Chronic Obstructive Pulmonary Disease (COPD) Treatment & Management

The goal of COPD management is to improve a patient’s functional status and quality of life by preserving optimal lung function, improving symptoms, and preventing the recurrence of exacerbations. Currently, no treatments aside from lung transplantation have been shown to significantly improve lung function or decrease mortality; however, oxygen therapy (when appropriate) and smoking cessation may reduce mortality. Once the diagnosis of COPD is established, it is important to educate the patient about the disease and to encourage his or her active participation in therapy.

Results of a randomized controlled trial showed that a comprehensive disease management strategy, which included a patient education session, a self-treatment plan for exacerbations, and a monthly follow-up call from a case manager, is associated with a lower hospitalization rate and fewer emergency department visits. ^[46] A study by Dewan et al determined that a multicomponent disease management program in patients with COPD was cost-effective, saving $593 per patient. ^[47]

Indications for intensive care admission are confusion, lethargy, respiratory muscle fatigue, worsening hypoxemia, and respiratory acidosis (pH < 7.30), as well as clinical concern for impending or active respiratory failure. (BiPAP can be done on the floor in some hospitals, including widely in the United Kingdom).

Oral and inhaled medications are used for patients with stable disease to reduce dyspnea and improve exercise tolerance. Most of the medications used are directed at the following 4 potentially reversible causes of airflow limitation in a disease state that has largely fixed obstruction:

• Bronchial smooth muscle contraction

• Bronchial mucosal congestion and edema

• Airway inflammation

• Increased airway secretions

Diet

Inadequate nutritional status associated with low body weight in patients with COPD is associated with impaired pulmonary status, reduced diaphragmatic mass, lower exercise capacity, and higher mortality rates. Nutritional support is an important part of comprehensive care in patients with COPD.

Bronchodilation

Bronchodilators are the backbone of any COPD treatment regimen. They work by dilating airways, thereby decreasing airflow resistance. This increases airflow and decreases dynamic hyperinflation. Lack of response in pulmonary function testing should not preclude their use. These drugs provide symptomatic relief but do not alter disease progression or decrease mortality.

Beta2 agonists and cholinergic/muscarinic antagonists

The initial choice of agent remains in debate. Historically, beta2 agonists were considered first line and anticholinergics were added as adjuncts. Not surprisingly, studies have shown combination therapy results in greater bronchodilator response and provides greater relief. Monotherapy with either agent and combination therapy with both are acceptable options. The adverse effect profile may help guide therapy. Generally, long-acting bronchodilators are more beneficial than short-acting ones. ^{[2, 11, 16]}

Beta2-agonist bronchodilators activate specific B2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cyclic adenosine monophosphate (cAMP) and smooth muscle relaxation. Even patients who have no measurable increase in post-bronchodilator expiratory airflow may benefit from treatment with beta2 agonists. The inhaled route is preferred because it minimizes adverse systemic effects. The adverse effects are predictable and include tachycardia and tremors. Although rare, beta2 agonists may also precipitate a cardiac arrhythmia.

Anticholinergic drugs compete with acetylcholine for postganglionic muscarinic receptors, thereby inhibiting cholinergically mediated bronchomotor tone, resulting in bronchodilation. They block vagally mediated reflex arcs that cause bronchoconstriction. Clinical benefit is gained through a decrease in exercise-induced dynamic hyperinflation. These agents are poorly absorbed systemically and are relatively safe. Reported adverse effects include dry mouth, dry eyes, metallic taste, and prostatic symptoms.

In a study of men with COPD aged 66 years or older from Ontario, Canada, acute urinary retention (AUR) was found to be significantly more prevalent in users of inhaled anticholinergic medications (IACs) than in nonusers. The risk of AUR was higher in patients receiving both short-acting and long-acting IACs than in patients using a single IAC, and evidence of benign prostatic hyperplasia also increased the AUR risk. ^[48]

Inhaled delivery of medications is preferred over the oral route to help minimize potential adverse effects. Some patients may have difficulty achieving effective delivery of the medication using a metered-dose inhaler; use of a spacer or nebulizer may be beneficial in these patients.

The use of newly prescribed inhaled long-acting beta-agonist and long-acting anticholinergic drugs for COPD was associated with a 31% increased risk of experiencing a cardiovascular event in a recent nested case-control analysis of a retrospective cohort study. Both agents showed an increased risk of acute coronary syndrome and heart failure, but not arrhythmias or stroke. With both agents, the risk of events was highest within the first 2 or 3 weeks of initiating treatment. There was no significant difference in events between the 2 treatments. ^{[49, 50]}

In 2013, the results from the SPARK trial showed that in patients with severe COPD, a once-daily fixed-dose combination of indacaterol (a beta2 agonist) and glycopyrronium (a muscarinic antagonist) can improve lung functioning and reduce exacerbations, as compared with monotherapy with either glycopyrronium or tiotropium (both of which are muscarinic antagonists). ^[51]

Also in 2013, indacaterol and tiotropium were shown to be equally effective in a 52-week, randomized, blinded, parallel-group study consisting of more than 3400 patients with severe COPD who had had at least one exacerbation in the past year. ^{[52, 53]} Results from use of the 2 agents demonstrated similar improvements in baseline dyspnea and health status, with similar safety profiles.

Patients treated with indacaterol had a 29% higher exacerbation rate, but needed rescue medication less frequently than patients treated with tiotropium. ^{[52, 53]} In both groups, improvements were observed from baseline in trough FEV₁ at week 12 (0.114 L with indacaterol and 0.126 L with tiotropium) and at week 52 (0.073 L with indacaterol and 0.092 L with tiotropium). ^{[52, 53]}

In 2015, glycopyrrolate was approved as a new respiratory inhalant dosage form. Glycopyrrolate is a long-acting muscarinic antagonist (LAMA) that produces bronchodilation by inhibiting acetylcholine’s effect on muscarinic receptors in the airway smooth muscle. It is available alone (Seebri Neohaler, encapsulated powder for inhalation; Lonhala Magnair, solution for nebulization) and in combination with indacaterol, a long-acting beta2-agonist (Utibron Neohaler).

Approval of indacaterol/glycopyrrolate inhaler was based the FLIGHT1 and FLIGHT2 12-week trials (n=2038) that measured lung function compared with its individual bronchodilator components, as well as placebo. Indacaterol/glycopyrrolate was statistically superior in terms of FEV₁ area under the curve from 0-12 hours compared with its individual components (P< .001). Statistically and clinically meaningful improvements in St. George's Respiratory Questionnaire total score, transition dyspnea index total score, and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo (P< .001). ^[54]

Glycopyrrolate inhaled/formoterol (Bevespi Aerosphere) is a long-acting muscarinic antagonist (LAMA)/long-acting beta2-agonist (LABA) combination that was approved in April 2016. It is indicated for the long-term, maintenance treatment of airflow obstruction with COPD, including chronic bronchitis and/or emphysema. Approval is based on the PINNACLE trial program, which demonstrated that the glycopyrrolate/formoterol combination inhalant achieved statistically significant improvement in morning predose FEV₁ at 24 weeks (P< .001) compared with the individual components of the combination and placebo. ^[55]

Umeclidinium bromide and vilanterol (Anoro Ellipta) is a LAMA and LABA inhalation powder approved by the FDA for long-term maintenance of COPD. ^{[56, 57]} Approval was based on a series of dose-ranging studies in more than 2400 patients—two 6-month, placebo-controlled efficacy and safety studies; two 6-month, active-controlled efficacy and safety studies; and a 12-month safety study. ^{[57, 58]} This agent carries a boxed warning regarding use of LABAs and an increased risk of asthma-related death, ^{[56, 57]} but not in COPD. Umeclidinium and vilanterol inhalation powder is not approved for asthma therapy, and it is not meant to be used as rescue therapy for sudden breathing problems (eg, acute bronchospasm). Serious adverse effects include paradoxical bronchospasm, cardiovascular effects, acute narrow-angle glaucoma, and worsening of urinary retention. ^{[56, 57]} No LAMA or LABA are approved with the addition of inhaled corticosteroids, as listed in the Global Initiative for Asthma step 5.

Olodaterol inhaled (Stirverdi Respimat) was approved by the FDA in July, 2014, for maintenance bronchodilator treatment in patients with COPD. Olodaterol is a long-acting beta2 agonist (LABA) that activates specific β2-adrenergic receptors on the surface of smooth muscle cells, which increases intracellular cAMP and smooth muscle relaxation. Approval was based on data from more than 3,000 patients with COPD studied over a 48-week period. Results demonstrated the long-term efficacy (eg, improved FEV1 at 0-3 hr and trough FEV1) and safety of once-daily olodaterol 5 mcg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy. ^{[59, 60]}

Tiotropium

Although the results of the Understanding Potential Long Term Impacts on Function With Tiotropium (UPLIFT) trial did not show a change in the rate of decline of FEV₁ or mortality when compared with placebo, it did show a significant reduction in the frequency of COPD exacerbations and hospitalizations and an improvement in quality of life. ^{[61, 62, 63, 64]}

Evidence is mounting of the efficacy of tiotropium over long-acting beta agonists. Two large, randomized trials have compared tiotropium, salmeterol (Serevent), and placebo. ^{[62, 65]} Both studies showed greater improvement in lung function, dyspnea, and quality of life in the tiotropium group versus the salmeterol group. A study by Brusasco et al also showed a delay in first exacerbations and fewer exacerbations per year in the tiotropium group. ^[65]

A 1-year, randomized, double-blind, double-dummy, parallel group study by Vogelmeier et al determined that tiotropium is more effective than salmeterol in preventing exacerbations in patients with moderate-to-very-severe COPD. ^[66]

Tiotropium is available in a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. For adults, the contents of 1 capsule (18 mcg) are inhaled every day via the HandiHaler device. Contraindications, drug interactions, and adverse effects are similar to those of ipratropium.

A systematic review and meta-analysis by Singh et al of 5 randomized controlled trials of the Respimat tiotropium mist inhaler in patients with COPD found a 52% increased risk of mortality (all cause) versus placebo. ^[67] A randomized study comparing the Respimat mist inhaler to the HandiHaler inhalation device is ongoing as of August 2011.

Aclidinium

Aclidinium (Tudorza Pressair), a long-acting, antimuscarinic (M3) metered-dose inhaler was approved by the FDA in July 2012. Approval was based on randomized, placebo-controlled, clinical trials involving 1276 patients aged >40 years with COPD. The mean 12-week predose FEV1 improvements vs placebo were 0.12 L, 0.07 L, and 0.11 L (P< 0.001) in the trials, with a 24-week improvement of 0.13 L in the 6-month trial. Mean peak improvements in lung function (FEV1) assessed after the first dose were similar to those observed at week 12 in each study. ^[68]

Umeclidinium bromide

Umeclidinium bromide blocks the action of acetylcholine at muscarinic receptors in the bronchial airways (M3) by preventing increase in intracellular calcium concentration, leading to relaxation of airway smooth muscle. It is available in the United States as a combination inhaled powder with vilanterol (Anoro Ellipta), and is the first once-daily dual bronchodilator approved. It is also available as a single entity inhaler (Incruse Ellipta). Approval for the combination was based on 7 phase III trials including nearly 6,000 patients with COPD. Four 24-week primary efficacy studies (measuring improvement of trough FEV1) and a 52-week long-term safety study were the key studies. Two 12-week exercise/lung function studies provided supportive lung function data and contributed to safety data. ^{[69, 70]}

Revefenacin

Revefenacin is a once-daily, long-acting muscarinic antagonist that inhibits smooth-muscle M3 receptors in the airway, leading to bronchodilation. It is indicated for maintenance treatment of COPD. Revefenacin is administered by nebulizer using a mouthpiece. Approval was based on two 12-week, phase III trials including more than 1200 patients with COPD. Revefenacin demonstrated a significant improvement in baseline trough FEV1 compared with placebo in both trials. ^[71]

Phosphodiesterase inhibitors

Phosphodiesterase inhibitors increase intracellular cyclic adenosine monophosphate (cAMP) and result in bronchodilation. Additionally, they may improve diaphragm muscle contractility and stimulate the respiratory center.

Theophylline is a nonspecific phosphodiesterase inhibitor and is now limited to use as an adjunctive agent. Theophylline has a narrow therapeutic window with significant adverse effects, including anxiety, tremors, insomnia, nausea, cardiac arrhythmia (particularly multifocal atrial tachycardia), and seizures. It is reserved for patients with hard-to-control COPD or for individuals who are not able to use inhaled agents effectively.

Theophylline is metabolized primarily via the hepatic cytochrome P450 system, a process affected by age, cardiac status, and liver abnormalities. Serum levels of theophylline need to be monitored because of the potential for toxicity. The previously recommended target range of 15-20 mg/dL has now been reduced to 8-13 mg/dL.

Roflumilast (Daliresp) and cilomilast (Ariflo) are second-generation, selective phosphodiesterase-4 inhibitors. They cause a reduction of the inflammatory process (macrophages and CD8⁺ lymphocytes) in patients with COPD. Cilomilast is completely absorbed following oral administration and has a half-life of approximately 6.5 hours. A dose of 15 mg twice daily has been found to be clinically effective. Nausea, presumably of central origin, is the principal adverse reaction. The FDA advisory panel rejected approval of cilomilast in 2002.

Roflumilast was approved by the FDA in 2011 as a treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. In 2 randomized, double-blind, placebo-controlled, multicenter trials, increased FEV₁ levels were found in patients who received roflumilast, and the rate of COPD exacerbations was reduced by 17% in these patients. ^[72]

Endogenous opioids

A study by Gifford et al found that the administration of endogenous opioids modulated the intensity and unpleasantness of breathlessness in patients with COPD. ^[73]

Beta-adrenergic antagonists (beta-blockers)

Cardiovascular disease is common in patients with COPD and is a leading cause of mortality; however, use of beta-blockers has been discouraged in these patients due to a perceived risk of bronchospasm and concern about inhibition of beta-agonist medication. However, a study by Short et al of 5977 patients in Scotland found that the addition of a cardioselective beta-blocker to established inhaled treatment did not appear to harm pulmonary function and did reduce COPD exacerbations, hospital admissions, and all cause mortality versus controls over a mean follow-up of 4.35 years. ^[74]

Smoking cessation continues to be the most important therapeutic intervention for COPD. Most patients with COPD have a history of smoking or are currently smoking tobacco products. A smoking cessation plan is an essential part of a comprehensive management plan.

However, the success rates for cessation programs are low because of the addictive power of nicotine. These rates can also be negatively impacted by such factors as conditioned responses to smoking-associated stimuli, poor education, forceful promotional campaigns by the tobacco industry, and psychological problems, including depression. The process of smoking cessation typically requires multiple interventional approaches, including both pharmacologic and non-pharmacologic modalities, and will likely require multiple attempts to maintain success.

The transition from smoking to not smoking occurs in the following 5 stages:

• Precontemplation

• Contemplation

• Preparation

• Action

• Maintenance

Smoking intervention programs include self-help, group, health care provider delivered, workplace, and community programs.

Setting a quit date may be helpful. Physicians and other health care providers should participate in setting the target date and follow-up with respect to maintenance.

Successful cessation programs usually use the following resources and tools:

• Patient education

• A target date to quit

• Follow-up support

• Relapse prevention

• Advice for healthy lifestyle changes

• Social support systems

• Adjuncts to treatment (ie, pharmacologic agents)

Mottillo et al reported meta-analysis results indicating that intensive behavioral interventions, including (but not limited to) individual counseling and telephone counseling, offer considerable benefit for increasing smoking abstinence. ^[75]

Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs.

Nicotine is the ingredient in cigarettes primarily responsible for tobacco addiction. Withdrawal from nicotine may cause unpleasant adverse effects, including anxiety, irritability, difficulty concentrating, anger, fatigue, drowsiness, depression, and sleep disruption. These effects usually occur during the first several weeks.

Nicotine replacement therapies after smoking cessation reduce withdrawal symptoms. If a smoker requires his or her first cigarette within 30 minutes of waking, the individual most likely is highly addicted and would benefit from nicotine replacement therapy.

Several nicotine replacement therapies are available.

Nicotine polacrilex (Nicorette, Nicorette Plus) is a chewing gum and has better quit rates than does counseling alone. Nicotine replacement therapy chewing pieces are marketed in 2 strengths (2 mg, 4 mg). An individual who smokes 1 pack per day should use 4-mg pieces. The 2-mg pieces are to be used by individuals who smoke less than 1 pack per day. Instruct patients to chew hourly and also to chew when needed for their initial cravings for 2 weeks. Gradually reduce the amount chewed over the next 3 months.

Transdermal nicotine patches are readily available for replacement therapy. Long-term success rates are 22-42%, compared with 2-25% for placebo. These agents are well tolerated, and the adverse effects are limited to local skin reactions. Nicotine replacement therapy patches are sold under the trade names NicoDerm, Nicotrol, and Habitrol. Each of these products is dosed with a scheduled graduated decrease in nicotine over 6-10 weeks.

The use of the antidepressant bupropion (Zyban) is also effective for smoking cessation. This nonnicotine aid to smoking cessation enhances central nervous system nonadrenergic function. One study demonstrated that 23% of patients sustained cessation at 1 year, compared with 12% who sustained cessation with the placebo. Bupropion may also be effective in patients who have not been able to quit smoking with nicotine replacement therapy.

Another drug used in smoking cessation is varenicline (Chantix). Varenicline is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors. Its action is thought to result from activity at a nicotinic receptor subtype, where its binding produces agonist activity while simultaneously preventing nicotine binding. Agonistic activity is significantly lower than nicotine.

Inflammation plays a significant role in the pathogenesis of COPD. Systemic and inhaled corticosteroids attempt to temper this inflammation and positively alter the course of disease.

The use of systemic steroids in the treatment of acute exacerbations is widely accepted and recommended, given their high efficacy. A meta-analysis concluded that oral and parenteral corticosteroids significantly reduced treatment failure and the need for additional medical treatment and that they increased the rate of improvement in lung function and dyspnea over the first 72 hours. ^[76] Note that systemic steroids are not as effective in treating COPD exacerbations as they are in treating bronchial asthma exacerbations.

On the other hand, the use of oral steroids in persons with chronic stable COPD is widely discouraged, given their adverse effects, which include hypertension, glucose intolerance, osteoporosis, fractures, and cataracts. A Cochrane review showed no benefit at low-dose therapy and short-lived benefit with higher doses (>30 mg of prednisolone). ^[77]

Inhaled corticosteroids provide a more direct route of administration to the airways and, similar to other inhaled agents, are only minimally absorbed. Consequently, aside from the development of thrush, the systemic adverse effects of these medications at standard doses are negligible. Despite the theoretical benefit, the current consensus is that inhaled corticosteroids do not decrease the decline in FEV₁, although they have been shown to decrease the frequency of exacerbations and improve quality of life for symptomatic patients with an FEV₁ of less than 50%. ^[78]

Inhaled corticosteroids are not recommended as monotherapy and should be added to a regimen that already includes a long-acting bronchodilator. The Towards a Revolution in COPD Health (TORCH) trial showed that a combination of an inhaled corticosteroid and a long-acting beta agonist was more beneficial than inhaled corticosteroids alone. ^[79] These data suggest that in patients with COPD, inhaled corticosteroids should be used only in conjunction with a long-acting beta agonist.

However, patients treated with inhaled corticosteroids were noted to have an increased rate of pneumonia. The debate continues on the use of inhaled corticosteroids and the risk for pneumonia in patients with COPD. For example, no significant difference in pneumonia risk was found between patients who used inhaled budesonide and those who did not in a study by Sin et al. The authors analyzed data from 7 large clinical trials (n = 7042) of patients with stable COPD who used inhaled budesonide (n = 3801), with or without formoterol (Symbicort or Pulmicort, respectively) or a control regimen (placebo or formoterol alone [Oxis]). Increasing age and decreasing percent of predicted FEV₁ were the only variables that were significantly associated with occurrence of pneumonia. ^[80]

Research has demonstrated that blood eosinophil count appears to be a promising biomarker of response to inhaled corticosteroids in patients with COPD. In one study, those patients with elevated eosinophil count reductions in exacerbations with combination inhaled corticosteroids and LABAs, compared with LABAs alone, were 24% in patients with baseline eosinophil counts of greater than or equal to 2% to less than 4%, 32% for those with counts of 4% to less than 6%, and 42% for those with eosinophil counts of greater than or equal to 6%. ^[81] Similar results were found in two other studies. ^{[82, 83]}

Despite the possible increased risk of pneumonia associated with inhaled corticosteroids, a retrospective cohort study showed that in patients with COPD hospitalized with pneumonia, prior use of inhaled corticosteroids was actually associated with decreased mortality and less mechanical ventilation. ^[84] Therefore the benefit of inhaled corticosteroids in selected patients will likely continue to outweigh the risks.

Intravenous steroids are often used in high doses for acute exacerbations in the inpatient setting; recent research suggests that there is likely no benefit of IV over oral steroid formulations in acute exacerbations, and thus IV steroids should be reserved only for those patients unable to tolerate oral intake.

Nonsteroidal anti-inflammatory medications have not been shown conclusively to have any benefit in COPD. No response has been shown to medications targeting interleukin-8 and tumor necrosis factor-alpha. Leukotriene inhibitors commonly used in asthma have also not proven to be beneficial in COPD.

However, macrolide antibiotics have been shown to have anti-inflammatory effects in the airways of COPD patients. More specifically, azithromycin has been shown to improve the phagocytic function of pulmonary macrophages and to be a potent anti-inflammatory. ^[8]

Azithromycin is used clinically for its anti-inflammatory effects in patients with cystic fibrosis and in lung transplantation patients with chronic rejection. Furthermore, one study showed that erythromycin reduced the frequency of exacerbations in 109 patients with COPD treated over 12 months. ^[85] A subsequent larger randomized controlled trial of 1142 patients showed a slight decrease in COPD exacerbations for patients given azithromycin over 1 year compared with placebo. ^[86] However, this study also noted an increase in hearing decrements in the patients receiving azithromycin (25% in the treatment group compared with 20% in the placebo group; P =0.04). The noted side effect combined with the concern for breeding antimicrobial resistance continues to prevent widespread use of azithromycin for prevention of COPD exacerbations.

In patients with COPD, chronic infection or colonization of the lower airways is common from S pneumoniae, H influenzae, and M catarrhalis. In patients with chronic severe airway obstruction, P aeruginosa infection may also be prevalent. The use of antibiotics for the treatment of acute exacerbations is well supported. ^[23] Patients who benefited most from antibiotic therapy were those with exacerbations that were characterized by at least 2 of the following: increases in dyspnea, sputum production, and sputum purulence (The Winnipeg criteria). No evidence supports the continuous or prophylactic use of antibiotics to prevent exacerbations.

Empiric antimicrobial therapy is recommended in patients with an acute exacerbation (as evidenced by an increase in baseline dyspnea and/or a change in the quantity or quality of cough) and evidence of an infectious process, such as fever, leukocytosis, or an infiltrate on chest radiograph. The antibiotic choice must be comprehensive and should cover all likely pathogens in the context of the clinical setting and local resistance patterns. ^[4]

In a study by Daniels et al, the addition to doxycycline to corticosteroids was found to somewhat improve treatment for acute exacerbation of COPD (AECOPD). The investigators conducted a randomized, placebo-controlled trial that compared the addition of doxycycline to corticosteroids on clinical outcome in patients hospitalized with AECOPD. In addition to clinical outcome, other parameters were measured, including microbiological outcome, lung function, and systemic inflammation. The 223 patients enrolled in the study represented 265 COPD exacerbations. In addition to systemic corticosteroids, patients received either doxycycline at 200 mg or placebo for 7 days.

Results at 30 days were similar between the 2 groups. At 10 days, the doxycycline group showed superiority in clinical success compared with placebo in the intention-to-treat arm but not in the per-protocol arm. Also at day 10, doxycycline was superior for clinical cure, microbiological outcome, use of open label antibiotics, and symptoms. ^[87]

Mucolytic agents reduce sputum viscosity and improve secretion clearance. Viscous lung secretions in patients with COPD consist of mucus-derived glycoproteins and leukocyte-derived DNA.

The oral agent N -acetylcysteine has antioxidant and mucokinetic properties and is used to treat patients with COPD. However, the efficacy of mucolytic agents in the treatment of COPD remains controversial. Although they have been shown to decrease cough and chest discomfort, they have not been shown to improve dyspnea or lung function, and they have also been shown to elicit bronchospasm. When used as an inhalational therapy, N -acetylcysteine should be administered along with a bronchodilator such as albuterol in order to counteract potential induction of bronchospasm.

In patients with COPD, the addition of a proton pump inhibitor (PPI) to conventional therapy may significantly decrease COPD exacerbations but not the incidence of the common cold, according to a study by Sasaki et al. ^[88] The investigators conducted a randomized, observer-blind, controlled trial to determine whether PPIs reduce the incidence of common colds in patients with COPD. Patients (n = 100) were assigned to conventional therapy (control group) or conventional therapy plus PPI (lansoprazole [Prevacid] 15 mg/d).

In the study by Sasaki et al, the frequency of common colds and COPD exacerbations was measured, and it was determined that the number of exacerbations per person over 12 months was significantly lower in the PPI group than in the control group. However, no significant difference in the frequency of common colds was observed between the 2 groups. The authors concluded that although the patients who took lansoprazole showed a significant decrease in COPD exacerbations, more definitive clinical trials are required. ^[88]

COPD is commonly associated with progressive hypoxemia. Oxygen administration reduces mortality rates in patients with advanced COPD because of the favorable effects on pulmonary hemodynamics.

Long-term oxygen therapy improves survival 2-fold or more in hypoxemic patients with COPD, according to 2 landmark trials, the British Medical Research Council (MRC) study and the US National Heart, Lung and Blood Institute’s Nocturnal Oxygen Therapy Trial (NOTT). Hypoxemia is defined as PaO₂ (partial pressure of oxygen in arterial blood) of less than 55 mm Hg or oxygen saturation of less than 90%. Oxygen was used for 15-19 hours per day. ^{[89, 90, 91]}

Therefore, specialists recommend long-term oxygen therapy for patients with a PaO₂ of less than 55 mm Hg, a PaO₂ of less than 59 mm Hg with evidence of polycythemia, or cor pulmonale. Reevaluate these patients 1-3 months after initiating therapy, because some patients may not require long-term oxygen.

Many patients with COPD who are not hypoxemic at rest worsen during exertion. Home supplemental oxygen commonly is prescribed for these patients. Oxygen supplementation during exercise can prevent increases in pulmonary artery pressure, reduce dyspnea, and improve exercise tolerance.

In a 2008 study, however, patients with COPD-related hypoxemia and exertional desaturation who completed a program of pulmonary rehabilitation failed to show any benefit in domestic activity, health-related quality of life, or time spent outside of the home when compared with those who received placebo. ^[92] Hence, the benefits of home ambulatory oxygen for this subset of patients remain controversial.

Oxygen therapy generally is safe. Oxygen toxicity from high inspired concentrations (>60%) is well recognized. Little is known about the long-term effects of low-flow oxygen. However, the increased survival and quality-of-life benefits of long-term oxygen therapy outweigh the possible risks of oxygen toxicity.

Carbon dioxide retention from depression of hypoxic drive has been overemphasized. Despite the widely held belief that too much oxygen causes significant respiratory depression, multiple studies in the literature dispute this view. With administration of oxygen, PaCO₂ rises, but not in proportion to the very minor changes in respiratory drive. Carbon dioxide retention is more likely a consequence of ventilation-perfusion mismatching rather than respiratory center depression. While this complication is not common, it is best avoided by titrating oxygen delivery to maintain the PaO₂ at 60-65 mm Hg.

The major physical hazards of oxygen therapy are fires or explosions. Patients, family, and other caregivers must be warned not to smoke. Overall, major accidents are rare and can be avoided by good patient and family training.

The continuous-flow nasal cannula is the standard means of oxygen delivery for the stable hypoxemic patient. It is simple, reliable, and generally well tolerated. Each liter of oxygen flow adds 3-4% to the fraction of inspired oxygen (FiO₂). Nasal oxygen delivery also is beneficial for most mouth-breathing patients. Humidification generally is not necessary when the patient receives oxygen by nasal cannula at flows of less than 5 L/min. (See the images below.)

Oxygen-conserving devices function by delivering all of the supplemental oxygen during early inhalation. These devices improve the portability of oxygen therapy and may reduce overall costs. Three distinct oxygen-conserving devices are available: reservoir cannulas, demand-pulse delivery devices, and transtracheal oxygen delivery. Transtracheal oxygen delivery involves the insertion of a catheter percutaneously between the second and third tracheal interspace. Transtracheal oxygen delivery is invasive and requires special training for the physician, the patient, and the caregiver. The procedure has risks as well as medical benefits but has limited application.

NIPPV for hypercapneic respiratory failure

Noninvasive positive-pressure ventilation (NIPPV), as the name suggests, allows the delivery of positive-pressure ventilation without the use of an endotracheal tube. In place of the tube is a tight-fitting nasal or facial mask that is attached to a continuous positive airway pressure (CPAP) or a bilevel positive airway pressure (BiPAP) machine (as seen below). The positive pressure is beneficial in hypercapneic respiratory failure by decreasing the work of breathing, allowing a larger tidal volume for a given respiratory effort, and hence improving alveolar ventilation. ^[93]

NIPPV has been shown to provide significant benefits in selected patients with acute hypercapneic respiratory failure due to COPD, including a reduction in the need for endotracheal intubation, reduced hospital stay, and a mortality benefit. ^{[94, 95]} This modality should not be used in patients who are unable to protect their airway, are hemodynamically unstable, have significant secretions, are uncooperative, or have an Acute Physiology and Chronic Health Evaluation (APACHE) score of greater than 29. ^[96]

Another study suggests that in patients with chronic hypercapneic respiratory failure who are undergoing pulmonary rehabilitation, nocturnal NIPPV may improve quality of life, daytime PaCO₂, and exercise tolerance. ^[89]

Infections can lead to COPD exacerbations. Vaccinations are a safe and effective modality to reduce infections in susceptible COPD patients. The pneumococcal vaccine should be offered to all patients older than 65 years or to patients of any age who have an FEV₁ of less than 40% of predicted. The influenza vaccine should be given annually to all COPD patients.

The treatment strategies for AAT deficiency involve reducing the neutrophil elastase burden, primarily by smoking cessation, and augmenting the levels of AAT. Available augmentation strategies include pharmacologic attempts to increase endogenous production of AAT by the liver (ie, danazol, tamoxifen) and administration of purified AAT by periodic intravenous infusion or by inhalation. Tamoxifen can increase endogenous production of AAT to a limited extent, so this may be beneficial in persons with the PISZ phenotype.

Intravenous AAT augmentation therapy is the only available approach that can increase serum levels to greater than 11 mmol/L, the protective threshold. Studies show that the infusions can maintain levels of more than 11 mmol/L, and replacement is administered weekly (60 mg/kg), biweekly (120 mg/kg), or monthly (250 mg/kg).

Purified AAT is currently available in 3 formulations, with trade names of Prolastin, Zemaira, and Aralast, all of which are derived from donor blood. Synthetic formulations of AAT are under development but not yet available. The ability of intravenous AAT augmentation to alter the clinical course of patients with AAT deficiency has not been demonstrated. Uncontrolled observations of patients suggest that the FEV₁ may fall at a slower rate in patients who receive AAT replacement. ^[97]

Treatment of acute exacerbation of COPD

Acute exacerbations (AE) of COPDs are a major reason for hospital admission in the United States, although mild episodes may be treated in an outpatient setting. Indications for admission include failure of outpatient treatment, marked increase in dyspnea, altered mental status, increase in hypoxemia or hypercapnia, and inability to tolerate oral medications such as antibiotics or steroids. Care must be taken to evaluate for other conditions that may mimic AECOPD.

Patients with COPD are susceptible to many insults that can lead rapidly to an acute deterioration superimposed on chronic disease. AECOPD—an important, but occasionally overlooked, parameter—is defined as worsening of cough, increase in sputum production, change in sputum quality, and increase in dyspnea.

AECOPDs are very common, affecting about 20% of patients with moderate to severe COPD (1.3 events per year in patients with 40-45% of predicted FEV₁). Quick and accurate recognition of these patients, along with aggressive and prompt intervention, may be the only action that prevents frank respiratory failure. Care must also be taken to evaluate for other conditions that may mimic acute exacerbations of COPD. 

AECOPDs occur in clusters, not at random, as previously thought, according to an analysis by Hurst et al. ^[98] Their study showed that patients with an AECOPD are at an increased risk of another attack in the 8 weeks following the initial episode. Close follow-up during this “brittle” period may lead to earlier treatment and better clinical outcomes.

A stepwise approach to drug therapy is recommended that takes into consideration the causes and complications related to the exacerbation, the degree of reversible bronchospasm, recent drug use, and contraindications to treatment. Sedation and pain management must be provided to ensure patient comfort and safety, despite a potential for respiratory depression.

Assisted ventilation

Progressive airflow obstruction may impair oxygenation and/or ventilation to the degree that the patient requires assisted ventilation. The general guidelines indicate that the ideal time to initiate ventilatory support are (1) when patients have experienced progressive worsening of respiratory acidosis and/or altered mental status and (2) when clinically significant hypoxemia exists despite supplemental oxygen.

Patients may be treated with noninvasive mask ventilation or with translaryngeal intubation and mechanical ventilation.

The bullae in patients with emphysema generally range from 1-4 cm in diameter; on occasion, bullae can occupy more than 33% of the hemithorax (ie, giant bullae). Giant bullae may compress adjacent lung tissue, thereby reducing blood flow and ventilation to healthier tissue.

Removal of these bullae, a standard treatment in selected patients for many years, may result in the expansion of compressed lung tissue and improved function. Patients who are symptomatic and have an FEV₁ of less than 50% of the predicted value have a better outcome after bullectomy.

Bullectomy is performed through a midline sternotomy or a lateral incision, or by video-assisted thoracoscopy. Postoperative bronchopleural air leak is the major potential complication.

Nearly 40 years ago, Brantigan et al first reported resectional surgery for diffuse emphysema in 33 patients. They resected 20-30% of each lung that appeared most diseased. The investigators hypothesized that removal of a portion of the emphysematous lung would increase radial traction on the airways in the remaining lung, thereby reducing symptoms by improving expiratory airflow and mechanical function.

Lung volume reduction surgery is carried out using a midline sternotomy with stapling of the lung margins. Surgeons generally resect 20-30% of each lung from the upper zones. The lung volume reduction procedure has a mortality rate of 0-18%. Several complications, including pneumonia and prolonged air leaks, have been observed.

Several studies, including the large, multicenter National Emphysema Treatment Trial (NETT), have demonstrated significant benefit in spirometry, exercise tolerance, dyspnea, health-related quality of life, and mortality in selected patients after LVRS. ^[99]

Those who benefit most are patients with heterogeneous (upper lobe) disease and a low exercise capacity despite optimal medical therapy and cardiopulmonary rehabilitation. Patients with an FEV₁ of less than 20% of predicted and either homogenous disease or DLCO (diffusing capacity of lung for carbon monoxide) of less than 20% of predicted are considered high risk for this procedure.

Lung transplantation is performed only at select tertiary care centers around the world. Patients with COPD are the largest single category of patients who undergo the procedure.

When evaluating a potential candidate, several factors need be taken into account, including symptomatology, comorbid conditions, and projected survival without transplantation (eg, BODE index >5). Generally speaking, most centers set an age limit of 65 years.

The mean survival after lung transplantation is 5 years. The survival at 1 year is 80-90%. ^{[100, 101]} Whether this procedure has any effect on the survival of patients with COPD is controversial; the main purpose of lung transplantation is to improve symptomatology and quality of life.

Follow-up

Disposition after an AECOPD depends on the clinical picture for each patient more than on any single laboratory value or test. In general, the longer the exacerbation, the more airway edema and debris are present. Nearly all discharged patients should receive a short steroid burst and an increase in the frequency of inhaler therapy. Close follow-up should be arranged with the patient's regular care provider. Other therapies should be considered on a case-by-case basis.

Additional follow-up recommendations are as follows:

• Patients with severe or unstable disease should be seen monthly

• When their condition is stable, patients may be seen biannually

• Check theophylline level with each dose adjustment, when interacting medications are added, and routinely every 6-12 months

• For patients on home oxygen, check arterial blood gases (ABGs) yearly or with any change in condition

• Monitor oxygen saturation more frequently than ABGs

Pulmonary rehabilitation

Many patients with COPD are unable to enjoy life to the fullest because of shortness of breath, physical limitations, and inactivity. Pulmonary rehabilitation encompasses an array of therapeutic modalities designed to improve the patient's quality of life by decreasing airflow limitation, preventing secondary medical complications, and alleviating respiratory symptoms. The 3 major goals of the comprehensive management of COPD are the following:

• Lessen airflow limitation

• Prevent and treat secondary medical complications (eg, hypoxemia, infection)

• Decrease respiratory symptoms and improve quality of life

Successful implementation of a pulmonary rehabilitation program usually requires a team approach, with individual components provided by healthcare professionals who have experience in managing COPD (eg, physician, dietitian, nurse, respiratory therapist, exercise physiologist, physical therapist, occupational therapist, recreational therapist, cardiorespiratory technician, pharmacist, psychosocial professionals). This multidisciplinary approach emphasizes the following:

• Patient and family education

• Smoking cessation

• Medical management (including oxygen and immunization)

• Respiratory and chest physiotherapy

• Physical therapy with bronchopulmonary hygiene, exercise, and vocational rehabilitation

• Psychosocial support

As a result of rehabilitation, improvements have been shown in objective measures of patients’ quality of life, well-being, and health status, including reduction in respiratory symptoms, increases in exercise tolerance and functional activities (eg, walking), reduction in anxiety and depression, and increases in feelings of control and self-esteem.

An observational study has shown that pulmonary rehabilitation also improves the BODE index score in patients with COPD and is associated with better outcomes. ^[102] Quality of life improvements after pulmonary rehabilitation can also be measured using the COPD Assessment Test (CAT), an 8-question patient-completed instrument. ^[103] In addition, pulmonary rehabilitation results in substantial savings in health care costs by reducing hospitalizations and the use of medical resources.

Pulmonary rehabilitation programs usually are conducted in an outpatient setting. A rehabilitation program may include a number of components and should be tailored to the needs of the individual patient. Provide all patients who complete the program with guidelines for continuing at home.

Education is key to comprehensive pulmonary rehabilitation. The educational component prepares the patient and family to be actively involved in providing care. This reliance on patients to assume charge of their care is known as collaborative self-management.

Exercise training is a mandatory component of pulmonary rehabilitation. Patients with COPD should perform aerobic lower extremity endurance exercises regularly to enhance performance of daily activities and reduce dyspnea. Upper extremity exercise training improves dyspnea and allows increased activities of daily living requiring the use of upper extremities.

Breathing retraining techniques (eg, diaphragmatic, pursed lip breathing) may improve the ventilatory pattern and prevent dynamic airway compression.

Special concerns

Many commercial airplanes fly at altitudes of 30,000-40,000 feet. However, the cabin is pressurized to an altitude of 5000-8000 feet. At these altitudes, atmospheric partial pressure of oxygen (PO₂) is 132-109 mm Hg, compared with 159 mm Hg at sea level.

Acute reduction in PO₂ stimulates peripheral chemoreceptors, which results in hyperventilation. When determining whether or not a COPD patient can safely fly, the clinician should first use a prediction equation to determine whether the patient will become hypoxemic at high altitudes. A prediction equation used to estimate PaO₂ at 8000 feet (2440 m) is as follows:

PaO₂ = 22.8 - 2.74X + 0.68Y

(X = altitude; Y = arterial PO₂ at sea level)

A predicted PaO₂ of 50 mm Hg or less at an altitude of 8000 feet is an indication for supplemental oxygen. Arrange supplemental oxygen prior to the flight directly through the airline or through the airline agent (at an extra expense). If there is any question regarding the calculation, many pulmonary physiology labs can also perform altitude simulation tests to confirm or refute the need for in-flight oxygen.

Patients with COPD may develop substantial decreases in nocturnal PaO₂ during all phases of sleep, but particularly during the rapid eye movement phase. These episodes are associated initially with a rise in pulmonary arterial pressures and a disturbance in sleep architecture, but they may develop into pulmonary arterial hypertension and cor pulmonale if hypoxemia remains untreated.

Prescribe oxygen for patients who have daytime PaO₂ greater than 60 mm Hg but who demonstrate substantial nocturnal hypoxemia.

COPD is a chronic disease that is preventable and treatable but largely incurable. Given the progressive nature of the disease, as well as the morbidity and mortality associated with it, clinicians should always include end-of-life care discussions in their visits with patients. These discussions should focus on palliative efforts to improve quality of life, as well as assistance with advanced directives, advanced care planning, and referrals for hospice and home care when needed.