#98813: Chronic Obstructive Pulmonary Disease (COPD)

The chronic inflammatory process of COPD is mediated by a proliferation of inflammatory cells such as neutrophils, macrophages, B-cells, and CD8+ T-cells, particularly in the small airways (Table 3) [33,195]. The degree of inflammation mirrors the severity of disease.

It is suggested that neutrophils play a primary role in the generation of mucous metaplasia in chronic bronchitis and the destruction of lung tissue in emphysema. The neutrophilic inflammatory response appears to account for the excessive mucus secretion observed in response to an acute secretagogue and for augmentation of the bronchial mucus-producing apparatus observed in these patients [34,35]. There is a strong correlation between peripheral airway dysfunction in COPD and sputum neutrophil counts [36].

Macrophages are the predominant inflammatory cells present in lavage fluid in patients with COPD [37]. Numerous studies have demonstrated a direct correlation between the number of alveolar macrophage in the lung tissue and the severity of lung destruction [38].

In COPD, the total T-cell count is elevated. CD8+ cells are the predominant subtype [39].

A number of inflammatory mediators are increased in patients with COPD (Table 4) [195]. These mediators function to attract inflammatory cells from the circulation (chemotactic factors), amplify the inflammatory process (proinflammatory cytokines), and induce structural changes (growth factors).

The insidious onset and progression of dyspnea is so characteristic as to be a hallmark symptom of COPD. The majority of patients who seek medical opinion do so because of dyspnea and its associated disability and anxiety. As discussed, breathlessness is initially only noted on increased physical activity, such as running up a flight of stairs or walking. However, as the disease progresses and lung function worsens, breathlessness can be experienced even with slight physical effort. Finally, dyspnea will interfere with activities of daily living and even at rest. The degree of dyspnea varies from patient to patient, but it is usually not difficult to distinguish the dyspnea of COPD from that due to other causes. The Medical Research Council (MRC) Breathlessness Scale can be used to evaluate the impact of dyspnea on a patient's health status (Table 5) [197]. This questionnaire not only relates well to other measures of health status but also predicts future mortality risk.

Chronic cough, usually the first symptom of COPD to develop, is often initially attributed to smoking or environmental exposures. In early stages, the cough usually comes and goes, but later it is present almost every day or even the entire day. Some patients have significant airflow limitation even in absence of cough. However, there are other possible causes of chronic cough, and chest x-ray and differential diagnosis is necessary (Table 6).

Individuals with COPD usually expectorate or swallow small quantities of sputum after coughing spells. Regular sputum production for three or more months in two consecutive years is indicative of chronic bronchitis. Patients producing copious amount of sputum may have underlying bronchiectasis.

As noted, wheezing and chest tightness are nonspecific symptoms of COPD. They may be present in the early stages of COPD, becoming more prominent in the later stages of the disease.

Weight loss and anorexia are frequently present in advanced stages of COPD and are important prognostic markers. Therefore, these symptoms should be thoroughly investigated. In severe cases, coughing spells may cause patients to experience cough syncope (caused by rapid increases in intrathoracic pressure) or can cause rib fractures, especially in osteoporotic patients. Those persons with COPD who develop cor pulmonale usually develop ankle swelling.

Shallow and rapid breathing with respiratory rate of more than 20 breaths per minute may be noted [17]. The presence of central cyanosis is hard to visualize in artificial light and in darker-skinned patients, but it may be present in severe cases. Ankle or lower leg edema may be a sign of cor pulmonale.

Common chest wall abnormalities indicative of pulmonary hyperinflation (emphysema) may be seen in COPD, such as "barrel-shaped" chest, relatively horizontal ribs, and protruding abdomen. Flattening of the hemidiaphragms may be evident on percussion over the posterior chest or noted on chest x-ray.

Patients with advanced COPD/emphysema often show pursed-lip breathing, which slows expiratory flow and allows better lung emptying [18]. Patients in the later stages of COPD use accessory muscles (e.g., scalene and sternocleidomastoid muscles) to force breaths. Resting muscle activation while lying supine can also be seen in these patients.

Palpation and percussion are of limited value but may disclose a subtle degree of increased A-P diameter and increased resonance. Pulmonary hyperinflation will make the heart apex beat more difficult to detect. Hyperinflation also causes downward displacement of the liver, and it is easy to palpate this organ even with no enlargement.

Patients with COPD often have diminished breath sounds on auscultation [47]. The presence of wheezes during quiet breathing indicates airflow limitation. But, it is important to note that wheezing heard only after forced expiration is not diagnostic for COPD. Inspiratory crackles are also not diagnostically important in COPD.

In patients with pulmonary hypertension, the heart sounds may be distant and the pulmonary component of the second heart sound may be loud. Generally, heart sounds are best heard over the xiphoid area.

Bronchodilator and oral corticosteroid reversibility testing are not accurate in predicting disease progression, whether indicated by decline in FEV1, worsening of health status, or number of exacerbations in persons with COPD [58,59]. However, minor deviation in initial airway caliber can lead to different classification of reversibility status depending on the day of testing, and the lower the prebronchodilator FEV1, the greater the chance of a patient being classified as reversible [59].

Abnormal findings detected on chest x-ray are often not definitive for diagnostic purposes. It is helpful in ruling out other conditions, such as lung carcinoma, and for confirming significant comorbidities, such as heart failure. Possible radiologic changes associated with COPD include:

Computed tomography (CT) of the chest has advanced understanding of COPD and has an important role in the clinical assessment of selected patients. Chest CT can identify the presence and extent of disease patterns that impact prognosis and influence the management of patients with COPD [10]. CT imaging features that are associated with adverse clinical outcomes include early interstitial lung abnormalities, bronchiectasis, presence and pattern of emphysema, airway wall thickness, and expiratory gas trapping [224]. The addition of expiratory CT scans has enabled measurement of small airway disease. Chest CT also may reveal extrapulmonary findings of importance, such as coronary artery calcification, cardiac chamber enlargement, and early-stage lung cancer. The presence of predominantly upper-lobe emphysema on CT imaging identifies the patient who is a good candidate for surgical lung-volume reduction [60].

In patients with advanced COPD, analysis of arterial blood gases while the patient is breathing room air provides oxygenation status of the individual. If the resting oxygen saturation is less than 90%, then prompt measurement of arterial blood gases is necessary to assess the need for supplemental oxygen [199]. The test should be undertaken in stable patients with FEV1 <50% predicted or in patients with suspected cor pulmonale or respiratory failure.

White patients who experience COPD at a young age (i.e., younger than 45 years) or who have a positive family history of COPD may be screened for alpha-1 antitrypsin deficiency. A serum concentration of alpha-1 antitrypsin less than 15% to 20% of the normal expected value indicates a high probability of homozygous alpha-1 antitrypsin deficiency.

Behavioral Modifications

Behavioral interventions are nonpharmacologic treatments delivered directly to individual smokers [209]. The main disadvantage of this approach is that relatively few smokers (about 5%) are interested in attending specific classes at any given time [210]. Therefore, group sessions appear to be the most cost-effective approach to delivering smoking cessation interventions [211]. Although relatively few patients want to go to classes, healthcare professionals should still have a list of referral smoking cessation clinics in their area for those smokers who express an interest in attending them and for those who have failed to respond to other approaches. Simple computer-tailored cessation messages may also be an effective alternative for behavioral support, doubling the cessation rates. This concept has been incorporated into patient support programs provided by several manufacturers of smoking cessation products [210].

There are several behavioral interventions that have empirical support, such as multicomponent coping skills training (e.g., coping response therapy, problem-focused treatment, relapse prevention training, and cognitive-behavioral therapy). This training includes social support and didactic information about nicotine dependence, withdrawal symptoms, and situations that are risks for relapse (e.g., alcohol use, negative moods, or presence of other smokers) as well as training in the use of cognitive and behavioral responses to cope with urges to smoke that reduce the risk of relapse [212,213]. Aversive therapy for smoking cessation, known as rapid smoking, involves smokers in a controlled clinical setting who deeply inhale on cigarettes at six-second intervals. Up to nine cigarettes would be smoked per treatment session to produce strong aversive reactions to cigarettes [214]. Aversive cigarette use greatly declined after the introduction of nicotine-replacement therapies (NRTs), but it has been rediscovered and is being investigated as an aftercare strategy to reduce cravings and prevent relapse [215]. Another behavioral treatment, scheduled reduced smoking, involves three weeks of gradually reduced nicotine intake. In contrast with other smoking cessation strategies involving reduction of smoking, the patient does not control when and where smoking will occur. Rather, an algorithm is used to determine when each cigarette is to be smoked based on the passage of time [216].

Pharmacotherapy

The first-line pharmacologic interventions for smoking cessation are NRT, bupropion, and varenicline [217,218]. However, no pharmacotherapy has been approved for use among pregnant or nursing women. The five forms of NRT available are the patch, gum, lozenge, nasal spray, and inhaler.

The nicotine transdermal system, otherwise known as the patch, releases nicotine steadily during an extended period, with blood levels rising within the first 2 to 4 hours and then remaining relatively constant between 8 and 24 hours after application, depending on the product used [219]. Nicotine chewing gum is a type of NRT that may aid in smoking cessation and/or quitting smokeless tobacco. Chewing allows nicotine to be delivered quickly into the bloodstream. Typically available in either 2- or 4-mg doses, nicotine chewing gum is expected to last one to two hours.

The nicotine lozenge is similar to a hard candy. It slowly dissolves in the mouth (for 20 minutes or so) to release nicotine to the brain more quickly than the patch. A 2-mg sublingual nicotine tablet has shown efficacy in several studies and has been approved in Europe to manage nicotine withdrawal [220,221,222].

Nasal nicotine spray was approved by the FDA in 1997. Available by prescription, each spray contains 0.5 mg of nicotine, and a dose is defined as one spray in each nostril. In clinical trials, subjects were allowed to take up to five doses/hour, with a maximum of 40 doses/day (40 mg of nicotine). The cessation rates in trials with nicotine nasal spray at one year ranged from 15% to 25% [63,64,65].

The FDA also approved a nicotine inhalation system consisting of a mouthpiece and a nicotine-containing cartridge. Available with a prescription, each inhaler contains 10 mg of nicotine and 1 mg of menthol, of which 4 mg of nicotine can be extracted and 2 mg are systemically available. Shallow or deep puffing results in similar nicotine absorption.

Quitting smoking can be a difficult process, even with use of NRT. When subjects were given denicotinized cigarettes along with IV saline or nicotine, the variable most responsible for craving satisfaction, psychologic reward, and craving reduction was the denicotinized cigarette [66]. When ad libitum smoking of preferred brands was also allowed, the combination of nicotine-less cigarette and bolus IV nicotine were the most effective in lowering craving, negative affect, and total amount smoked [67]. Sensations in the tongue, nose, back of mouth, throat, windpipe, and chest showed strong correlation between nicotine-less cigarettes and the usual brand smoked by the subjects, perhaps explaining the strong effects on smoking suppression observed [66]. Therefore, it is important to recognize that while NRT is a key part of cessation therapy, it does not address all aspects of smoking behavior.

Bupropion is an atypical antidepressant that has both dopaminergic and adrenergic actions [68]. In 1998, the slow-release preparation of bupropion became available as a prescription item specifically for smoking cessation, with the trade name Zyban. This treatment could be appropriate for smokers who do not wish to use an NRT or for those whose treatment with NRT has failed. Unlike NRT, smokers begin bupropion treatment one week prior to cessation. The suggested dosage is 300 mg/day, and the duration of treatment is 7 to 12 weeks [69].

Another non-nicotine therapy for smoking cessation is varenicline tartrate (Chantix), a partial agonist selective for nicotine acetylcholine receptor subtypes. Released in 2006, varenicline is available in monthly dose packs (0.5-mg and 1-mg tablets) and is approved for a 12-week course of treatment [217].

The two second-line drugs for smoking cessation are clonidine and nortriptyline [218]. Clonidine is an antihypertensive medication that is administered orally or transdermally. It appears to increase the smoking cessation rate by approximately 11%; however, clonidine is known to produce such side effects as dry mouth, dizziness, sedation, and orthostatic hypotension [70]. Clonidine has not been approved by the FDA for smoking cessation but has been used with individuals who have failed NRT or bupropion. Nortriptyline is a tricyclic antidepressant that has been used to assist smoking cessation, although this is an unlabeled use [218].

For patients with stable COPD, respiratory symptoms, and FEV1 <60% predicted, the ACP, the ACCP, the ATS, and the ERS recommend treatment with inhaled bronchodilators.

(https://www.thoracic.org/statements/resources/copd/179full.pdf Last Accessed: October 25, 2022)

Strength of Recommendation: Strong (Benefits clearly outweigh risks and burden)

Bronchodilators are the cornerstone of treatment of COPD and are recommended as first-line therapy in patients with demonstrable airflow limitation or other symptoms. They are effective in significantly improving COPD symptoms and quality of life, predominantly by emptying trapped air through the dilatation of distal airways. However, bronchodilators offer symptomatic relief only and do not modify the disease process. They are prescribed on an as-needed basis for symptomatic relief (short-acting) or on a regular basis (long-acting) to reduce or prevent COPD symptoms. Short-acting bronchodilators often result in medical noncompliance due to the problems caused by multiple dosing. This has shifted the focus to the development of long-acting and ultra-long-acting bronchodilators that can induce sustained bronchodilation (12 to 24 hours). This once- or twice-daily dosing regimen improves compliance. As such, long-acting inhaled bronchodilators (i.e., beta2-agonists and muscarinic antagonists [LAMA]) now form the backbone of COPD management [176; 177; 178].

The side effects of bronchodilators are dose dependent and typically predictable. Adverse effects are more common in older patients and those with advanced COPD and comorbidities. However, they usually resolve promptly after medication withdrawal.

Bronchodilators increase FEV1 and affect other spirometric variables, usually by relaxing smooth muscle tone in the airway. They improve lung emptying, reduce dynamic hyperinflation at rest and during exercise, and increase exercise performance (Table 14) [8]. The degree of these changes, particularly in more advanced COPD, is difficult to predict from the improvement in FEV1. While these drugs reduce impedance to air flow and improve the efficiency of expiration, lung elastic recoil remains unchanged. Bronchodilators that act predominantly on the smooth muscles of the airway do not have a significant impact on the decline of lung function or disease prognosis.

Inhaled bronchodilators require attention to training in inhaler technique for proper drug delivery. The choice of inhaler device and bronchodilator depends on:

Inhaled bronchodilators are administered via metered-dose inhaler, dry powder inhaler, or nebulizer (jet or ultrasonic).

Metered-dose inhalers rely on a mixture of medication, preservatives, and liquid propellant gas to deliver medicine into the lungs in aerosol form. Some metered-dose inhalers discharge medication after a trigger is pressed, but newer versions are breath activated. For patients with poor coordination or impaired hand function, such as those with arthritis or with a history of stroke, breath-activated devices may improve medication delivery. The drawback of the breath-activated inhalers is that a lack of air may make device triggering difficult. Some patients require the assistance of a spacer when using an inhaler.

Breath-activated dry powder inhalers incorporate the same benefits as other breath-activated inhalers; patients are not required to coordinate inhaling with releasing medication. Some dry powder inhalers have a different delivery system involving the insertion of a capsule with medicated, fine powder into the canister. Depending upon the patient's ability to breathe in deeply, variable amounts of medication may be inhaled. Another concern involves the effect of humidity on dry powder, which may influence dose strength.

The nebulizer acts as a vaporizer or humidifier, delivering microdroplets of asthma medication in spray form and allowing a patient to breathe it in through a mouthpiece or face mask. Larger doses from nebulizers may increase the risk of side effects, and studies have shown metered-dose inhalers to be as effective as nebulizers in delivering medication to the lungs [71,72]. Wet nebulizers are usually not prescribed for regular treatment of COPD because they are more expensive and need regular maintenance [81].

Three classes of bronchodilators are available for the treatment of COPD and may be used alone or in combination: beta2-agonists, muscarinic antagonists (also referred to as anticholinergics), and methylxanthines. All classes of bronchodilators exhibit a similar effect on FEV1 with identical dose of medication. Toxicity with bronchodilators is dose dependent.

Beta2-Agonists

Beta2-agonists stimulate beta2-adrenergic receptors, resulting in increases in cyclic adenosine monophosphate and bronchodilation. Inhaled beta2-agonists produce a rapid bronchodilator effect, a response observed more quickly in asthma patients than those with COPD. Short-acting beta2-agonists produce bronchodilation for a duration of not more than 4 to 6 hours, while long-acting agents, such as salmeterol and formoterol, produce bronchodilation for more than 12 hours [87]. More recently, vilanterol and olodaterol were approved for use in the treatment of COPD. These novel beta2-agonists have 24-hour duration of action, allowing for once-daily dosing [86,226].

It has been observed that increasing the dose of either a beta 2-agonist or a muscarinic antagonist by an order of magnitude, particularly when given via wet nebulizer, offers subjective relief in acute episodes of COPD but is not necessarily beneficial in stable disease [199]. Rather than increasing dose for increased disease severity, another agent should be added to the treatment regimen.

In rare cases, inhaled beta2-agonists can cause resting sinus tachycardia and cardiac arrhythmias in patients with COPD [199]. At higher doses, these agents can cause exaggerated somatic tremor in the elderly. In fact, the risk of all adverse effects increases in a dose dependent manner, so the dose should be monitored carefully. Hypokalemia may occur, particularly when beta2-agonists are given together with a thiazide diuretic. Some patients experience a mild reduction in partial pressure of oxygen (PaO₂) if short- and long-acting beta2-agonists are administered together. Despite the concerns raised related to beta2-agonists in the management of asthma, further detailed study has found no association between beta2-agonist use and an accelerated loss of lung function or increased mortality in COPD [199].

Muscarinic Antagonists

Muscarinic antagonists act to block acetylcholine's effect on M3 receptors. Short-acting muscarinic antagonists also alter neurotransmission at the pre-ganglionic junction and block M2 receptors. Tiotropium, a long-acting muscarinic antagonist, is M3- and M1-muscarinic receptor selective and is effective for more than 24 hours [88,89,90]. Short-acting inhaled anticholinergics produce bronchodilation for a longer duration than short-acting beta2-agonists, but their use is generally limited to the treatment of exacerbations.

Regular use of muscarinic antagonists, both short- and long-acting, improves overall clinical and health status, enhances the effectiveness of pulmonary rehabilitation, and reduces the rate of exacerbations [84,85]. These agents are often the preferred bronchodilators for COPD due to their greater efficacy and minimal cardiac stimulatory effects compared to those of beta2-agonists.

Muscarinic antagonists are comparatively safer to use and have fewer side effects than other available bronchodilators. The main side effects result from antimuscarinic activity and include xerostomia and a bitter, metallic taste. Studies indicate an increased risk for cardiovascular events, specifically heart failure, acute coronary syndrome, or dysrhythmias) associated with the muscarinic antagonist ipratropium bromide, making tiotropium the preferred agent [91]. Acute glaucoma has been observed in a few patients after wet nebulization with a face mask. These drugs do not have any effect on mucociliary clearance, and there is no increased risk of respiratory infection.

Methylxanthines

Methylxanthines have weak bronchodilator and respiratory stimulant properties. Both of the available methylxanthines (aminophylline and theophylline) are administered orally and have variable durations of action (up to 24 hours). The inhaled bronchodilators are preferred over these oral agents, as the latter tends to be less predictable and more toxic. Although useful for some patients, the methylxanthines are a third-line option in the treatment of stable COPD [199].

The therapeutic ratio of methylxanthines is small, meaning that near-toxic doses are often required to achieve efficacy. Side effects include nausea, headache, heartburn, insomnia, cardiac arrhythmias, and convulsions. The risk of overdose (accidental or intentional) is high with these agents. Several drugs and other factors affect the metabolism of methylxanthines, including anticonvulsants, quinolone antibiotics, alcohol, nicotine, and erythromycin [104].

Combination Bronchodilator Therapy

Combining bronchodilators can improve the impact of therapy with similar or fewer adverse effects. The combination of a beta2-agonist and a LAMA has been shown to be more effective than monotherapy with either agent [126,146,147,148,149,150,151,152]. This is believed to be related to the synergistic effect of combining the different mechanisms of action. One of the disadvantages of such an approach is delivery of LAMA and long-acting beta2-agonists at different locations in the lung, which results in a lowering of their synergistic potential.

Bronchodilator Research

The single molecule GSK961081 has dual properties of both antimuscarinic and beta2-agonist agents and is being investigated for its bronchodilator effect. This molecule can deliver the drugs to the same location, leading to optimum synergistic effect [180].

Discovery of novel classes of bronchodilator drugs has proved to be difficult. The focus has shifted to developing drugs that inhibit the contractile machinery in airway smooth muscle, including rho kinase inhibitors, myosin light chain kinase inhibitors, and direct smooth muscle myosin inhibitors. Even as research focuses on novel approaches to address the underlying pathophysiology of COPD, management of the disease remains largely palliative, with minimal impact on the inflammatory process that ultimately leads to a decline in lung function.

Corticosteroids, both oral and inhaled, have a limited role in the treatment of COPD except for exacerbations. Although used in the past to identify patients who would be more likely to respond to inhaled steroids, a number of studies have observed that improvement on a short course of oral corticosteroids is not a reliable predictor of the long-term response [199]. Therefore, it is difficult to recommend a therapeutic trial with oral corticosteroids in late stage (moderate to very severe) COPD.

Some retrospective studies have evaluated the effect of oral corticosteroids on long-term FEV1 changes in patients with moderate to very severe COPD [154,155]. However, long-term oral treatment is not recommended for patients with COPD because of numerous side effects and limited therapeutic benefit. Extended use of systemic corticosteroids can result in a variety of adverse effects, including steroid myopathy, respiratory failure, osteoporosis, and Cushing syndrome.

Although regular treatment with inhaled corticosteroids does not result in the long-term reduction of FEV1 in patients with COPD, it does reduce the frequency of exacerbations and positively impacts overall health status in certain patients [92,93,94,95]. Withdrawal from such treatment may result in COPD exacerbations in these patients [96]. Treatment with inhaled corticosteroids can be recommended for patients with advanced COPD (FEV1 <50%) with frequent exacerbations. Some pooled studies observed that this treatment reduces mortality, but this observation requires further evidence [97]. An inhaled corticosteroid in combination with a long-acting beta2-agonist has a higher efficacy than either drug alone [98,99].

Reversal of Corticosteroid Resistance

There is mounting evidence that resistance to corticosteroid treatment is the result of a reduction in histone deacetylase-2 (HDAC2) due to oxidative and nitrative stress [188]. Reversal of this corticosteroid resistance by increasing the expression and activity of HDAC2 may be beneficial in the treatment of COPD.

Animal studies have shown that low-dose oral theophylline may increase HDAC2 expression in alveolar macrophages and restore steroid responsiveness in patients with COPD [189]. Further studies may provide novel therapeutic strategies to restore corticosteroid responsiveness with fewer side effects and adverse effects.

Antioxidants. Patients with COPD have increased oxidative stress, especially during exacerbations. Oxidative stress lowers steroid responsiveness by reducing HDAC2 activity and expression, and antioxidants may reverse corticosteroid resistance and reduce inflammation. Glutathione-based antioxidants are weak and easily inactivated by oxidative stress; therefore, researchers are now focusing on more potent and stable antioxidants, such as superoxide dismutase mimics and nicotinamide adenine dinucleotide phosphate oxidase inhibitors [190].

Macrolides. Azithromycin taken on a regular basis has been shown to reduce the frequency of exacerbations in former smokers with COPD prone to exacerbations. In a double-blind, placebo-controlled trial involving patients with three or more COPD exacerbations the previous year, 500 mg azithromycin three times per week for one year was associated with a significant reduction in the adjusted exacerbation rate per year (1.94 vs. 3.22 exacerbations in the placebo group) [192]. The decision to administer a macrolide on a chronic basis should take into account the potential risks of ototoxicity and the induction of respiratory tract bacterial resistance [199].

Alternative Anti-Inflammatory Treatments

Because inflammation in COPD lungs is predominantly corticosteroid-resistant, alternative anti-inflammatory treatment is often required [184,185]. The majority of broad-spectrum anti-inflammatory agents are systemic in nature, and there are doubts over the safety of such drugs. Therefore, an inhaled delivery may be the optimum mode to increase efficacy and decrease side effects.

Phosphodiesterase-4 (PDE4) is the principal PDE expressed in neutrophils, T-cells, and macrophages, indicating that PDE4 inhibitors would be effective in controlling inflammation in COPD [186]. Oral PDE4 inhibitors have good potential because there are fewer compliance issues and easy availability. Roflumilast, a selective PDE4 inhibitor that inhibits lung inflammation and emphysema, has been developed and approved for treatment of COPD. It is an orally administered drug found to marginally improve FEV1 compared to tiotropium [181]. Roflumilast is recommended for patients with moderate and severe COPD and chronic bronchitis who have frequent exacerbations treated with systemic corticosteroids [199]. However, PDE4 inhibitors have gastrointestinal side effects, such as nausea, diarrhea, reduced appetite, and weight loss. Roflumilast should be avoided in underweight patients.

Influenza and pneumococcal vaccines are effective in preventing some of the infections that cause COPD exacerbations and should be administered to all patients with COPD. Annual vaccination against influenza reduces the incidence of serious illness and mortality [100]. Influenza vaccines containing killed or live, inactivated viruses have a greater efficacy in elderly patients with COPD and therefore are highly recommended. Because of antigenic drift, newly attuned vaccines are developed each year in order to assure appropriate efficacy; therefore, the patient with COPD should be immunized against influenza annually [101].

Pneumococcal vaccines have improved over time by broadening the coverage of serotypes in the vaccine to include those that cause the most common invasive infections. At present, the CDC recommends either a single dose of 20-valent pneumococcal conjugate vaccine (PCV20) (Prevnar 20) or one dose of PCV15 may be administered followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) given at least one year after the PCV15 dose [102]. A minimum interval of eight weeks between PCV15 and PPSV23 can be considered for adults with COPD to minimize the risk of invasive pneumococcal disease caused by serotypes unique to PPSV23 in these vulnerable groups [102,103]. Current information, schedules, and guidance for adult immunizations is maintained by the CDC at https://www.cdc.gov/vaccines/schedules.

Alpha-1 antitrypsin augmentation therapy (i.e., weekly infusion of alpha-1 antitrypsin protein from healthy donors) is suitable for young patients who have severe hereditary alpha-1 antitrypsin deficiency and emphysema [199]. However, this therapy is quite expensive and is available in only a few countries. It is not recommended for patients without alpha-1 antitrypsin deficiency.

The ACP, the ACCP, the ATS, and the ERS recommend that clinicians should prescribe pulmonary rehabilitation for symptomatic patients with an FEV1 <50% predicted.

(https://www.thoracic.org/statements/resources/copd/179full.pdf Last Accessed: October 25, 2022)

Strength of Recommendation: Strong (Benefits clearly outweigh risks and burden)

Pulmonary rehabilitation is a multidisciplinary and comprehensive intervention that is individually tailored for patients with COPD. Its principal goals are to:

Pulmonary rehabilitation can address nonpulmonary conditions that are not addressed by the medical management of COPD, including:

Addressing and treating such problems can disrupt the "vicious circle" in COPD, leading to overall improvement in all aspects of COPD. Patients involved in pulmonary rehabilitation experience an 11% increase in peak oxygen consumption, an 18% increase in peak workload, and an 87% increase in endurance time [105].

Exercise training programs are beneficial at all stages of COPD and can improve exercise tolerance and reduce symptoms of dyspnea and fatigue. Pulmonary rehabilitation requires a multidisciplinary approach involving a number of health professionals from different specialties and may be conducted in outpatient, inpatient, or home settings.

The following factors should be considered in choosing patients for pulmonary rehabilitation [199]:

Program Components

The components of pulmonary rehabilitation vary widely from program to program, but a comprehensive pulmonary rehabilitation program includes proper exercise training, nutrition counseling, and education.

Bicycle ergometry or treadmill exercise is usually the best option to evaluate exercise tolerance, with measurement of maximum heart rate, maximum work performed, and maximum oxygen consumption. Another simple approach is the self-paced, timed walking test (e.g., six-minute walking distance). These tests require at least one practice session before the interpretation of data. Shuttle walking tests are easier to perform than treadmill tests and provide more detailed information compared to a self-paced test. Exercise training lasts 10 to 45 minutes per session and can be performed daily or weekly. Severely disabled patients should use a simple wheeled walking aid, as it improves walking distance and dyspnea [107]. Other modes of improving outcomes include use of oxygen during exercise, exercising while breathing heliox gas mixtures, unloading the ventilatory muscles while exercising, or use of pursed lip breathing [108,109]. Anabolic steroids, specific strength training, and the use of neuromuscular electrical stimulation are also being investigated for their perceived benefits in COPD rehabilitation programs [106].

Studies have observed that programs involving less than 28 sessions demonstrate inferior results compared to those with longer treatment periods [199]. The minimum duration of an effective rehabilitation program is six weeks. But long-term beneficial effects are not usually maintained after cessation of rehabilitation regardless of program [110].

Patients who are not able to participate in a formal rehabilitation program should be encouraged to exercise on their own. The addition of upper limb exercises or other strength training to aerobic training is beneficial in improving strength; however, it has no beneficial effect on overall quality of life or exercise tolerance [199].

Nutritional status is a key determinant of morbidity and mortality, disability, symptom severity, and overall prognosis in an individual with COPD, and nutrition counseling is an important part of rehabilitation. Approximately 25% of patients with stage 2–4 (moderate to very severe) disease have a low BMI and fat-free mass. Reduced BMI is associated with increased mortality in patients with COPD. Healthcare providers should identify and correct the factors responsible for reduced calorie intake and take steps to improve overall nutrition status in such cases. Patients should be advised to take frequent, small meals, especially those who experience dyspnea while eating. Proper dental hygiene and correction of poor dentition is also vital.

Improvement in the nutritional status of patients with COPD leads to an increase in respiratory muscle strength. However, the cost-effectiveness of this treatment is controversial. Increased calorie intake and an exercise regimen can also be beneficial in patients with COPD without significant nutritional depletion [111]. Anabolic steroids increase body weight and lean body mass in patients with weight loss, but they are not effective in increasing exercise capacity [113,114].

As noted, the majority of pulmonary rehabilitation programs include an educational component. However, the benefits of continuing patient education have not been established.

Assessment and Follow-Up

Baseline and outcome evaluation should be assessed to quantify individual benefits and scope for improvement. This should include:

In patients with COPD who suffer from muscle wasting, lower limb strength and inspiratory and expiratory muscle strength should be evaluated. Patient history and physical examination are not useful in outcome assessment but are the principal criteria for baseline status and establishing entry suitability.

Several questionnaires are being used to aid in the assessment of health and mental health status, including questionnaires that are specifically designed for patients with COPD. The Medical Outcomes Study Short Form, the Dyspnea Management Questionnaire, and/or the Hospital Anxiety and Depression Scale (HADS) may be useful to improve identification and management of COPD symptoms [112,129,130].

Oxygen therapy is one of the main nonpharmacologic treatments for stage 4 COPD and can be administered as long-term continuous therapy, therapy during exercise, or therapy to relieve acute dyspnea.

The primary goal of oxygen therapy is to maintain or increase the baseline PaO₂ to at least 8.0 kPa (60 mm Hg) at sea level and rest and/or to produce an oxygen saturation (SaO₂) of at least 90%, which will protect vital organ function by ensuring sufficient delivery of oxygen. Long-term oxygen therapy (i.e., more than 15 hours per day) has been shown to improve survival in patients with chronic respiratory failure [199]. It also has a positive effect on lung function, hemodynamics, exercise tolerance, hematologic characteristics, and mental health [115]. Oxygen therapy may also prevent the progression of pulmonary hypertension.

Long-term oxygen therapy is usually indicated in stage 4 COPD for patients who have [199]:

Oxygen is usually delivered by a facemask, with inspiratory flow rates ranging between 24% and 35%. During air travel, patients should be instructed to increase the flow by 1–2 L/min. The facemask allows appropriate and accurate titration of oxygen, which is especially beneficial in patients who are susceptible to CO₂ retention. However, facemasks are readily dislodged and hinder eating and conversation, so many patients prefer nasal cannulae. Oxygen delivery by nasal cannulae necessitates additional blood gas monitoring.

The ACP, the ACCP, the ATS, and the ERS assert that use of supplemental oxygen for 15 or more hours daily can help improve survival in patients with COPD who have severe resting hypoxemia (PaO₂ ≤55 mm Hg or SaO₂ ≤88%).

(https://www.thoracic.org/statements/resources/copd/179full.pdf Last Accessed: October 25, 2022)

Strength of Recommendation: Strong (Benefits clearly outweigh risks and burden)

More sophisticated and specialized methods of oxygen delivery are available but should only be used in specialized facilities. Long-term home oxygen therapy may be provided from a fixed oxygen concentrator with plastic piping, allowing the patient to use oxygen at home. Duration of treatment should be at least 15 hours per day, preferably longer.

An extra supply of oxygen should be given to allow patients to go outdoors for an appropriate period of time and to exercise while maintaining oxygen saturation greater than 90%. Oxygen therapy during exercise can increase endurance and/or reduce the degree of end-exercise dyspnea or breathlessness. However, studies have observed that ambulatory oxygen therapy has a poor compliance in patients with COPD [116].

Supplemental home oxygen is generally the most expensive component of outpatient therapy for patients who require it. Oxygen concentrator devices may be less expensive than cylinder delivery systems.

Noninvasive ventilation, via the use of both negative and positive pressure ventilation devices, is extensively used to treat acute exacerbations of COPD. Noninvasive ventilation should be the treatment of choice for persistent hypercapnic ventilatory failure during COPD exacerbations in spite of optimal medical treatment [199]. Negative pressure ventilation is not recommended for the chronic management of stage 4 COPD with or without CO₂ retention. Data do not support combination noninvasive intermittent positive pressure ventilation (NIPPV) with long-term oxygen therapy [117]. However, the addition of NIPPV can reduce CO₂ retention and improve dyspnea in some patients [118].

Possible complications of NIPPV include nasal congestion, nasal bridge ulceration, and facial skin erythema. In addition, contraindications for NIPPV include:

Surgical intervention may be indicated for selected patients with severe COPD and decreased exercise endurance that is responding poorly to medical management. CT evaluation of lung anatomy helps determine whether surgical intervention will be of benefit. Patient selection criteria vary by the surgical technique, but in general, patients who undergo surgical intervention have stage 4 COPD.

There is a limit beyond which it is inadvisable to perform surgery for high-risk patients, as the risks outweigh the perceived benefits. Patients undergoing pneumonectomy with a preoperative FEV1 <2 L or 50% predicted and/or a carbon monoxide diffusing capacity (DLCO) <50% predicted have a high risk of postoperative respiratory failure [119]. Patients with poor lung function should be thoroughly investigated for regional distribution of perfusion and exercise capacity [120]. Surgery should not be performed during COPD exacerbations.

Postoperative pulmonary complications are a principal element of the increased risk associated with surgery in patients with COPD. The main risk factors are smoking, age, poor health, obesity, and COPD severity. All COPD candidates for lung resection should undergo a number of tests prior to surgery, including:

Bullectomy

Bullectomy is an older procedure that may be of use for patients with COPD and bullous emphysema. It involves the resection of a large, nonfunctional bulla that is compressing the adjacent lung parenchyma.

Thoracoscopic bullectomy is beneficial in reducing dyspnea and improving lung function [132]. It may also reduce hemoptysis, infection, and chest pain and facilitate re-expansion of a compressed lung region. A thoracic CT scan, arterial blood gas measurement, and comprehensive lung function tests are required before making a decision for bullectomy. Indications for this surgical intervention include the absence of significant hypoxemia, normal or near normal diffusing capacity, and evidence of regional reduction in perfusion with good perfusion in the remaining lung. Several other factors predict a positive or negative outcome with bullectomy (Table 15) [73].

Lung Volume Reduction Surgery

Lung volume reduction surgery (LVRS) is a surgical procedure in which damaged parts of the lung are resected to reduce hyperinflation, thus improving efficacy of respiratory muscles. LVRS also improves expiratory flow rates by increasing the elastic recoil pressure of the lung. LVRS is considered for patients with bilateral emphysema on HRCT and severe obstruction with hyperinflation and air trapping [194]. As with bullectomy, certain characteristics may indicate the likelihood of a favorable or unfavorable outcome with LVRS (Table 16) [73].

Lung Transplantation

Lung transplantation is a therapeutic option in appropriately selected patients with very advanced COPD. Criteria for referral for lung transplantation include COPD with a BODE index exceeding 5. Recommended criteria for listing include a BODE index of 7–10 and at least one of the following [199]:

Patients must remain symptomatic despite optimal medical treatment in order to be considered for transplant. In addition, prognosis should be assessed. Only patients with predicted disease-related survival equal to or less than the predicted survival after transplantation should be selected [194]. Transplantation improves lung function, exercise capacity, quality of life, and survival in patients with end-stage disease [133].

The number of lung transplantations performed is curtailed by a shortage of donor organs. To address this, specialized centers are adopting the single-lung technique. Common complications of this procedure include:

Despite making strides in understanding the mechanism and pathophysiology of COPD, treatment strategies have not changed significantly in the last few decades. However, the possibility of lung regeneration is offering a hope of cure. Lung regeneration has the potential to replace or repair nonfunctional tissue via restoration of functional alveoli and alveolar ducts. Advances made in the field of stem cells (embryonic and adult-derived) and the ability to differentiate them into chosen cell types offer a glimpse into the future of lung regeneration. Two main approaches are being evaluated for possible reversal of structural disease:

Extrinsic Cell Therapy

Human exogenous stem cells can differentiate into type II pneumocytes and can possibly regenerate lung parenchyma, including alveoli. Sophisticated technologies and methods are being used to produce pure populations of exogenous stem cells, which is necessary to prevent the development of teratomas. However, there are two major hurdles for the development of this therapy. The first is an ethical issue, as stem cells are extracted from human embryos, which has been controversial in the United States. The second hurdle is risk of rejection, because the differentiated type II cells would not be autologous. The use of autologous adult stem cells can solve both these problems. Direct administration of differentiated type II cells is better than intravenous administration of mesenchymal stem cells [182].

Endogenous stem cell therapy avoids complications related to extrinsic cell therapy, particularly rejection. Tissue-specific stem cell populations have the capability to regenerate lung parenchyma. Research is being done to induce lung tissue regeneration without utilizing specific stem cell populations [182].

Retinoic Acid

Retinoic acid, particularly all-trans-retinoic acid (ATRA), plays an important role in fetal lung development and increases alveolar septation. ATRA also restores the normal lung structure in rats with emphysema. However, ATRA has not definitely shown beneficial effects in patients with emphysema [183].

Patients experiencing an exacerbation of COPD may have difficulty performing even a simple pulmonary function test such as spirometry. Spirometric measurements are not reliable during an acute exacerbation and thus are not recommended.

Pulse oximetry is helpful in determining a patient's need for supplemental oxygen therapy during exacerbations. Accurate arterial blood gas measurement is also crucial to assess the severity of an exacerbation, especially in patients requiring hospitalization for their COPD. Respiratory failure is characterized by a PaO₂ <8.0 kPa (60 mm Hg) and/or SaO₂ <90% with or without PaCO₂ >6.7 kPa (50 mm Hg) when breathing room air. Mechanical ventilation is indicated when there is moderate-to-severe respiratory acidosis (pH ≤7.35) plus hypercapnia (PaCO₂ >6–8 kPa or 45–60 mm Hg) in a patient with COPD and severe dyspnea with clinical signs suggestive of respiratory muscle fatigue, increased work of breathing, or both, such as use of respiratory accessory muscles, paradoxical motion of the abdomen, or retraction of the intercostal spaces [199].

Pulmonary embolism (without infarction) has a similar clinical presentation to an exacerbation of COPD, and it may be difficult to distinguish between the two, particularly in patients with advanced COPD who may already have developed clinical, radiographic, and electrocardiographic (ECG) signs of right heart strain. A history of transient syncope, hypotension, or an inability to increase PaO₂ greater than 8.0 kPa (60 mm Hg) despite high-flow oxygen should raise suspicion for pulmonary embolism. The two conditions are not mutually exclusive; in fact, cor pulmonale is a risk factor for pulmonary embolism. Treatment for both, at least initially, may be the best option when pulmonary embolism is suspected and the diagnosis is unclear.

Chest radiographs with posterior/anterior and lateral views, combined with ECG, are helpful in differentiating other diseases that can mimic COPD exacerbations. These include cardiac arrhythmias, right ventricular hypertrophy, and myocardial ischemia.

A complete blood count may detect polycythemia (i.e., hematocrit >55%) or bleeding, but white blood cell counts do not provide any concrete information regarding exacerbations. Antibiotic treatment should be initiated promptly if there is fever or purulent sputum. Bacterial infections with S. pneumoniae, H. influenzae, or Moraxella catarrhalis are most frequently involved in COPD exacerbations. A sputum culture and an antibiogram are required when antibiotic treatment is ineffective against a COPD exacerbation.

Abnormal biochemical test results can be linked to COPD exacerbations and comorbid conditions. Common test abnormalities include metabolic acid-base disorder, electrolyte disturbance, and poor glucose control.

Beta2-agonists are highly effective in the home management of COPD exacerbations. Increasing the dose and/or frequency of beta2-agonists is beneficial in such cases. There is insufficient data to compare efficacy of different classes of short-acting bronchodilators; bronchodilator therapy delivered by metered-dose inhaler with a spacer and by hand-held nebulizer yield similar clinical responses.

For patients experiencing an exacerbation, systemic corticosteroids act by improving lung function, shortening recovery time, improving hypoxemia, and reducing the risk of early relapse, treatment failure, and duration of hospital stay. If the patient's baseline FEV1 is less than 50% predicted corticosteroids may be added to the bronchodilator(s) to improve the response to treatment. A regimen commonly used is prednisone 30–40 mg daily for 7 to 10 days. There is little reason to taper the dosage as exogenous steroids administered for less than 10 days rarely causes significant adrenal suppression.

Antimicrobial therapy is indicated for patients who present with all the cardinal features of a COPD exacerbation, but if there is little change in sputum volume and no shift toward purulence, then, absent fever, antibiotics are unlikely to be of benefit. Sputum culture requires 48 to 72 hours for meaningful results and thus is of limited usefulness in outpatient management of COPD. The selection of a specific antimicrobial should be made in consideration of the patient's age, severity of airway obstruction, comorbidities, and anticipated respiratory bacterial pathogens [25]. Amoxicillin/clavulanate or trimethoprim/sulfamethoxazole is a good choice for many patients; a macrolide or tetracycline has the advantage of covering atypical pathogens such as mycoplasma and Chlamydia species. A respiratory fluoroquinolone is preferred in patients with comorbidities, recent hospital discharge, or recent use of other antimicrobials.

Controlled oxygen therapy is a main component of the hospital treatment of acute COPD exacerbations. Careful titration of supplemental oxygen is essential to improve the patient's hypoxemia. Safer levels of oxygenation (PaO₂ >8.0 kPa/60 mm Hg or SaO₂ >90%) can be easily attained in uncomplicated COPD exacerbations; however, there is a danger of CO₂ retention that can develop insidiously. Arterial blood gases should be measured 30 to 60 minutes after the initiation of oxygen therapy to ensure adequate levels of oxygenation without acidosis or CO₂ retention. Compared to nasal prongs, Venturi masks provide more accurate delivery of controlled oxygen but are less well tolerated by patients.

A short-acting inhaled beta2-agonist administered by nebulizer every one to four hours is usually the bronchodilator of choice for initial treatment of COPD exacerbations. The addition of a muscarinic antagonist is recommended if prompt relief is not provided by the beta2-agonist. Methylxanthines may be considered as second-line intravenous therapy when there is insufficient response to short-acting bronchodilators [199].

Corticosteroid, administered orally or intravenously, is recommended for moderate-to-severe acute exacerbations [199]. A dose equivalent to 30–40 mg prednisone daily is commonly used for a 7- to 10-day period [104,199]. Corticosteroid therapy for longer than two weeks is rarely necessary, and extended use increases the risk of adverse effects.

As noted, acute exacerbations frequently occur in association with viral and/or bacterial upper respiratory infections. As a practical matter, most patients receive empirical antimicrobial therapy, and studies have observed a small beneficial effect of antibiotics on lung function in COPD exacerbations [199]. One clinical trial demonstrated a significant beneficial effect of antibiotics in patients who presented with increased breathlessness, sputum volume, and sputum purulence [199].

Based on the available evidence, antibiotics should be prescribed for patients with cough accompanied by increased sputum volume and purulence, increased dyspnea, and/or fever. Patients experiencing COPD exacerbation that necessitates mechanical ventilation (invasive or noninvasive) should also receive antibiotics.

The bacterial pathogens most commonly associated with COPD exacerbations are H. influenzae, S. pneumoniae, and M. catarrhalis. Atypical pathogens, such as Mycoplasma pneumoniae and Chlamydia pneumoniae, have also been detected in patients with COPD exacerbations. As FEV1 declines and patients have more frequent exacerbations and/or comorbid diseases, infections with H. influenzae and M. catarrhalis become more frequent. Pseudomonas aeruginosa is a consideration in patients with severe airway limitation or history of bronchiectasis [199].

The mode of administration depends on the ability of the patient to eat and the pharmacokinetics of the antibiotic. The oral route is the preferred mode of administration, but hospitalized patients should be treated parenterally, switching to the oral route when clinical stabilization permits. The initial selection of therapy, pending results of sputum culture, should address the most likely pathogens, taking into account local antimicrobial resistance patterns.

Respiratory stimulants are not prescribed for patients with COPD and acute respiratory failure. However, doxapram, a nonspecific but relatively safe respiratory stimulant, may be used only in cases when noninvasive intermittent ventilation (NIV) is not available or not recommended [125]. For these patients, doxapram can increase tidal volume and respiratory rate.

COPD exacerbations cause bronchoconstriction, airway inflammation, increased mucus production, and loss of elastic recoil, all of which reduce passive functional residual capacity at the end of expiration, shrink dynamic hyperinflation, and increase breathing effort [128]. These deficits may be managed with ventilator support in certain patients. The principal goals of ventilatory support are to reduce breathing load and to encourage efficient gas exchange and alveolar ventilation, which in turn decreases mortality and morbidity and relieves symptoms.

Ventilatory support can be categorized as:

Noninvasive Intermittent Ventilation

NIV is indicated for persistent hypercapnic ventilatory failure during exacerbations refractory to medical treatment. It should be provided only by specialized staff experienced and educated in this field.

Several clinical studies have successfully demonstrated the efficacy of NIV in acute respiratory failure, with success rates of 80% to 85% [126]. NIV decreases the rate of respiration, incidence of respiratory acidosis, severity of dyspnea or breathlessness, duration of hospitalization, and mortality and intubation rates [127]. NIV is not preferred for patients whose primary diagnosis is cardiac failure or pneumonia; however, it may be indicated in patients with these complications if escalation to intubation and ventilation is perceived to be inappropriate.

The selection criteria for NIV are based on clinical observations and gas exchange measurements. Patients with moderate-to-severe dyspnea with signs of increased breathing load (i.e., use of accessory muscles and paradoxical abdominal motion) and tachypnea (>25 breaths per minute) as well as moderate-to-severe acidosis (pH ≤7.35) and/or hypercapnia (PaCO₂ >6.0 kPa OR 45 mm Hg) are considered candidates for NIV [199]. Relative contraindications include [199]:

Certain factors are useful predictors of failure of NIV. These include:

Invasive Mechanical Ventilation

With the advent of better and more sophisticated technology, a number of indications for invasive mechanical ventilation are now being effectively treated with NIV. However, some patients will require more intensive ventilatory support. The indications for initiating invasive mechanical ventilation during exacerbations of COPD include:

The choice of whether or not to initiate invasive ventilation may also be influenced by non-medical factors. Cultural and psychologic aspects should be considered, as should any financial limitations. The major risks associated with mechanical ventilation are increased susceptibility to ventilator-acquired pneumonia (particularly when multidrug-resistant organisms are present), pulmonary barotrauma, and failure to wean to spontaneous ventilation [199]. However, ventilator-associated fatalities among patients with COPD and respiratory failure are comparatively fewer than among patients ventilated for non-COPD causes.

Weaning off mechanical ventilation can be difficult and potentially dangerous in patients with COPD. The key determinant of mechanical ventilatory dependency is the balance between the respiratory load and the ability of the respiratory muscles to deal with this load. The best method to wean patients from ventilator still remains unclear.

There are no clear guidelines for the optimal duration of hospitalization for patients with COPD exacerbation. Patients may be considered for discharge if they meet the following criteria:

Patients hospitalized with COPD exacerbations may be discharged earlier if visits by a home nurse are ensured. In patients who experience hypoxemia during a COPD exacerbation, arterial blood gas measurements and/or pulse oximetry should be conducted before discharge and in the following three months. Long-term supplemental oxygen therapy may be necessary in hypoxemic patients. Strategies to prevent future exacerbations should be evaluated before hospital discharge, with greater emphasis on smoking cessation, vaccination, medical compliance, inhaler technique, and recognition of exacerbation symptoms.

Patients should be scheduled for follow-up four to six weeks after discharge. Follow-up should include an assessment of the patient's ability to manage in his or her usual environment, FEV, inhaler technique, and understanding of the recommended treatment plan. Patients with stage 4 COPD should be assessed for the need for long-term oxygen therapy and/or home nebulizer.

The use of long-acting inhaled bronchodilators, inhaled corticosteroids, and combination inhalers should be specifically considered. Long-acting inhaled bronchodilators reduce the number of exacerbations and hospitalizations and delay the time of first/next hospitalization. Early outpatient pulmonary rehabilitation immediately following discharge is a safe and effective way to improve exercise capacity and health status. Social problems should be identified and discussed in detail if the patient experiences persisting disability.

Pitting ankle edema and elevated jugular venous pressure are the most common findings in patients with COPD and cor pulmonale. Because fluctuations in intrathoracic pressure are common, it is usually difficult to evaluate jugular venous pressure in patients with COPD. Several other studies, such as MRI, echocardiography, electrocardiography, and radionucleotide scintigraphy, are crucial for diagnosing cor pulmonale in these patients. Sleep studies may be necessary if cor pulmonale or hypoxemia develops with relatively mild airflow limitation or when sleep apnea is suspected.

Anemia affects approximately 25% of patients with COPD [61]. Smokers usually develop polycythemia in the presence of arterial hypoxemia, which is indicated by increase in hematocrit of more than 55%. However, a low hematocrit signifies a poor prognosis in patients receiving long-term oxygen therapy [62].

Beta-Blockers

Beta-blockers are effective in helping to control hypertension and coronary artery disease, but practice guidelines generally indicate that these agents are contraindicated in patients with COPD [199]. This was based primarily on case reports of acute bronchospasm precipitated by high doses of noncardioselective beta-blockers, but evidence increasingly supports the use of cardioselective beta-blockers for the management of cardiovascular comorbidities in patients with COPD [161]. A Cochrane review found that cardioselective beta-blockers were safe and effective in patients with COPD with cardiac failure and should not be withheld, even in the presence of severe airflow limitation [142]. Short et al. observed a reduction in all-cause mortality in patients with COPD being treated with beta-blockers [143]. Beta-blocker use was also not associated with a decline in lung function. Among study participants, use of beta-blockers reduced the risk of cardiac death, respiratory death, oral corticosteroid use, and respiratory-related hospitalizations.

Statins

Statins have the beneficial effect of lowering lipid levels in patients with COPD with cardiovascular disease. Statins have been shown to reduce all-cause mortality, COPD-related mortality, and the need for respiratory-related urgent care [163]. Several single studies have observed a reduction in the number of exacerbations, exertional dyspnea, and inflammation and a minimal decline in lung function [163].

Anticoagulation is the mainstay of pulmonary embolism treatment in all cases. This involves the administration of anticoagulants such as unfractionated heparin, low-molecular-weight heparin, or fondaparinux. Warfarin, acenocoumarol, or phenprocoumon therapy is started within several days of this initial treatment.

Systemic thrombolysis is highly effective in treating pulmonary embolism, especially massive and submassive pulmonary embolisms. Commonly used fibrinolytic drugs to address thrombolysis include streptokinase, urokinase, and recombinant tissue plasminogen activators such as alteplase, reteplase, and tenecteplase. Surgical or catheter embolectomy is indicated when fibrinolytic drugs fail to induce improvement, thrombolysis is contraindicated, or persistent pulmonary vascular obstruction is present.