Pathophysiology

In the past several decades the discovery that chronic airway inflammation plays a central role in the pathophysiology of asthma has led to an important change in its management, specifically, the liberal use of corticosteroids for treating moderate to severe disease. Airway inflammation is also at the center of the pathophysiology of COPD, but the inflammatory process of COPD differs from that of asthma. In COPD, neutrophils, CD8+ lymphocytes, and macrophages predominate in bronchial washings, whereas in asthma the cellular response is characterized by the presence of eosinophils.⁸ The inflammatory mediators differ in COPD, and several mediators, such as tumor necrosis factor, leukotriene B4, and interleukin-8, are linked to the destruction of parenchyma. These differences in the nature of the inflammatory response in COPD may account for its relatively poor response to current anti-inflammatory treatment compared with asthma.

Pathologically, the abnormalities in COPD are found throughout the lungs. Although certain changes may be more or less prominent in a given patient, most patients have at least some component of the two main pathologic entities: chronic obstructive bronchitis and emphysema. Evidence of airway inflammation is found from the trachea down to the smallest peripheral airways, which become progressively scarred and narrowed. An increase in both the number and size of mucus-secreting goblet cells results in the formation of mucous plugs, which further contributes to airflow obstruction. Damage to the endothelium impairs the mucociliary response that clears bacteria and mucus. The lung parenchyma is progressively destroyed over time, usually in a pattern of centrilobular emphysema. This consists of a destruction of alveoli, loss of lung elasticity, and the closure of small airways, which rely on the radial support of surrounding connective tissues to maintain their patency during expiration.

The combination of airway obstruction and obliteration of the pulmonary vascular bed results in a failure of gas exchange. Thus arterial blood gases (ABGs) may reveal both hypoxemia and hypercapnia. As the overall size of the pulmonary vascular bed decreases with time, chronic hypoxia induces a thickening of the vessel walls. Both of these factors contribute to the development of pulmonary hypertension, polycythemia and, eventually, right-sided heart failure (cor pulmonale).

The pathophysiology of COPD reflects the apparent imbalance between proteases and antiproteases that favors the destruction of connective tissue in the lungs. In one small subset of COPD patients with congenital α₁-antitrypsin deficiency, a lack of α₁-antitrypsin, an enzyme that inhibits neutrophil elastase, leads to the pathology of severe panacinar emphysema. In the majority of patients, however, the specific genetic factors are less well elucidated. Oxidative stress, the imbalance of oxidant to antioxidant activity in favor of oxidants, is another important facet of the pathophysiology of COPD. External oxidants are found in cigarette smoke, whereas the products of the inflammatory process result in intrinsic oxidants. Not only may oxidants cause direct parenchymal damage, but oxidative stress indirectly fuels further inflammation and protease activity.

Cigarette smoking, the most significant risk factor for the development of COPD, exerts its effects at multiple points in the inflammatory cascade of COPD, negatively affecting both the protease to antiprotease and oxidant to antioxidant balances. Although smoking cessation slows the progression of the disease, it does not end the chronic inflammatory process within the airways, indicating that mechanisms independent of smoking are involved.⁹ Moreover, although a majority of COPD patients have a significant smoking history, only a minority of smokers ever develop airflow limitation. This suggests the importance of other factors, both environmental and genetic.¹ Other identified causative factors include heavy occupational exposure to dusts and air pollution from indoor cooking, particularly in the developing world.^10–12 Long-term passive exposure to tobacco smoke and urban air pollution also appear to be contributory.^13,14 Although there is an association between early childhood lower respiratory tract infections and later development of COPD, a causal relationship is less certain.

Compensatory physiologic responses in COPD vary according to the balance of underlying pathologic derangements seen in individual patients. In a minority of patients, ventilatory drive is increased to maintain a near normal partial pressure of oxygen (PO₂), preventing any cyanosis. The resultant tachypnea may also cause a slightly low partial pressure of carbon dioxide (PCO₂). In patients with relatively normal blood gases, pulmonary hypertension and cor pulmonale may not occur until very late in the course of the disease.

Although the precise mechanisms are ill-defined, the pathologic processes of COPD extend beyond the cardiac and pulmonary systems. The effects of circulating inflammatory mediators, oxidative stress, and protease-antiprotease imbalance may be responsible for the weight loss, muscular wasting, metabolic derangements, and depression often seen in the later stages of disease. These features of COPD are partly responsible for the influence of COPD as a comorbid illness, even when the presenting complaint is nonpulmonary. COPD influences a variety of management decisions in the emergency department (ED), ranging from the choice of agents for procedural sedation and rapid sequence intubation to the appropriate disposition of patients with nonpulmonary diagnoses.

Staging the Severity of Disease

Most classifications of disease severity are based on quantitative measurements of airflow limitation, such as the forced expiratory volume in 1 second (FEV₁) and FEV₁/forced vital capacity (FVC) ratio. These indices are measured after any reversible airflow limitation is addressed by treatment with bronchodilator medications. The GOLD collaborators define four stages, beginning with a mild stage (stage I), when spirometry is abnormal but symptoms may not yet be apparent, and ending in very severe COPD (stage IV), when FEV₁ is less than 30% of predicted (Table 74-1). Frequent exacerbations are usually seen when the FEV₁ falls below 50% predicted (stages III and IV).^4,15,16

Acute Exacerbations

Unlike asthma exacerbations, COPD exacerbations are not necessarily associated with major reductions in peak flow and FEV₁ measurements. As with COPD itself, the definition of an acute exacerbation is imprecise and relies on clinical parameters that are often subjective. The definition adopted by the GOLD collaborators is “an event in the natural course of the disease characterized by a change in the patient’s baseline dyspnea, cough, and/or sputum that is beyond normal day-to-day variations, is acute in onset, and may warrant change in regular medication in a patient with underlying COPD.”

As with asthma, viral infection appears to be a frequent inciting agent in COPD exacerbations. Commonly implicated viruses include rhinovirus, respiratory syncytial virus, coronavirus, and influenza virus.17–19 Exacerbations associated with a viral cause are longer and more severe than those without an apparent inciting agent.^18,20

Controversy remains regarding the role of bacterial pathogens in acute exacerbations of COPD, because the evidence for the role of bacteria in the pathogenesis remains indirect. Almost half of all exacerbations are associated with negative cultures for the typical respiratory pathogens, such as Haemophilus influenzae, Streptococcus pneumoniae, Moraxella (Branhamella) catarrhalis, and Pseudomonas aeruginosa. In addition, these organisms are recovered from the tracheobronchial tree of patients in their chronic, steady state, suggesting that bacteria may play a more important role in the pathogenesis of chronic COPD than in acute exacerbations.²¹ Although molecular typing shows that recent colonization with new serotypes of the common pathogens is associated with an exacerbation, there is a possibility that this relationship is not causal. Experimental evidence of specific immunologic responses to bacteria in exacerbations suggests, however, that they do play a significant role.^22,23

Environmental factors, such as air pollution, are also implicated in COPD exacerbations. Indirect evidence for this relationship is largely derived from hospitalization rates for exacerbations during periods of increased air pollution.²⁴ Finally, in as many as one third of all COPD exacerbations, no specific cause can be identified.

In addition to having acute exacerbations, patients with COPD may experience worsening symptoms because of comorbid conditions, such as pneumonia, congestive heart failure (CHF), pneumothorax, pulmonary embolism (PE), lobar atelectasis, pleural effusion, or dysrhythmias. All of these are associated with COPD and may mimic or coexist with an acute exacerbation.

Symptoms and Natural History

COPD patients have a long premorbid course during which decreases in air flow indices can be measured in the absence of symptoms. Intermittent cough or shortness of breath on exertion may be easily misattributed to poor physical conditioning. Moreover, patients may remain asymptomatic for many years by gradually limiting their activities in proportion to their pulmonary reserve. After several years, a daily productive cough frequently develops, and periods of dyspnea, the cardinal symptom of airflow limitation, increase. The clinical progression of COPD is slow and insidious, with gradual decreases in airflow punctuated by increasingly frequent and debilitating exacerbations. Eventually the patient becomes truly incapacitated by dyspnea on minimal or no exertion. Profound muscle wasting and weight loss and the emergence of cor pulmonale or chronic ventilatory failure are characteristic of end-stage disease. Figure 74-1 depicts the progression of COPD over time.

Physical Examination

The division of patients with COPD into two phenotypes, the “blue bloater” (for the patient with chronic obstructive bronchitis) and the “pink puffer” (for the patient with emphysema), is outdated because many patients with COPD do not conform to these descriptions. Nonetheless, these classic images do highlight some of the important clinical features that may be encountered in the patient with COPD and have implications for management. Most patients have some combination of chronic obstructive bronchitis and emphysema and appear with a mixture of the syndromes described later. The precise identification of which process is predominant is less important than the evaluation of each patient and formulation of a specific treatment plan based on the individual clinical findings. In particular, the degree of chronic hypoxemia and dependence on home oxygen therapy, the presence of cor pulmonale, and evidence of comorbid illness, such as ischemic heart disease, should be determined.

In patients in whom chronic obstructive bronchitis predominates, the findings are those of chronic respiratory failure and cor pulmonale. Little air hunger or anxiety is present, and the combination of polycythemia and hypoxemia creates a plethoric, cyanotic appearance. Cough, as the clinical hallmark of bronchitis, is prominent and, when vigorous, causes expectoration. If acute ventilatory failure is present, the patient’s consciousness is clouded. This often is described as “irritable somnolence,” and asterixis may be present. Chronic ventilatory failure and cor pulmonale account for the prominent peripheral edema and chronic jugular venous distention. If there is relatively little emphysema, the thoracic anteroposterior diameter is normal, and the diaphragm is not abnormally low. The presence of severe bronchopulmonary secretions is evidenced by scattered rhonchi and rales, especially at both lung bases posterolaterally. These patients often have chronic carbon dioxide (CO₂) retention, requiring close monitoring of oxygen therapy because of their relative dependency on hypoxemic drive for ventilation.

When emphysema predominates, the patient is often thin, anxious, alert and oriented, dyspneic, and tachypneic and uses accessory muscles of breathing. The patient often self-administers positive end-expiratory pressure (PEEP) by using a pursed lip exhalation pattern to increase intraluminal bronchial pressure and provide internal support for bronchial walls that have lost their external support. Such patients usually assume a sedentary existence, chronically hunched forward. Gross lung overinflation occurs, with a low immobile diaphragm and an increased anteroposterior diameter of the thorax. Percussion of the chest reveals hyper-resonance, and auscultation demonstrates diminished breath sounds with faint end-expiratory rhonchi. Despite air hunger caused by the extensive lung parenchyma destruction, the patient maintains adequate oxygen saturation and often has near-normal ABG levels. The heart is small and hypodynamic, and the blood pressure is usually low.

Cardiac examination in a patient with suspected COPD is crucial in the diagnosis of cor pulmonale and coexisting left ventricular failure. A subxiphoid or retrosternal heave suggests chronic right ventricular hypertrophy (RVH), an S₄ suggests decreased left ventricular compliance, an S₃ indicates left ventricular failure, and a holosystolic blowing murmur of tricuspid insufficiency is secondary to right ventricular and tricuspid ring dilation. Accentuation of the pulmonic component of the secondary sound reflects pulmonary hypertension. Chronic visceral congestion causes hepatomegaly, hepatojugular reflux, and sometimes prominent abnormalities of liver function.

Pulse Oximetry, Arterial Blood Gas Analysis, and Waveform Capnography

Pulse oximetry is part of the evaluation and monitoring of every patient with a COPD exacerbation. Comparison with prior values, both in crisis and in baseline state, helps to interpret measurements obtained during an acute exacerbation. The change in pulse oximetry from baseline or in response to emergency therapy is generally more important than absolute levels.

The stages of COPD severity correlate with arterial gas tensions. Abnormal ventilation-perfusion relationships of COPD produce only modest decrements in arterial partial pressure of oxygen (PaO₂) in its early stages (80-100 mm Hg). Later in the course of the disease, hypoxemia below 60 mm Hg stimulates respiratory centers, producing hyperventilation (PCO₂ over 35) and acute respiratory alkalosis. As pulmonary dysfunction progresses, the work of hyperventilation becomes cost-ineffective—that is, more CO₂ is produced by the effort than is cleared by the increased ventilation. Eventually, alveolar hypoventilation impairs gas exchange, leading to CO₂ retention and acute respiratory acidosis. With renal compensation through bicarbonate retention, the pH normalizes. Finally, when acute ventilatory failure is superimposed at this stage of the disease, an elevated PCO₂, lowered pH, and elevated bicarbonate are found.

ABG values, once a mainstay of ED evaluation of COPD patients, are of limited value in management of acute COPD episodes. Status and response to therapy often are monitored noninvasively by capnography and pulse oximetry. The presence of respiratory failure unresponsive to therapy (defined as PaO₂ <40 mm Hg, PaCO₂ >60 mm Hg, and pH <7.25 mm Hg) warrants consideration of admission to an intensive care unit, but clinical evaluation is much more important than any particular blood gas values.⁴ When baseline blood gas levels are not available, the usefulness of ABGs is even more limited, and interpretation should be based on the degree of acidemia present, which likely represents the extent of acute CO₂ retention. ABGs should not be used to determine whether a patient requires intubation or noninvasive ventilatory support (NIVS). These decisions should rather be guided by the overall state of the patient, progression of fatigue, comorbid illness, and response to therapy. Patients with very poor blood gas values may do well without intubation or NIVS, but others with mildly disturbed values may require urgent airway intervention. Thus measurement of ABGs should not be performed routinely in the ED and should be undertaken only in response to specific circumstances, such as irregular or apparently unreliable pulse oximetry values or when a single baseline correlation with end-tidal carbon dioxide (ETCO₂) is desired.

Waveform capnography represents the continuous quantitative measurement of exhaled CO₂. It has emerged as a potential diagnostic and monitoring tool in patients with acute respiratory distress. The appearance of the waveform may assist the clinician in differentiating acute exacerbation of COPD from other causes of acute dyspnea, such as CHF. In patients with obstructed airways, the plateau phase of the waveform typically steepens in proportion to the severity of the obstruction, as depicted in Figure 74-2. Unfortunately, in patients with COPD, the actual end-tidal PCO₂ measurements obtained from capnography do not correlate well with arterial PCO₂ measurements, especially in more severe disease. Nonetheless, the patterns and trends from capnography may be helpful in guiding management and assessing response to therapy.²⁵

Chest Radiography

In patients who are known to have COPD, the primary role of the chest radiograph is to determine whether there is an acute, treatable cause for clinical deterioration, especially pneumothorax or parenchymal consolidation (atelectasis secondary to mucous plugging, pneumonia, or obstruction by tumor). Otherwise, the chest radiograph is of limited use and may exhibit a range of chronic changes, depending on disease severity and the relative degree of the various pathologic processes. Findings may include hyperinflated lung fields, decreased vascular markings, and a small cardiac silhouette or, in contrast, normal inflation with increased vascular markings and an enlarged heart.26,27 In cor pulmonale, impingement on the retrosternal airspace by the enlarged right ventricle can be seen on the lateral film.

Bullae may also be present and may mimic or mask a pneumothorax. In addition, chest radiography may reveal important coexistent pathology, including CHF, effusions, and tumors. Routine chest radiography, although challenged, is appropriate in patients with acute exacerbations of COPD.

Forced Expiratory Volume and Peak Expiratory Flow Rate

Pulmonary function tests (PFTs) are more useful in asthma, in which there is a significant reversible component of airway obstruction. In addition, the patient in acute respiratory distress is often unable to cooperate, making testing unreliable. Thus PFTs add little to decision-making in cases of acute COPD exacerbation.

Sputum Examination

During acute exacerbations of bronchitis, sputum may be thicker and grossly purulent, but neither Gram’s stain nor culture of sputum is of value in acute COPD exacerbation.

Electrocardiogram and Cardiac Monitoring

The classic descriptions of P pulmonale (peaked P waves in leads II, III, and aVF), low QRS voltage, clockwise rotation, and poor R wave progression in the precordial leads are interesting correlates of COPD but are both insensitive and nonspecific. The presence of electrocardiogram (ECG) criteria for RVH suggests established cor pulmonale. These findings, however, can be easily obscured on the ECG by other processes, and the absence of criteria for RVH cannot be relied on to rule out cor pulmonale.²⁸