Effect of supplemental oxygen on Borg dyspnea scores in 10 patients with COPD performing constant work rate exercise (isotime values). Adapted by permission from Reference 185. 

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... may be sensed directly as a reduced sense of effort. Improvement in the operating characteristics of the inspiratory muscles secondary to lung deflation would be expected to enhance neuromuscular coupling—the muscle spindles, in particular, may have an important role in sensing this. It is clear that there are numerous mechanosensors throughout the lungs, airways, and chest wall whose integrated afferent inputs can potentially convey the awareness of improved thoracic motion or volume displacement (after bronchodilator therapy) ( see neurophysiology section of this roundtable). It is reasonable to speculate that altered peripheral sensory inputs from these sources together with reduced central corollary discharge culmi- nate, in ways that are yet not fully understood, in a decrease in perceived effort and a sense of more satisfied inspiration during physical exertion. Emerging evidence supports the idea that the salutary effects of bronchodilators on respiratory sensation in patients with COPD are ultimately linked to reduced volume restriction, reduced contractile muscle effort, and enhanced neuromechanical coupling of the respiratory system. Patients with moderate-to-severe COPD are usually substantially limited in their exercise tolerance; for most, exercise intol- erance is their chief complaint. Exercise limitation in COPD is usually due to ventilatory limitation (173)—as work rate increases, the ventilatory requirement exceeds the ability of the ventilatory apparatus to ventilate the lungs. This occurs both because altered lung mechanics limits ventilatory capacity and because the ventilatory requirement is high for a given level of exercise. Increased ventilatory requirement is dictated by inefficient pulmonary gas exchange (i.e., high V d /V t ), as well as by abnormally high stimulation of the respiratory chemoreceptors. Carotid body stimulation is increased in COPD both by hypoxemia and, at heavy exercise levels, by early onset of lactic acidosis, resulting from poor muscle oxygen delivery and muscle dysfunction. Two inhaled gases have been found capable of increasing exercise tolerance in patients with COPD, though their mechanisms of action are quite different. The mechanisms by which supplemental oxygen and heliox breathing decrease dyspnea on exertion and increase exercise tolerance are discussed in this section. Roughly one million patients receive long-term oxygen therapy in the United States; most carry the diagnosis of COPD. We prescribe this treatment principally because of studies reported a quarter of a century ago, which demonstrated that hypoxemic patients with COPD live longer when prescribed supplemental oxygen (174, 175). However, the benefits of oxygen go beyond prolongation of life and also accrue to patients whose hypoxemia is less severe than those currently meeting criteria for long-term oxygen therapy. Three physiologic effects of supplemental oxygen have the potential to increase exercise tolerance of the hypoxemic patient with COPD: ( 1 ) hypoxic stimulation of the carotid bodies is reduced, ( 2 ) the pulmonary circulation vasodilates, and ( 3 ) arterial oxygen content increases. The latter two mechanisms have the potential to indirectly reduce carotid body stimulation at heavy levels of exercise by increasing oxygen delivery to the exercising muscles and reducing carotid body stimulation by lactic acidemia. The predominant mechanism for oxygen’s effect on exercise tolerance has recently been clarified ( see below ). Ambulatory oxygen therapy has widely been shown to increase exercise performance and to relieve exertional dyspnea in patients with COPD (176–185). Recent studies indicate that reduction in hyperinflation plays an important role in the oxygen- linked relief of dyspnea (176, 183, 184). Interestingly, supplemental oxygen generally increases exercise tolerance in patients with only mild-to-moderate hypoxemia (i.e., levels of hypoxemia not meeting guidelines for long-term oxygen therapy) (179, 181, 183, 185). We recently demonstrated these principles in a study of 10 patients with severe COPD who did not have clinically significant O 2 desaturation during exercise (185). Each performed five cycle exercise tests at 75% of maximally tolerated work rate. Inspired oxygen fraction (F i O2 ) was varied (0.21, 0.3, 0.5, 0.75, and 1.0) among tests in randomized order. Pulmonary ventilation (V e ) was measured breath-by-breath and subjects performed inspiratory capacity maneuvers every two minutes. Inspiratory reserve volume was assessed as the difference between inspiratory capacity and tidal volume. At isotime, compared with room air, there were significant reductions in dyspnea score, V e , and respiratory rate with F i O2 ϭ 0.3. Figure 18 shows that respiratory rate fall was paralleled by a substantial increase in inspiratory reserve volume, denoting decreased hyperinflation. The isotime dyspnea rating decrease paralleled that of the respiratory rate decrease (Figure 19). Compared with room air breathing, endurance time increased substantially with F i O2 ϭ 0.3 (by 92 Ϯ 20%, mean Ϯ SE) and increased further with F i O2 ϭ 0.5 (by 157 Ϯ 30%). Thus, oxygen supplementation during exercise induced a dose- dependent improvement in endurance and symptom perception in nonhypoxemic patients with COPD, which is apparently related to the decreased hyperinflation and the slower breathing pattern. This effect is maximized at F i of 0.5. These subjects also performed four repetitions of the transi- tion between rest and 10 minutes of moderate-intensity constant work rate exercise while breathing air or 40% oxygen in randomized order (186). V e , gas exchange, and heart rate were recorded breath-by-breath and arterialized venous pH, P co 2 , and lactate were measured serially. During air breathing, the on-transient time constants ( ␶ ) for oxygen uptake, carbon dioxide output, heart rate, and V e kinetic responses were slower in patients with COPD (70 Ϯ 8 s, 98 Ϯ 14 s, 86 Ϯ 8 s, and 81 Ϯ 7 s, respectively) than those seen in healthy subjects. Hyperoxia decreased end- exercise V e . Hyperoxia did not speed V o 2 kinetics, but significantly slowed V co 2 and V e response dynamics. Only small increases in lactate occurred with exercise, and this increase did not correlate with the ␶ for V o 2. These results seem inconsistent with a role for increased oxygen delivery in the reduced ventilatory response associated with oxygen breathing. The mechanisms of hyperoxia-induced decreases in V e are debated. Short-term studies in health generally show either no change (186–189), or a reduction in V e during exercise due to a drop in breathing frequency, especially at higher submaximal exercise levels (190–192). In nonhypoxic patients with COPD, the reported range of reduction in exercise V e varies between 6 and 15% ( ف 2–6 L/min), again due to a decrease in breathing frequency (190–192). Studies on the effect of hyperoxia on oxygen uptake and ventilatory kinetics and blood lactate levels in normoxic COPD show conflicting results, with the majority showing that V e –lactate relationships are maintained during hyperoxia (181, 185, 193). Hogan and coworkers (194) recently showed that an oxygen-rich environment in the exercising muscles of healthy individuals attenuated muscle fatigue. A similar effect was suggested during 30% O 2 in mildly hypoxemic patients with COPD (195). Improved oxygenation may alter sensory afferent inputs from muscle mechanoreceptors and metaboreceptors or enhance neuromuscular coupling. Reduced fatigue would result in reduced central motor command output and, possibly, attendant reductions in ventilation (196). Helium is a low-density gas and will reduce airflow resistance when flow is turbulent (197). Replacing nitrogen with helium in the respired air (i.e., 79% helium, 21% oxygen—heliox) should reduce airflow resistance especially when high ventilatory demand engenders turbulent airflow. Reducing expiratory airflow resistance should, at least in theory, benefit the patient with COPD by allowing expiration to proceed more rapidly and with less effort. Resistive work of breathing will be reduced. Moreover (and perhaps more importantly), dynamic hyperinflation should be reduced by the same mechanism seen when bronchodilators are administered. At a given level of exercise (and ventilatory demand), a fuller exhalation should be possible and end- expiratory lung volume should be lower. During high-intensity exercise, this reduction in operating lung volume should result in less encroachment on lung volumes near the total lung capacity, where flattening of the pressure–volume relationship yields high elastic work of breathing. Surprisingly, convincing demonstration that heliox improves exercise tolerance in patients with COPD has come only recently. Bradley and colleagues (197) studied the responses of seven patients with COPD to incremental exercise and could not detect differences in exercise tolerance between tests in which subjects inhaled heliox and air. In eight patients with severe COPD (average FEV 1 ϭ 0.56 L) performing incremental exercise tests, Oelberg and colleagues (198) demonstrated that heliox (as compared with air) breathing yielded higher peak V e (and lower Pa CO2 ), but that exercise tolerance was not improved. Johnson and colleagues (199) studied the responses of 33 patients with COPD (average FEV 1 ϭ 34% predicted) who performed incremental treadmill exercise breathing air or a helium–oxygen mixture and found no differences in exercise tolerance. This study can be considered flawed, as a heliox mixture was administered at 10 L/min by nonrebreathing mask; at high levels of ventilation this certainly resulted in low effective helium fractions (likely in the 20–30% range rather than the “desired” 79%). Constant work rate testing has been found to be a more sensitive measure of the ability of interventions to improve exercise tolerance than ...