Treatment of the Stable Patient with Chronic Obstructive Pulmonary Disease

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Chapter 42 Treatment of the Stable Patient with Chronic Obstructive Pulmonary Disease

Bartolome R. Celli

The airflow obstruction of chronic obstructive pulmonary disease (COPD), as defined by the forced expiratory volume in 1 second (FEV₁), is thought to be only partially irreversible. This physiologic fact has been perpetuated over the years and has generated an unjustified negativist therapeutic attitude in many health care providers. The evidence suggests that the airflow obstruction of COPD does reverse with therapy, and that therapies aimed at the extrapulmonary manifestations of the disease do improve patient outcomes. An optimistic attitude toward these patients helps relieve fears and misconceptions. In contrast to many other diseases, some forms of intervention in COPD improve survival, such as smoking cessation, long-term oxygen therapy in hypoxemic patients, lung volume reduction surgery in certain patients with inhomogeneous upper lobe emphysema, and even pharmacologic therapy. Other interventions, such as pulmonary rehabilitation, lung transplantation, and bronchodilator therapy, improve symptoms and the quality of a patient’s life once the diagnosis of COPD has been established.

Box 42-1 summarizes the available therapeutic options for patients with COPD. This chapter reviews medical management of COPD that centers on three goals: (1) prevent deterioration in lung function, (2) alleviate symptoms, and (3) treat complications as they arise. Once diagnosed, patients with COPD should be encouraged to participate actively in their management; collaborative management improves their self-reliance and self-esteem. All patients should be encouraged to lead a healthy life and exercise regularly. Preventive care is extremely important, and all patients should receive immunizations, including pneumococcal vaccine every 5 years and yearly influenza vaccine. Figure 42-1 provides an algorithm detailing this comprehensive approach.

Figure 42-1 Algorithm describing the comprehensive management of patients with chronic obstructive pulmonary disease. FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity; BODE, body mass index, degree of airflow obstruction and dyspnea, and exercise capacity; BMI, body mass index; MMRC, Modified Medical Research Council Scale; 6MWD, 6-minute walking distance.

Multicomponent Disease

Increasing evidence shows that independent of the degree of airflow limitation, the lung volumes are important in the development of symptoms in patients with more advanced COPD. Studies have demonstrated that dyspnea perceived during exercise, including walking, more closely relates to development of dynamic hyperinflation than to changes in FEV₁. Further, the improvement in exercise brought about by several therapies, including bronchodilators, oxygen, lung reduction surgery, and even rehabilitation, is more closely related to delaying dynamic hyperinflations than by changing the degree of airflow obstruction. Hyperinflation, expressed as the ratio of inspiratory capacity to total lung capacity, was shown to predict survival better than the FEV₁. This not only provides new insights into pathogenesis, but also opens the door for novel ways to alter lung volumes and perhaps impact COPD progression.

The association between COPD and important systemic manifestations in patients with more advanced disease is now accepted. Because of a persistent systemic inflammatory state or other, yet-unproven mechanisms (e.g., imbalanced oxidative stress, abnormal immunologic or reparative response), many patients with COPD may have decreased fat-free mass (FFM), impaired systemic muscle function, anemia, osteoporosis, depression, pulmonary hypertension, and cor pulmonale, all of which are important determinants of outcome. Indeed, dyspnea measured with a simple tool such as the UK Modified Medical Research Council (MMRC) scale, the body mass index (BMI; kg/m²), and the 6-minute walking distance (6MWD) are all better predictors of mortality than the FEV₁. The incorporation of these variables into the multidimensional BODE index (BMI, airflow obstruction, dyspnea, exercise capacity) predicts survival even better. The BODE index is also responsive to exacerbations and, more importantly, acts as a surrogate marker of future outcome after interventions, thus providing clinicians with a useful tool to help determine the comprehensive severity of the disease. Other multidimensional indices (e.g., age, dyspnea, and obstruction [ADO]; dyspnea, obstruction, smoking, and exacerbation [DOSE]), have also shown important outcome predictive capacity and could be used to test novel forms of therapy.

Based on the multidimensional nature of COPD and the availability of multiple effective therapies, the approach shown in Figure 42-1 may more accurately help clinicians evaluate patients and choose therapies than the current approach, using primarily the FEV₁ percentage from reference values.

Treatable Disease

Current evidence suggests that besides smoking cessation, long-term oxygen therapy in hypoxemic patients, mechanical ventilation in acute respiratory failure, and lung volume reduction surgery for patients with upper lobe emphysema and poor exercise capacity improve survival. The TORCH study (Towards a Revolution in COPD Health) in more than 6000 patients showed not only that the combination of salmeterol and fluticasone improved lung function and health status, but also that the relative mortality risk over the 3 years of the study decreased by 17.5%. This is not exclusive of this drug combination; the Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) study also observed a decrease in mortality risk over 4 years in patients taking tiotropium, a long-acting anticholinergic. Other therapies, such as pulmonary rehabilitation and lung transplantation, improve symptoms and quality of life (QOL) once the diagnosis has been established.

Respiratory Manifestations

Once diagnosed, the patient with COPD should be encouraged to participate in disease management, confident that if not cured, COPD can certainly be treated.

Smoking Cessation and Smoke Pollutants

Smoking is the major cause of COPD, and thus smoking cessation is the most important component of therapy for patients who still smoke. Because secondhand smoke is known to damage lung function, limitation of exposure to involuntary smoke, particularly in children, should be encouraged.

Many factors cause patients to smoke, including the addictive nature of nicotine, conditional responses to stimuli surrounding smoking, psychosocial problems such as depression, poor education and low income, and forceful advertising campaigns. Therefore, smoking cessation programs should also involve multiple interventions. The clinician should always participate in the treatment of smoking addiction, because a physician’s advice and the appropriate medications (nicotine patch, gum, or inhalers; bupropion; varenicline) help obtain successful results.

Decreased Exposure to Biomass Fuel

The significant burden of COPD in patients exposed to biomass fuel in certain areas of the world should improve by changing to more efficient and less polluting sources of energy.

Pharmacologic Therapy of Airflow Obstruction

Most patients with COPD require pharmacologic therapy. This should be organized according to the severity of symptoms, the degree of lung dysfunction, and the tolerance of the patient to specific drugs. A stepwise approach similar to that developed for systemic hypertension may be helpful, because medications alleviate symptoms, improve exercise tolerance and QOL, and may decrease mortality. Tables 42-1 and 42-2 summarize the evidence supporting the effect of individual and combined therapies on outcomes of importance in patients with COPD. Because most patients with COPD are elderly, care must be taken when prescribing drugs for this population. Comorbidities are frequently present in patients with COPD, mandating caution to ensure that therapy takes these into account.

Table 42-1 Effect of Single Pharmacologic Agents on Important Outcomes in Chronic Obstructive Pulmonary Disease Patients

Table 42-2 Effect of Combined Pharmacologic Agents on Important Outcomes in Chronic Obstructive Pulmonary Disease Patients

Bronchodilators

Several important concepts guide the use of bronchodilators. In some patients, changes in FEV₁ may be small, and the symptomatic benefit may result from other mechanisms, such as a decrease in hyperinflation of the lung. Some older COPD patients cannot effectively activate metered dose inhalers (MDIs), and clinicians should work with the patient to achieve mastery of the MDI. If this is not possible, use of a spacer or nebulizer to facilitate inhalation of the medication will help achieve the desired results. Mucosal deposition in the mouth will result in local side effects (e.g., thrush with inhaled steroids) or general absorption and its consequences (e.g., tremor after β₂-agonists). The inhaled route is preferred over oral administration, and long-acting bronchodilators are more effective than short-acting agents. The currently available bronchodilators are described next.

Beta₂-Agonists

The β₂-adrenoceptor agonists increase cyclic adenosine monophosphate (cAMP) within many cells and promote airway smooth muscle relaxation. Other nonbronchodilator effects have been observed, but their significance is uncertain. In the minority of COPD patients with mild intermittent symptoms, it is reasonable to initiate drug therapy with an MDI of a short-acting β₂-agonist as needed for relief of symptoms. Patients with persistent symptoms should receive long-acting β₂-agonists twice daily or once daily if the new ultra-long-acting agents are available. These prevent nocturnal bronchospasm, increase exercise endurance, and improve QOL. The safety profile of salmeterol in the TORCH trial and formoterol fumarate in the SUN and SHINE studies, as well as that of the longer-acting indacaterol, is reassuring to clinicians, who frequently prescribe selective long-acting β₂-agonists for their patients with COPD.

Anticholinergics

Anticholinergic drugs act by blocking muscarinic receptors known to be functional in COPD. The appropriate dosage of the short-acting ipratropium bromide is 2 to 4 puffs three or four times daily, but some patients require and tolerate larger doses. The therapeutic effect is a decrease in exercise-induced increased lung inflation or dynamic hyperinflation. The long-acting tiotropium (Spiriva) is effective in inducing prolonged bronchodilation and decreasing lung volume in patients with COPD. In addition, tiotropium improves dyspnea, decreases exacerbations, and improves health-related QOL compared with placebo and even ipratroprium. The results of the large UPLIFT trial confirmed the effectiveness of tiotropium as a disease-modifying agent in that it improved QOL, decreased exacerbation rate, and provided more bronchial dilation when used with regular treatment. These results place tiotropium as a good first-line agent for COPD patients with persistent symptoms. Other new long-acting anticholinergic agents, such as aclidinium bromide and glycopyrrolate, are being developed and will become available to clinicians worldwide.

Phosphodiesterase Inhibitors

Theophylline is a nonspecific phosphodiesterase inhibitor that increases intracellular cAMP within airway smooth muscle. The bronchodilator effects of these drugs are best seen at high doses, which also carry a higher risk of toxicity. Theophylline’s potential for toxicity has led to a decline in its popularity. Theophylline is of particular value for less compliant or less capable patients who cannot use aerosol therapy optimally. The previously recommended therapeutic serum levels of 15 to 20 mg/dL are too close to the toxic range and are frequently associated with side effects. Therefore, a lower target range of 8 to 13 mg/dL is safer and still therapeutic in nature. Some research suggests that theophylline could help reestablish the corticosteroid sensitivity that appears to be absent in patients with COPD.

The specific phosphodiesterase E4 (PDE4) inhibitor roflumilast has antiinflammatory and bronchodilator effects, with minimal gastrointestinal irritation. Roflumilast has proved useful in decreasing exacerbations in COPD patients with cough and sputum production.

Other Antiinflammatory Therapy

In contrast to their value in asthma management, antiinflammatory drugs have not been documented to have a significant role in the routine treatment of patients with stable COPD. Cromolyn and nedocromil have not been established as useful agents, although they could possibly be helpful if the patient has associated respiratory tract allergy. One study using monoclonal antibodies against interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-α) failed to detect a response. However, patients were selected according to the degree of airflow obstruction, not the presence or level of the specific targeted molecule. The groups of leukotriene inhibitors useful in asthma have not been adequately tested in COPD, so a conclusion about their potential use cannot be drawn.

Corticosteroids

Glucocorticoids act at multiple points within the inflammatory cascade, although their effects in COPD appear to be more modest compared with bronchial asthma. In outpatients, COPD exacerbations necessitate a course of oral steroids, as discussed later, but it is important to wean patients quickly; older COPD patients are susceptible to complications such as skin damage, cataracts, diabetes, osteoporosis, and secondary infections. These risks do not accompany standard doses of inhaled corticosteroid aerosols, which may cause thrush but pose a negligible risk for other outcomes, such as cataract and osteoporosis.

Several large multicenter trials evaluated the role of inhaled corticosteroids (ICS) in preventing or slowing the progressive course of symptomatic COPD. The results of these earlier studies showed minimal, if any, benefits in the rate of decline of lung function. On the other hand, in the one study that evaluated it, inhaled fluticasone decreased exacerbations and the rate of loss of health-related QOL. Recent retrospective analysis of large databases suggesting a possible effect of ICS on improving survival was not confirmed in the TORCH trial, in which the ICS-only arm did not show improved survival compared with placebo, whereas the combination arm was significantly more effective than ICS alone. In TORCH the combination was superior in terms of all outcomes evaluated. Along with the more frequent development of pneumonia in the patients receiving ICS, this suggests that ICS should not be prescribed alone but rather with a long-acting β₂-agonist (LABA).

Combination Therapy

All the studies on combinations of agents show significant improvements over single agents alone, and clinicians should now consider combination therapy as first-line therapy. Initially, the combination of inhaled ipatroprium and albuterol proved effective in the management of COPD. More recently, the combination of tiotropium and formoterol, even when administered once daily, was almost as effective as tiotropium once daily added to the recommended twice-daily dose of formoterol. Similarly, the combination of theophylline and salmeterol was significantly more effective than either agent alone.

The TORCH study showed better effects of the salmeterol-fluticasone combination on survival, FEV₁, exacerbation rate, and QOL than placebo and the individual components alone, confirming earlier studies evaluating the combination of beta agonists and corticosteroids. Recent trials compared tiotropium plus placebo with tiotropium plus salmeterol and with tiotropium plus the combination of salmeterol and fluticasone in a large patient group. The number of hospitalizations related to exacerbations, health-related QOL, and lung function were significantly better in the group receiving triple therapy (LABA, long-acting muscarinic antagonist [LAMA], ICS). Thus, the institution of triple therapy for COPD is consistent with good medicine, if the patient has failed less intense therapy.

Mucokinetic Agents

The mucokinetic drugs decrease sputum viscosity and adhesiveness to facilitate expectoration. The only controlled study in the United States suggesting a value for mucokinetics in the chronic management of bronchitis was a multicenter evaluation of organic iodide, which demonstrated symptomatic benefits. Oral acetylcysteine is favored in Europe for its antioxidant effects; however, a recent large trial failed to document any substantial benefit. Genetically engineered ribonuclease seems to be useful in cystic fibrosis but is of no value in COPD patients.

Antibiotics

In patients with evidence of respiratory tract infection, such as fever, leukocytosis, and a change in the chest radiograph, antibiotics have proved effective. If recurrent infections occur, particularly in winter, continuous or intermittent, prolonged courses of antibiotics may be useful. The major bacterial strains to be considered are Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella (Branhamella) catarrhalis. The antibiotic choice will depend on local experience, supported by sputum culture and sensitivities if the patient is moderately ill or requires hospital admission. Two recent randomized multicenter trials of the macrolide antibiotic clarithromycin show a beneficial impact on exacerbations, likely from the drug’s antiinflammatory action.

Alpha₁-Antitrypsin

Although supplemental weekly or monthly administration of the enzyme α₁-antitrypsin may be indicated in nonsmoking, younger patients with genetically determined emphysema, such therapy is difficult to initiate in practice. Evidence shows that the administration of α₁-antitrypsin is relatively safe. Although not entirely clear, the most likely candidates for replacement therapy would be patients with mild to moderate COPD.

Vaccination

Ideally, infectious complications of the respiratory tract should be prevented in patients with COPD by using effective vaccines. Thus, routine prophylaxis with pneumococcal and influenza vaccines is recommended.

Systemic Manifestations

The systemic manifestations of COPD include peripheral muscle dysfunction, malnutrition, cardiovascular compromise, osteoporosis, depression, anemia, and lung cancer. Some may be responsive to pulmonary and exercise therapy and may benefit patients with minimal response to conventional pharmacologic therapy.

Pulmonary Rehabilitation

Pulmonary rehabilitation has gradually become the “gold standard” treatment for patients with symptomatic COPD. By definition, rehabilitation services are provided to patients with symptoms, most of them with advanced lung disease. Because new therapeutic strategies such as surgical and nonsurgical lung volume reduction and lung transplantation require well-conditioned patients, pulmonary rehabilitation is becoming a crucial component of the overall treatment strategy of many patients previously deemed untreatable.

The most important concept in pulmonary rehabilitation is that any program must attempt to treat each patient enrolled as an individual. The variation that arises from the need to individualize therapy from one patient to another is one factor that makes the objective evaluation of each group of patients enrolled in a rehabilitation program difficult.

Because pulmonary rehabilitation is multidisciplinary and uses different therapeutic components, it is difficult to attribute improved global outcomes to the effect of individual elements of a program. Independent of the study design used, conventional pulmonary function tests do not usually change after pulmonary rehabilitation. Nevertheless, well-controlled studies show significant improvement in different outcomes, including increased exercise capacity, improved health-related QOL, and decreased dyspnea and hospital admissions.

Objectives and Goals

The definition of pulmonary rehabilitation provides three major objectives:

1. Control, alleviate, and as much as possible, reverse the symptoms and pathophysiologic processes leading to respiratory impairment.

2. Improve the quality of life, and attempt to prolong the patient’s life.

3. Reduce health care use and costs.

Patient Selection

Any patient symptomatic from a respiratory disease with some functional limitation is a candidate for rehabilitation. It is preferable to choose patients with moderate to moderately severe disease, to prevent the disabling effects of end-stage respiratory failure. This is an important issue because it seems intuitive that patients with minimal functional limitation benefit minimally from programs designed to improve function. On the other hand, patients who are “too” advanced along the course of their illness could be considered “unlikely to benefit” from rehabilitation. This is not true; patients with the most severe degree of lung disease, such as those awaiting lung transplantation and lung volume reduction surgery, have shown significant functional improvement and increased exercise endurance after pulmonary rehabilitation.

The mild COPD state may not justify the intense effort employed to rehabilitate disabled patients. Other barriers to successful rehabilitation are disabling diseases (e.g., severe heart failure, arthritis), low educational level, hazardous occupation, lack of support, and most importantly, motivation. Although it is customary not to consider patients with cancer as candidates for pulmonary rehabilitation, its inclusion in the preoperative conditioning of patients undergoing lung transplantation or lung volume reduction surgery has expanded the list of indications for rehabilitation.

Therapeutic Modalities That Improve Patient Performance

Exercise Conditioning

Exercise conditioning is based on three physiologic principles: specificity of training, which attributes improvement only for the type of exercise practiced; intensity of training, which establishes that only a load higher than baseline will induce a training effect; and reversal of the training effect, which states that once discontinued, the training effect will disappear. The first two have been extensively applied in the rehabilitation of patients with severe COPD.

Lower Extremity Exercise

Several controlled trials prove that pulmonary rehabilitation is more effective than conventional treatment in symptomatic COPD patients. Exercise training is the most important component of a pulmonary rehabilitation program. A rehabilitation program that includes lower extremity exercise is better than other forms of therapy, such as optimization of medication, education, breathing retraining, and group therapy.

All studies report an increase in exercise endurance, a modest but significant improvement in work rate or oxygen uptake, and a decrease in the perception of dyspnea. One study randomized 119 patients to education (62) and education with exercise training (57). After 6 months, the trained patients significantly increased their exercise endurance time and peak O₂ uptake and reported an improvement in the perception of dyspnea and self-assessed efficacy for walking compared with controls. A follow-up showed that the gains were lost after 1 year, and that a once-a-month follow-up training visit was not sufficient to maintain the gained effects.

With exercise, patients with COPD may become desensitized to the dyspnea induced by the ventilatory load. However, randomized studies have documented evidence for a true training effect. Muscle biopsies of trained patients, but not those of the controls, manifested significant increases in all enzymes responsible for oxidative muscle function, with important physiologic outcomes, as supported by a reduction in exercise lactic acidosis and minute ventilation after training.

All willing symptomatic patients capable of some exercise are candidates for rehabilitation. In 50 patients with severe COPD evaluated before and after exercise training, an inverse relationship was seen between the baseline 12-minute walking distance and O₂ uptake and the improvement.

Upper Extremity Exercise

Most knowledge about exercise conditioning is derived from programs emphasizing leg training. This is unfortunate, because the performance of many everyday tasks requires not only the hands but also the concerted action of other muscle groups that are also used in upper torso and arm positioning. Some of these serve a dual function (respiratory and postural), and arm exercise will decrease the capacity to participate in ventilation. These observations suggest that if the arms are trained to perform more work, or if the ventilatory requirement for the same work is decreased, as previously shown, this could improve the capacity to perform activities of daily living.

Arm training results in improved performance, which is primarily task-specific. One study compared two forms of arm exercise—gravity resistance and modified proprioceptive neuromuscular facilitation—with no arm exercise in 45 patients with COPD. The 20 patients who completed the program improved performance on the tests specific for the training. The patients also reported a decrease in fatigue for all tests performed.

Unsupported arm training (against gravity) decreases O₂ uptake at the same workload compared with arm-cranking training. Unsupported arm exercise may be more effective to train patients in activities similar to those of daily living. Cystic fibrosis patients who underwent upper extremity training (swimming and canoeing for hours daily) exhibited increased upper extremity endurance after 6 weeks; most importantly, their increase in maximal sustainable ventilatory capacity was similar to that obtained with ventilatory muscle training. This suggests that arm exercise training programs can train ventilatory muscles.

Because simple arm elevation results in significant increases in minute ventilation (VE), oxygen uptake (VO₂), and carbon dioxide production (VCO₂), my group studied 14 patients with COPD before and after 8 weeks of three-times-weekly 20-minute sessions of unsupported arm and leg exercise. Our study was part of a comprehensive rehabilitation program to test whether arm training decreases the ventilatory requirement for arm activity. There was a 35% decrease in the rise of VO₂ and VCO₂ brought about by arm elevation, associated with a significant decrease in VO₂. Because the patients also trained their legs, we could not conclude that the improvement resulted from the arm exercise. To answer this question, we had 25 patients with COPD undergo either unsupported arm training (11) or resistance breathing training (14). After 24 sessions, arm endurance increased only for the unsupported arm training group. Interestingly, maximal inspiratory pressure increased significantly for both groups, indicating that training the arms may induce ventilatory muscle exercise for rib cage muscles that hinge on the shoulder girdle.

Physical Modalities of Ventilatory Therapy

Physical modalities include controlled breathing techniques (diaphragmatic breathing exercise, pursed-lip breathing, bending forward), chest physical therapy (postural drainage, chest percussion, vibration position), and respiratory muscle endurance or strength training. The benefits of these modalities include less dyspnea, fewer anxiety and panic attacks, and improved well-being. Although strength and endurance training of the respiratory muscle is associated with an increase in exercise endurance, the clinical significance of these effects remains debatable. These modalities require careful instruction by specialists and should be initiated under close supervision until the patient shows thorough understanding of the techniques. It is often necessary to involve the family because many of these modalities require the assistance of another person (e.g., chest percussion).

Breathing Training

Breathing training is aimed at controlling the respiratory rate and breathing pattern, thus decreasing air trapping. It also attempts to decrease the work of breathing and improve the position and function of the respiratory muscles. The simplest maneuver is pursed-lip breathing. Patients inhale through the nose and exhale between 4 and 6 seconds through lips pursed in a whistling-kissing position. The exact mechanism by which this maneuver decreases dyspnea is unknown. Diaphragmatic breathing is a technique to change the breathing pattern from having the rib cage muscles as the predominant pressure generators to a more normal pattern in which the pressures are generated with the diaphragm. Diaphragmatic breathing is usually practiced for at least 20 minutes two to three times daily. Although most patients report improvement in dyspnea and perception of dyspnea, this technique results in minimal if any changes in oxygen uptake and resting lung volume. Similar to pursed-lip breathing, there is usually a fall in respiratory rate, minute ventilation, and increased tidal volume with diaphragmatic breathing.

Chest Physical Therapy

The goal of chest physiotherapy is that of removing airway secretions, thereby decreasing airflow resistance and bronchopulmonary infection. These techniques include postural drainage, chest percussion, vibration, and directed cough. Postural drainage uses gravity to help drain the individual lung segments. Chest percussion should be performed with care in patients with osteoporosis or bone problems. The single most important criterion for chest physical therapy is the presence of sputum production.

Ventilatory Muscle Strength and Endurance Training

It has been shown that in normal individuals the respiratory muscles, as with their skeletal counterparts, can be specifically trained to improve their strength or endurance. Subsequently, several studies showed that a training response will occur if there is sufficient stimulus. An increase in inspiratory muscle strength (and perhaps endurance) should result in improved respiratory muscle function by decreasing the ratio of the pressure required to breathe (PI) and the maximal pressure that the respiratory system can generate (PI_max). The PI/PI_max ratio, which represents the effort required to complete each breath as a function of the force reserve, is the most important determinant of fatigue in loaded respiratory muscles. Because patients with COPD have reduced inspiratory muscle strength, considerable efforts have been made to define the role of respiratory muscle training in these patients.

Studies show an increase in PI_max when the respiratory muscles have been specifically trained for strength. Decreasing PI/PI_max through respiratory muscle strength training does not appear to be clinically important. However, respiratory muscle strength often increases as a byproduct of endurance training achieved using resistive loads. Some benefits observed after endurance training may relate to the increased strength. Endurance is achieved through low-intensity, high-frequency training programs; the three types are flow resistive loading, threshold loading, and voluntary isocapneic hyperpnea.

Because many studies have not been controlled, it is difficult to attribute their results to the training. Many show an increase in the endurance time during which the ventilatory muscles could tolerate a known load; some show a significant increase in strength and a decrease in dyspnea during the performance of inspiratory load and exercise. Studies of systemic exercise performance found a minimal increase in walking distance or constant-load exercise endurance. Ventilatory muscle training with resistive breathing clearly results in improved ventilatory muscle strength and endurance. In COPD, however, it is not clear whether this effort results in decreased morbidity or mortality or offers any clinical advantage. In many studies, compliance has been low, with up to 50% of all pulmonary patients failing to complete the programs. Larger multicenter studies with clinical outcomes are needed to select the appropriate patients who may benefit from this labor-intensive form of therapy. Currently, ventilatory muscle training is recommended for patients with symptoms and evidence of ventilatory muscle weakness.

Respiratory muscle training results in increased strength and capacity of the muscles to endure a respiratory load. Whether it also results in improved exercise or performance of activities of daily living is debatable. Knowing the respiratory muscle factors that may contribute to ventilatory limitation in COPD might help predict that increases in strength and endurance should help respiratory muscle function. However, this may be important only in the capacity of the COPD patient to handle inspiratory loads, such as during acute exacerbations. It is less likely that ventilatory muscle training will substantially affect systemic exercise performance.

Respiratory Muscle Resting

Respiratory muscles that must work against a large enough load may become fatigued. Experimentally, this has occurred in both normal volunteers and patients with COPD. Clinically, respiratory muscle fatigue seems to play an important role in the acute respiratory failure of patients with COPD. Noninvasive ventilation (NIV) should be helpful in patients with acute or chronic respiratory failure and impending respiratory muscle fatigue, as confirmed by several randomized trials evaluating different outcomes, including the rate of intubation, length of intensive care unit (ICU) and hospital stay, dyspnea, and mortality. Although not all showed the same results in mortality, there was uniform agreement that positive-pressure NIV was effective in reversing acute respiratory failure. The most successfully treated patients were able to cooperate and had elevated partial pressure of carbon dioxide in arterial blood (PaCO₂) but no other important comorbid problems (no sepsis or severe pneumonia). Because positive-pressure NIV is potentially dangerous, patients considered for this therapy should be closely monitored and treated by clinicians familiar with these ventilatory techniques.

The possibility that the respiratory muscles of patients with stable severe COPD were functioning close to the fatigue threshold led numerous investigators to explore the role of muscle resting using negative-pressure and positive-pressure NIV. With one exception, the controlled trials using both forms of ventilation showed no benefit in most of the outcomes studied. Therefore, routine use of NIV in stable COPD patients remains controversial.

Nutrition Evaluation

Many patients with emphysema appear thin and emaciated and may have anemia, leading to a poor prognosis. Although no evidence suggests a plan that would result in unequivocal benefits for the respiratory system, most authorities agree that any deficiencies should be corrected. Correction of factors such as anemia (to improve oxygen-carrying capacity) and electrolyte imbalances (sodium, potassium, phosphorus, magnesium) could result in improved cardiopulmonary performance. Similarly, simple measures such as encouraging the patient to take small amounts of food at more frequent intervals result in less abdominal distention and decrease dyspnea after meals. My group also recommends evaluating oxygen saturation (SaO₂) during meals. If hypoexmia is present, this can be alleviated by supplementing O₂ at feeding time.

Psychological Support

Most patients with advanced lung disease have minor psychological problems, mainly reactive depression and anxiety. Fortunately, these problems are likely to improve as the patients become involved in a rehabilitation program that improves activity and performance. Simple measures, such as being able to exercise under the supervision of supportive specialists, frequently result in desensitization to symptoms, including dyspnea and fear. From 15 to 20 rehabilitation sessions that include education, exercise, physical therapy, breathing techniques, and relaxation are more effective in reducing anxiety than a similar number of psychotherapy sessions. Occasionally, patients have major psychological problems and require primary psychiatric evaluation and treatment.

Home Oxygen Therapy

Therapeutic oxygen has been used systemically since the association between hypoxemia and right-sided heart failure was first recognized and the benefit of continuous O₂ delivery to patients with severe COPD was documented. Since then, much has been learned about the effects of oxygen and hypoxemia, and progress has been made in the area of mechanical O₂ delivery devices. The results of the Nocturnal Oxygen Therapy Trial and UK Medical Research Council studies established that continuous home oxygen improves survival in hypoxemic COPD patients, and that survival is related to the number of hours of supplemental O₂ per day. Other beneficial effects of long-term O₂ include reduction in polycythemia (perhaps resulting more from lowered carboxyhemoglobin levels than improved arterial saturation), reduction in pulmonary artery pressure (Ppa), dyspnea, and rapid eye movement–related hypoxemia during sleep. Oxygen also improves sleep and may reduce nocturnal arrhythmias. Importantly, O₂ can also improve neuropsychiatric testing and exercise tolerance, attributed to central mechanisms causing reduced minute ventilation at the same workload, thereby delaying ventilatory limitation. The improved arterial oxygenation enables greater O₂ delivery, reversal of hypoxemia-induced bronchoconstriction, and the effect of O₂ on respiratory muscle recruitment.

Prescribing Home Oxygen

Patients are evaluated for long-term O₂ therapy by measuring the partial pressure of oxygen in arterial blood (PaO₂). Therefore the recommendation is that PaO₂ measurement, not pulse oximetry for SaO₂, should be the clinical standard for initiating long-term O₂ therapy, particularly during rest. Oximetry may be used to adjust O₂ flow settings over time. If hypercapnia or acidosis is suspected, arterial blood gases (ABGs) must be measured. Some COPD patients who were not hypoxemic before their exacerbation will eventually recover to the point they no longer need oxygen. It is therefore recommended that the need for long-term O₂ be reassessed in 30 to 90 days, when the patient is clinically stable and receiving adequate medical management. O₂ therapy can be discontinued if the patient does not meet ABG criteria.

As with any drug, oxygen may have deleterious effects, particularly in older patients. The hazardous effects of O₂ therapy can be considered under three broad headings. First, physical risks include fire hazard or tank explosion, trauma from catheters or masks, and drying of mucous membranes caused by high flow rates and inadequate humidification. Second, functional effects are related to increased CO₂ retention and absorptive atelectasis. Elevated PaCO₂ in response to supplemental O₂ is a well-recognized complication in a minority of patients, traditionally attributed to reductions in hypoxic ventilatory drive. In many patients, however, the decrease in minute ventilation is minimal. The most consistent finding is a worsening of the pulmonary ventilation/perfusion distribution, with an increase in the dead space/tidal volume ratio. This presumably results from oxygen’s blockage of local hypoxic vasoconstriction, thereby increasing perfusion of poorly ventilated areas. Third, although possible, cytotoxic effects and atelectasis have not been clearly demonstrated with the low flow rates (1-5 L/min; fraction of inspired oxygen [FIO₂] of 24%-36%) typically used for chronic home O₂ therapy in COPD patients.

Oxygen Delivery Systems

Long-term home O₂ therapy is available from three different delivery systems: oxygen concentrators, liquid systems, and compressed gas. Each system has advantages and disadvantages, and the correct system for each patient depends on patient limitations and the clinical application. Oxygen systems were recently compared on the basis of weight, cost, portability, ease of refilling, and availability; the first three factors may be of particular importance in elderly, often debilitated patients.

Administration Devices

Oxygen is typically administered with continuous flow by a nasal cannula. However, because alveolar delivery occurs during a small portion of a spontaneous respiratory cycle (approximately the first sixth), with the rest of the cycle used to fill dead space and for exhalation, the majority of continuously flowing O₂ is not used by the patient and is wasted into the atmosphere. To improve efficiency and increase patient mobility, several devices are available that focus on O₂ conservation and delivery during early inspiration, including reservoir cannulas, demand-type systems, and transtracheal catheters.

Reservoir nasal cannulas and pendants store oxygen during expiration and deliver a 20-mL bolus during early inspiration. Because more alveolar O₂ is delivered, flows may be reduced proportionally, resulting in a 2 : 1 to 4 : 1 O₂ savings at rest and with exercise. Cosmetic considerations have traditionally limited patient acceptance of these devices.

Demand valve systems have an electronic sensor that delivers O₂ only during early inspiration or provides an additional pulse early in inspiration as an adjuvant to the continuous flow. By restricting or accentuating O₂ during inspiration, wasted delivery into dead space or during exhalation is minimized. This results in a 2 : 1 to 7 : 1 O₂ savings. The effect of mouth breathing on efficacy is not yet clear.

Transtracheal oxygen therapy introduces a thin flexible catheter into the lower trachea for delivery of continuous (or pulsed) O₂. Because O₂ is delivered directly into the trachea, dead space is reduced, and the upper trachea serves as a reservoir of undiluted O₂. This provides a 2 : 1 to 3 : 1 O₂ savings over a nasal cannula. However, the widespread use of transtracheal O₂ has been limited by the rate of complications, requiring administration in specialized centers.

Exacerbations, Hospitalization, and Discharge Criteria

Although acute exacerbations are difficult to define and their pathogenesis is poorly understood, impaired lung function can lead to respiratory failure, requiring intubation and mechanical ventilation. In addition, repeated exacerbations are associated with poor outcome. The purpose of acute treatment is to manage the patient’s decompensation and comorbid conditions to prevent further deterioration and readmission (see Chapter 43).

The therapy of an exacerbation is based on the administration of the same medications that are given in the stable patient, with preference for nebulized medications. In addition, the administration of systemic corticosteroids has resulted in improved outcomes. If a bacterial infection is suspected, antibiotics are administered based on the local prevalence of bacteria.

Traditionally, the decision for hospital admission derives from subjective interpretation of clinical features, such as the severity of dyspnea, determination of respiratory failure, short-term response to emergency department (ED) therapy, presence of right-sided heart failure, and presence of complications (e.g., severe bronchitis, pneumonia, comorbidities). This approach to decision making is less than ideal in that up to 28% of patients with an acute exacerbation of COPD discharged from an ED have recurrent symptoms within 14 days. Additionally, 17% of patients discharged after ED management of COPD will relapse and require hospitalization. Few clinical studies have investigated patient-specific objective clinical and laboratory features that identify patients with COPD who require hospitalization. A general consensus supports the need for hospitalization in patients with severe acute hypoxemia or acute hypercarbia; less extreme ABG abnormalities, however, do not assist with decision making.

Other factors that identify high-risk patients include a previous ED visit within 7 days, number of doses of nebulized bronchodilators, use of home oxygen, previous relapse rate, administration of aminophylline, and use of corticosteroids and antibiotics at ED discharge.

Once improved, clinical assessment plans for modifying drug regimens, use of home oxygen, or potential benefits from pulmonary rehabilitation programs should be prepared. The duration of hospitalization for the COPD patient depends at least partly on a multidisciplinary team present to direct respiratory management.

Because of the complex management issues in caring for COPD patients with impending or frank respiratory failure, physician specialists with extensive COPD experience should participate in the care of hospitalized patients who present with underlying severe disease. This includes patients who require invasive or noninvasive mechanical ventilation or who develop hypoxemia unresponsive to FIO₂ of 0.50 or have new-onset hypercarbia, as well as those who require steroids more than 48 hours to maintain adequate respiratory function, undergo thoracoabdominal surgery, or require specialized techniques to manage copious airway secretions.

The indications for hospital admission vary according to local practices and regulations. The expert consensus considers the severity of the underlying respiratory dysfunction, progression of symptoms, response to outpatient therapy, existence of comorbid conditions, necessity of surgical interventions that may affect pulmonary function, and the availability of adequate home care. The severity of respiratory dysfunction dictates the need for ICU admission. Depending on available resources, patients with severe exacerbations of COPD may be admitted to intermediate or special respiratory care units to identify and manage acute respiratory failure successfully. Limited data support the discharge criteria, but the patient’s capacity to function independently and lack of comorbidities help in the decision.

Controversies and Pitfalls

The paradigm that COPD is a disease associated with poor therapy response has shifted to the general sense that patients do respond to therapy. However, the following controversies still remain:

1. Should asymptomatic patients who are diagnosed with airflow obstruction by spirometry be treated?

2. Should symptomatic patients with mild obstruction be treated, and if so, what is the best initial choice for therapy?

3. Should most patients with persistent symptoms be treated with double- or triple-drug therapy?

4. If double-agent therapy is selected, is it better to treat with a β₂-agonist plus inhaled corticosteroids or a long-acting β₂-agonist (LABA) and long-acting muscarinic antagonist (LAMA)?

5. For which patients is pulmonary rehabilitation more effective?

6. Do maintenance programs of pulmonary rehabilitation need to be developed? Are they useful?

7. Is there a definitive role for chronic antibiotic therapy for patients with COPD, and if so, which agents in which schedule?

Although such questions remain unanswered, studies are unraveling the mechanistic processes that result in COPD to develop therapies capable of reversing disease progression. Recent evidence proving the presence of stem cells in the lungs indicates that regenerative therapy may help repair damaged lungs.

Conclusion

Knowledge of COPD has increased significantly in recent years. Smoking cessation campaigns have resulted in a significant decrease in smoking prevalence in the United States. Similar efforts worldwide should have the same impact. The consequence should be a future decrease in the incidence of COPD. The widespread application of long-term oxygen therapy for hypoxemic patients has resulted in increased survival. An expanded drug therapy armamentarium has effectively improved dyspnea and quality of life, and pulmonary rehabilitation has documented benefits. Noninvasive ventilation has offered new alternatives for the patient with acute or chronic respiratory failure. Surgical and more innovative nonsurgical volume reduction may serve as an alternative to lung transplantation for patients with severe COPD who are still symptomatic after maximal medical therapy. All these options offer new hope for the patient with chronic obstructive pulmonary disease.

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