Pathophysiology of exercise dyspnea in healthy subjects and in patients with chronic obstructive pulmonary disease (COPD)

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1 Respiratory Medicine (2005) 99, Pathophysiology of exercise dyspnea in healthy subjects and in patients with chronic obstructive pulmonary disease (COPD) Michela Grazzini, Loredana Stendardi, Francesco Gigliotti, Giorgio Scano Department of Internal Medicine, Respiratory Disease Section, University of Florence, and Fondazione Don C. Gnocchi, IRCCS, Pozzolatico, Florence, Italy Received 28 February 2005 KEYWORDS Dyspnea; Respiratory muscles; Exercise; Hyperinflation; Cardiac function; Arterial blood gases Summary In patients with a number of cardio-respiratory disorders, breathlessness is the most common symptom limiting exercise capacity. Increased respiratory effort is frequently the chosen descriptor cluster both in normal subjects and in patients with chronic obstructive pulmonary disease (COPD) during exercise. The body of evidence indicates that dyspnea may be due to a central perception of an overall increase in central respiratory motor output directed preferentially to the rib cage muscles. On the other hand, the disparity between respiratory motor output and mechanical response of the system is also thought to play an important role in the increased perception of exercise in patients. The expiratory muscles also contribute to exercise dyspnea: a decrease in Borg scores is related to a decrease in end-expiratory lung volume and to a decrease in end-expiratory gastric pressure at isowork after lung volume reduction surgery. Changes in respiratory mechanics and intrathoracic pressure surrounding the heart can reduce cardiac output by affecting the return of blood to the heart from the periphery, or by interfering with the ability of the heart to eject blood into the peripheral circulation. Change in arterial blood gas content may affect breathlessness via direct or indirect effects. Old and more recent data have demonstrated that hypercapnia makes an independent contribution to breathlessness. In hypercapnic COPD patients an increase in PaCO 2 seems to be the most important stimulus overriding all other inputs for dyspnea. Hypoxia may act indirectly by increasing ventilation (VE), and directly, independent of change in VE. Finally, chemical (metabolic) ventilatory stimuli do not have a specific effect on breathlessness other than via their stimulation of VE. We conclude that exercise provides a stimulus contributing to dyspnea, which can be applied to many diseases. & 2005 Elsevier Ltd. All rights reserved. Corresponding author. Department of Internal Medicine, Section of Clinical Immunology, Allergology and Respiratory Disease, University of Florence, Viale Morgagni 87, Firenze, Italy. Tel.: ; fax: address: g.scano@dmi.unifi.it (G. Scano) /$ - see front matter & 2005 Elsevier Ltd. All rights reserved. doi: /j.rmed

2 1404 Introduction Dyspnea is a general term used to characterize a range of different descriptors which varies in intensity, and influenced by a wide variety of factors, such as cultural expectations and the patient s experiences. 1 Many different clinical disorders that affect the heart, lungs and neuromuscular apparatus produce symptoms of dyspnea. In healthy humans, dyspnea can result from many different interventions, including exercise. In patients with chronic obstructive pulmonary disease (COPD) dyspnea is the most common symptom limiting exercise capacity and the major reason for referral to respiratory rehabilitation programs. 1,2 Giving 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. This review represents an attempt to identify the pathophysiological basis of dyspnea during exercise. We shall be considering the contribution of the respiratory muscles (effort, recruitment, weakness and fatigue), operational lung volumes, vascular factors, and arterial blood gases to dyspnea. The inspiratory muscles Respiratory effort Increased respiratory effort is frequently a chosen descriptor of dyspnea both in normal subjects and in patients with COPD during exercise. 3 Studies in healthy humans have shown that the increase in effort represents the increase in motor command. 4,5 The effort required to sustain any given power increases with the duration with which the activity is sustained. It is noteworthy that inspiratory effort is not synonymous with inspiratory pressure. For a given pressure per breath (Pbr), the perception of effort is a function of maximal inspiratory pressure (MIP) such that the greater the Pbr/MIP ratio, the greater the perception of respiratory effort. 4,5 During exercise, respiratory impedance can experimentally be either increased, resulting in greater pressure and lesser velocity of contraction, or decreased, resulting in a greater velocity of shortening and less pressure; both peak of pressure and velocity of inspiratory muscle shortening contribute independently and collectively to dyspnea. 4 With exercise, a greater tidal volume (VT) increases end-inspiratory lung volume forcing the subject to breathe at higher volumes in the flat part of the pressure volume curve, and - MIP B TLC FRC A FRC Pbr V. increasing the inspiratory pressure per breath 3,4 ; moreover, the maximal pressure-generating capacity diminishes at high lung volumes and decreases with the increase in velocity of muscle shortening for any given lung volume (Fig. 1 left panel). 5 Maximal pressure-generating capacity declines linearly by 1.7% for each 1% of total lung capacity increase in volume above the functional residual capacity, and by 5% for each 1 L/s increase in inspiratory flow. 4 In turn, pressure per breath to maximal pressure-generating capacity ratio increases during progressive exercise in proportion to the sense of effort. O Donnell et al. 6 showed that CPAP support increases exercise endurance and reduces the sensations of dyspnea in patients with COPD. 6,7 Leblanc et al. 5 emphasize 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. Thus, the awareness of effort seems to be the dominant descriptor of dyspnea in most circumstances. One must be cautious, however, about equating the grading of effort with dyspnea in all situations. Any hypothesis purporting to explain all respiratory sensation should be viewed with suspicion. Respiratory muscle recruitment M. Grazzini et al. TLC Figure 1 Tidal pleural pressure/volume loops (left) and tidal flow/volume loops (right) before and during exercise in a patient with COPD. Tidal pressure/volume loops are shown in relation to the subject s maximum inspiratory pressure; tidal flow/volume loops are shown in relation to the subject s maximum expiratory flow/ volume curve. During exercise FRC increases and MIP decreases so that Pbr becomes a greater fraction of MIP. Dashed line depicts elastic characteristics of the lung A ¼ control, B ¼ exercise, Pbr ¼ Pressure per breath, V ¼ flow, MIP ¼ maximal inspiratory pressure, TLC ¼ total lung capacity, FRC ¼ functional residual capacity. Dyspnea may be the signal that rib cage inspiratory muscles are being recruited to assist the A B

3 Pathophysiology of exercise dyspnea in healthy subjects and in patients with COPD 1405 diaphragm. 8 Although the diaphragm is recruited progressively, that is, its power progressively increase with exercise or chemical ventilatory stimuli (see below), it is not recruited to the same degree as the inspiratory muscles of the rib cage. 9 An important observation is that the velocity of shortening of rib cage inspiratory muscles also correlated with the perception of effort. 10 In turn, the body of evidence indicates the contribution of the rib cage muscle activation to the sensation of effort in healthy subjects: dyspnea may be due to a central perception of an overall increase in central respiratory motor output directed preferentially to the rib cage muscles In this regard, Maltais et al. demonstrated that 11 cm H 2 O of pressure support unloading the respiratory muscles produce a substantial reduction in inspiratory effort and dyspnea in patients with COPD. 13 However, they found a significant correlation between changes in dyspnea and corresponding changes in the magnitude of the pressure time integral not only of esophageal pressure, i.e., the pressure generated by rib cage muscles, but also of transdiaphragmatic pressure, i.e., the pressure generated by the diaphragm. With increase 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. 14 When exercise involves arm elevation, the participation of the accessory muscles in ventilation (VE) may be decreased and the rapid and shallow pattern of breathing likely contributes to the sensation of dyspnea. 15 Criner and Celli 16 reported that some patients with severe airflow obstruction experience greater dyspnea and demonstrate dyssynchronous thoraco-abdominal breathing during unsupported arm exercise but not during leg cycling. To explain this uncoordinated respiratory movement of the thoraco-abdominal compartments, these authors postulated that during unsupported arm exercise the respiratory muscles of the rib cage actively help to maintain the position of the upper torso and extended arms, and therefore decrease their participation in respiration. Celli et al. 17 also showed that in COPD patients, dyspnea is worse with arm exercise than it is with leg exercise at the same total body oxygen consumption, suggesting that the load borne by the other inspiratory muscles must increase for the same level of VE. In turn, an increased central output to the rib cage muscles contribute importantly to exercise dyspnea. Respiratory muscle weakness The intensity of dyspnea is greater in patients with cardio-respiratory 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, the greater the increase in muscle force, the greater the increase in maximal power output; for a given maximal power output the weaker the inspiratory muscles the greater the dyspnea, with a 2-fold increase in MIP resulting in about 30% decrease in dyspnea. 18 Similar data were found in terms of perceived leg effort when maximal power output was plotted vs. knee extensor force. 18 Therefore, in addition to the contribution of ventilatory gas exchange and circulatory impairments (see below) consideration must be given to the contribution of muscle weakness to the increased dyspnea perception and reduced work capacity. 18 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. 19 During a course of loading the extent to which the diaphragm could be activated decreases progressively providing the evidence of the development of central diaphragmatic fatigue. A fatigue threshold exists for the respiratory muscles, with fatigue occurring only when the level of pressure time generated exceeds this threshold level. Above a critical threshold, task failure occurs for the diaphragm after a time limit which is inversely related to its pressure time index. 19 The role of inspiratory muscle fatigue on dyspnea has long been investigated. Bradley et al. could demonstrate in healthy subjects at rest during inspiratory resistive loading that whether the diaphragmatic patterns of contraction were fatiguing or not, the sensation of inspiratory effort was directly related to negative intrathoracic pressure, i.e., the driving pressure for inspiration. 20 The fatiguing and non-fatiguing patterns were obtained by varying the contribution of esophageal and gastric pressures to transdiaphragmatic pressure. These findings are in line with the belief that the generation of intrathoracic pressure is the most important stimulus for the sensation of inspiratory effort. Fatigue, however, has no major effect on the sensation of dyspnea during exercise in healthy subjects. 12 High intensity exercise causes quadriceps fatigue 21 but not diaphragmatic fatigue 22,23 in most patients with COPD of moderate severity.

4 1406 Central inhibitory fatigue of the diaphragm, i.e., a low level of activation of the muscle, does not take place in COPD while exercising to exhaustion; dynamic hyperinflation during exhaustive exercise reduces diaphragm pressure-generating capacity, while promoting a high level of diaphragm activation. 24 On the other hand, available data in man show the influence of heavy intensity whole body exercise on diaphragm fatigue, likely due to less blood flow availability to the diaphragm in the face of high blood flow demands by locomotor muscles. 8 In turn, while data in COPD argue against inspiratory muscle fatigue contributing to dyspnea, respiratory muscle fatigue could limit exercise performance via an increased sensation of dyspnea in healthy subjects. 8 The expiratory muscles Previous and recent data have reported the progressive recruitment of expiratory muscles during exercise in healthy humans 10,12,25 28 and in patients with COPD Potter et al. 29 suggested that when expiratory flow is limited during exercise, the enforced slowing of expiratory muscle velocity of shortening increases expiratory pressure, according to the muscles force/velocity relationships, and that this could have circulatory effects (see below). Dodd et al. found markedly positive expiratory pressure measurements and suggested that the increased expiratory work makes a useful contribution to inspiration. 31 The relaxation of expiratory muscles provides gravitational assistance to a downward movement of the diaphragm, while the relief of end-expired gas compression expands the lungs. During severe exercise, patients with COPD adjust respiratory muscle activity on expiration to optimise expiratory flow, and thoraco-abdominal configuration to assist the onset of inspiration. 31,32,34 About the role of the expiratory muscles in exercise dyspnea, Martinez et al. showed that lung volume reduction surgery (LVRS) decreases both dyspnea and endexpiratory-lung-volume (EELV). 30 Decrease in change in dyspnea correlates with decreases in EELV and with a decrease in esophageal (Pes) and gastric (Pga) end-expiratory pressures at isowork after surgery. Expiratory muscle recruitment is enhanced by flow limitation both in healthy humans 10,27 and in patients with COPD. 29 Unlike the diaphragm, the expiratory muscles contribute importantly to the perception of dyspnea during incremental exercise with expiratory flow limitation. 10 Accordingly, a decreased central output to expiratory muscles could account for the decrease in dyspnea during reduction in dynamic hyperinflation. Operational lung volumes M. Grazzini et al. 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 exercise dyspnea in patients with COPD In presence of flow limitation the compression of airways downstream from the flow-limiting segment may elicit a reflex mechanism that influences breathing pattern by terminating expiration prematurely, thus increasing EELV. 39 Flow limitation, dynamic hyperinflation, and probably airway narrowing are involved in the perception of dyspnea. 36,38 In patients with COPD, hyperinflation during exercise probably contributes more to the mechanical problems, i.e., elastic and threshold loads, than the increase in airflow resistance or decrease in dynamic pulmonary compliance Change in inspiratory capacity, a measure of increase in dynamic hyperinflation, along with a change in VT, and respiratory frequency account for 61% of the variance in ratings of breathing difficulty in exercising patients with COPD. 36 Even though hyperinflation maximizes tidal expiratory flow rates 29,40 43 breathing at high lung volumes has serious mechanical and sensory consequences (Fig. 1, right panel). VT becomes positioned closer to total lung capacity where there is a significant elastic loading to the inspiratory muscles ,44 Hyperinflation also shortens the operating length of the inspiratory muscles, thereby compromising their ability to generate pressure. Nonetheless, has shown in the left panel of Fig. 1, inspiratory muscles are forced to use a large fraction of their maximal force generating capacity during VT. 36,37,44,45 An important consequence of hyperinflation is the severe mechanical constraint on VT expansion. Effort production without an adequate concurrent volume or flow reflects the neuro-ventilatory dissociation of the respiratory pump 37,46 (Fig. 2). When exercising, healthy subjects with chest strapping, 47 and patients with either COPD 36,37,44 or interstitial lung disease 48 describe dyspnea as inspiratory difficulty, unsatisfied inspiration, shallow breathing, which are all linked to the discrepancy between increased respiratory effort and a smaller VT. 36,37 Reduced elastic recoil and airway tethering effects are responsible for expiratory flow limitation and limited volume expansion. Thus,

5 Pathophysiology of exercise dyspnea in healthy subjects and in patients with COPD 1407 Neuroventilatory Dissociation 10 INSPIRATORY EFFORT (Pes/PImax) ITL CAL Mechanical Load +/- MuscularWeakness NORMAL Severe Breathlessness No Breathlessness Borg (a.u.) emphysematous patients with lower diffusion lung properties (DLco) and greater static hyperinflation, exhibit greater rates of dynamic hyperinflation at a lower exercise level, greater exertional dyspnea, earlier attainment of critical volume constraints, and accelerated breathing frequency, than patients with a better preserved DLco. 44 A decrease in EELV during exercise due to pharmacological treatment, 35 bullectomy, 49 lung volume reduction surgery, 30,50 or pulmonary rehabilitation program, 51 reduces dyspnea (Fig. 3). Laghi et al. found an increased diaphragmatic neuromechanical coupling correlated with a decrease in dyspnea after LVRS. 50 A decrease in EELV during exercise was found in double lung transplantation (DLT) recipients as compared to single lung transplantation (SLT) recipients. 52 Peak dyspnea was lower in DLTwhereas the slope of dyspnea perception score to the inspiratory effort or inspiratory flow was the same in DLT as in SLT. The data suggest that the origin and extent of dyspnea sensation during exercise is similar in DTL and SLT recipients. 52 Therefore, the body of evidence indicates the contribution of mechanical constraint on VT expansion to dyspnea. Vascular factors ISTANTANEOUS FLOW +/- VOLUME Figure 2 For a given breath in normal subjects there is a harmonious relationship between effort (esophageal pressure/maximal inspiratory pressure) (Pes/Pi max ) and instantaneous ventilatory output refereed to as neuroventilatory coupling. In chronic airflow limitation (CAL), because of intrinsic mechanical loading and functional muscle weakness, this relationship is disrupted ( neuroventilatory dissociation ) and greater levels of inspiratory difficulty or breathlessness are experienced. ITL ¼ inspiratory threshold load (from O Donnell, 37 with permission). Unlike studies showing the contribution of muscle effort to dyspnea, some other investigations found VE (L/min) Figure 3 Slopes of exercise dyspnea (Borg ratings) relative to ventilation (VE) significantly fell in response to exercise training (EXT) (Po0:0005). Open symbols indicate before EXT; closed symbols indicate after EXT; circles indicate quiet breathing; triangles indicate standardized work rate (WR) (from Gigliotti et al., 51 with permission). no relationship between mechanical load on the ventilatory muscles and sensation of dyspnea in patients with COPD. 29,53 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. Potter et al. 29 showed that during strenuous exercise expiratory pleural pressures are greater in patients than they had previously described in healthy subjects. They found that transpulmonary pressure is related to various levels of dyspnea: total pressure swings tend to increase from the time dyspnea is first noted until exercise is stopped, but there are several exceptions. In view of the variability among subjects, Potter et al. 29 did not believe that the pressures could be related in any precise manner to the perception of the degree of dyspnea. The consequence of the positive pressure swings 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 manoeuvre. Montes de Oca et al. 33 have recently shown that peak exercise capacity, maximal O 2 pulse (O 2 P max ) and inspiratory intrathoracic pressure are strongly related to each other. This has suggested to the authors that the severe respiratory mechanical changes in patients with severe COPD are responsible for their hemodynamic abnormalities and diminished exercise performance. The implication is a potential link between abnormal mechanics of breathing and impaired exercise performance via

6 1408 the circulation rather than a malfunctioning ventilatory pump per se. 32 In this regard, it is well known that changes in respiratory mechanics and intrathoracic pressure surrounding the heart may influence cardiac function, can reduce cardiac output by affecting the return of blood to the heart from the periphery (systemic venous return), or by interfering with the ability of the heart to eject blood into the peripheral circulation [left ventricular (LV) dysfunction]. LV performance can also be influenced by the effect of an increased negative pressure which acts according to two basic mechanisms: increased right ventricular afterload 57 and increase in left ventricular transmural pressure Aliverti et al. 27 and Iandelli et al. 28 stressed the role of increase in expiratory chest wall pressure which shifts the blood flow from trunk to extremities in man. Iandelli et al. 28 maintain that high expiratory pressures cause severe dyspnea and the possibility of adverse circulatory events, both of which would impair exercise performance. The increase in expiratory time and decrease in inspiratory time combined with pressures mimic a Valsalva manoeuvre. Two recent papers 61,62 have shown that unloading the respiratory muscles with proportional assist VE during strenuous exercise in cyclists reduces oxygen uptake and the perception of both dyspnea and leg discomfort, indicating that the work of breathing significantly influences exercise performance. The effect of the normal respiratory muscle load on exercise performance in trained cyclists may be due to the associated reduction in leg blood flow which increases both leg fatigue and the intensity with which leg effort and respiratory muscle effort are perceived. This also explains the difficulty of discriminating between the two sensations. The link between respiratory work and exercise performance is likely to be due to a vasoconstrictor effect from the diaphragm to the limb muscle vasculature. This occurs during heavy exercise with sustained work of breathing, and cardiac output limited in its ability to distribute flow adequately to both respiratory and locomotor muscles; the same may happen in conditions of moderate exercise when cardiac output is abnormally low, likely to occur in exercising heart failure patients. 61 By applying inspiratory pressure support in patients with congestive heart failure, O Donnell et al. showed that inspiratory pressure support decreases leg effort probably by reducing left ventricular afterload, increasing peripheral blood flow, and improving local acid base equilibrium which reduces muscular afferents associated with the perception of effort. 63 Thus, the available data indicate potential interrelationships among a malfunctioning ventilatory pump, circulation, and dyspnea. Arterial blood gases M. Grazzini et al. Hypercapnia and hypoxia drive breathing and therefore must influence the perception of the motor events. The hypothesis that dyspnea is better described as a sense of respiratory effort does not account for the findings that at a comparable level of VE dyspnea is greater during hypercapnic hyperpnea than during exercise hyperpnea in healthy subjects. 64 Also, dyspnea increases when the difference in carbon dioxide tension between hypercapnia and exercise rises for similar levels of VE. Hypercapnia generates an unpleasant urge to breath which occurs even in the absence of the motor act. Old and more recent data demonstrated indeed that hypercapnia makes an independent contribution to dyspnea In particular, Banzett et al. 65 showed the effect of increasing hypercapnia in mechanically ventilated quadriplegics in whom air hunger as dyspnea descriptor increased when end tidal CO 2 fraction (Pet CO 2 ) was raised by 7 11 mm Hg. Similar results obtained in ventilated healthy subjects 66 indicated that severe dyspnea can occur in circumstances that do not give rise to a strong sense of effort, but do not refute the idea that effort can give rise to respiratory discomfort in other circumstances. Marin and Celli investigated the role of hypercapnic central drive on the perception of dyspnea in exercising COPD patients. 67 As reported by the same group, central chemoresponsiveness explains about 28% of the variance in peak dyspnea whereas no mechanical factor appears to be involved. 33 Cloosterman et al. have recently shown, in patients with a wide range of obstructive pulmonary disease performing an incremental cycle ergometer test, that ventilatory muscle load is one of the important factors that correlates with the sensation of dyspnea in the group without CO 2 retention, whereas in the group with CO 2 retention an increase in PaCO 2 seems to be the most important stimulus, overriding all other inputs for dyspnea. 68 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 the arterial oxygen content declines (i.e., altitude or anemia). Muscles fatigue more readily, and more effort is required as the muscle fatigue.

7 Pathophysiology of exercise dyspnea in healthy subjects and in patients with COPD 1409 Change in O 2 content may affect dyspnea directly or indirectly. Hypoxia may act indirectly, by increasing VE, and directly, independent of change in VE in normal subjects 69 and in patients with COPD as well. 70 Swinburn et al. 71 showed similar relationship of VE with dyspnea whether COPD patients breathed air or 60% oxygen. The authors concluded that hypoxia had no dyspnogenic effect and that it caused dyspnea by stimulating VE. Other studies in healthy subjects showed that when combined with exercise, hypoxic ventilatory stimulus does not have a specific effect on the intensity of the sensation of dyspnea, in addition to its stimulation of VE. 72 Supplemental oxygen during exercise improves exercise tolerance 73 and reduces exertional dyspnea in COPD patients. 70,74,75 Recent evidence in mildly hypoxemic patients 74 shows that the slopes of both dyspnea and leg effort over time fall significantly during exercise on 60% oxygen compared to room air; exercise time also increases significantly. Furthermore, the slope of lactate over time also falls significantly in hyperoxia. Importantly, Borg and VE fall proportionally. The slopes in air and oxygen are superimposed, indicating that the decrease in Borg is associated with reduced ventilatory demand (Fig. 4). The association with reduced blood lactate levels indicates an improved aerobic metabolism. As a consequence, dyspnea decreases at iso-work load, 74 particularly in patients with more severe degrees of obstruction and hypoxemia. 75 Fig. 4 also shows that the effect of supplemental oxygen on dyspnea may be disjointed from ventilatory changes, indicating the role of central mechanism(s) on the perception of dyspnea. 69,70 Oxygen may also modify the strategy of respiratory muscle recruitment in patients with COPD. 76,77 Criner and Celli showed that 30% oxygen increases exercise performance of the diaphragm in mildly hypoxic, severe, obstructed patients. 77 This pattern was thought to prevent overloading other ventilatory muscles (accessory inspiratory and abdominal muscles). In other words, the diaphragm takes over the ventilatory task of unloading accessory and abdominal muscles; this results in less dyspnea. These observations are in line with studies showing that dyspnea correlates with the electromyographic activity of sternomastoid, but not of the diaphragm in man. 11 A recent study has shown in nonhypoxemic COPD patients that providing supplemental oxygen during high-intensity endurance training adds to the benefit of training: endurance capacity and dyspnea improve significantly. 78 Lane and Adams 79 investigated in healthy subjects the significance of another reflex ventilatory stimulus, such as metabolic acidosis, in the genesis of dyspnea. VE increased during progressive exercise test before and after NH 4 CL-induced metabolic acidosis, with no statistically significant differences in increasing dyspnea scores with metabolic acidosis compared to control. The results indicate that with metabolic acidosis there is no change in the relationship between the intensity of dyspnea and VE. Therefore, metabolic acidosis does not have a specific effect on dyspnea other than via its stimulation of VE. All these data indicate the independent contribution of hypercapnia to dyspnea. Hypoxia may also act independent of change in VE. BORG VE control hyperoxia Figure 4 Effect of oxygen on dyspnea: During control condition dyspnea increases with increase in ventilation (VE) (continuous line). During oxygen administration two pattern are likely: (1) dyspnea and ventilation both decrease and the line of the relationship does not differ from control (dashed line), (2) ventilation is unchanged and dyspnea alone decreases (dotted line). In the latter case, at any given VE, there less dyspnea suggesting central mechanism(s). Conclusion Regardless of the relationships between respiratory and cardiovascular factors, a consistent amount of the variability of the dyspnea score 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, behavioural influences, and the patient s ability to describe sensations. In summary: (1) exercise provides a stimulus contributing to dyspnea, which can be applied to all disease states, (2) symptom measurement complements physiologic measurements. Both are essential and fundamental to comprehensive

8 1410 M. Grazzini et al. NVD ventilation vascular factors dynamic hyperinflation understanding of exercise tolerance. (3) the mechanisms contributing to dyspnea must be approached in an integrative manner, (4) 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 a number of respiratory disorders (Fig. 5), and (5) the identification of other factors that contribute to decreased variability in dyspnea during exercise could result in improvement of patients exercise capacity. References Independent contributors to dyspnea dyaphragm Fatigue(?) motor command accessory muscles RC muscles expiratory muscle Figure 5 Schematic representation of the independent contributors to exercise dyspnea. 1. American Thoracic Society Dyspnea. Mechanisms, assessment, and management: A consensus Statement. Am J Respir Crit Care Med 1999;159: ACCP/AACVPR. Pulmonary Rehabilitation, Joint ACCP/ AACVPR. Evidence-Based Guidelines. Chest 1997;112: O Donnell DE, Bertley JC, Chau LK, et al. Qualitative aspects of exertional breathlessness in chronic airflow limitation. Am J Respir Crit Care Med 1997;115: El-Manshawi A, Killian KJ, Summers E, et al. Breathlessness during exercise with and without resistive loading. J Appl Physiol 1986;61: Leblanc P, Summers E, Inman MD, et al. Inspiratory muscles during exercise: a problem of supply and demand. J Appl Physiol 1988;64: O Donnell DE, Sanij R, Giesbrecht G, et al. Effect of continuous positive airway pressure on respiratory sensation in patients with chronic obstructive pulmonary disease during submaximal exercise. Am Rev Respir Dis 1988; 138: O Donnell DE, Sanij R, Younes M. Improvement in exercise endurance in patients with chronic airflow limitation using continuous positive airway pressure. Am Rev Respir Dis 1988;138: Babcock MA, Pegelow DF, McLaran SR, et al. Contribution of diaphragmatic power output to exercise-induced diaphragm fatigue. J Appl Physiol 1995;78: Grimby A, Goldman M, Mead J. Respiratory muscle action inferred from rib cage and abdominal V P partitioning. J Appl Physiol 1976;41: Kayser B, Sliwinski P, Yan S, et al. Respiratory effort Sensation during exercise with induced expiratory flow limitation in healthy humans. J Appl Physiol 1997;83: Ward ME, Eidelman DG, Stubbing DG, et al. Respiratory sensation and pattern of respiratory muscle activation during diaphragm fatigue. J Appl Physiol 1988;65: Sliwinski P, Yan S, Gauthier AP, et al. Influence of global inspiratory muscle fatigue on breathing during exercise. J Appl Physiol 1996;80: Maltais F, Reissman H, Gottfried SB. Pressure support reduces inspiratory effort and dyspnea during exercise in chronic airflow obstruction. Am J Respir Crit Care Med 1995;151: Martinez FJ, Couser JI, Celli BR. Factors influencing ventilatory muscle recruitment in patients with chronic airflow obstruction. Am Rev Respir Dis 1990;142: Dolmage TE, Maestro L, Avendano MA, et al. The ventilatory response to arm elevation of patients with chronic obstructive pulmonary disease. Chest 1993;104: Criner G, Celli BR. Effect of unsupported arm exercise on ventilatory muscle recruitment in patients with severe chronic airflow obstruction. Am Rev Respir Dis 1988;138: Celli B, Rassulo J, Make BJ. Dyssynchronous breathing during arm but not leg exercise in patients with chronic airflow obstruction. N Engl J Med 1986;314: Hamilton AL, Killian KJ, Summers E, et al. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med 1995;152: NHLB Workshop. Respiratory muscle fatigue. Report of the respiratory muscle fatigue workshop group. Am Rev Respir Dis 1990;142: Bradley TD, Chartrand DA, Fitting JW, et al. The relation of inspiratory effort sensation to fatiguing patterns of the diaphragm. Am Rev Respir Dis 1986;134: Mador MJ, Kufel TJ, Pineda L. Quadriceps fatigue after cycle exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: Mador MJ, Kufel TJ, Pineda LA, et al. Diaphragmatic fatigue and high-intensity exercise in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161: Polkey MI, Kyroussis D, Keilty SE, et al. Exhaustive treadmill exercise does not reduce twitch transdiaphragmatic pressure in patients with COPD. Am J Respir Crit Care Med 1995;152(3): Sinderby C, Spahija J, Beck J, et al. Diaphragm activation during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:

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