Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder that leads to a gradual decline in lung function and worsening dyspnea ...
Editorials
825
Heliox in Chronic Obstructive Pulmonary Disease Lightening the Airflow Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disorder that leads to a gradual decline in lung function and worsening dyspnea and health status. Exertional dyspnea in COPD leads to reduction in daily activities and time spent outdoors, resulting in the patient becoming eventually housebound (1). In patients with COPD, end expiratory lung volume increases during exercise, leading to dynamic hyperinflation, which is closely related to the symptom of dyspnea. However, relationships between dynamic hyperinflation and dyspnea are complex and other mechanical factors, such as respiratory muscle activity, also play a part. Reduction of dyspnea has become an important focus for therapeutic interventions in COPD, especially in patients with more severe COPD. Bronchodilators have been shown to reduce dynamic hyperinflation (2, 3) and reduce dyspnea, although exercise capacity does not improve consistently despite an improvement in lung mechanics (4). Physical training as part of a pulmonary rehabilitation program is one of the most effective interventions for reduction of exertional dyspnea and has been shown to improve exercise capacity and health status (5), although patients with very severe dyspnea (MRC [Medical Research Council] grade 5) show less consistent improvement as this degree of impairment may limit the intensity of training that is required (6). Considerable recent effort has been placed into evaluating interventions that can be used as an adjunct to pulmonary rehabilitation, especially in patients with more severe COPD and disabling breathlessness. The combination of a long-acting bronchodilator and pulmonary rehabilitation produced greater improvements in dyspnea and exercise capacity than pulmonary rehabilitation alone (7). Ambulatory oxygen therapy reduces dyspnea and improves exercise tolerance in severe COPD, but this benefit is multifactorial and reflects changes in lung mechanics and dynamic hyperinflation, ventilatory drive, and metabolic load (8). Responses to ambulatory oxygen are heterogeneous and patients with arterial oxygen desaturation on exercise are most likely to benefit. However, the use of ambulatory oxygen has only been studied in relatively short-term studies and the benefit of using supplemental oxygen in combination with exercise training has shown variable results. One study showed that the use of supplemental oxygen during high-intensity training resulted in a greater improvement in exercise tolerance (9), but another study reported that supplemental oxygen did not enhance exercise tolerance, although there was a small benefit related to dyspnea after the combination of physical training and oxygen (10). There have been a number of studies on the combination of positive-pressure ventilation and exercise training, either using ventilatory support during training (11) or at home during the rehabilitation program (12). Generally, improvements are seen in dyspnea and exercise capacity with ventilatory support, probably due to reduction in the high inspiratory muscle load secondary to the effects of hyperinflation. However, the use of ventilatory support with training has not been widely introduced due to practical difficulties of exercising with the equipment. In this issue (pp. 865–870), Laude and colleagues describe a randomized, double-blind, crossover study of the effects of helium and oxygen (Heliox) mixtures on exercise capacity in severe COPD (13). The rationale of using Heliox to reduce breathlessness is based on the principle that nitrogen in inspired air is replaced with helium at a lower density. Introduction of the
lower density helium reduces turbulent flow and resistance in the airway and thus improves ventilation and gas exchange. Heliox reduces inspiratory effort in the postextubation period (14). Short-term use of Heliox in combination with noninvasive ventilation in a small study in patients with exacerbations of COPD showed benefits on work of breathing and gas exchange (15), but larger controlled studies of the use of Heliox at COPD exacerbation are required. There have been a number of studies of Heliox mixtures on exercise capacity in COPD, but with relatively small numbers of patients recruited. These studies have shown varied benefits of Heliox on dyspnea and dynamic hyperinflation (16), although one study comparing the effect of Heliox and ventilatory support in patients with severe COPD undergoing exercise training showed no short- or long-term advantage of using Heliox mixtures (17). The novel aspect of the study by Laude and colleagues is that the effect of reducing gas density with Heliox was studied in patients with COPD with changing inspired oxygen levels with the objective of evaluating the short-term effects of the contribution of each gas to dyspnea and exercise capacity (13). Patients with COPD were tested in a crossover manner with Heliox 28 (72% He/28% O2), Heliox 21 (79% He/21% O2), 28% oxygen, or air. The main results show that endurance walking distance improved by 64% when inspired helium and 28% oxygen were combined as Heliox 28, compared with Heliox 21 or 28% oxygen, and all these three treatments showed improvements in exercise capacity compared with exercising on air alone. Further interaction analysis showed that the beneficial effect of increasing the inspired oxygen concentration was independent of the response when using the Heliox mixtures; this is consistent with different mechanisms and time course of action of inspired helium and oxygen. An interesting finding of this study is that the responses to 28% oxygen and Heliox 21 were normally distributed, but with Heliox 28, the walking distance showed a skewed distribution, indicating that patients with the most severe COPD had the greatest improvements in exercise capacity. Can these findings be applied in clinical practice? The most promising use of Heliox mixtures would be as an adjunct to pulmonary rehabilitation in patients with severe COPD, who are still disabled by dyspnea and are unable to achieve full benefits of training, despite pharmacologic treatment and ambulatory oxygen therapy. Use of Heliox with rehabilitation needs to be tested in large controlled studies with appropriate outcome measures. Heliox is also easier for the patient to tolerate during exercise than noninvasive ventilation, but the two treatments will need formal comparisons. However, before any further development of Heliox therapy for COPD, improved methods for delivery of Heliox to the hospital clinic and community would need to be developed. Recent data show that, despite benefits in patients with COPD, compliance with ambulatory oxygen in the community is relatively poor (18). Thus, we must evaluate carefully any new intervention and target the patients that are most likely to benefit. While studying the effects of Heliox mixtures, I am sure that we have much more to learn about the complex mechanisms of dyspnea in patients with severe COPD. Conflict of Interest Statement : J.A.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
Jadwiga A. Wedzicha, M.D. University College London London, United Kingdom
826
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 173 2006
References 1. Donaldson GC, Wilkinson TMA, Hurst JR. Perera WR, Wedzicha JA. Exacerbations, and time spent outdoors in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;171:446–452. 2. O’Donnell DE, Fluge T, Gerken F, Hamilton A, Webb K, Aguilaniu B, Make B, Magnussen H. Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. Eur Respir J 2004;23:832–840. 3. Aliverti A, Rodger K, Dellaca` RL, Stevenson N, Mauro AL, Pedotti A, Calverley PMA. Effect of salbutamol on lung function and chest wall volumes at rest and during exercise in COPD. Thorax 2005;60:916–924. 4. Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty GF, Donaldson N, Polkey MI, Moxham J. Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD. Thorax 2004;59:471–476. 5. Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, et al. Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial. Lancet 2000;355:362–368. 6. Wedzicha JA, Bestall J, Garnham R, Garrod R, Paul EA, Jones PW. Randomised controlled trial of pulmonary rehabilitation in patients with severe chronic obstructive pulmonary disease stratified for disability. Eur Respir J 1998;12:363–369. 7. Casaburi R, Kukafka D, Cooper CB, Witek TJ Jr, Kesten S. Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest 2005;127:809–817. 8. O’Donnell DE, D’Arsigny C, Webb KA. Effects of hyperoxia on ventilatory limitation during exercise in advanced chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:892–898 9. Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R. Benefits of supplemental oxygen in exercise training in nonhypoxaemic chronic obstructive pulmonary disease patients. Am J Respir Crit Care Med 2003;168:1034–1042.
10. Garrod R, Paul EA, Wedzicha JA. Supplemental oxygen during pulmonary rehabiltation in COPD patients with exercise hypoxaemia. Thorax 2000;55:539–543. 11. Hawkins P, Johnson LC, Nikoletou D, Hamnegard CH, Sherwood R, Polkey MI, Moxham J. Proportional assist ventilation as an aid to exercise training in severe chronic obstructive pulmonary disease. Thorax 2002;57:853–859. 12. Garrod R, Paul EA, Wedzicha JA. Randomised controlled trial of the addition of noninvasive positive pressure ventilation to physical training in patients with severe COPD. Am J Respir Crit Care Med 2000; 162:1335–1341. 13. Laude EA, Duffy NC, Baveystock C, Dougill B, Campbell MJ, Lawson R, Jones PW, Calverley PM. The effect of helium and oxygen on exercise performance in chronic obstructive pulmonary disease: a randomized crossover trial. Am J Respir Crit Care Med 2006;173:865–870. 14. Jaber S, Carlucci A, Boussarsar M, Fodil R, Pigeot J, Maggiore S, Harf A, Isabey D, Brochard L. Helium-oxygen in the postextubation period decreases inspiratory effort. Am J Respir Crit Care Med 2001;164:633– 637. 15. Jaber S, Fodil R, Carlucci A, Boussarsar M, Pigeot J, Lemaire F, Harf A, Lofaso F, Isabey D, Brochard L. Noninvasive ventilation with helium-oxygen in acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000;161:1191–1200. 16. Pecchiari M, Pelucchi A, D’Angelo E, Foresi A, Milic-Emili J, D’Angelo E. Effect of heliox breathing on dynamic hyperinflation in COPD patients. Chest 2004;125:2075–2082. 17. Johnson JE, Gavin DJ, Adams-Dramiga S. Effects of training with heliox and noninvasive positive pressure ventilation on exercise ability in patients with severe COPD. Chest 2002;122:464–472. 18. Lacasse Y, Lecours R, Pelletier C, Begin R, Maltais F. Randomised trial of ambulatory oxygen in oxygen-dependent COPD. Eur Respir J 2005;25:1032–1038. DOI: 10.1164/rccm.2512007
