Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD): Outcome-Effective Antimicrobial Selection and Recent Advances in Outpatient Management
Part I: Patient Assessment, Antibiotic Overview, Evidence-Based Trials, and Multi-Modal Drug Therapy
Authors: Charles L. Emerman, MD, Chairman, Department of Emergency
Medicine, Cleveland Clinic Foundation, MetroHealth Medical Center; Associ- ate Professor of Emergency Medicine, Cleveland Clinic Foundation; and Gideon Bosker, MD FACEP, Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT, Associate Clinical Professor, Oregon Health Sciences University.
Peer Consensus Panel: Jeremy Brown, MD, Department of Emergency Medi- cine, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; Jonathan Edlow, MD, Associate Chief, Department of Emergency Medicine, Beth-Israel Deaconess Medical Center; Assistant Professor of Medi- cine, Harvard Medical School, Boston, MA; Susan B. Promes, MD, Associate Residency Director, Department of Emergency Medicine, Alameda County Medical Center-Highland Campus, Oakland, CA, Assistant Professor of Clini- cal Medicine, University of California, San Francisco; Albert C. Weihl, MD, FACEP, Education Director, Section of Emergency Medicine, Yale University School of Medicine, New Haven, CT.
The clinical challenges of managing patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are well known to emergency physicians, pulmonologists, and primary care physicians. With their strenuous respiration, agitation, tachypnea, sputum production, and/or shortness of breath, these recurrent visitors are among the most difficult patients encountered in the acute-care setting.
Typically, patients with bacterial exacerbation of chronic obstructive pulmonary disease (COPD) present in acute distress that may be characterized by a worsening, productive cough, increasing dyspnea on exertion, and difficulty breathing. Not infrequently, these individuals will report a low-grade fever, a change in the color and tenacity of their sputum, and mild pleuritic chest pain. Difficult (but critical) decisions, including choice of stabilizing medical therapy, selection of an outcome-effective antibiotic, use of invasive vs. non-invasive ventilation techniques, and patient disposition, must be made promptly based on objective physical as well as historical information.
The construction of a safe, effective drug regimen is always an important consideration, both in patients requiring hospitalization and those deemed suitable for management as outpatients. Polypharmacy with such drugs as inhaled and systemic cortico- steroids, antibiotics, and/or bronchodilators is the rule rather than the exception.
Combination drug therapy has the advantage of improving functional status, permitting outpatient management, and reducing frequency of exacerbations, but has the potential disadvantages of drug interactions, dose-related toxicity, and cost. Identifying therapeutic agents that maximize medication compliance, reduce duration of therapy, and decrease risk of drug-drug interactions is of paramount importance.
There is a general consensus that patients with AECOPD, who frequently suffer from other co-morbid conditions, can be difficult to diagnose and even more problematic to stabilize. In addition, it may be difficult to distinguish bacterial from non-bacterial (i.e., viral) exacerbations. Accordingly, to optimize clinical outcomes, evaluation of patients with AECOPD should focus on identifying inciting factors and accurate assessment of disease severity.
Unfortunately, universally accepted, consistent guidelines and critical pathways for managing patients with AECOPD are not available, primarily because long-term, prospective studies comparing the effectiveness of specific agents, including antibiotics, in well-matched subgroups have not been performed. Consequently, recommendations generated by consensus groups, national associations, and managed care organizations frequently differ in their approach to risk stratification and selection of antimicrobial therapy.
Most of the support for using antibiotics in patients with AECOPD has been derived from meta-analysis data, which have the limitation of comparing older agents under varying, region-specific conditions of antimicrobial resistance. Because these resistance patterns may have changed over time, new approaches to antimicrobial therapy may be warranted. Moreover, risk-stratification strategies have not been standardized in these studies, which has made it difficult to determine when intensification and amplification of coverage from one class of antibiotics (macrolides) to another (quinolones) are appropriate in specific patient subgroups.
Although experts in the field of emergency and pulmonary medicine agree that acute management should be directed at reducing airflow obstruction, treating complications, decreasing frequency of future exacerbations, and preventing acute respiratory deterioration, the precise approach to patients with AECOPD is in evolution. What is clear, however, is that the clinical mission statement for patients with AECOPD is to identify a safe, effective regimen that will improve functional status and prevent future relapse.
With these considerations in mind, this consensus review provides a practical, although detailed and comprehensive, approach for initial evaluation and treatment of patients with acute bacterial exacerbations of COPD. Providing specific clinical pathways and therapeutic strategies, this monograph emphasizes the importance of the history, physical examination, laboratory data, and radiologic modalities for maximizing clinical outcomes.
In part II of this two-part series, risk-stratification of patients and its usefulness for selecting antimicrobial agents in patients with AECOPD are discussed within the framework of the Severity of Exacerbation and Risk Factors (SERF) Pathway for subgroup categorization of patients with AECOPD. Pharmatectural criteria, including cost, compliance, coverage, drug-drug interactions, and side effects, are used to guide antibiotic selection.1 Finally, a wide range of pharmacological interventions are discussed in detail, and indications for invasive and non-invasive ventilatory assistance are outlined.
— The Editor
Overview
Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality among smokers 55 years of age and older. It is estimated that this condition affects more than 20 million Americans,2 and among Medicare patients, COPD accounts for about 150,000 hospitalizations per year.3 While the overall in-hospital mortality rate from COPD has not changed dramatically over the past decade, an increasing number of patients require placement in extended care facilities.
From a disease categorization standpoint, COPD is occasionally referred to as chronic obstructive lung disease (COLD), and from a clinical perspective, this condition is composed of three distinct entities: 1) chronic bronchitis; 2) emphysema; and 3) peripheral airways disease.4 It should be stressed that the diagnosis of chronic bronchitis or emphysema is not synonymous with irreversible airflow obstruction and that these patients can benefit from bronchodilators, steroids, antibiotics, and other therapeutic measures.
The greatest percentage of patients with COPD have evidence of chronic bronchitis, a diagnosis that is based on a history of productive cough for three months of the year for two successive years. Patients with chronic bronchitis have an increase in the number and size of submucosal glands in the bronchi and evidence of bronchiolar inflammation. In contrast, the diagnosis of emphysema is based on the presence of airway enlargement. Most patients with COPD and emphysema have enlargement in the respiratory bronchioles. Clinically, emphysema is manifested by an elongated, hyperresonant chest. Diaphragmatic flattening and increased radiolucency is seen on the chest x-ray. Finally, patients with peripheral airways disease have inflammation of the terminal bronchioles and abnormal pulmonary function tests.
Differential Diagnosis. Patients may have any combination of these three entities. In fact, some degree of chronic bronchitis, emphysema, and/or peripheral airways disease with chronic airflow limitation usually coexists in most patients. Further complicating the picture is the fact that asthma presents with many of the same signs and symptoms observed in COPD.3-5 Differentiating between these two conditions can be difficult, and older patients may not have a clearly established diagnosis. Distinguishing between asthma and COPD is important in the emergency department because management strategies are different for each condition.
The clinical history, which must include a detailed inquiry into precipitating factors, a careful record of character and severity of previous exacerbations, response to pharmacotherapeutic agents, and features of the current episode, will usually guide the practitioner toward the most appropriate assessment and management pathway. For example, the diagnosis usually is straightforward when an older patient presents with the late adult onset of respiratory disease associated with a long history of cigarette smoke. Similarly, a younger adult with a life-long history of asthma and no smoking history will generally be treated as having an asthma exacerbation. But many cases will be more ambiguous and differentiation of these patients may require formal pulmonary function testing with possible histamine challenge by a pulmonologist.
The majority of patients with COPD will have either a history of cigarette smoking or exposure to second-hand cigarette smoke. Occasionally, patients will develop COPD from occupational exposure. A minority of patients develop emphysema as a result of alpha-1-protease inhibitor deficiency or intravenous drug abuse. These patients develop emphysema earlier in life than those who acquire COPD secondary to cigarette smoke.
Prognosis. COPD is associated with decreased long-term survival. A number of predicting factors have been linked with the increased mortality rates reported in patients with chronic airflow limitation.5 In this regard, patients with a FEV1 less than 40% or an FEV1/FVC ratio less than 40% have decreased survival as do those with a baseline Pa02 less than 55 mmHg, CO2 retention, cor pulmonale, and decreased diffusion capacity. Overall, these high-risk patients have a 12-year survival probability of about 40%.5
As might be expected, acute respiratory failure is associated with an increased risk of short-term mortality. Patients requiring intensive care unit admission for COPD have an inpatient mortality rate ranging between 10% and 30%.5,6 In some studies, however, the need for mechanical ventilation did not imply an increased mortality rate among patients requiring intensive care unit admission.
Issues regarding the potential pitfalls of mechanical ventilation have been fiercely debated among intensivists, emergency physicians, and pulmonary specialists. From a prognostic perspective, however, decisions regarding mechanical ventilation for patients with COPD must be made on a patient-by-patient basis, using sound clinical judgment. Many clinicians may be concerned that a large percentage of intubated patients will go on to require chronic mechanical ventilation. However, the data appear to suggest that the majority of patients who require intubation for COPD can be successfully weaned from mechanical ventilation over the course of 7-14 days, even after severe, life-threatening exacerbations.6-8
Nevertheless, the mortality rate for these patients over the next 1-2 years is substantial, ranging between 40% and 60%.6-8 In most studies, short-term survival following an acute exacerbation is related to age, pulmonary function, oxygenation, the presence of congestive heart failure (CHF), and evidence of cor pulmonale. Many patients with COPD have co-existing cardiac disease which, in the form of left ventricular dysfunction, also is predictive of an increased mortality rate.8
The likelihood that patients with COPD will require hospitalization for their condition depends on the number, frequency, and severity of their exacerbations. More than three acute exacerbations of COPD per four-month period is associated with an increased risk of hospitalization. Hence, from an emergency medicine and primary care perspective, the most important clinical goal is to provide definitive treatment that is sufficiently aggressive to produce resolution of acute exacerbation and prolong the period between exacerbations.
Patient Assessment
Patients who present to the emergency department with an acute exacerbation of COPD may arrive in varying degrees of clinical distress. The patient in extreme distress will require immediate therapy. Generally speaking, efforts to obtain a comprehensive history, conduct a physical examination, and perform diagnostic studies may need to be delayed pending the initiation of rapid treatment, which may include oxygen, bronchodilators, and invasive or non-invasive ventilation. In less severe cases, or as the patient improves with therapy, the individual with AECOPD should be questioned about historical features that may aid in the differential diagnosis and guide management.
Clinical Differentiation. Although the patient with AECOPD usually will complain of either cough, sputum production, and/or dyspnea, the emergency physician should attempt to elicit other symptoms that may help identify the etiology of this attack. For example, acute exacerbations may be precipitated by an infectious process, exposure to noxious stimuli, or environmental changes such as a change in ambient temperature, humidity, or air pollution. In addition, signs and symptoms of COPD may mimic those seen in other diseases, such as lung carcinoma, decompensated CHF, pneumonia, or pulmonary embolism.
Even in patients who carry a diagnosis of COPD, the astute clinician must consider other life-threatening causes of shortness of breath and chest pain, especially in elderly patients with known obstructive disease. In particular, when there is a history of change in sputum character and a long course of corticosteroids, the diagnosis of pneumonia should be considered. A chest x-ray will help confirm this suspicion. Ischemic heart disease, with or without CHF, also may be accompanied by shortness of breath or chest pain. All patients should be questioned about medication use and compliance, as well as social factors such as continued cigarette smoking. In addition, it is important to characterize and compare the current illness with the severity of previous episodes and to be aware of previous intubation or admissions to the ICU. Some individuals with longstanding COPD may even be aware of their baseline FEV1 or arterial blood gases (ABGs).
The elderly patient may present special challenges, one of which is the difficulty in distinguishing between decompensated CHF and an acute bacterial exacerbation of COPD. The distinction can be especially difficult, most notably in patients who have a preexisting history of both conditions. Nevertheless, certain findings may help make this distinction. For example, a peak expiratory flow rate (PEFR) greater than 150 L/min may suggest the possibility of CHF5,9 especially in the presence of jugular venous distention, hepatic congestion, or pedal edema. It should be stressed that jugular venous distension, hepatic congestion, and pedal edema can occur in cor pulmonale as well as CHF. Differentiation between asthma and COPD also can be problematic, since both conditions may respond favorably to acute administration of aerosolized beta-agonists.
Pulmonary embolism (PE) can be very difficult to confirm in patients with COPD on the basis of clinical evaluation alone.6 The ventilation/perfusion scan is frequently indeterminate in patients with COPD. Evidence of calf swelling, tenderness, increased warmth, erythema, or the presence of a tender venous cord may suggest the diagnosis of deep venous thrombosis, which may be verified by impedance plethysmography, ultrasound, venography, or d-dimer.
When these symptoms are accompanied by typical manifestations of PE, this diagnosis is strongly suggested. Recent studies have suggested the utility of chest computed tomography to diagnose pulmonary embolism in the setting of COPD. However, this modality is not widely accepted and requires interpretation by a radiologist proficient in this particular test. The spiral CT scan has relatively good specificity for pulmonary embolism, but it still lacks adequate sensitivity to replace other established modalities (ventilation/perfusion scan and pulmonary angiography) whose utility in pulmonary embolism has been confirmed.10
Finally, with respect to the severity of an acute attack, the clinician should be aware that although physical findings can be misleading, they should nevertheless be documented. Cyanosis is a late and uncommon finding. The patient who is confused, combative, or agitated is probably severely hypoxemic, although relatively few patients present initially with this constellation of findings. Intercostal retractions, accessory muscle use, and an increase in the pulsus paradoxus usually suggest significant airway obstruction.7 Wheezing is variably associated with airway obstruction. Biphasic wheezing tends to imply a more significant airway obstruction, although this is not universally true. Wheezing disappears when pulmonary function rises to 60% of the predicted normal value.8,11
Community-Acquired Pneumonia in COPD
Clinicians should note that patients with COPD are also at high risk for developing community-acquired pneumonia (CAP), a condition that always requires treatment with antibiotics when bacterial organisms are suspected or implicated. Unfortunately, the exact incidence of pneumonia in patients with obstructive lung disease is uncertain. Not surprisingly, the clinical presentation of acute bronchitis superimposed on chronic lung disease can be difficult to differentiate from bacterial pneumonia in the patient with COPD. Symptoms such as fever, sputum production, and abnormal lung sounds are findings common to both conditions. In addition, many patients with COPD have abnormal chest radiographs.12 Furthermore, a variety of noninfectious conditions can mimic pneumonia in patients with COPD, including pulmonary infarction, CHF, drug reaction, pulmonary cancers, pulmonary hemorrhage, and chemical inhalation.13 Nevertheless, the appearance of new radiographic abnormalities (lobar consolidation, atelectasis, infiltrates, pleural effusions, and other findings) in association with symptoms of acute pulmonary infection should probably prompt the emergency physician to treat the patient for bacterial pneumonia.
As is the case when CAP occurs in individuals without COPD, Streptococcus pneumoniae is the most common organism isolated from patients with CAP who have underlying COPD, although this organism is being demonstrated with decreasing frequency. Hemophilus influenzae and Moraxella catarrhalis are also commonly isolated from COPD patients with CAP; their frequency increases during the winter months. Legionella pneumophila can be encountered any time of the year and chronic lung disease is a risk factor for CAP caused by Legionella pneumophila. Pneumonia caused by this agent is associated with a variable clinical presentation ranging from a mild cough to life-threatening respiratory infection and ventilatory failure. Pseudomonas aeruginosa is a common organism isolated from the sputum of patients with COPD, and in a significant percentage of cases, isolation of this organism represents colonization of the respiratory tract. Although pseudomonas pneumonia is uncommon in ambulatory patients with COPD, it must be considered in patients with more severe presentations, especially as a nosocomial infection in the hospital environment.21-24
Staphylococcal pneumonia is not a common cause of CAP in patients with COPD. However, in patients with chronic lung disease, it appears that viral infection with influenza predisposes patients to subsequent bacterial pneumonia, including both streptococcal and staphylococcal disease. Studies using the influenza vaccine have shown an overall decreased mortality rate, although they have not been done exclusively on patients with COPD.131 Pneumococcal vaccination has been shown to be cost-effective in high-risk patients, and most experts agree that Pneumovax 23 is indicated in the subset of patients with COPD.14 At present, it seems reasonable and prudent to advocate use of pneumococcal and influenza vaccine for patients with COPD.
Infectious Precipitants of AECOPD
The role of bacterial and viral-mediated infection as precipitants of acute respiratory decompensation in the setting of COPD has been controversial. Certainly, numerous studies have confirmed the role of viral infection in acute exacerbations of COPD.15-17 In one study, 32% of patients with an acute exacerbation had evidence of viral infection.16 In these and other investigations evaluating the role of viral infection, the most common agents identified include influenza virus, parainfluenzae, and respiratory syncytial (RSV) virus.15-19
Interestingly, although many treatment guidelines for AECOPD do not mandate empirical antimicrobial coverage of atypical organisms, among them, Mycoplasma pneumoniae, Chlamydia pneumoniae, and legionella, for patients with AECOPD, studies show that atypical organisms such as mycoplasma or chlamydia may occasionally be associated with decompensation in patients with COPD. In fact, many patients with COPD have serologic evidence of previous Chlamydia infection. On the other hand, recent studies suggest that acute Chlamydia pneumoniae infection occurs in only about 5% of acute exacerbations of COPD.17,18
Epidemiology. The precise role of bacterial infection is more difficult to ascertain, and equally problematic to confirm in the individual patient. Nevertheless, it is clear that bacterial precipitants play an important etiologic role in AECOPD. In one Canadian study enrolling 1687 patients (80% of which had AECOPD), sputum cultures were obtained in 125 patients (7.4%). Normal flora was found in 76 of 125 sputum specimens (61%), and a pathogen was found in 49 (39%). Of all the patients having sputum cultures, H. influenzae was the most common pathogen, occurring in 24 cases (19%), followed by Streptococcus pneumoniae in 15 (12%) and Moraxella catarrhalis in 10 (8%).20 Complicating confirmation of a linkage between acute bacterial infection and clinical deterioration in COPD is the fact that patients with COPD have chronic colonization of the respiratory tree with such organisms as Streptococcus pneumoniae, Hemophilus influenzae, and Hemophilus parainfluenzae.19 In addition, Moraxella catarrhalis is being recognized with increasing frequency.
Role of Antibiotics. One way of delineating the precise role of bacterial infection in AECOPD is to evaluate the efficacy of antibiotics in producing symptomatic and functional improvement in patients during an acute exacerbation of COPD. A number of trials dating back to the 1950s have been performed to assess the relationships between antibiotic treatment and resolution of symptoms, many of them using tetracycline as the therapeutic agent.15 Some of these studies demonstrated a role for antibiotics during the acute exacerbation, while others did not find a significant advantage.
However, a recent meta-analysis of nine studies performed between 1957 and 1992 confirms that there is a small, but statistically significant benefit when antibiotics are used for acute exacerbations of COPD.21 The benefits are relatively greater for those patients with AECOPD who require hospitalization. It should be noted that these studies were performed prior to the availability of more potent, compliance-enhancing agents, many of which, such as azithromycin and the new-generation fluoroquinolones, are not only active against atypical organisms, but also against beta-lactamase-producing H. influenzae and M. catarrhalis. Furthermore, the failure rate of older antibiotics may be as high as 25%.22,23
Clinical studies of acute exacerbations of COPD are difficult to interpret because of the heterogeneous nature of COPD, diffuse symptoms that can vary spontaneously, and difficulties in defining clinical response both in the short and long term. Although the role of bacterial infection—and as a result, empiric use of antibiotics—in COPD is somewhat controversial, the most currently available evidence shows that bacterial infection has a significant role in acute exacerbations, but its role in disease progression is less certain. Moreover, based on the preponderance of published evidence, antibiotic therapy is recommended in all patients with AECOPD who present with infectious symptoms (i.e., increased sputum production, change in character of the sputum, increased coughing and shortness of breath) suggesting that antimicrobial therapy will produce a better outcome.20,24-27
Upper respiratory tract commensals, such as nontypable Haemophilus influenzae, cause most bronchial infections by exploiting deficiencies in the host defenses.24 Some COPD patients are chronically colonized by bacteria between exacerbations, which represents an equilibrium in which the numbers of bacteria are contained by the host defenses but not eliminated. When an exacerbation occurs, this equilibrium is upset and bacterial numbers increase, which incites an inflammatory response. Neutrophil products can further impair the mucosal defenses, favoring the bacteria, but if the infection is managed, symptoms resolve. However, if the infection persists, chronic inflammation may cause lung damage. About 50% of exacerbations involve bacterial infection, but these patients are not easy to differentiate from those who are uninfected, which means that antibiotics should be given empirically to the majority of patients who present with AECOPD. Further research is needed to characterize those patients in whom bacterial infection may play a more important role and in whom more intensive antibiotic coverage is required.
Old vs. New Agents. The antibiotic arsenal available for treatment of acute bacterial exacerbations of COPD includes a wide range of older and newer agents representing several drug classes. Although many of the studies confirming efficacy of antibiotics in AECOPD were performed with such older agents as amoxicillin and tetracycline, usage patterns are changing in favor of newer agents such as macrolides with a broader spectrum of coverage and which also have compliance-enhancing features.
There is evidence-based justification for this evolution in prescribing practices.20,24-26 In the past, antibiotics such as amoxicillin, ampicillin, tetracycline, erythromycin, and co-trimoxazole were widely employed. Many of the meta-analysis trials demonstrating the usefulness of antibiotics drew upon studies using these agents. But resistance patterns have changed.24-29 In particular, during the last 10 years, there has been a steady rise in the frequency of b-lactamase production by H. influenzae and M. catarrhalis, and more recently, strains of penicillin-resistant pneumococci have emerged.24-30
Fortunately, these older antibiotics have been joined by newer agents with either a wider spectrum of activity in vitro, better pharmacokinetics, lower incidence of side effects, more convenient dosing, and/or a shorter duration of therapy. Among the antibiotics approved for acute bacterial exacerbations of COPD, and which also have evidence-based support for their efficacy in this condition, the azalide azithromycin and quinolones such as levofloxacin are playing an increasingly important role as first-line therapy.26-31 In addition, b-lactamase inhibitors, including second- and third-generation cephalosporins, also are available.24 A more detailed discussion of antibiotic therapy and the selection process are presented in subsequent sections of this review.
Antibiotic Outcome-Effectiveness and Total Cost of Therapy. Unfortunately, limited data exist to guide physicians in the cost-effective treatment of acute exacerbation of chronic bronchitis (AECOPD). One important study, however, attempted to determine the antimicrobial efficacy of various agents and compared total outcome costs for patients with AECOPD.32 For the purpose of this analysis, a retrospective review was performed of 60 outpatient medical records of individuals with a diagnosis of COPD associated with acute episodes seen in the pulmonary clinic of a teaching institution.
The participating patients had a total of 224 episodes of AECOPD requiring antibiotic treatment. Before review, empirical antibiotic choices were divided into first-line (amoxicillin, co-trimoxazole, tetracyclines, erythromycin); second-line (cephradine, cefuroxime, cefaclor, cefprozil); and third-line (azithromycin, amoxicillin-clavulanate, ciprofloxacin) agents. The designations "first-line," "second-line," and "third-line" were based on a consensus of resident pulmonologists, and was not intended to indicate superiority of one group of drugs vs. another. The residents were asked, "What antibiotic would you choose to treat a patient with AECOPD on their initial presentation, on their second presentation, and on a subsequent presentation, if each episode was separated by 2-4 weeks?"33
The results have potentially interesting implications for antibiotic selection in the outpatient environment. In this study, patients receiving first-line agents (amoxicillin, co-trimoxazole, tetracyclines, erythromycin) failed significantly more frequently (19% vs 7%; P < 0.05) than those treated with third-line agents (azithromycin, amoxicillin-clavulanate, ciprofloxacin). Moreover, patients prescribed first-line agents were hospitalized significantly more often for AECOPD within two weeks of outpatient treatment as compared with patients prescribed third-line agents (18.0% vs 5.3% for third-line agents; P < 0.02). Time between subsequent AECOPD episodes requiring treatment was significantly longer for patients receiving third-line agents compared with first-line and second-line agents (P < 0.005).32 The high failure rate with such older agents as amoxicillin, tetracycline, and erythromycin correlates well with recent reports of increasing antibiotic resistance.33-35
As might be expected, initial pharmacy acquisition costs were lowest with first-line agents (first-line U.S. $10.30 ± 8.76; second-line U.S. $24.45 ± 25.65; third-line U.S. $45.40 ± 11.11; P < 0.0001), but third-line agents showed a trend toward lower mean total costs of AECOPD treatment (first-line U.S. $942 ± 2173; second-line, U.S. $563 ± 2296; third-line, U.S. $542 ± 1946). The use of so-called third-line antimicrobials, azithromycin, amoxicillin-clavulanate, or ciprofloxacin, significantly reduced the failure rate and need for hospitalization, prolonged the time between AECOPD episodes, and were associated with a lower total cost of management for AECOPD. Well-designed, prospective studies are needed to confirm these findings and determine how critical pathways should be constructed to maximize outcome-effectiveness of antibiotics used for AECOPD.
Based on these results, the authors of this retrospective analysis suggest that these trends should be of interest to the following groups: 1) managed care decision-makers involved in the formulary selection process; 2) physicians whose objective is to optimize outcome-effectiveness of antibiotic therapy; and 3) to patients with AECOPD, since definitive treatment of the initial presentation is necessary to minimize work disability, to permit continuance of normal activities, to reduce hospitalizations requiring more intensive therapy, and to prevent further clinical deterioration from bronchitis to pneumonia.33
In addition, the reduction in hospitalization rate observed with second-line and third-line agents, when compared with first-line agents, may have potential impact on the mortality of patients with COPD. In a recent study of 458 patients with COPD who required admission to hospital for acute exacerbation of chronic bronchitis (AECB), mortality was 13% after a median length of stay of 10 days; mortality at 180 days was 35%.36 The severity of ventilator-related impairment of lung function in patients with COPD is strongly related to death both from obstructive lung disease and from all causes.36-37 Moreover, patients who experience frequent episodes of AECOPD are at risk for accelerated loss of lung function and effective antibiotic therapy may slow this decline. The use of third-line antibiotics in the outpatient setting could decrease the number of hospitalizations and the degenerative disease process, and thus prolong the survival of patients with COPD. Further evaluation of this hypothesis is required.33,35-38
Based on the data collected in this study, the use of azithromycin, amoxicillin-clavulanate, or ciprofloxacin for the treatment of AECB resulted in significantly fewer physician office visits and appeared to prevent hospitalizations when compared with first- or second-line antimicrobial therapy.33 Whether there is any difference among these agents remains to be evaluated longitudinally. Additionally, the repetitive nature of return visits to the emergency department or outpatient clinic for AECOPD may assist in identifying patients who require initial treatment with more effective agents in order to prevent AECOPD-related hospital admissions and progression of the disease.
Diagnostic Testing
Although the physical examination and history provide important information for guiding therapy, it is nevertheless difficult to estimate the degree of airway obstruction and exclude conditions which can mimic AECOPD without ancillary diagnostic tests. Not infrequently, clinical findings can abate even though patients still may have moderate to severe obstruction. Signs typically associated with severe obstruction, such as pulsus paradoxus, cyanosis, or retractions, are seen in a minority of patients, and their absence does not rule out significant obstruction. Even experienced pulmonologists may be unable to accurately estimate pulmonary function. Studies in the emergency department setting suggest that clinicians are unable to accurately predict pulmonary function and, frequently, cannot determine whether patients, in fact, have had an objective improvement in expiratory airflow.12,18,19,21-23,39 Because of the limitations based on physical assessment alone, it is important to make objective measurements of lung function.
Pulse Oximetry. The mainstay of acute, intra-departmental evaluation of patients with AECOPD, pulse oximetry is an inexpensive, noninvasive procedure for assessing oxygen saturation. Unlike blood gas sampling, pulse oximetry is noninvasive; in addition, results are available immediately and can be followed continuously, thereby permitting the physician to evaluate patient progress in response to therapy. Pulse oximetry measurements are based on the fact that oxyhemoglobin absorbs more light in the infra-red band (800-1000 nm) than reduced hemoglobin, which absorbs more light in the red band (600-750 nm).40 Dynamic responsiveness depends on pulmonary oxygen stores, distribution of ventilation, blood transit times, and the electronics of the system.41 Response time has been estimated at about six seconds plus the transit time of 20 seconds for blood to reach the finger (or about 15 seconds for it to reach the ear).42 The response to resaturation is faster than response to desaturation.
As a general rule, oximetry is accurate to within 3-5% at saturations greater than 70%.42 However, oximetry is less reliable at oxygen saturations less than 65-70%, because no empirical correlation exists.40 The relationship between the Pa02 and oxygen saturation is complex and varies depending on many factors, including the PO2 and the acid-base status. Most importantly, however, the pulse oximetry provides a relatively rapid means of categorizing patients into mild, moderate, and severe respiratory impairment. In addition, time-dependent trends in the oxygen saturation provide important, objective information that reflects the efficacy of therapy. Capnometry can also be used as an adjunct to pulse oximetry in order to moniter evolving respiratory failure or response to treatment.
Arterial Blood Gases. Both hypercarbia and hypoxemia occur when pulmonary function falls below 25-30% of the predicted normal value.43 Severe hypoxemia can occur in patients with acute exacerbations of COPD, even though their pulmonary function approaches 50% of the predicted normal value.44 As is the case with asthma, severe hypercarbia generally occurs only with severe airway obstruction (i.e., when pulmonary function is below 25% of the predicted normal value).
Some clinicians routinely obtain ABGs on all patients with acute exacerbation of COPD upon arrival to the hospital. Comparison of ABG values during an acute exacerbation with baseline values can help establish the severity of an exacerbation and risk-stratify the patient. However, the practice of obtaining routine ABGs is not universal, especially since pulse oximetry can provide useful, accurate information about a patient’s respiratory status, but it does not provide information about CO2-dependent ventilatory drive. Unlike patients with acute asthma, the patient with COPD may develop acute respiratory failure due to administration of supplemental oxygen. It had been previously thought that acute respiratory acidosis occurs as a result of the diminished hypoxic drive when oxygen was administered. While this may occur, part of the explanation is that acute respiratory acidosis also occurs because of ventilation perfusion abnormalities and gas transfer between alveoli secondary to emphysematous changes.45
In the patient whose initial arterial blood gas does not demonstrate a life-threatening abnormality, the remainder of the ED course usually can be followed using pulse oximetry.46 Patients who have significant abnormalities on the first arterial blood gas will require repeat analysis in order to confirm resolution of the abnormality and aid in disposition.
Pulmonary Function Tests. Pulmonary function testing is a useful means for assessing ventilatory function. Relatively inexpensive peak flow meters are available that can provide a quick assessment of expiratory function. It should be stressed that the peak expiratory flow meter is effort-dependent. In addition, most of the formulae used to derive expected peak flow have been derived from young, healthy patient populations. Furthermore, peak flow meters overestimate lung function in their midrange and lose accuracy after 200 examinations.
Portable spirometers also are readily available and are simple to operate. Fortunately, newer spirometers have eliminated many of the disadvantages that plagued the older, water-sealed devices. Modern spirometers are lightweight, portable, and computerized, permitting rapid calculation of critical clinical values. Furthermore, the spirometer provides for a graphic output, which permits the clinician to visually assess the adequacy of the effort. In addition, many spirometers will display a flow volume loop that can help differentiate between obstructive, restrictive, and proximal obstructive disease.
The spirometer has some advantages over the peak flow meter in that it is easily calibrated. The FEV1 is less effort-dependent than the peak expiratory flow rate, and the spirometer provides a graphic output, which can be entered into the medical record. Additionally, the spirometer allows for the differentiation between restrictive, obstructive, and proximal airway disease. Many patients in acute respiratory distress will have a restrictive pattern because of inadequate forced expiratory maneuver, chest hyperexpansion, and chest wall discomfort. This pattern may resolve with therapy, giving more typical obstructive pattern.
Compared to the FEV1, the peak expiratory flow rate tends to underestimate the degree of airway obstruction.47 Although there is general correlation between the peak expiratory flow rate (PEFR) and the FEV1 in COPD, significant differences may be seen between the two measurements. It appears that there are some advantages to performing spirometry in the emergency department. However, it should be emphasized that some measure of expiratory function is preferable even if it is limited to the peak expiratory flow rate.
Spirometry is useful because patients with COPD frequently have alterations of gas exchange. These patients have chronic airway obstruction and may have chronic CO2 retention. In addition, there is impairment of pulmonary diffusion capacity and there are ventilation perfusion abnormalities that may lead to hypoxemia. In general, the results of pulmonary function testing help predict the presence of hypercarbia.48 Significant hypercarbia is unlikely to occur with patients with a FEV1 less than 35% of predicted normal.48 On the other hand, patients may have severe hypoxemia even in the presence of moderate airway obstruction.
Various authors have advocated selective use of arterial blood gases in patients with AECOPD. While selective use of ABGs may reduce costs of care in some patients, it is not yet clear how patient outcomes might be affected by restricting the use of this modality. Based on these observations and recommendations, it appears reasonable and prudent to use a combination of techniques to identify patients with severe respiratory impairment. To this end, spirometry can help identify patients at risk for hypercarbia, and pulse-oximetry can be used to identify patients with oxygen desaturation. In patients with significant deviations from baseline based on spirometric and pulse oximetric data, ABGs can further elucidate the acuity of decompensation, the patient’s acid-base status, and the need for urgent ventilatory support. However, this scheme has not been tested prospectively in a rigorous manner.
Chest Radiography. A significant percentage of patients with COPD will have abnormalities on their chest radiographs. From an emergency treatment perspective, new abnormalities must be distinguished from chronic changes, and the ability to identify patients with COPD who have community-acquired pneumonia is especially important. Some authors have tried to develop decision rules to increase the yield of chest radiographs. One proposed scheme suggests that a chest radiograph should be obtained in patients with a history of CHF, leukocytosis or a left-shift, or peripheral edema.40 Unfortunately, these high-yield criteria have not been validated in subsequent studies,12,13 and therefore, radiographs should be performed based on the severity of the clinical presentation.
Overall, about 15% of patients with acute exacerbation of COPD will have significant new abnormalities on chest radiography.14 Given the extensive differential diagnosis in patients who present with symptoms typical of acute exacerbation of COPD (cough, sputum production, change in sputum character, fever, shortness of breath), routine chest radiography may be warranted.14 In particular, the chest radiograph will permit identification of those individuals with pneumonia, pneumothorax, and decompensated CHF; on occasion, a new lung mass suggesting malignancy may be detected. Portable radiographs may be necessary for patients who are clinically unstable; studies suggest that portable radiographs will detect more than 90% of abnormalities detectable on a standard PA and posteriolateral radiograph.14
Laboratory Tests. Although a variety of laboratory tests may be obtained in patients with COPD, these studies should be tailored to the specific clinical situation. For example, patients with COPD may be at higher risk for acquiring coronary artery disease because of their history of cigarette smoking. In this subgroup, an ECG may be useful, particularly in patients who have a history of chest pain, syncope, palpitations, and when the differential diagnosis includes CHF.
As a general rule, the complete blood count (CBC) is not particularly useful as a routine test in patients with acute exacerbation of COPD unless pneumonia is suspected, in which case chest radiography is more sensitive and specific. Moreover, COPD patients with chronic, systemic corticosteroid use may have elevated white blood cell counts reflecting drug-induced changes. In addition, the hematocrit is frequently elevated as a result of chronic hypoxemia. Serum electrolytes are generally not required as a part of the routine assessment of these patients, although hypokalemia can result from aggressive use of beta-agonists, systemic corticosteroids, and thiazide diuretics.41
Both to guide therapy and avoid drug toxicity, a serum theophylline level should be obtained in patients who are taking theophylline on an outpatient basis.49 Unfortunately, the theophylline level, which is frequently in the low therapeutic range, cannot be predicted on the basis of a medication history. The serum theophylline may vary because of comorbid illnesses, patient compliance, acute respiratory acidosis, or the concomitant administration of medications that impair its metabolism. (See Table 1.) Loading doses of aminophylline should not be given to patients until a serum theophylline level has been obtained. In general, each milligram per kilogram of aminophylline raises the serum theophylline level by 2 mcg/mL.
| Table 1. Factors Affecting Clearance of Theophylline | ||
| INCREASE | DECREASE | |
| Smoking | Advanced age | Propafenone |
| Younger age | CHF | Mexiletine |
| High-protein, low-carbohydrate diet | Cor pulmonale Pneumonia/fever | Tocainide Cimetidine |
| Phenobarbital | Erythromycin | Clarithromycin |
| Phenytoin | Allopurinol | Cirrhosis |
| Rifampin | Quinolones | Oral contraceptives |
Pharmacotherapy for Patient Stabilization: A Multi-Modal Approach for Optimizing Clinical Outcomes
Optimizing outcomes in patients with AECOPD requires prudent but prompt administration of pharmacological agents directed at relieving bronchoconstriction and improving oxygenation. A multi-modal approach to initial stabilization is the rule rather than the exception. As might be expected, pharmacological approaches for chronic maintenance therapy differ somewhat from those used for acute management. In both cases, it should be stressed that the response to various pharmacotherapeutic modalities may vary from one patient to another; hence, sequencing and combining therapy (using such agents as oxygen, beta-agonists, anticholinergics, and/or corticosteroids) according to previously documented patterns of clinical response may represent the most logical approach in the majority of patients. The role of antibiotic therapy is discussed in a separate section.
Oxygen. Patients with COPD may have hypoxemia due to structural lung abnormalities, impairment of diffusion capacity, or ventilation perfusion mismatch. In a small minority of patients, beta-agonist therapy may slightly worsen ventilation perfusion mismatch. Accordingly, patients in respiratory distress should receive supplemental oxygen therapy, the administration of which should be guided by pulse-oximetry and arterial blood gases when available.
Oxygen therapy usually is initiated by nasal cannula. The typical target point is to maintain an O2 saturation greater than 90%. Patients with hypercarbia may require controlled oxygen therapy using a Venturi mask in order to achieve more precise control of the FiO2. Oxygen administered via nasal cannulae has a varying FiO2, which is influenced by the respiratory rate and mouth breathing. FiO2 admin-istered via a Venturi mask is more predictable. Therapy can be initiated with one of these masks, with upward adjustment based on the arterial blood gas and subsequent monitoring by pulse oximetry.
Acute exacerbation of hypercarbia may, but does not invariably, occur when high flow oxygen therapy is administered to patients with chronic CO2 retention. There is a common misconception that the increase in CO2 retention occurs from the elimination of the hypoxemic stimulus to respiratory drive. In fact, this is a rare phenomenon inasmuch as studies have demonstrated that minute ventilation, cardiac output, and oxygen uptake remain relatively constant during supplemental oxygen therapy in spite of rising PaO2 and PCO2.50-52 These findings suggest that the rise in PCO2 that accompanies the correction of hypoxemia is due to the Haldane effect (a shift of the hemoglobin-CO2 binding curve) and increases in CO2 production, as well as changes in physiologic dead-space.53
From a practical perspective, the clinician will not be able to predict worsening hypercarbia by assessing the patients respiratory rate. Since the PCO2 can rise in the absence of hypoventilation, the clinician must strike a balance between worsening hypercarbia and the significant benefits of relieving hypoxemia. In those patients in whom oxygen administration is accompanied rising PCO2, the concept of "permissive hypercapnia" has been advocated. According to this strategy for patients with respiratory failure, it may be advantageous to tolerate slight increases in the PCO2 for the purpose of maintaining adequate oxygenation as long as the pH remains greater than 7.26. Precise, sequential measurement of ABGs usually is required in this patient subgroup. There may be a role for measurement of end-tidal CO2.
Beta-agonists. The majority of patients with COPD have airway obstruction that, to some degree, will show clinically significant reversibility in response to beta-agonist therapy. The effectiveness of beta-agonist-mediated airway expansion can be dramatic, with at least one study suggesting that the the response to bronchodilators acutely does not help to differentiate between patients with asthma and those with COPD.11 Furthermore, in the setting of severe respiratory distress, even modest improvements in ventilatory resistance may be of significant clinical benefit.54
Beta-agonists may improve dyspnea and improve pulmonary functional status even in the absence of dramatic improvements in the peak expiratory flow rate. As a result, inhaled beta-agonists are considered to be first-line therapy for AECOPD. Beta-agonists can be administered via small volume nebulizers. Drug delivery is enhanced by dilution of the drug to 2-3 cc, with airflow in the range of 6-8 L/min. In addition, beta-agonists can be delivered by metered-dose inhalers which, in conjunction with a spacer, have been shown to be equivalent to the use of air driven, small volume nebulizers. (See Table 2.)
| Table 2. Technique for Using a Metered-Dose Inhaler | ||
| 1. Invert inhaler so that opening pointed is downward after shaking briskly. | ||
| 2. Hold inhaler about four finger-widths in front of open mouth. | ||
| 3. Exhale normally to functional residual capacity. | ||
| 4. Activate inhaler at beginning of inspiration. | ||
| 5. Inhale slowly and deeply to total lung capacity. | ||
| 6. Hold breath for 10 seconds. | ||
| 7. Exhale slowly. | ||
A variety of beta-agonists are available for use in patients with AECOPD. (See Table 3.) In general, the onset of action of inhaled beta-agonists is rapid, usually on the order of about 10 minutes. The various beta-agonist agents vary in terms of duration of action and relative beta-2 agonist selectivity. (See Table 4.) For example, isoproterenol and isoetharine are very rapid-acting agents, but they have limited beta-2 agonist selectivity. Their duration of action is on the order of 1-2 hours.
| Table 3. Beta-Agonist Dosages | ||
| BETA-AGONISTS | MDI | AEROSOL |
| Albuterol (Proventil, Ventolin) | 2-4 puffs q4h | 0.5 cc (2.5 mg) in 2.5 cc NS |
| Bitolterol (Tornalate) | 2 puffs q8h | 0.5 cc (0.2% [1 mg]) in 2 cc NS |
| Isoetharine (Bronkosol) | 4 puffs q4h | 0.5 cc (0.25%) in 3 cc NS |
| Isoproterenol (Isuprel) | 5-15 puffs (1:200) q4h | 0.5 cc (0.5%) in 3 cc NS |
| Metaproterenol (Alupent, Metaprel) | 2-3 puffs q3-4h | 0.3 cc (1.5 mg) in 2.5 cc NS |
| Pirbuterol (Maxair) | 2 puffs q4-6h | |
| Terbutaline (Brethine) | 2 puffs q4-6h | |
| Salmeterol (Serevent) | 2 puffs q12h | |
| Table 4. Characteristics of Bronchodilators Delivered by Metered-Dose Inhalers | |||||||
| LEVEL OF ACTIVITY | TIME OF EFFECT | ||||||
| Medication | Dose (mg)/Puff | Beta-1-Agonist* | Beta-2-Agonist* | Anticholinergic* | Onset (Min) | Peak (Min) | Duration (Min) |
| Isoproterenol | 0.08 | + + + | + + + | - | 3-5 | 5-10 | 60-90 |
| Isoetharine | 0.34 | + + | + + | - | 3-5 | 5-20 | 60-150 |
| Metaproterenol | 0.65 | + | + + + | - | 5-15 | 10-60 | 60-180 |
| Terbutaline | 0.20 | + | + + + + | - | 5-30 | 60-120 | 180-360 |
| Albuterol | 0.09 | + | + + + + | - | 5-15 | 60-90 | 240-360 |
| Bitolterolv | 0.37 | + | + + + + | - | 5-10 | 60-90 | 300-480 |
| Pirbuterol | 0.20 | + | + + + | - | 5-10 | 30-60 | 180-240 |
| Salmeterol | 0.04 | + | + + + + | - | 10-20 | 180 | 720 |
| Ipratropium | 0.18 | - | - | + + + + | 5-15 | 60-120 | 240-480 |
| * The number of plus signs denotes the relative level of activity. | |||||||
Metaproterenol, terbutaline, and albuterol are among the beta-2 selective agents; albuterol is probably the most widely used agent. These formulations achieve their peak effect at around one hour and have a duration of action that can be as long as six hours. Salmeterol is a very long-acting beta-2 selective agonist, which has duration of action on the order of 12 hours. Because it has a delayed peak effect, its use is not recommended for acute respiratory distress. In fact, patients who are on this agent for home therapy need to be warned about the lack of efficacy for acute exacerbations of COPD.
In theory, based on target receptor selectivity, the beta-2 selective agents should have fewer undesirable cardiovascular side effects than non-selective beta-agonists. There is evidence of a decreased incidence of hypotension, palpitations, hypokalemia, anxiety, tremulous, or vomiting. Nevertheless, these agents can lead to tachycardia and supraventricular arrhythmias, particularly in patients with pre-existing cardiac arrhythmias or hypoxemia.55 Patients suffering from AECOPD, however, rarely deteriorate due to cardiac arrhythmias. In the acute exacerbation, there is little evidence conclusively establishing that any specific agent has superior efficacy as compared to others. However, there may be some advantages to the longer-acting agents in that there will be prolonged bronchodilation. Aside from these considerations, selection of beta-agonist, to a great degree, is a matter of personal preference.
Adrenergic agents also can be administered by injection. Although tradition has held that patients with COPD should receive terbutaline instead of epinephrine, one study has shown there are no differences in the side effect profile when these two agents are given to older patients with airway disease.56 In theory, patients with significant bronchoconstriction may not achieve adequate delivery of drug to the distal airways when given by inhalation. Some have advocated initiating therapy with injectable agents followed by inhaled agents. This approach has not been demonstrated to lead to greater clinical efficacy.
Finally, there is a great deal of controversy regarding the timing and optimal dose of inhaled beta-agonists. Whereas these agents once were administered at a moderate dose every hour, there has been a trend toward increasing frequency and size of dosing for inhaled beta-agonists. One study failed to demonstrate a significant advantage by giving albuterol more frequently than once every 60 minutes.57 Recommendations for management in patients with asthma include administration of an agent such as albuterol in a dose of 2.5-5 mg every 20 minutes. There is no evidence to suggest that this approach is necessary in patients with AECOPD.
Anticholinergic Agents. Anticholinergic therapy has been studied as an adjunct with beta-agonists in the treatment of acute exacerbation of COPD. Anticholinergic drugs produce preferential dilatation of the larger central airways, in contrast to beta-agonists, which affect the peripheral airways. Until recently, atropine was the primary anticholinergic agent used in nebulization. It acts more rapidly than ipratropium but has a shorter duration of action. Atropine is readily absorbed through the airway mucosa, leading to potential anticholinergic side effects such as tachycardia, flushing, dry mouth, blurred vision, and confusion. It can also precipitate glaucoma and acute urinary retention in susceptible patients. It should be emphasized that anticholinergic agents have a slower onset of action and take longer to reach peak effect than beta-agonists. The mechanism of action is thought to occur through inhibition of vagal stimulation on the bronchial tree, thereby blocking smooth-muscle contraction and bronchial gland secretion.
Generally speaking, the precise clinical role of anticholinergic compounds in the acute exacerbation of COPD is unclear, although these agents may have selective advantages for managing patients who respond poorly to beta-agonist therapy alone. Since these agents are relatively safe, their use should be considered in patients with severe respiratory distress or respiratory failure who fail to respond to usual measures.
Most studies using anticholinergic agents have used one of the quaternary ammonium compounds, since they have a better safety profile than nebulized atropine. In particular, glycopyrrolate is another quaternary ammonium compound with few atropine-like side effects.The drug has been used for a number of years to minimize secretions during operative procedures. There have been case reports of reversal of bronchospasm in patients with acute exacerbation of COPD when given intravenously.58 It has recently been shown that the combination of glycopyrrolate and albuterol results in a greater improvement in pulmonary function than albuterol alone.59
Some studies have found a beneficial effect by using combination treatment with glycopyrrolate and either albuterol or metaproterenol.60,61 Glycopyrrolate is commonly available in most hospitals since it is used in the operating room. In combination with metaproterenol, glycopyrrolate leads to greater peak effect, with maximal activity at around 2-3 hours.60 Another study reported that in combination with albuterol, glycopyrrolate lead to a significantly greater improvement in FEV1 among patients presenting to the emergency department with AECOPD.62 Unfortunately, the typical pre-anesthetic dose of glycopyrrolate (0.2 mg) is far lower than the therapeutic dose required for an acute exacerbation of COPD (2.0 mg). If glycopyrrolate is not available in a multidose vial in a given hospital, it requires significant nursing effort in order to prepare an appropriate dose.
Some authors consider ipratropium to be one of the first-line therapeutic options for chronic, outpatient management of stable patients with COPD.63-67 The margin of safety with ipratropium is wide, since more than 10 times the usual dose can be given before side effects are seen. When administered via metered-dose inhaler, the usual dose is 2-4 puffs every six hours. To maximize results, patients should be instructed in the proper use of the metered-dose inhaler. There have been about six studies comparing ipratropium in combination with beta-agonists for AECOPD. Most of these studies however, have found no particular added benefit to the addition of ipratropium to inhaled beta-agonists.59,68 Consequently, the role of ipratropium in patients with an acute exacerbation is not clear and requires more investigation. Ipratropium is available both as a metered dose inhaler and as a solution for inhalation.
Corticosteroids. The administration of corticosteroids is part of the mainstay of treatment of patients with acute asthma. With contradictory results in COPD, their role in managing AECOPD is evolving but not yet fully elaborated.69-71 In general, however, there is mounting evidence that rapidly tapering courses of corticosteroids, in combination with bronchodilators and antibiotics, when indicated, are effective in preventing relapses and maintaining longer symptom-free intervals in patients who have had AECOPD.
It should be stressed that the studies evaluating steroid therapy vary in design and to some extent, have produced conflicting results.69-73 A small number of studies have demonstrated a role for corticosteroids in patients with AECOPD. For example, one study performed almost 20 years ago demonstrated improvement in pulmonary function among patients admitted for acute exacerbations of COPD when methylprednisolone was administered at a dose of 0.5 mg/kg.72 Another study, however, found that the administration of steroids did not lead to a change in the short course of treatment in the emergency department.73
Several studies have suggested that patients with an acute exacerbation of COPD should receive steroids as a mainstay of outpatient therapy.69,70 One trial reported improvement in both recovery of oxygenation and pulmonary function over the course of a nine-day tapering dose of prednisone.70 Another trial found that the administration of steroids either in the emergency department or as an outpatient resulted in a significantly lower relapse rate among patients who were discharged from the emergency department for acute exacerbation of COPD.69 A more recent study of hospitalized VA patients demonstrated that a two-week tapering course of prednisone decreased the rate of treatment failure for up to three months.71 Among patients with stable COPD, the addition of inhaled steroids seems to result in improved pulmonary function and decreased beta-agonist use in about 25% of patients.74 There does not appear to be a role for inhaled corticosteroids in the treatment of acute exacerbations.
Theophylline. Methylxanthines, including theophylline and aminophylline, are still used in the treatment of COPD, but their role remains controversial. In fact, many experts feel there is little if any role for theophylline as part of multi-modal therapy in the setting of AECOPD. The exact mechanism of action of theophylline in clinical doses for acute airway obstruction remains controversial. Although it was postulated that theophylline produced salutory effects by inhibiting phosphodiesterase, other actions, including alteration of calcium flux, interference of prostaglandin synthesis, or inhibition of adenosine receptors, probably also play a role. In addition, theophylline may also improve diaphragmatic muscle strength.
Relatively few studies have been performed on the clinical effect of theophylline in acute exacerbations of COPD. Of the two larger studies that have been performed, the results were contradictory.75,76 It should be stressed that the medication history is an inaccurate guide to drug levels for patients with COPD. Theophylline has a relatively narrow therapeutic index with side effects that range from minor, such as nausea, vomiting, and tremor, up to more serious side effects, including intractable seizures and ventricular arrhythmias. A theophylline level should be measured prior to administering theophylline in patients on chronic therapy.
There is insufficient evidence at this time to conclusively determine whether aminophylline has any role in the ED management of acute exacerbation of COPD. Although some authors suggest this agent should be considered in patients who are unresponsive to other therapies, others maintain there is no role for its use at the present time.74-76
Magnesium. Magnesium has been studied in several series, most of which have evaluated its effectiveness in the setting of acute asthma. Magnesium presumably acts by opposing calcium-induced bronchoconstriction. One recent study demonstrated a significant improvement in pulmonary function in patients given magnesium during an acute exacerbation of COPD.77 Given at a dose of 1-2 gm over 20 minutes, magnesium significantly improved peak expiratory flow, although there was a nonsignificant decrease in the hospitalization rate. At these doses, magnesium is relatively safe. Adverse effects can include flushing sensation, transient hypotension, and at higher doses, cardiac conduction delays. Magnesium levels may be elevated in patients with renal insufficiency.
Heliox. Helium/oxygen mixtures have been found to decrease dyspnea in patients with COPD by minimizing the risks of gas flow, since helium is only 14% as dense as nitrogen. This decrease in expiratory resistance has been thought to enhance ventilation and lower PCO2. There have been anecdotal reports of beneficial effects in improving peak expiratory flow. There are no large-scale studies evaluating the use of helium/oxygen mixtures in patients with acute exacerbation of COPD. Its use should probably be limited to experimental studies or as a last alternative for patients in extremis.
Summary of Therapeutic Approaches. Patients with an acute exacerbation of COPD should receive oxygen therapy, guided by pulse oximetry. Patients with baseline hypercarbia or severe airway obstruction (less than 35% of predicted normal) should have arterial blood gases in order to insure that oxygen therapy is not leading to a worsening of hypercarbia and acute systemic, respiratory acidosis; controlled flow oxygen masks may be needed in patients at risk for hypercarbia.
Beta-agonist therapy, using any of the available rapid-onset agents administered by small volume nebulizer or meter dose inhaler with spacer, should be initiated promptly. The timing and dose have not been well established, but a reasonable regimen would be to initiate therapy with albuterol at a dose of 2.5 mg every 20 minutes. In patients who are not responding to these pharmacological maneuvers, consideration may be given to adding ipratropium to the aerosolization.
In those individuals who still fail to respond, the clinician can consider administration of intravenous theophylline (after measuring the theophylline level), or magnesium at a dose of 2 gm over 20 minutes. Oral or parenteral steroids can be administered at the time of the exacerbation, although acute clinical benefits may not be evident. As a rule, these agents should be considered in patients who are deteriorating in spite of adequate beta-agonist therapy.
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Physician CME Questions
57. Compared to the peak expiratory flow rate, the FEV1 is:
A. more effort dependent.
B. a useful means of differentiating restrictive from obstructive disease.
C. more difficult to calibrate.
D. more likely to underestimate the degree of airway obstruction.
58. Beta-agonist therapy in acute exacerbation of COPD:
A. is generally not useful because patients have fixed obstruction.
B. is best accomplished using Salmeterol since it is long acting.
C. can be given either by nebulizer or metered-dose inhaler.
D. frequently precipitates cardiac arrhythmias.
59. The role of steroids in the acute exacerbation of COPD:
A. has been clearly shown to be of benefit in the ED.
B. is useful in about half of patients with stable COPD.
C. may decrease treatment failures following hospital discharge.
D. has clearly been established to be beneficial using inhaled steroids for the acute exacerbation.
60. Adverse side effects to magnesium include which of the following?
A. Flushing sensation
B. Transient hypotension
C. Cardiac conduction delays
D. All of the above
61. Each of the following is commonly associated with bronchitis in patients with COPD except:
A. Chlamydia.
B. Hemophilus influenzae.
C. Parainfluenza virus.
D. Streptococcus pneumoniae.
62. High-risk patients with COPD have a 12-year survivability of about:
A. 10%.
B. 20%.
C. 30%.
D. 40%.
E. none of the above.
63. Patients with COPD requiring ICU admission have a mortality rate of:
A. less than 10%.
B. 10-30%.
C. 30-50%.
D. 50-70%.
E. none of the above.
64. Which of the following newer antibiotics are playing an increasingly important role in AECOPD?
A. Tetracycline and nitrofurantoin
B. Sulfonamides and amoxicillin
C. Azithromycin and levofloxacin
D. Erythromycin and vancomycin
E. None of the above
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