Chronic Obstructive Pulmonary Disease (COPD) and Emphysema in Emergency Medicine

Background

Chronic obstructive pulmonary disease (COPD) is estimated to affect 32 million persons in the United States and is the fourth leading cause of death in this country. Patients typically have symptoms of both chronic bronchitis and emphysema, but the classic triad also includes asthma. Most of the time COPD is secondary to tobacco abuse, although cystic fibrosis, alpha-1 antitrypsin deficiency, bronchiectasis, and some rare forms of bullous lung diseases may be causes as well.

Patients with COPD are susceptible to many insults that can lead rapidly to an acute deterioration superimposed on chronic disease. COPD exacerbation is an important but occasionally overlooked parameter. COPD exacerbations are very common, affecting about 20% of patients with moderate-to-severe COPD (1.3 events per year in patients with 40-45% predicted FEV1). A large observational cohort study found that the rate of COPD exacerbations reflects an independent susceptibility phenotype. [1] Knowledge of this susceptibility phenotype may have implications for targeting treatment of exacerbation and prevention across all COPD severities. Quick and accurate recognition of these patients along with aggressive and prompt intervention may be the only action that prevents frank respiratory failure.

Pathophysiology

Chronic obstructive pulmonary disease (COPD) is a mixture of three separate disease processes that together form the complete clinical and pathophysiological picture. These processes are chronic bronchitis, emphysema and, to a lesser extent, asthma. Progression of COPD is characterized by the accumulation of inflammatory mucous exudates in the lumens of small airways and the thickening of their walls. These walls become infiltrated by adaptive and innate inflammatory immune cells. Infiltration of the airways with substances such as polynuclear and mononuclear phagocytes and CD4 T cells increases with each stage of disease progression. This is also true for B cells and CD8 T cells, which organize into lymphoid follicles. This chronic inflammatory process is associated with tissue repair and remodeling that ultimately determines the pathologic type of COPD. It appears that smoking may overcome the body's natural mechanisms for limiting this immune response. This process can continue in susceptible individuals even after smoking cessation. Even if the original noxious insults are removed, COPD is still characterized by progressive accumulation of cells of the immune system, fibrosis, and mucus hypersecretion. The molecular basis for the lung inflammation seen in COPD is still an area of great research and debate, with the potential roles of cytokines, complex autoimmune processes, and immune modulation from chronic infection all under investigation. The defining feature of COPD is irreversible airflow limitation during forced expiration. This may be a result of a loss of elastic recoil due to lung tissue destruction or an increase in the resistance of the conducting airways. The standard measure of COPD is the measure of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC), FEV1/FVC. Each case of COPD is unique in the blend of processes; however, 2 main types of the disease are recognized. Chronic bronchitis In this type, chronic bronchitis plays the major role. Chronic bronchitis is defined by excessive mucus production with airway obstruction and notable hyperplasia of mucus-producing glands, as depicted in the images below.

Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells.

Chronic obstructive pulmonary disease (COPD). Histopathology of chronic bronchitis showing hyperplasia of mucous glands and infiltration of the airway wall with inflammatory cells (high-powered view). Damage to the endothelium impairs the mucociliary response that clears bacteria and mucus. Inflammation and secretions provide the obstructive component of chronic bronchitis. In contrast to emphysema, chronic bronchitis is associated with a relatively undamaged pulmonary capillary bed. Emphysema is present to a variable degree but usually is centrilobular rather than panlobular. The body responds by decreasing ventilation and increasing cardiac output. This V/Q mismatch results in rapid circulation in a poorly ventilated lung, leading to hypoxemia and polycythemia. Eventually, hypercapnia and respiratory acidosis develop, leading to pulmonary artery vasoconstriction and cor pulmonale. With the ensuing hypoxemia, polycythemia, and increased CO2 retention, these patients have signs of right heart failure and are known as "blue bloaters." Emphysema The second major type is that in which emphysema is the primary underlying process. Emphysema is defined by destruction of airways distal to the terminal bronchiole. Physiology of emphysema involves gradual destruction of alveolar septae and of the pulmonary capillary bed, leading to decreased ability to oxygenate blood. The body compensates with lowered cardiac output and hyperventilation. This V/Q mismatch results in relatively limited blood flow through a fairly well oxygenated lung with normal blood gases and pressures in the lung, in contrast to the situation in blue bloaters. Because of low cardiac output, however, the rest of the body suffers from tissue hypoxia and pulmonary cachexia. Eventually, these patients develop muscle wasting and weight loss and are identified as "pink puffers."

Etiology of COPD

In general, the vast majority of chronic obstructive pulmonary disease (COPD) cases are the direct result of tobacco abuse. [2] While other causes are known, such as alpha-1 antitrypsin deficiency, cystic fibrosis, air pollution, occupational exposure (eg, firefighters), and bronchiectasis, this is a disease process that is somewhat unique in its direct correlation to a human activity.

Epidemiology

US frequency In smokers, two thirds of men and one fourth of women have emphysema at death. Overall, 6.3% of the US adult population have been told by a healthcare worker that they have chronic obstructive pulmonary disease (COPD), or about 15 million individuals. It is notable that many more have never been formally diagnosed. Sex Men are more likely to have COPD than women. Age COPD occurs predominantly in individuals older than 40 years.

Prognosis Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States, affecting 32 million adults. It is also the sixth leading cause of death worldwide. [3] Patient's age and postbronchodilator FEV1 are the most important predictors of prognosis. Young age and FEV1 greater than 50% of predicted are associated with a good prognosis. Older patients and those with more severe lung disease do worse. Supplemental oxygen (when indicated) has been shown to increase survival rates. Smoking cessation improves the prognosis. Cor pulmonale, hypercapnia, tachycardia, and malnutrition indicate a poor prognosis.

Clinical Presentation

History Patients with chronic obstructive pulmonary disease (COPD) present with a combination of signs and symptoms of chronic bronchitis, emphysema, and asthma. Symptoms include worsening dyspnea, progressive exercise intolerance, and alteration in mental status. In addition, some important clinical and historical differences can exist between the types of COPD. In the chronic bronchitis group, classic symptoms include the following:

Productive cough, with progression over time to intermittent dyspnea
Frequent and recurrent pulmonary infections
Progressive cardiac/respiratory failure over time, with edema and weight gain

In the emphysema group, the history is somewhat different and may include the following set of classic symptoms:

A long history of progressive dyspnea with late onset of nonproductive cough
Occasional mucopurulent relapses
Eventual cachexia and respiratory failure

Physical Examination Depending on the type of chronic obstructive pulmonary disease (COPD), physical examination findings may vary. Chronic bronchitis (blue bloaters) findings may be as follows:

Patients may be obese.
Frequent cough and expectoration are typical.
Use of accessory muscles of respiration is common.
Coarse rhonchi and wheezing may be heard on auscultation.
Patients may have signs of right heart failure (ie, cor pulmonale), such as edema and cyanosis.
Because they share many of the same physical signs, COPD may be difficult to distinguish from congestive heart failure (CHF). One crude bedside test for distinguishing COPD from CHF is peak expiratory flow. If patients blow 150-200 mL or less, they are probably having a COPD exacerbation; higher flows indicate a probable CHF exacerbation.

Emphysema (pink puffers) findings may be as follows:

Patients may be very thin with a barrel chest.
They typically have little or no cough or expectoration.
Breathing may be assisted by pursed lips and use of accessory respiratory muscles; they may adopt the tripod sitting position. In this manner, the patient is trying to maintain a certain amount of positive end-expiratory pressure (PEEP) at the end of expiration, to help keep their lungs open, owing to the loss of lung structure from the disease.
The chest may be hyperresonant, and wheezing may be heard; heart sounds are very distant.
Overall appearance is more like classic COPD exacerbation.

Complications Some complications that must be anticipated in COPD treatment include the following:

Incidence of pneumothorax due to bleb formation is relatively high; consider pneumothorax in all patients with COPD who have increased shortness of breath.
In patients who require long-term steroid use, the possibility of adrenal crisis is very real; at a minimum, patients with steroid-dependent COPD should receive stress dosing in the event of an exacerbation or any other stressor.
Infection (common)
Cor pulmonale
Secondary polycythemia
Bullous lung disease
Acute or chronic respiratory failure
Pulmonary hypertension
Malnutrition

Differential Diagnoses

Workup

Laboratory Studies Arterial blood gas Arterial blood gas (ABG) analysis provides the best clues as to acuteness and severity. In general, renal compensation occurs even in chronic CO2 retainers (ie, bronchitics); thus, pH usually is near normal. Generally, consider any pH below 7.3 a sign of acute respiratory compromise. Serum chemistry These patients tend to retain sodium. Diuretics, beta-adrenergic agonists, and theophylline act to lower potassium levels; thus, serum potassium should be monitored carefully. Beta-adrenergic agonists also increase renal excretion of serum calcium and magnesium, which may be important in the presence of hypokalemia. CBC count CBC count may reveal polycythemia. Brain natriuretic peptide (BNP) Human BNP binds to particulate guanylate cyclase receptors of vascular smooth muscle and endothelial cells. Binding to the receptors causes an increase in cyclic guanosine monophosphate (GMP), which serves as a secondary messenger to dilate veins and arteries. By measuring the BNP level, it was thought that the ability to differentiate between CHF and COPD exacerbations in blue bloaters would have become much easier. However, clinical observation and research has demonstrated that, in the cases of mild CHF exacerbations, the ability to differentiate between CHF and COPD is still not straightforward. A mild elevation of a BNP level still must be taken in context with the overall clinical picture. Lactate level With the use of beta-adrenergic agents during acute exacerbations (eg, albuterol), there can be a notable increase in serum lactate levels, which can confuse the clinical picture. Albuterol functions by activating beta2-adrenergic receptors on airway smooth muscles, stimulating adenyl cyclase and increasing production of cyclic adenosine monophosphate (cAMP), causing relaxation of the smooth muscle and bronchodilation. Beta-2 receptor activation produces excess glycogenolysis and lipolysis. Increased glycogenolysis eventually leads to increased concentrations of pyruvate. Pyruvate is converted to acetyl coenzyme A (CoA), which enters the citric acid cycle. If pyruvate does not enter this aerobic pathway, it is converted to lactate instead, thereby potentially causing lactic acidosis. In addition, an increased lipolysis also increases acetyl CoA concentration through a different pathway. An increased acetyl CoA concentration potentially further inhibits pyruvate oxidation to acetyl CoA and leads to excess pyruvate. Finally, beta-2 receptor stimulation also inhibits the pyruvate dehydrogenase complex, and this might even further limit the rate that pyruvate is oxidized to acetyl CoA. [4] It is also thought that albuterol creates a hyperadrenergic state. High levels of these catecholamines can aggravate hyperlactatemia by reducing tissue perfusion and overstimulating the beta-2 adrenoceptor. [5] This, in turn, enhances glycogenolysis and gluconeogenesis and subsequently increases glycolysis and pyruvate production. This is important to remember during treatment for COPD exacerbations. Patients with wheezing are usually initially treated with albuterol, among other strategies (see Treatment). When a patient has had too much albuterol and a subsequent increase in lactic acid, it creates a paradoxical picture. The bronchospasm may improve, but the patient may appear more dyspneic or tachypneic. Initially with the increased respiratory rate, patients are physiologically compensating for the metabolic acidosis that is occurring. This may lead providers to interpret these signs and symptoms as worsening asthma and therefore give more albuterol, which may not be indicated. Astute clinical observation of the patient, repeated reexamination of the breath sounds, and discussion with the patient of how he or she is feeling should be part of the basics of treatment with these patients. This will most often yield a much better clinical picture of response to treatment than relying on a simple lactate level.

Imaging Studies Chest radiography Chronic bronchitis is associated with increased bronchovascular markings and cardiomegaly. Emphysema is associated with a small heart, hyperinflation, flat hemidiaphragms, and possible bullous changes. Typical findings are shown in the radiographs below.

Chronic obstructive pulmonary disease (COPD). A lung with emphysema shows increased anteroposterior (AP) diameter, increased retrosternal airspace, and flattened diaphragms on lateral chest radiograph

Posteroanterior (PA) and lateral chest radiograph in a patient with severe chronic obstructive pulmonary disease (COPD). Hyperinflation, depressed diaphragms, increased retrosternal space, and hypovascularity of lung parenchyma is demonstrated.

Subcutaneous emphysema and pneumothorax.

Other Tests Pulse oximetry Pulse oximetry does not offer as much information as ABG analysis. When combined with clinical observation, this test can be a powerful tool for instant feedback on the patient's status. Electrocardiography The presence of underlying cardiac disease is highly likely. Establish that hypoxia is not resulting in ischemia. Establish that the underlying cause of respiratory difficulty is not cardiac in nature. It is also important to look for changes associated with potassium abnormalities. Pulmonary function tests Forced expiratory volume in 1 second (FEV1) is decreased, with concomitant reduction in FEV1/forced vital capacity (FVC) ratio. Patients have poor/absent reversibility with bronchodilators. FVC is normal or reduced. Total lung capacity (TLC) is normal or increased. Residual volume (RV) is increased. Diffusing capacity is normal or reduced.

Treatment & Management

Prehospital Care in COPD The mainstays of therapy for acute exacerbations of chronic obstructive pulmonary disease (COPD) are oxygen, bronchodilators, and definitive airway management. Oxygen Adequate oxygen should be given to relieve hypoxia. A belief (ingrained from medical school) is held widely that too much oxygen causes significant respiratory depression. Multiple studies in the literature dispute this view. With administration of oxygen, PO2 and PCO2 rise but not in proportion to the very minor changes in respiratory drive. However, a prehospital study of patients with acute exacerbations of chronic obstructive pulmonary disease by Austin et al documented lower morbidity and mortality with titrated versus standard high-flow oxygen treatment. In a cluster randomized, controlled parallel group trial in 405 patients, titrated oxygen treatment significantly reduced mortality, hypercapnia, and respiratory acidosis. [6] The need for intubation can be established quickly at the bedside by asking the patient to hold the nebulizer in his or her hand. If the patient becomes so sleepy that the nebulizer starts to fall away, consider intubation regardless of PCO2 level. The cause of increased CO2 production is not decreased respiratory drive but probably reversal of hypoxic arterial vasoconstriction in areas of less-ventilated lung tissue, which increases the extent of ventilation/perfusion defects and thus CO2. "Stated another way, there is probably no single value for arterial PCO2, pH, or PO2 that by itself constitutes an indication for [intermittent positive pressure ventilation (IPPV)]." [7] Occasionally, large increases in CO2 can lead to deterioration of mental status, causing stupor and obtundation. In such cases, decreasing O2 delivery is the wrong action. The CO2 narcosis inhibits respiratory drive to the point that decreasing O2 delivery leads only to worsening of hypoxia. The correct action is immediate intubation and oxygenation. Supply the patient with enough oxygen to maintain a near normal saturation (above 90%) and do not be concerned about oxygen supplementation leading to clinical deterioration. If the patient's condition is that tenuous, intubation most likely is needed anyway. Bronchodilator In the prehospital setting, administer short-acting beta-agonist nebulizer therapy, which should be given as needed. In addition, short-acting anticholinergics, such as ipratropium, can be given. If necessary and available, continuous positive airway pressure (CPAP) may be used. Of course, in times of respiratory failure, patients may need intubation in the field.

Emergency Department Care in COPD In addition to oxygen, proper ED care may comprise bronchodilators, antibiotics, magnesium, CPAP or biphasic positive airway pressure (BiPAP), Heliox (ie, mixture of helium and oxygen), and definitive airway management via intubation. [2] All of these should be considered in the context of the individual patient's condition. Not all chronic obstructive pulmonary disease (COPD) exacerbations have a reversible (bronchospastic) component to their process, but predicting which ones will and which ones will not is an exercise in futility. Some evidence even shows that the amount of bronchospasm and response to bronchodilators may vary with the same patient from exacerbation to exacerbation. Keep in mind that altered level of consciousness is a contraindication for BiPAP, so carefully examine patients to determine appropriateness of its use.

Medical Care Continuous positive airway pressure (CPAP) and bilevel positive airway pressure (BiPAP) These devices help to decrease the work of breathing and maintain positive end-expiratory pressure (PEEP). In patients with chronic obstructive pulmonary disease (COPD) who are in extremis, CPAP or BiPAP may be attempted prior to intubation. This can be started in the ED and continued for several hours in the hospital. Usual recommended settings are an inspiratory positive airway pressure (IPAP) of 10 cm water and an expiratory positive airway pressure (EPAP) of 2 cm water, with further adjustments based on the individual. This is contingent on the patient's ability to withstand the mask. This treatment is not a substitute for intubation; rather, it is a means of trying to avoid intubation. Keep in mind that altered level of consciousness is a contraindication for BiPAP, so carefully examine patients to determine appropriateness of its use. Heliox is an additional strategy that can be attempted prior to intubation. Whether Heliox or CPAP is used will depend on the individual patient and local hospital availability. Again, like several other therapies mentioned in this article, study results both for and against Heliox have been published. The current summation of that literature indicates that Heliox may actually decrease the work of breathing while the patient is breathing the mixture, but its effects are not long lasting once it is removed. The proper mixture of the gases and the ability to deliver enough oxygen to the patient are also issues. Inhaled nitric oxide has been suggested, but at this point does not seem to have a role in acute treatment. Lung volume reduction surgery has also been touted as effective, but most recent studies demonstrate varying levels of success.

Prevention For the vast majority of patients, cessation of smoking is the only true means of prevention.

Long-Term Monitoring Disposition from the ED depends on the clinical picture for each patient more than any single laboratory value or test. In general, the longer the exacerbation, the more airway edema and debris are present, making resolution in the ED increasingly more difficult. Patients who state that they "feel back to normal" and have no overt reason for admission can reasonably be discharged home with follow-up arrangements. The corollary to this is that patients who state they "do not feel comfortable," regardless of the numbers, are the best predictors of outcome and probably should be admitted. Data on risk factors for relapse and need for admission are limited at present. For patients who are sent home, nearly all 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. 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, then every 6-12 months. For patients on home oxygen, check ABGs yearly or with any change in condition. Monitor oxygen saturation more frequently than ABGs.

Medication

Medication Summary Medicines available for ED treatment of chronic obstructive pulmonary disease (COPD) include beta2-adrenoceptor agonists, anticholinergics, oxygen, methylxanthines, corticosteroids, some newer experimental classes of medication, and, possibly magnesium. Terbutaline can be considered for patients with such significant exacerbations that they are not moving enough air to take full advantage of nebulizer therapy. Beta2-adrenoceptor agonists These agents are first-line therapy for COPD, both for acute exacerbations and for acute treatment. [11] Bronchodilators are given on an as-needed basis or on a regular basis to prevent or reduce symptoms. [2] Short-acting agents are usually used for immediate relief of symptoms, whereas long-acting inhaled agents are better for day-to-day mitigation of the disease. The longer-acting agent, indacaterol, is now approved and allows once-daily dosing. [12] Combinations of bronchodilators may improve efficacy and reduce risk of adverse effects rather than increasing the dose of a single agent. Keep in mind that, based on several studies, the acute response to short-acting agents does not predict the future response to long-acting agents. Most of the beta-agonists used are racemic compounds that contain both the R and S enantiomers of the agonist. Much of the pharmacologic activity seems to reside in the R enantiomer, with the S thought to induce the negative side effects. Recently, the R enantiomer of both the short-acting agent albuterol (levalbuterol) and the long-acting agent formoterol (aformoterol) were approved for use in COPD. However, the cost effectiveness of these agents, in light of marginal observed clinical differences, remains controversial and needs further exploration. Although the major action of beta2-agonists is relaxation of airway smooth muscles, they have also been shown to have several other potential effects. They seem to inhibit airway smooth muscle proliferation and inflammatory mediator release, as well as stimulation of mucociliary transport, cytoprotection of the mucosa, and attenuation of neutrophil recruitment and activation. Multiple studies have demonstrated enhanced benefits of action when coadministered with inhaled anticholinergics and with corticosteroids. The greatest single problem that persists in the acute phase is the under dosing of beta-agonists and the nonutilization of anticholinergics. Although only a small subset of patients respond to beta-agonists, a reasonable dose approaches continuous nebulization, as is seen in current asthma treatment.Keep in mind that with larger doses and continuous nebulization, elevated lactate levels are possible. Note that, in mild or moderate exacerbations, the use of MDIs with an aerosol chamber in higher doses (6-12 puffs) can achieve equivalent bronchodilation as the use of a nebulizer. This is particularly important in the office and prehospital setting. Epinephrine or terbutaline can be administered subcutaneously when intravenous access is not possible or the patient is moving so little air that nebulizer therapy is ineffective. Terbutaline is thought to be safer in older patients, and it has shown to be more efficacious than epinephrine. Anticholinergics Anticholinergics have an important role in the acute treatment of COPD exacerbations. The anticholinergics reduce airway tone and improve expiratory flow limitation, primarily by blocking parasympathetic activity in the large and medium-sized airways. They also block the release of acetylcholine, which has been linked to increased bronchial smooth muscle tone and mucus hypersecretion. These are not as effective as beta-agonists in acute attacks, but they have synergistic properties with the beta-agonists, and the combination of both agents is superior to either by themselves. They act by antagonizing the vagal innervation of the tracheobronchial tree. Vagal tone can be increased by as much as 50% in patients with COPD. Anticholinergic agents include short-acting agents appropriate for management of acute exacerbations (eg, ipratropium) and long-acting agents (eg, tiotropium, aclidinium, and umeclidinium). Methylxanthines These agents (eg, theophylline) increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. Despite this, many questions exist as to their true efficacy, and they have no real role in the acute exacerbation of COPD, except to increase the risk of adverse effects. [13] Patients may subjectively feel better, but no data suggest any real change in measureable outcomes or disease progression. In general, if the patient is already on theophylline and has a subtherapeutic level, a mini-loading dose could be considered but is certainly not considered first-line therapy. If the patient is not on theophylline, the delay before benefit of the oral form makes it not worth using. Intravenous aminophylline has a propensity to cause arrhythmias, especially in a population that already has cholinergic excess coupled with coronary disease. Phosphodiesterase-4 (PDE-4) inhibitors Selective PDE-4 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. Antibiotics These patients are almost uniformly heavily colonized with Haemophilus influenzae, streptococcal pneumonia, and others [3] ; however, researchers have not proven these organisms to be the cause of the exacerbation. In fact, viruses are thought to be the instigating factor in as many as half of the cases. The particular antibiotic chosen seems to have much less effect on outcome than the particular host factors of the patient in some studies, with other studies suggesting fluoroquinolones are the best strategy. This may really be a factor of the severity of the exacerbation and whether antibiotics are really indicated for minor exacerbations. [14] However, in a retrospective study of 84,621 hospitalized patients, improved outcomes were seen for all patients with COPD with early antibiotic treatment regardless of disease severity. [15] If antibiotics are given, the choice should provide coverage against pneumococcus, H influenzae,Legionella species, and gram-negative enterics. Daniels et al conducted a randomized, placebo-controlled trial that compared the addition of doxycycline to corticosteroids on clinical outcome in patients hospitalized with acute exacerbation of COPD (n=223). [16] 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 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 for 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. In cases of severe acute exacerbations of chronic bronchitis (AECB), guidelines suggest using fluoroquinolone antibiotics as first-line therapy. [17, 18] This suggestion is based on level I evidence from several trials that show clinical and microbial superiority of these agents. Use of fluoroquinolones has also been shown to shorten hospital stay, reduce recurrences, and lower costs. Fortunately, resistance to these agents is still very low, and reserving them for use in populations at risk should preserve their effectiveness for some time. Be aware of the potential for complications with Clostridium difficile colitis, QT prolongation, and musculoskeletal damage from fluoroquinolones, especially in this patient group. Magnesium Though controversial, administration of magnesium is thought to produce bronchodilation through the counteraction of calcium-mediated smooth muscle constriction. The addition of intravenous magnesium is now considered to have class B evidence supporting its use in difficult and life-threatening exacerbations. Heliox Heliox usually is a 60:40 mixture of helium and oxygen. Helium is a smaller particle than oxygen and in small airways promotes laminar flow and facilitates both oxygen transport and carbon dioxide diffusion. Many patients who seem to breathe better on Heliox return to a worsened respiratory state when removed from Heliox. Because of helium's low density, some class B evidence now exists for its use as the medium to drive nebulizer therapy. In theory, a mixture of helium and oxygen could improve gas exchange in patients who have an airway obstruction. In the realm of COPD exacerbations, however, the evidence is more slight, and more investigation is needed. Leukotriene receptor antagonists Intravenous leukotriene receptor antagonists have been shown to have benefit in asthma in limited studies, but, at this time, they have no role in COPD exacerbations. Corticosteroids These also have bronchodilatory properties, although they primarily act by decreasing inflammation in the tracheobronchial tree. Although 8-12 hours are required for full effect, corticosteroids should be administered in the ED, as some mild improvements may be noted much earlier.

Bronchodilators

Class Summary These agents act to decrease muscle tone in both small and large airways in the lungs, thus increasing ventilation. The category includes beta2-adrenergic agonists, methylxanthines, and cholinergic/muscarinic antagonists. Note that only 10-15% of all patients with COPD have a true reversible (ie, bronchospastic) component; however, because predicting response is impossible on presentation, all patients should be treated with aggressive bronchodilator therapy. Terbutaline (Brethaire, Bricanyl)

Terbutaline acts directly on beta2-receptors to relax bronchial smooth muscle, relieving bronchospasm and reducing airway resistance. Albuterol (Proventil)

Albuterol is a beta-agonist useful in the treatment of bronchospasm. This drug selectively stimulates the beta2-adrenergic receptors of lungs. Bronchodilation results from relaxation of bronchial smooth muscle, which relieves bronchospasm and reduces airway resistance. Note that prior use of long-acting agents, such as salmeterol, does not seem to compromise the response to albuterol during acute attacks. Use a 5-mg/mL solution for nebulization; it is usually underdosed in acute settings. Many studies have demonstrated that high-dose therapy is most efficacious. The goal is continuous therapy in the initial treatment phase. Note that a properly used MDI with a spacer is equal in effectiveness to nebulized therapy. Theophylline (Theo-Dur, Slo-bid, Theo-24)

Theophylline acts to increase collateral ventilation, respiratory muscle function, mucociliary clearance, and central respiratory drive. It acts partly by inhibiting phosphodiesterase, elevating cellular cyclic AMP levels, or antagonizing adenosine receptors in the bronchi, resulting in relaxation of smooth muscle. However, clinical efficacy is controversial, especially in the acute setting. This author advocates this medicine only if the patient was taking medicine already and had a subtherapeutic level. Do not give the intravenous form (aminophylline) because it can precipitate arrhythmias, especially in patients such as these who are already in an excess-catecholamine state. Measure the serum level to adjust the dose. Note that most recent meta-analyses and other literature have failed to show a benefit from the use of methylxanthines in acute exacerbations. Ipratropium bromide (Atrovent)

The ipratropium bromide dose can (and should) be mixed with the first beta-agonist nebulizer because it can take up to 20 minutes to begin having an effect. Controversy exists regarding the efficacy of ipratropium, but it still should be part of the total treatment picture. It is available as a nebulized solution and a metered-dose inhaler. It is an anticholinergic medication that appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, specifically with the muscarinic receptor on bronchial smooth muscle. Vagal tone can be increased by as much as 50% in patients with COPD, so this can have a profound effect. Albuterol/ipratropium (Combivent Respimat)

Ipratropium is chemically related to atropine. It elicits antisecretory properties and, when applied locally, inhibits secretions from serous and seromucous glands lining the nasal mucosa. Albuterol is a beta2-agonist for bronchospasm refractory to epinephrine. It relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Tiotropium (Spiriva)

Tiotropium is not a rescue inhaler. It is indicated as maintenance treatment for COPD. Tiotropium is a long-acting, once-daily quaternary ammonium compound. It elicits anticholinergic/antimuscarinic effects with inhibitory effects on M3receptors on airway smooth muscles, leading to bronchodilation. It is available as a capsule dosage form containing a dry powder for oral inhalation via the HandiHaler inhalation device. It helps patients with COPD by dilating narrowed airways and keeping them open for 24 hours. Aclidinium (Tudorza Pressair)

Aclidinium is not a rescue inhaler. Aclidinium is a twice-daily, long-acting selective muscarinic (M3) antagonist (anticholinergic) indicated for long-term maintenance of COPD including bronchitis and emphysema. It is available as breath-activated, dry powder metered-dose inhaler. Salmeterol (Serevent Diskus)

Salmeterol is not a rescue inhaler. It is indicated as maintenance treatment for COPD. It is a long-acting beta2-agonist. By relaxing the smooth muscles of the bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis, salmeterol can relieve bronchospasms. Its effect also may facilitate expectoration. Salmeterol has been shown to improve symptoms and morning peak flows. It may be useful when bronchodilators are used frequently. More studies are needed to establish the role for these agents. When administered at high or more frequent doses than recommended, the incidence of adverse effects is higher. The bronchodilating effect lasts more than 12 hours. It is used on a fixed schedule in addition to regular use of anticholinergic agents. Indacaterol, inhaled (Arcapta Neohaler)

Inhaled indacaterol is not a rescue inhaler. It is a long-acting beta2-agonist (LABA) indicated for long-term, once-daily maintenance bronchodilator treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. LABAs act locally in the lungs as bronchodilators. It stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP; increased cyclic AMP levels cause relaxation of bronchial smooth muscle. It is not for use as initial therapy in patients with acute deteriorating COPD. Umeclidinium bromide/vilanterol inhaled (Anoro Ellipta)

Umeclidinium bromide and vilanterol is a long-acting muscarinic antagonist (LAMA) and LABA inhalation powder. It is the first once-daily dual bronchodilator approved. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Indacaterol, inhaled/glycopyrrolate inhaled (Utibron Neohaler)

This agent contains glycopyrronium, which is a LAMA that produces bronchodilation by inhibiting acetylcholine’s effect on the muscarinic receptor in the airway smooth muscle. It also contains indacaterol, a LABA that stimulates intracellular adenyl cyclase, causing conversion of ATP to cyclic AMP, and thereby relaxes bronchial smooth muscle. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Glycopyrrolate inhaled (Breztri, Lonhala Magnair, Seebri Neohaler)

This agent contains glycopyrronium, which is a LAMA that produces bronchodilation by inhibiting acetylcholine’s effect on the muscarinic receptor in the airway smooth muscle. It is indicated for long-term maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and/or emphysema. Seebri Neohaler is available as an encapsulated powder for inhalation that is used with the Neohaler device. Lonhala Magnair is available as a solution for nebulization used with the Magnair device.

Corticosteroids

Class Summary These agents have been shown to be effective in accelerating recovery from acute COPD exacerbations. Although they may not make a clinical difference in the ED, they have some effect by 6-8 hous into therapy; therefore, early dosing is critical. Some newer studies are suggesting that inhaled corticosteroids (eg, nebulized budesonide) may be equally effective as intravenous or oral steroids in the mild-to-moderate exacerbation. In addition, level B evidence suggests that the addition of inhaled corticosteroids to oral agents at discharge may be very beneficial. Methylprednisolone (Solu-Medrol, Medrol)

Methylprednisolone is usually given in intravenous form in the ED for initiation of corticosteroid therapy, although the oral form theoretically is equally efficacious. The two forms are equal in potency, time of onset, and adverse effects. Inhaled corticosteroids are probably equally efficacious and have fewer adverse effects for patients discharged from ED.

Phosphodiesterase-4 Inhibitors

Class Summary Selective phosphodiesterase-4 (PDE-4) inhibitors reduce exacerbations, improve dyspnea, and increase lung function in patients with severe COPD. Roflumilast (Daliresp)

Roflumilast is a selective phosphodiesterase-4 (PDE-4) inhibitor. The specific mechanism of action is not well defined but is thought to be related to the effects of increased intracellular cyclic AMP in lung cells. It is indicated to decrease the frequency of exacerbations or the worsening of symptoms from severe COPD.

Electrolyte supplements

Class Summary Magnesium is used to replenish stores that become depleted in periods of adrenergic excess such as asthma attacks, COPD exacerbations, and diuretic use. Magnesium sulfate

Magnesium sulfate is thought to produce bronchodilation through the counteraction of calcium-mediated smooth muscle constriction. Again, for every study showing a positive finding, probably another shows no benefit, but given properly, magnesium is safe and may have some benefit.

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