increased ratio of inspiratory effort to thoracic displacement; the latter ultimately reflects severe neuromechanical uncoupling of the respiratory pump (Fig. 5.6) [6,9,14]. Further indirect evidence of the importance of DH in dyspnoea causation comes from a number of recent studies which have shown that dyspnoea can effectively be ameliorated by interventions that reduce operational lung volumes, either pharmacologically [5-7] or surgically [16,17]. We can conclude therefore, that measurements of resting and dynamic lung volumes in COPD may be more relevant to functional disability than traditional spirometric expiratory measurements. Further studies are required to determine if lung volume (or capacity) estimations such as inspiratory capacity (which reflects EELVdyn), slow or timed vital capacity (which reflects residual volume), or direct plethysmographic measurements of thoracic gas volume, correlate better with disability in COPD than expiratory flow measurements per se, and whether such measurements are more sensitive when assessing responses to combination bronchodilator therapy.
The level of disability can be greatly influenced by the interaction of dynamic mechanics and ventilatory drive. An excessive ventilatory response, regardless of its cause (i.e. exercise, anxiety, infective exacerbations, acute metabolic alterations) will amplify the mechanical derangements outlined above. In other words, DH is increased at high ventilation levels and causes earlier limiting ventilatory constraints of flow and volume generation. Thus, for a given level of expiratory flow limitation, the extent of DH and its negative mechanical and sensory consequences will vary with ventilatory demand. Factors contributing to excessive ventilation in COPD during exercise include: high physiological deadspace, early lactate acidosis, hypoxemia, high O2 cost of breathing, low arterial carbon dioxide (CO2) set points, and other non-metabolic sources of ventilatory stimulation (i.e. anxiety, hyperventilation) [18-21]. Several studies have shown that dyspnoea during exercise in COPD
correlated strongly with the change in ventilation expressed in absolute terms or as a fraction of the estimated maximal breathing capacity [14,22,23]. Studies have shown that for a given FEV1, COPD patients with low diffusion capacity for carbon monoxide and with higher ventilatory demands during exercise (as a result of higher physiological deadspace) experience greater acute and chronic activity-related dyspnoea than those with normal ven-tilatory responses to exercise [15,22]. Indirect evidence of the importance of excessive ventilation in contributing to exertional dyspnoea and exercise limitation in COPD comes from a number of studies which have shown that exercise training, oxygen therapy and opiate medication relieve dyspnoea and improve exercise performance, in part, by reducing submaximal ventilation levels [24-27]. It has become clear that even modest reductions in ventilation (i.e. 3-6L/min) can provide important symptomatic alleviation in severely mechanically compromised patients [24-27].
Does arterial oxygen desaturation cause dyspnoea in COPD?
In some patients, arterial hypoxemia during rest or exercise may contribute to dyspnoea through ventilatory stimulation secondary to an altered metabolic load (i.e. excessive acidosis during exercise secondary to reduced O2 delivery or utilization), or directly via altered peripheral chemoreceptor activation, independent of the level of ventilation [25,26,28]. While large controlled studies have provided convincing evidence of the beneficial effects of continuous oxygen therapy on survival in severely hypoxemic patients with COPD, the effects of such therapy on chronic symptoms and disability is unknown. Case-controlled studies during exercise have shown that symptomatic responses to supplemental oxygen are entirely unpredictable in an individual patient with COPD, regardless of the level of baseline or exertional arterial oxygen desaturation [25,26,28]. Patients who do not improve their dyspnoea or exercise endurance during added oxygen (compared with placebo) likely have other predominant sources of symptom generation such as mechanical abnormalities. It must be remembered that hypoxia, increased ventilatory stimulation and dynamic lung hyperinflation are inextricably linked such that supplemental oxygen, by depressing ventilation, will reduce air trapping for a given level of expiratory flow limitation and improve symptoms and activity levels in those patients who respond (Fig. 5.7) . Since responses to ambulatory oxygen therapy are unpredictable in COPD, a single blind, constant-load exercise study with measurements of symptoms and exercise endurance time is required to identify responders . Even COPD patients, who are normoxic at rest and exercise, have been shown to benefit in a dose-response manner from incremental supplemental oxygen during exercise: Somfrey et al.  have shown progressive
Fig. 5.7 Comparison of maximal and tidal resting and exercise flow-volume loops at a standardized exercise level in a patient with COPD during exercise receiving either room air (a) or supplemental oxygen (b). Added oxygen resulted in reduced ventilation (by 5 L/min) with consequent reductions in dynamic hyperinflation and reduced exertional dyspnoea (Borg scale).
VE = 30 L/min reduction in lung hyperinflation and increase in inspiratory reserve volumes during exercise, with a plateau effect at a fractional oxygen concentration of 0.5.
It is well established that patients with chronic hypoxemia can develop secondary pulmonary hypertension, which may be further aggravated acutely during activity. Such patients often experience severe activity-induced dyspnoea. In these patients, the relative contribution to dyspnoea generation of cardiovascular factors (i.e. activation of pulmonary and right sided cardiac receptors), mechanical factors and excessive ventilation has never been determined with precision. It is possible that direct afferent inputs from the right heart and vasculature may directly give rise to unpleasant respiratory sensations, but this remains speculative .
Patients with COPD are known to have a higher incidence of anxiety-depressive states than a healthy population, and these psychological factors undoubtedly contribute to perceptions of respiratory distress and general disability . Anxiety may of itself, induce dyspnoea in mechanically compromised patients: for example, the accompanying tachypnoea may worsen lung hyperinflation. Alternatively, anxiety may represent the affective response to unpleasant respiratory sensations. There is anecdotal evidence that in some patients with COPD, treatment of morbid anxiety by psychological counselling and sedative medication can reduce dyspnoea and improve activity levels but, in general, responses to these interventions in the published literature are highly variable.
The importance of psychological factors in contributing to disability is borne out by the favourable responses achieved following supervised exercise training in such patients . Many of the benefits of pulmonary rehabilitation programs are attributable to the patient's overcoming their anxiety or fear of breathlessness during activity.
Do exercise tests add anything to the assessment of disability?
Resting physiological measurements are poorly predictive of maximal exercise capacity (i.e. peak symptom-limited oxygen consumption) or exercise endurance in individual patients with COPD; therefore, direct assessment of exercise performance is required to assess functional disability. Exercise tests vary considerably in their level of sophistication. The simple observation of the patient as he/she walks along the corridor, or climbs a flight of stairs, provides useful qualitative information. Supervised timed walking distances, such as the 12-minute walk distance or the more convenient 6-minute walk distance (6MWD) tests have been used extensively as a measure of functional disability . Concurrent measurements of dyspnoea intensity using validated scales enhance the value of this test.
Although the 6MWD is a useful clinical indicator of functional disability, and correlates with both quality of life and mortality, it has limitations. Such tests are highly motivationally dependent. It is impossible to control the pace of walking or power output during the test and this becomes important, particularly when comparisons of two tests are being made in the same individual over time. Because of a definite learning effect, it is recommended that two 'familiarization' tests be conducted and that the third test should be accepted as the baseline test . If tests are to be compared over time, great care must be taken by the supervisor to standardize the instruction and encouragement of the patient . These recommendations collectively increase the complexity of testing. In addition, access to adequate facilities to conduct the test (i.e. long unimpeded corridors) is also a definite practical consideration. Concomitant measurement of dyspnoea (using validated scales [34,35]) and arterial oxygen saturation enhance the value of the test. The inability to carry out pertinent physiological measurements during the 6MWD test is a potential disadvantage. Because of these limitations, modifications in timed walking distance tests have been made. For example, 6-minute testing using a treadmill, where the power output can be controlled and where physiological measurements can be more easily undertaken, may have advantages over the traditional hallway testing .
The incremental shuttle test is designed to overcome some of the limitations of the 6MW test, and there is evidence of its reliability and responsiveness, at least to exercise training . With this test the pace, or work rate, is progressively increased using an auditory cue, which allows observation of the patient over a range of activity levels. The patient walks fixed distances of 10 m between two cones [37,38]. The time available to complete each 10-metre distance is progressively decreased and the distance walked when the patient stops becomes the outcome measure of interest. The test is terminated when patients develop intolerable symptoms and heart rate reaches 85% of maximum. The endurance shuttle test at a fixed fraction of the pre-established peak power output during the incremental shuttle test is likely to be more responsive than the incremental test in evaluating the effects of therapeutic interventions, such as ambulatory O2 [38-40]. However, its sensitivity in the evaluation of bronchodilator efficacy remains unknown. There is anecdotal evidence that, in patients with severe functional disability, the 6MWD is more sensitive in assessing bronchodilator efficacy. However, for less disabled patients, the shuttle test may prove superior.
Increasingly, disability and dyspnoea assessment is conducted in the setting of formal exercise testing in the laboratory (Fig. 5.8). This more rigorous, inte-grative approach to the measurement of the physiological and perceptual responses to exercise has several advantages:
1 It provides an accurate assessment of the patient's exercise capacity;
2 It measures the perceptual responses to a quantifiable dyspneogenic stimulus (i.e. O2 consumption (Vo2), ventilation, power output);
3 It provides insights into pathophysiological mechanisms of dyspnoea in a given patient (e.g. excessive ventilation, dynamic hyperinflation, arterial oxygen desaturation);
4 It can identify other coexisting conditions that contribute to dyspnoea and exercise limitation (i.e. cardiac disorders, intermittent claudication, musculoskeletal problems); and
5 Standardized comparisons of perceptual responses to measurable dyspnoea-provoking stimuli allow an accurate assessment of symptom responses to therapeutic interventions .
There is currently no consensus about which exercise testing protocol
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