The Roles of Bronchodilators, Supplemental Oxygen, and Ventilatory Assistance in the Pulmonary Rehabilitation of Patients with Chronic Obstructive Pulmonary Disease

Home , Minute ventilation, Respiratory rate

The Roles of Bronchodilators, Supplemental Oxygen, and Ventilatory Assistance in the Pulmonary Rehabilitation of Patients With Chronic Obstructive Pulmonary Disease

Richard L ZuWallack MD

Introduction What Pulmonary Rehabilitation Does and How It Works Enhancing the Effectiveness of Pulmonary Rehabilitation Exercise Training Bronchodilators Supplemental Oxygen Noninvasive Ventilation Summary

In patients with chronic obstructive pulmonary disease, pulmonary rehabilitation significantly improves dyspnea, exercise capacity, quality of life, and health-resource utilization. These benefits result from a combination of education (especially in the promotion of collaborative self-management strategies and physical activity), exercise training, and psychosocial support. Exercise training increases exercise capacity and reduces dyspnea. Positive outcomes from exercise training may be enhanced by 3 interventions that permit the patient to exercise train at a higher intensity: bronchodilators, supplemental oxygen (even for the nonhypoxemic patient), and noninvasive ventilatory support. Key words: bronchodilators, oxygen, mechanical ventilation, pulmonary rehabilitation, chronic obstructive pulmonary disease, COPD, dyspnea, exercise capacity, quality of life, exercise training, exercise capacity, noninvasive ventilation. [Respir Care 2008;53(9):1190–1195. © 2008 Daedalus Enterprises]

Introduction bilitation as “an evidence-based, multidisciplinary, and comprehensive intervention for patients with chronic respiratory A recent statement from the American Thoracic Society diseases who are symptomatic and often have decreased daily and European Respiratory Society defines pulmonary reha- life activities. Integrated into the individualized treatment of the patient, pulmonary rehabilitation is designed to reduce symptoms, optimize functional status, increase participation, Richard L ZuWallack MD is affiliated with the Section of Pulmonary and and reduce health-care costs by stabilizing or reversing sys- Critical Care, St Francis Hospital and Medical Center, Hartford, Con- temic manifestations of the disease.”1 Although individual necticut, and with the School of Medicine, University of Connecticut, pulmonary rehabilitation programs differ considerably in set- Farmington, Connecticut. ting, staff, composition, approach, and duration, most have Dr ZuWallack presented a version of this paper at the 23rd Annual New components of patient assessment, exercise training, educa- Horizons Symposium at the 53rd International Respiratory Congress of tion (especially promoting self-management strategies), psy- the American Association for Respiratory Care, held December 1-4, chosocial intervention, and outcome assessment. 2007, in Orlando, Florida.

The author reports no conflicts of interest related to the content of this What Pulmonary Rehabilitation Does paper. and How It Works

Correspondence: Richard L ZuWallack MD, Section of Pulmonary and Critical Care, St Francis Hospital and Medical Center, 114 Woodland It is still surprising to some that pulmonary rehabilita- Street, Hartford CT 06105. E-mail: [email protected]. tion, which has no significant effect on the physiologic and

1190 RESPIRATORY CARE • SEPTEMBER 2008 VOL 53 NO 9 BRONCHODILATORS,OXYGEN, AND VENTILATORY ASSISTANCE IN PULMONARY REHABILITATION functional respiratory impairments of individuals with motivation. In pulmonary rehabilitation, training intensity chronic lung disease, often substantially improves multiple up to or exceeding 60% of maximum symptom-limited outcomes important to patients.2 In fact, for patients with exercise capacity is a reasonable goal.1 Interventions that chronic obstructive pulmonary disease (COPD), pulmo- allow the patient to exercise-train at a higher intensity nary rehabilitation improves dyspnea, exercise capacity, should promote greater post-rehabilitation improvement. and health status more than any other therapy, including The following discussion will focus on 3 available ther- bronchodilators or supplemental oxygen. Newer studies apies that may enhance the benefits from pulmonary re- also suggest that pulmonary rehabilitation also reduces habilitation exercise training: bronchodilators, supplemen- subsequent health-care utilization.3,4 tal oxygen, and noninvasive ventilation (NIV). These Pulmonary rehabilitation works because patients with interventions may enhance the benefits of exercise training chronic respiratory disease usually have associated mor- by allowing the symptom-limited COPD patient to train at bidity and comorbidity that are often very responsive to a higher intensity. therapy. For example, patients with lung disease often un- Pulmonary rehabilitation is often complementary to other consciously adopt a sedentary lifestyle, probably because therapies in this regard: of distressing exertional dyspnea and fatigue. Exertional dyspnea usually develops gradually, and a patient might 1. Pulmonary rehabilitation often adds to the improve- attribute it to the normal aging process. The resultant phys- ments in dyspnea, functional status, and health status ical deconditioning and alterations in structure and func- obtained by therapies such as bronchodilators and sup- tion of the peripheral muscles results in even more exer- plemental oxygen. tional dyspnea and fatigue, which, in turn, leads to even 2. Bronchodilators, oxygen, and (occasionally) NIV can more sedentarism. Pulmonary rehabilitation interrupts this enhance the effectiveness of pulmonary rehabilitation vicious circle, especially by increasing exercise capacity exercise training. and promoting physical activity. Exercise training, especially at a higher intensity, can even cause favorable bio- Bronchodilators chemical alterations in exercising muscles, even in patients with COPD with “pump limitation.”5 There are undoubtedly multiple mechanisms by which It is very important to recognize that, although exercise bronchodilators reduce dyspnea in patients with COPD, training is integral to comprehensive pulmonary rehabili- but bronchodilators’ effects on reducing the resistive work tation, other components of pulmonary rehabilitation are of breathing (by increasing airway caliber) and the elastic also important in enhancing outcomes. In the vicious circle work of breathing (by decreasing hyperinflation) are prob- of sedentarism 3 dyspnea/fatigue 3 more sedentarism, ably most important.14-19 It is important to recognize that pulmonary rehabilitation also increases self-efficacy for bronchodilators decrease breathlessness by decreasing lung exercise,6 promotes increased physical activity at home, volumes.20 Hyperinflation, from decreased elastic recoil, and provides techniques for pacing; these also enhance increases the elastic work of breathing and reduces the benefits. mechanical advantage of the respiratory muscles.21 Addi- tionally, the increased metabolic requirements from exer- Enhancing the Effectiveness of Pulmonary cising muscles demand increased minute ventilation, usu- Rehabilitation Exercise Training ally from an increased tidal volume, then an increased respiratory rate. However, expiratory time in COPD is “If little labor, little are our gains; Man’s fortunes are prolonged, which makes it problematic to exhale com- according to his pains.”7 Exercise intolerance is a major pletely when forced to breathe at a higher frequency. The problem in patients with COPD, and strategies to improve combination of exertional dyspnea, the prolonged expira- the functioning of exercising muscles are needed to im- tory time, and the increased respiratory rate lead to more prove this functional limitation.8 This often involves an hyperinflation (dynamic hyperinflation) that further aggra- appropriate, patient-specific exercise prescription. The vates dyspnea. above quotation from Robert Herrick (1591Ϫ1674) can be Saey and colleagues22 demonstrated an important con- applied to the importance of training intensity (although cept that explains some of the variability in improvement without inflicting pain) in getting the most out of pulmo- in exercise capacity following bronchodilator therapy in nary rehabilitation. Even in patients with COPD, who have COPD. Of the 18 patients they studied, 9 demonstrated ventilatory pump and gas-exchange limitations, higher ex- muscle fatigue following constant-work-rate cycle exer- ercise training intensity provides more physiologic benefit cise after placebo inhalation. Muscle fatigue was defined and greater increase in exercise capacity.9-13 Training in- by a post-exercise reduction in quadriceps twitch tensity in the patient with COPD is affected by respiratory, force Ն 15%. After nebulization with a short-acting anti- cardiovascular, and peripheral-muscle impairments, and cholinergic bronchodilator, exercise endurance increased

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Fig. 1. Effect of bronchodilator on symptom-limitation during high- intensity constant-load exercise testing in 23 patients with chronic obstructive pulmonary disease. Without bronchodilator they were more frequently limited by breathing discomfort than by leg discomfort, whereas the reverse was true when they exercised following bronchodilator. With bronchodilator, 3 patients (not shown) listed “other” as their reasons for exercise termination. (Adapted Fig. 2. Effect of long-acting bronchodilator on treadmill endurance from Reference 14.) in patients with chronic obstructive pulmonary disease, before, during, and after a pulmonary rehabilitation program. The patients were randomized to receive either placebo plus as-needed albu- significantly more in the 9 patients without muscle fatigue. terol or a long-acting bronchodilator plus as-needed albuterol. Both groups had significantly increased treadmill endurance after This underscores the importance of ambulatory muscle the 8-week pulmonary rehabilitation exercise training, but those fatigue in COPD and explains some of the variability in who took the long-acting bronchodilator improved more (P Ͻ 0.05). the exercise response to bronchodilator. The differences in exercise capacity persisted 12 weeks after pul- A study by O’Donnell and colleagues14 illustrates an monary rehabilitation. This study illustrates the additive effect of bronchodilator to pulmonary rehabilitation exercise training. important concept in the effect of bronchodilator and ex- (Adapted from Reference 23.) ercise capacity. They evaluated the effect of a long-acting ␤-agonist bronchodilator on the ventilatory response to exercise in 23 patients with COPD. Of interest to this can enhance gains in exercise capacity from pulmonary discussion is the patients’ “locus of symptom limitation” rehabilitation. This concept is important. (ie, the primary reason for stopping constant-load, high- intensity exercise on a cycle ergometer) (Fig. 1). Exercise Supplemental Oxygen without bronchodilator was more likely to be limited by dyspnea, whereas exercise with bronchodilator was more Patients with COPD are aerobic organisms, and long- likely to be limited by leg fatigue. Thus, bronchodilator term supplemental oxygen for those with severe hypox- shifted the locus of symptom limitation somewhat away emia prolongs survival.24,25 It stands to reason that sup- from “pump-limitation,” so the patients could, presum- plemental oxygen is also clinically indicated for these ably, get more out of lower-extremity exercise training. patients during the exercise training in pulmonary rehabil- With the knowledge that bronchodilators allow some itation, and, in fact, the oxygen flow often has to be in- patients to exercise at a higher intensity and that higher- creased during exercise. From a safety perspective, it is intensity exercise promotes greater physiologic improve- reasonable to also administer supplemental oxygen during ments, the combination of these 2 modalities makes sense. exercise training in patients who are not hypoxemic at rest This additive relationship was demonstrated by Casaburi but have substantial exercise-induced hypoxemia. From a and colleagues in 2005, in an often-cited, double-blind practical viewpoint, patients who have COPD and require placebo-controlled trial.23 Patients with COPD who were oxygen are generally very sedentary and deconditioned, pulmonary rehabilitation candidates were randomized into and ambulatory oxygen may not increase their activity 2 groups: daily administration of a long-acting anticholin- level or health status.26 These patients stand to benefit ergic bronchodilator plus as-needed albuterol (n ϭ 47); from pulmonary rehabilitation as an adjunct to their oxy- and daily administration of an inhaled placebo plus as- gen therapy. needed albuterol (n ϭ 44). Both groups participated in an This discussion will focus on the concept of supplemen- 8-week pulmonary rehabilitation program that included tal oxygen therapy as an adjunct to pulmonary rehabilita- relatively high-intensity treadmill exercise training. Though tion. A distinction should be made between the short-term both groups improved their exercise capacity with pulmo- effect of oxygen on enhancing exercise capacity in the nary rehabilitation, those who took the long-acting bron- laboratory and the long-term effect of oxygen on enhanc- chodilator improved more (Fig. 2). Thus, bronchodilators ing outcomes from exercise training in pulmonary reha-

1192 RESPIRATORY CARE • SEPTEMBER 2008 VOL 53 NO 9 BRONCHODILATORS,OXYGEN, AND VENTILATORY ASSISTANCE IN PULMONARY REHABILITATION bilitation. Supplemental oxygen increases exercise capacity in the laboratory in hypoxemic and nonhypoxemic patients with COPD.27,28 The rationale for using oxygen to increase exercise capacity is that it reduces exertional breathlessness, probably through several mechanisms, including reducing hypoxic ventilatory drive, delaying the metabolic acidemia from exercise, and (indirectly) reducing dynamic hyperinflation28 (presumably by reducing the ventilatory drive and respiratory rate), which permits a longer expiratory time and more complete lung emptying. If oxygen increases exercise capacity in the laboratory, can it enhance exercise training in pulmonary rehabilitation? As stated earlier, the safety requirement usually re- quires supplemental oxygen in patients who have substan- Fig. 3. Work rate during exercise training sessions in a double- tial hypoxemia during exercise training. Can oxygen blinded study. Twenty-nine nonhypoxemic patients with chronic obstructive pulmonary disease were randomized to receive either enhance exercise-training effects in the nonhypoxemic pa- supplemental oxygen (at 3 L/min) or compressed air (at 3 L/min) tient, in whom oxygen is not clinically indicated? A recent during supervised, high-intensity cycle ergometry training. Those systemic review of patients with COPD who did not re- who received oxygen increased their work rate more rapidly than quire long-term oxygen addressed this issue. The analysis those who received compressed air. (Adapted from Reference 30, of the 5 randomized controlled trials that compared sup- with permission.) plemental oxygen to compressed air or room air in the exercise training component of pulmonary rehabilitation cles. Additionally, there is some evidence that short-term had mixed results.29 On pooled analyses, patients who administration of NIV to stable hypercapnic patients with received supplemental oxygen had longer exercise endur- COPD decreases hyperinflation,31 probably by increasing ance but did not have significantly greater improvement in expiratory time, allowing for more complete emptying of maximal exercise capacity, functional exercise capacity slow lung units.32 This might allow for a higher exercise (6-min walk distance), shuttle-walk distance, or health sta- intensity.33 A systematic review found that NIV signifi- tus. The total number of patients in those studies is rela- cantly improves dyspnea and exercise endurance.34 How- tively small and the study designs differed. ever, these benefits in the laboratory should be differenti- A double-blinded study of 29 nonhypoxemic patients ated from the ability to enhance outcomes from exercise with COPD, by Emtner et al,30 illustrates the potential training in pulmonary rehabilitation. The discussion below usefulness of supplemental oxygen in pulmonary rehabil- will focus on the latter. itation. These patients had severe COPD, as evidenced by Three clinical trials have evaluated NIV as an adjunct to a mean forced expiratory volume in the first second of an exercise training program. One trial used NIV at night 36% of predicted, but the study-inclusion criterion required only; the other 2 trials used NIV during the exercise train- arterial oxygen saturation (measured via pulse oximetry) ing program. The rationale for nocturnal NIV is to rest of Ն 88% during a constant-work-rate test. The patients respiratory muscles in patients with severe COPD between exercised at high intensity, under supervision, on cycle pulmonary rehabilitation exercise training sessions. In the ergometers, for 21 sessions over 7 weeks. One group re- study by Garrod et al, 45 patients were randomized to 12 ceived oxygen at 3 L/min. The other group received com- weeks of exercise training either with or without nocturnal pressed air at 3 L/min. Compared to those who breathed NIV via nasal mask.35 The median NIV inspiratory and compressed air, those who received oxygen increased their expiratory pressure settings were 16 cm H2Oand4cmH2O, work rate more rapidly (Fig. 3), trained at higher intensity, respectively. Nighttime NIV was associated with a signif- and by the completion of the program had a greater in- icantly greater increase in shuttle-walk test distance and crease in exercise endurance. The improvement in exercise improved health status following pulmonary rehabilitation. performance was accompanied by an iso-time reduction in Several trials have evaluated the adjunctive effect of respiratory rate hyperinflation at iso-time. A lower respi- NIV during supervised exercise training. Small numbers ratory rate in this setting would probably reduce the amount of subjects were studied, the study designs differed con- of dynamic hyperinflation. siderably, and drop-outs complicated the analyses. Most, but not all, showed some advantage to NIV in some ex- Noninvasive Ventilation ercise outcomes.36-38 A recent evidence-based-guidelines statement on pulmonary rehabilitation concluded that NIV NIV may serve as an adjunct to exercise training in may enhance outcomes in the immediate post-rehabilita- pulmonary rehabilitation by unloading the respiratory mus- tion period in patients with more advanced COPD.39 It

RESPIRATORY CARE • SEPTEMBER 2008 VOL 53 NO 9 1193 BRONCHODILATORS,OXYGEN, AND VENTILATORY ASSISTANCE IN PULMONARY REHABILITATION could be anticipated that NIV in that setting would be Finally, it should be emphasized again that pulmonary limited by several important factors, including problems rehabilitation is more than just exercise training. Though with patient acceptance and tolerance, and an inordinate adjunctive therapies to enhance exercise outcomes make amount of pulmonary-rehabilitation staff time required. sense, they should be viewed as only one aspect of a patient-individualized, multidisciplinary, comprehensive intervention. The complete package works best. Summary

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