Respiratory muscle fatigue. Report of the respiratory muscle fatigue workshop groupAm Rev Respir Dis142474802382912
  • O’DonnellDE2000Assessment of bronchodilator efficacy in symptomatic COPD. Is spirometry useful?Chest11742s47s10673474
  • O’DonnellDEBertleyJCChauLK1997Qualitative aspects of exertional breathlessness in chronic airflow limitationAm J Respir Crit Care Med11510915
  • O’DonnellDED’ArsignyCWebbKA2001Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary diseaseAm J Respir Crit Care Med163892811282762
  • O’DonnellDEFlugeTGerkenF2004Effects of tiotropium on lung hyperinflation, dyspnoea, and exercise tolerance in COPDEur Respir J238324015218994
  • O’DonnellDEHamiltonALWebbKA2006Sensory mechanical relationships during high intensity, constant work rate exercise in COPDJ Appl Physiol10110253516675610
  • O’DonnellDELamMWebbKA1999Spirometric correlates of improvement in exercise performance after anticholinergic therapy in COPDAm J Respir Crit Care Med16952449
  • O’DonnellDERevillSMWebbAK2001Dynamic hyperinflation and exercise intolerance in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med164770711549531
  • O’DonnellDEVoducNFitzpatrickM2004Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary diseaseEur Respir J24869415293609
  • O’DonnellDEWebbKA1993Exertional breathlessness in patients with chronic airflow limitation: the role of lung hyperinflationAm Rev Respir Dis148135178239175
  • OelbergDAKacmarekRMPappagianopoulosP1998Ventilatory and cardiovascular response to He-02 during exercise in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med1581876829847281
  • PalangePWagnerPD1999The skeletal muscle in chronic respiratory disease: summary of the ERS research seminar in Rome, Italy February 11–12, 1999Eur Respir Dis1580715
  • PalangePForteSOnoratiP2000Ventilatory and metabolic adaptations to walking and cycling in patients with COPDJ App Physiol88171520
  • PepinVSaeyDWhittonF2005Walking versus cycling: sensitivity to bronchodilation in COPDAm J Respir Crit Care Med17215172216166613
  • PolkeyMIHawkinsPKyroussisD2000Inspiratory pressure support prolongs exercise – induced lactacidemia in severe COPDThorax55547910856312
  • PotterWAOlafssonSHyattRE1971Ventilatory mechanics and expiratory flow limitation during exercise in patients with obstructive lung diseaseJ Clin Invest50910185547281
  • RichardsonRSSheldonJPooleDC1999Evidence of skeletal muscle metabolic reserve during whole body exercise in patients with chronic obstructive pulmonary diseaseAm J Respir Crit Care Med159881510051266
  • RossiAHillNS2000Pro-con debate: non invasive ventilation has been shown to be effective/ineffective in stable COPDAm J Respir Crit Care Med1616889110712304
  • ScanoGGrazziniMStendardiL2006Respiratory muscle energetics during exercise in healthy humans and patients with COPDRespir Med100189690616677807
  • ScanoGStendardiLGrazziniM2005Understanding dyspnoea by its languageEur Respir J25380515684306
  • ScanoGvan MeerhaegheAWilleputR1982Effect of oxygen on breathing during exercise in patients with COPDEur J Respir Dis6323306802664
  • SciurbaFCRogersRMKeenanRJ1996Improvement in pulmonary function and elastic recoil after lung reduction surgery for diffuse emphysemaN Eng J Med3341095659
  • SharpJTDruzWSMoisantT1980Postural relief of dyspnea in severe COPDAm Rev Respir Dis122201117416599
  • SimonMLeBlancPJobinJ2001Limitation of lower limb V02 cycling exercise in COPD patientsJ App Physiol90101319
  • SimonPMSchwartzsteinRMWeissJB1990Distinguishable types of dyspnea in patients with shortness of breathAm Rev Respir Dis1421009142240820
  • SinderbyCSpahijaJBeckJ2001Diaphragm activation during exercise in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med16316374111401887
  • SpahijaJDe MarchieMGrassinoA2005Effects of imposed pursed lips breathing on respiratory mechanics and dyspnea at rest and during exercise in COPDChest1286405016100149
  • StendardiLGrazziniMGigliottiF2005Dyspnea and leg effort during exerciseRespir Med999334215950133
  • SwinburnCRWakefieldIMJonesPW1984Relationship between ventilation and breathlessness during exercise in chronic obstructive airway disease is not altered by prevention of hypoxemiaClin Sci671469
  • TroostersTCasaburiRGosslinkR2005Pulmonary Rehabilitation in chronic obstructive pulmonary diseaseAm J Respir Crit Care Med172193815778487
  • VogiatzisIGeordgiadouOGolematiS2005Patterns of dynamic hyperinflation during exercise and recovery in patients with severe chronic obstructive pulmonary diseaseThorax6073229
  • WardMEEidelmanDGStubbingDG1988Respiratory sensation and pattern of respiratory muscle activation during diaphragm fatigueJ Appl Physiol65218193209561

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