Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD)
October 24, 1999 38 minutes read
Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD): Outcome-Effective Antimicrobial Selection and Recent Advances in Outpatient Management
Part II: Antibiotic Selection, Severity of Exacerbation and Risk Factors (SERF) Pathway, and Patient Disposition
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; Sandra M. Schneider, MD, FACEP, Professor and Chair, Department of Emergency Medicine, Uni- versity of Rochester, Rochester, NY; Albert C. Weihl, MD, FACEP, Educa- tion Director, Section of Emergency Medicine, Yale University School of Medicine, New Haven, CT.
Acute bacterial exacerbations of chronic obstructive pulmonary disease (ABE/COPD) are common, costly, and, above all, complex to manage. In fact, few conditions produce such a broad range of outcomes, require such customized approaches, or present so many options for treatment.
Although there have been important advances in patient assessment techniques and therapeutics—including pulmonary function testing, capnometry, pulse oximetry, disposition support tools, and antimicrobial therapy—ABE/COPD continues to be a leading cause of morbidity and mortality in the United States. From patient disposition to antimicrobial selection, optimizing management of these patients requires the clinician to integrate a number of clinical, laboratory, radiologic, and etiologic factors, and then initiate a course of action that accounts for all the risks, costs, and benefits of an individualized treatment plan.
Despite the plethora of guidelines and the availability of new, targeted spectrum antibiotics, the management of ABE/COPD remains extremely challenging. More than ever, it requires a multifactorial analysis of myriad clinical, historical, and laboratory parameters that predict success or possible failure for each individual case. In this regard, clinical decision-making in ABE/COPD can be treacherous for the emergency physician.
Achieving optimal patient outcomes for this potentially life-threatening condition requires the clinician to consider several features of each individual case. Factors that must be considered include the patient's age, response to medical therapy, overall pulmonary function, character and severity of previous exacerbations, bacterial colonization status of the patient, previous requirements for mechanical ventilation, and local antimicrobial resistance patterns. With this in mind, a Severity-of-Exacerbation and Risk Factor (SERF) pathway can be employed to help guide patient disposition, empiric antibiotic selection, and necessity for additional diagnostic investigation.
The antibiotic selection process for ABE/COPD is especially daunting. Currently, the pathogens most often responsible for causing "uncomplicated and typical" cases of ABE/COPD that can be treated in the outpatient environment include the bacterial organisms, S. pneumoniae, H. influenzae, and M. catarrhalis. Because it may be difficult, if not impossible, to identify a specific pathogen at the time of initial patient assessment, empiric antimicrobial coverage against all expected pathogens may be necessary to minimize treatment failures. Patients with advanced disease and multiple risk factors may have exacerbations caused by Klebsiella spp., Pseudomonas aeruginosa, and other gram-negative species.
In this vein, the development of advanced generation macrolides, such as azithromycin as well as extended spectrum quinolones, has made it possible to treat most patients using monotherapy. Finally, because there is a growing incidence of resistance among common bacterial agents that cause community acquired pneumonia (CAP) (in some areas of the United States, intermediate-to-complete resistance to penicillin among Streptococcus pneumoniae is reported to be greater than 25%), antibiotic selection must be guided by local and/or regional resistance patterns.
The purpose of this comprehensive review is to provide a state-of-the-art clinical resource outlining, in precise and practical detail, clinical protocols for acute management of ABE/COPD. To achieve this goal, all of the critical aspects entering into the equation for maximizing outcomes, while minimizing costs, including systematic patient evaluation, disposition decision trees, and outcome-effective antibiotic therapy, will be discussed in detail. Pharmacotherapy for patient stabilization in the ED, multi-modal approaches to optimizing clinical outcomes, and approaches to acute ventilatory management are discussed in detail.
In addition, because appropriate disposition of patients with ABE/COPD has become essential for cost-effective patient management, this issue includes critical pathways and treatment tables that incorporate risk stratification protocols and intensification-of-treatment trigger (IOTT) criteria that can be used to identify those patient subgroups that are suitably managed in the outpatient setting, and those more appropriately admitted to the hospital for more intensive care.
— The Editor
Antibiotic Therapy: The SERF Pathway for Outcome-Effective Drug Selection
Patients in whom exacerbation of chronic obstructive pulmonary disease (COPD) is associated with acute respiratory infection are at high risk for relapse unless treated.1 Patients with acute bronchitis that is unrelated to COPD probably do not benefit from antibiotic therapy. It should be noted, however, that in patients with COPD, antibiotics appear to have a role in the treatment of exacerbations caused by bacterial bronchitis (i.e., ABE/COPD). The patient with an increase in sputum quantity and/or a change in character or color, especially if accompanied by increasing cough and dyspnea, should be treated with antibiotics upon discharge from the emergency department or clinic. It should be stressed that many patients with COPD have colonization of their tracheal tract with Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis. Other organisms, such as Klebsiella species, Mycoplasma pneumoniae, Pseudomonas, Staphylococcus aureus, Proteus species, or Chlamydia TWAR may also be seen. Unfortunately, making an etiologic bacteria-specific diagnosis in ABE/COPD is usually not possible. Consequently, most patients will require empiric therapy directed at the most likely etiologic organisms.
Although a number of clinical decision support tools, consensus guidelines, and recommendations have been issued, none has universal support. In large part, this is because the etiologic agents responsible for ABE/COPD, the outcome-effectiveness of various antibiotics, and risk-stratification parameters are not as thoroughly elaborated as they are for CAP. Consequently, several authors have argued that there is an immediate need for guidelines on antibiotic use in COPD. Several attempts to formulate such protocols have resulted in broadly similar recommendations. Although the guidelines inevitably have been hampered by the lack of well-designed prospective studies, they have taken a practical approach that seems to be logical and can be used in the emergency department and primary care setting. (See Tables 1 and 2.) It must be emphasized, however, that the concepts on which the guidelines are based have not yet been verified by prospective clinical trials.2-4
| Table 1. Recommended Dosing and Duration of Antibiotic Therapy for Acute Exacerbation of COPD (ABE/COPD) |
| First-line Agents with Clinically acceptable coverage for ABE/COPD Caused by H. influenzae, M. catarrhalis, or S. pneumoniae § |
| Macrolides/Azalides |
| • Azithromycin (Zithromax): 500 mg on 1st day, 250 mg qd ´ 4 days. Five-day total course of therapy (preferred agent based on Pharmatectural and PPD criteria: cost, compliance, coverage, drug interaction, and side-effect profiles). |
| Penicillins |
| • Amoxicillin/clavulanate (Augmentin):500 mg tid ´ 10 days (bid therapy is also an option) |
| Fluoroquinolones |
| • Levofloxacin (Levaquin): 500 mg qd ´ 7-14 days |
| FIRST-LINE AGENTS WITH CLINICALLY ACCEPTABLE COVERAGE FOR ABE/COPD CAUSED BY H. influenzae, M. catarrhalis, or S. pneumoniae, PLUS acceptable coverage of some gram-negative species known to cause ABE/COPD in patients who have been risk-stratified to a more severe disease category § |
| Fluoroquinolones |
| • Levofloxacin (Levaquin): 500 mg qd ´ 7-14 days |
| Indicated for acute bacterial exacerbations of chronic bronchitis caused by H. parainfluenzae, M. catarrhalis, H. influenzae, S. pneumoniae, and S. aureus |
| • Ciprofloxacin (Cipro): 500 mg bid ´ 10 days |
| Although effective in clinical trials, ciprofloxacin is not considered the agent of first choice when ABE/COPD is secondary to S. pneumoniae infection |
| ALTERNATIVE, second-line AGENTS WITH CLINICALLY ACCEPTABLE COVERAGE OF ABE/COPD CAUSED BY H. influenzae, M. catarrhalis, or S. pneumoniae § |
| Second-Generation Macrolide |
| • Clarithromycin (Biaxin): 250 mg bid (for S. pneumoniae/M. catarrhalis); 500 mg bid (for above plus H. influenzae) ´ 7-14 days |
| • Dirithromycin (Dynabac): 500 mg qd ´ 7 days |
| Cephalosporins |
| • Cefixime (Suprax): 400 mg qd ´ 10 days |
| • Cefprozil (Cefzil): 500 mg bid ´ 10 days |
| • Cefuroxime (Ceftin): 500 po bid ´ 10 days |
| ALTERNATIVE AGENTS WITH CLINICALLY ACCEPTABLE COVERAGE FOR ABE/COPD CAUSED BY H. influenzae or M. catarrhalis (Lomefloxacin), or S. pneumoniae or H. influenzae (ofloxacin) |
| Quinolones |
| • Ofloxacin (Floxin): 400 mg bid ´ 10 days |
| Not indicated for ABE/COPD caused by M. catarrhalis |
| • Lomefloxacin (Maxaquin): 400 mg qd ´ 10 days |
| Indicated for ABE/COPD caused by H. influenzae or M. catarrhalis, but not indicated for the empiric treatment of ABE/COPD when S. pneumoniae is the causative organism |
| ALTERNATIVE AGENTS (GENERIC PREPARATIONS) FOR TREATMENT OF UNCOMPLICATED, ACUTE EXACERBATIONS OF CHRONIC BRONCHITIS |
| • Trimethoprim-sulfamethoxazole (Bactrim, Septra): 1 DS tab po bid 7-14 days |
| • Amoxicillin (Amoxil, Wymox): 500 mg tid ´ 7-14 days |
| • Tetracycline: 500 mg qid ´ 7-14 days |
| • Doxycycline (Doryx, Vibramycin): 100 mg bid ´ 7-14 days |
| § Possible b-lactam resistance may be encountered, especially among H. influenzae and M. catarrhalis; therefore, these first-line agents include specific antimicrobials likely to be active against such species.) |
| ¶ Emerging, clinically significant resistance among S. pneumoniae to sulfonamides, penicillins, and tetracyclines (as well as incidence of b-lacta-mase-producing species) has the potential to compromise clinical efficacy of these agents in ABE/COPD. Not recommended as first-line therapy. |
| Bosker G. Pharmatecture: Minimizing Medications to Maximize Results. St. Louis: Facts and Comparisons; 1999. |
| Table 2. Antibiotic Treatment of Acute Infectious Exacerbation of COPD | |||
| SERF pathway and iott CRITERIA/RISK FACTORS§ | PATHOGENS | ANTIBIOTIC TREATMENT | |
| Acute tracheobronchitis | |||
| No underlying structural disease | Usually viral | None, if viral infection is suspected. Azithromycin if bacterial etiology and ABE/COPD are likely | |
| Acute bacterial exacerbation of chronic bronchitis | |||
| FEV1 > 50%; two of three of the following are present: increased sputum volume, increased purulence, or increased cough | H. influenzae, M. catarrhalis, S. pneumoniae (possible b-lactam-resistant species can be encountered, especially among H. influenzae and M. catarrhalis) | Azithromycin, amoxicillin-clavulanate | |
| Acute bacterial exacerbation of complicated chronic bronchitis | |||
| FEV1 < 50%, advanced age, (four exacerbations/year;co-morbidity) | H. influenzae, M. catarrhalis, S. pneumoniae (possible b-lactam-resistant species can be encountered, especially among H. influenzae and M. catarrhalis). In addition, likelihood of infection with gram-negative organisms may be increased | Fluoroquinolone (levofloxacin, ciprofloxacin) if gram-negative enterobacteriaceae are strongly suspected; second-generation macrolide (azithromycin), if H. influenzae, M. catarrhalis, or S. pneumoniae aresupsected; or second-line alternative: cephalosporin | |
| Chronic bronchial infection | |||
| Advanced disease with M. catarrhalis, continuous sputum throughout year | H. influenzae, S. pneumoniae, plus Enterobacteria, P. aeruginosa | Quinolones | |
| Authors' recommended antibiotics appearing in this table are based on pharmatectural criteria of convenience of dosing, cost, side effects, spectrum of coverage, and risk of drug-drug interactions (See Bosker, G. Pharmatecture: Minimizing Medications To Maximize Results. St. Louis: Facts and comparisons; 1999.) | |||
| SERF = Severity of Exacerbation and Risk Factors | |||
| § IOTT= Intensity of Treatment Trigger | |||
| Framework adapted with permission from: Grossman RF. Chest 1997;112:3105-3125. | |||
Antibiotics. A number of relatively inexpensive, well-tolerated antibiotics are available, including amoxicillin, trimethoprim-sulfamethoxazole, doxycycline, and tetracycline. Antimicrobial-resistance, particularly involving H. influenzae, M. catarrhalis, and S. pneumoniae, has been a problem with many of these agents, specifically with older members of each of these drug classes. There is an increase amoxicillin-resistant, beta-lactamase-producing H. influenzae. New agents are providing solutions to these difficulties. The azalide antibiotic azithromycin has the advantage of an appropriate spectrum of coverage, an excellent safety profile, reasonable cost, and a patient-dosing schedule that improves patient compliance. The new fluoroquinolone levofloxacin also is advantageous when gram-negative bacteria predominate; ciprofloxacin is suitable in this subgroup of patients with ABE/COPD but is not the agent of choice when the bacterial exacerbation is suspected to be caused by S. pneumoniae. Amoxicillin-clavulanate also has in vitro activity against beta-lactamase-producing H. influenzae and M. catarrhalis; moreover, the agent’s clinical efficacy in lower respiratory tract infection attributable to enzyme-producing strains has been demonstrated.
Severity of Exacerbation and Risk Factors Pathway. The Severity of Exacerbation and Risk Factors (SERF) pathway for antibiotic selection in patients with ABE/COPD is a clinical decision, consensus-driven support tool based on epidemiology, efficacy, and prognostic data generated by many published clinical trials.3-21 In general, the need for intensification and amplification of antimicrobial coverage in patients with acute exacerbations of chronic obstructive lung disease (ABE/COPD) depends on the likelihood of infection with gram-negative enterobacteria, colonization status, the patient’s history of exacerbations and antimicrobial treatment response record, the ability of the patient to tolerate a treatment failure given his or her respiratory status, and other factors.
The SERF Pathway (See Table 3), which is based on evidence-based trials and consensus opinion, is designed as a clinical support tool to help guide empiric antibiotic therapy for outpatients with ABE/COPD. Final decisions regarding drug selection should be made by the clinician on a patient-by-patient basis using a comprehensive database including history, physical examination, and other diagnostic information. Specifically, the SERF pathway identifies a number of intensification-of-treatment trigger (IOTT) criteria that have been generated from consensus reports, reviews, and prospective trials in acute exacerbations of chronic obstructive pulmonary disease (AECOPD). These factors should be considered when selecting an antibiotic for empiric outpatient treatment of ABE/COPD. When at least 2-3 IOTT criteria are present (or any single IOTT criterion is of such severity as to predict a poor outcome) in any individual patient, clinicians should consider newer agents with evidence-based support as indicated, and recognize possible limitations of older agents such as sulfonamides, penicillins, and tetracyclines. (See Table 4.)
| Table 3. The SERF Risk-Stratification Pathway for Antibiotic Selection in ABE/COPD |
| Severity of Exacerbation and Risk Factor (SERF) Support Tool |
| Rationale |
| The need for intensification and amplification of antimicrobial coverage in patients with acute exacerbations of chronic obstructive lung disease (ABE/COPD) depends on: |
| • Likelihood of infection with gram-negative enterobacteria |
| • Colonization status |
| • Patient's history of exacerbations and antimicrobial treatment response record |
| • Ability of patient to tolerate a treatment failure given his or her respiratory status |
| • Other factors requiring sound clinical judgment. |
| The SERF Pathway |
| • Based on evidence-based trials and consensus opinion |
| • Designed as a clinical decision support tool to help guide empiric antibiotic therapy for outpatients with ABE/COPD. |
| Final decisions regarding drug selection should be made by the clinician on a patient-by-patient basis using on a comprehensive database including history, physical examination, and other diagnostic information. |
| Table 4. SERF Pathway: Intensification of Treatment Trigger (IOTT) Criteria for Risk-Stratification in ABE/COPD |
| Intensification-of-treatment trigger (IOTT) criteria should be considered when selecting an antibiotic for empiric outpatient treatment of ABE/COPD. |
| When IOTT criteria are present, clinicians should consider newer agents with evidence-based support as indicated and recognize possible limitations of older agents such as sulfonamides, penicillins, and tetracyclines. |
| IOTT criteria include the following: |
| • History of multiple bacterial exacerbations of COPD within a short time period (more than 3 exacerbations in < 4 months) |
| • Multiple antimicrobial treatment exposures |
| • Documentation of gram-negative (enterobacteria, pseudomonas, Klebsiella, etc.) respiratory tract colonization |
| • History of requiring mechanical ventilation after treatment failure of ABE/COPD |
| • History of gram-negative nosocomial lower respiratory tract infection |
| • Chronic, systemic corticosteroid use |
| • Multiple emergency department visits with relapse within a 10-day period |
| • Supplemental home oxygen |
| • Smoking |
| • High prevalence (documented) S. pneumoniae resistance to penicillin |
| • Chronic alcoholism associated with history of gram-negative (Klebsiella) lower respiratory tract infection |
| • Serious co-morbidity (immunosuppression, HIV, underlying malignancy, etc.) |
There is ample support in the medical literature for the SERF pathway and IOTT criteria proposed in Tables 3 and 4. Approximately one-half of all exacerbations of COPD can be attributed to bacterial infection, and antibiotic therapy has been demonstrated to improve clinical outcomes and accelerate clinical and physiologic recovery. The major pathogen continues to be H. influenzae, and resistance to beta-lactam antibiotics such as ampicillin can be expected in 20-40% of isolated strains.22 Certain high-risk patients, in whom the cost of clinical treatment failure is high, can be identified by simple clinical criteria.
Studies suggest, for example, patients with significant cardiopulmonary comorbidity, frequent purulent exacerbations of COPD, advanced age, generalized debility, malnutrition, chronic corticosteroid administration, long duration of COPD, and severe underlying lung function may be more likely to fail therapy with older drugs, such as ampicillin, and that early relapse can be expected.22 Treatment directed toward resistant pathogens using appropriate agents may be expected to lead to improved clinical outcomes and overall lower costs, particularly if hospital admissions and respiratory failure can be prevented. Future studies examining the role of antibiotics should enroll these high-risk patients to determine if new therapies have significant clinical, quality-of-life, and economic advantages over older agents.22
Other authors have proposed different classification schemes. There is general agreement that acute exacerbations of chronic bronchitis (AECB) can be defined as the presence of increases in cough/sputum, sputum purulence, and dyspnea. However, recent investigations suggest that the severity of AECB also may be divided into three stages based on the history of the patient: 1) previously healthy individuals; 2) patients with chronic cough and sputum and infrequent exacerbations; and 3) persons with frequent exacerbations or more severe chronic airflow limitation.
Recent Trials of Antibiotic Efficacy in Acute Bacterial Exacerbations of COPD. The goals of therapy for ABE/COPD are to resolve the infection expeditiously, maintain an infection-free interval for as long as possible, and select an antibiotic with the fewest adverse effects and most favorable compliance profile. Because patients with COPD frequently are on complicated, multi-modal drug therapy—consumption of many medications with a complicated dosing schedule is not uncommon—identifying effective, compliance-enhancing regimens for ABE/COPD is an important clinical objective. (See Table 5.) Moreover, because the key meta-analysis study supporting the efficacy of antibiotics in ABE/COPD was based on older trials with "older" agents, it is important that practitioners are aware of more recent studies evaluating effectiveness of newer antibiotics for this condition.
| Table 5. Multi-Modal Pharmacotherapy for ABE/COPD: Checklist of Agents Requiring Consideration |
| • Beta-agonists (selective agents preferred) |
| • Anticholinergic drug |
| • Home oxygen |
| • Systemic corticosteroids |
| • Inhaled corticosteroids |
| • Antibiotics (advanced generation macrolides and quinolones preferred) |
| • Theophylline (efficacy is controversial) |
Many excellent studies are now available. One randomized, multicenter, investigator-blinded, parallel-group study compared a five-day, once-daily course of azithromycin (two 250 mg capsules on day 1, followed by one 250 mg capsule on days 2-5) with a 10-day, three-times-daily course of amoxicillin-clavulanate (one 500 mg tablet tid) in 70 patients with acute bacterial exacerbations of chronic obstructive pulmonary disease (ABE/COPD).20 At the end of therapy, all 29 (100%) efficacy-assessable patients treated with azithromycin were cured or improved, compared with 25 (93%) of 27 assessable patients given amoxicillin-clavulanate (P = NS). Bacteriologic eradication rates were 86% (25 of 29 isolates) with azithromycin and 87% (20 of 23 isolates) with the comparative agent. Azithromycin was well tolerated; adverse events considered related or possibly related to treatment were reported in 28% of azithromycin recipients, compared with 39% of amoxicillin-clavulanate recipients (P = NS). The authors concluded that the five-day, once-daily regimen of azithromycin is comparable to a standard agent in the treatment of patients with ABE/COPD.20
The results of this study indicated that the administration of azithromycin once daily for five days is comparable to amoxicillin-clavulanate in the treatment of patients with ABE/COPD. The dosing schedule of azithromycin described in this trial is the shortest and simplest of the commonly prescribed oral antibiotics for ABE/COPD. Because reduced frequency of dosing and shorter therapy duration may improve patient compliance, and potentially, outcomes, practitioners should be aware of differences among effective agents as they relate to these compliance-sensitive parameters. Another Italian study comparing dirithromycin and azithromycin for the treatment of acute bacterial exacerbations of chronic bronchitis showed both drugs to be equally effective with cure or improvement at the immediate post-therapy period in the 90-92% range for both agents.21
An extended elimination half-life and good tissue penetration permit oral azithromycin to attain high and prolonged concentrations in infected tissues, yielding high antibacterial activity in vivo. However, there has been speculation among some authors, who have suggested that prolonged subinhibitory concentrations of azithromycin from two to four weeks after acute therapy may lead to the emergence of azithromycin resistance in vivo, compared with other macrolide antibiotics.24-26
This analysis is not universally accepted. In fact, data from two types of in vitro susceptibility studies, an animal tissue infection model, and a clinical pediatric study, demonstrated that prolonged tissue concentrations of azithromycin are unlikely to lead to the emergence of resistance in the clinical setting. Induction of resistance to macrolides in the laboratory is difficult, even with serial subculture and long-term experiments. Moreover, susceptibility testing of S. pneumoniae in one of the studies25 was performed using the E-test method. Other studies reviewed indicate that use of CO2 incubation can significantly overestimate the MIC values of bacterial strains exposed to macrolides, compared with standard and approved methodologies. This effect is particularly marked in the case of azithromycin. As a result, caution should be exercised when interpreting results generated by the E-test method when testing organisms such as S. pneumoniae, which require incubation in the presence of CO2.24-28
In another prospective, multicenter, double-blind study, the efficacy of ciprofloxacin was compared with that of clarithromycin as therapy for patients with acute bacterial exacerbations of chronic bronchitis (ABE/COPD) from whom a pretherapy pathogen was isolated; the efficacy was measured by the infection-free interval. Patients randomly received either ciprofloxacin or clarithromycin (500 mg twice a day for 14 days). Three hundred seventy-six patients with acute exacerbations of chronic bronchitis were enrolled in the study, 234 of whom had an ABE/COPD. Clinical resolution was observed in 90% (89 of 99) of ciprofloxacin recipients and 82% (75 of 91) of clarithromycin recipients for whom efficacy could be evaluated. The median infection-free interval was 142 days for ciprofloxacin recipients and 51 days for clarithromycin recipients (P = 0.15). Bacteriologic eradication rates were 91% (86 of 95) for ciprofloxacin recipients and 77% (67 of 87) for clarithromycin recipients (P = 0.01). The investigators concluded that compared with clarithromycin, treatment of ABE/COPD with ciprofloxacin was associated with a trend toward a longer infection-free interval and a statistically significantly higher bacteriologic eradication rate.29
Ventilatory Assistance
Despite appropriate and aggressive pharmacological treatment of AECOPD, some patients may require assisted ventilation in the emergency department. In the past, there may have been a reluctance to intubate these patients because of fear that once intubated, patients become ventilator-dependent. Most patients with COPD will survive an initial episode of acute respiratory failure, although the mortality rate over the next several years is high. On average, patients who survive an episode of acute respiratory failure are intubated for an average of about 10 days.31-33
The decision to use ventilatory assistance should be made on the basis of both clinical and laboratory parameters. A single arterial blood gas is generally not adequate to judge whether a patient requires artificial ventilation. The significance of the PCO2 is dependent on a number of factors, including evidence of chronic retention and the effects of oxygen administration. Patients with poor nutritional status or elevated APACHE II scores are likely to require intubation.34 Many patients will tolerate moderate hypercarbia, as long as pH above 7.26 and adequate oxygenation are maintained.
Nevertheless, patients with extreme dyspnea, discordant breathing, fatigue, inability to speak, or deteriorating mental status in the face of adequate therapy may require ventilatory assistance. Hypoxemia that does not respond to oxygen therapy or worsening of acid-base status in spite of controlled oxygen therapy may also indicate the need for ventilatory assistance. Once intubated, care should be taken to avoid precipitous drops in the PCO2 since this may lead to severe respiratory alkalosis.
Noninvasive Ventilation. One of the most important developments in the treatment of AECOPD over the past few years has been the acceptance of noninvasive, nasal, bilevel positive airway pressure (BiPAP). Studies conducted in the late 1980s have demonstrated the safety and efficacy of this approach. Patients with COPD have an intrinsic positive end expiratory pressure (PEEP) that significantly increases the inspiratory workload.35 By applying external positive airway pressure, this intrinsic PEEP can be overcome, improving the work of breathing. In addition, applying inspiratory, positive-pressure ventilation reduces diaphragmatic work and improves gas exchange.36 Noninvasive ventilation leads to improvement in respiratory rate, tidal volume, and minute ventilation. Mask ventilation decreases venous return and reduces left ventricular transmural pressure, which may lead to a drop in cardiac output and in systemic blood pressure.
Invasive ventilation can be associated with significant complications before, during, and after tube placement. This includes adverse events associated with intubation, including airway trauma, cardiac arrhythmias, transient hypoxemia, and aspiration of gastric contents. Post-intubation, the patient is at risk for tracheal stenosis, sinusitis, nosocomial pneumonia, and inadvertent extubation. Noninvasive positive pressure ventilation (NPPV) has a lower incidence of infection. Mask ventilation can be complicated by local skin irritation, aerophagia with subsequent emesis, and reduced cardiac output at high pressures. The advantages, however, are that patients are able to talk, swallow, and expectorate.
Overall, noninvasive ventilation is successful in about two out of three of patients37 and decreases ICU stay and overall mortality rate. Patients successfully treated with noninvasive ventilation have a lower incidence of pneumonia and sinusitis.38 The response to noninvasive ventilation is usually seen within the first hour. Patients who do not demonstrate improvement within the first hour will probably require mechanical ventilation over the course of several hours.
Nasal BiPAP. Nasal BiPAP requires a cooperative patient. The technique cannot be used in the apneic or comatose patient. Patients at high risk for aspiration may require intubation, although there are significant risks with this procedure as well. Patients requiring frequent suctioning may require intubation. Very obese patients (i.e., > 135 kilograms) may not obtain an adequate seal with the available masks.
The initial setup and monitoring techniques are time consuming. During the initiation of nasal BiPAP, a caregiver will probably be required at the bedside for some period of time. Nasal BiPAP is initiated with an explanation of the procedure to the patient. Expiratory pressure levels beginning around 3 cm H2O with inspiratory pressure of around 8 cm of H2O are typical settings. The inspiratory positive airway pressure (IPAP) is increased in 2-cm increments to titrate the PCO2, while the expiratory positive airway pressure (EPAP) is increased to titrate the PO2. The IPAP must be maintained above the EPAP.
The expiratory and inspiratory pressures are increased rapidly over the course of 15 minutes to achieve targeted oxygenation and CO2 levels. If a patient does not improve within 1-2 hours of initiation of nasal BiPAP, then intubation may be required. Most patients started on nasal BiPAP will require ventilatory support for 1-2 days before weaning. Randomized trials have demonstrated that a majority of patients started on noninvasive ventilation will have improvement in oxygenation and a decrease in hypercarbia.36-40 Patients successfully treated with nasal BiPAP have a decrease in complication rate with a markedly lower rate of sinusitis or pneumonia. In addition, patients treated with noninvasive ventilation have a decreased length of stay in the ICU and a lower total hospital ICU stay. In fact, one small case series has demonstrated that patients who have been treated with invasive ventilation on some occasions may respond on subsequent admissions to noninvasive ventilation.37-38
It should be emphasized that not all studies have demonstrated efficacy with nasal BiPAP.39 Patients who fail nasal BiPAP tend to have a greater severity of illness, are unable to minimize mouth leak because of lack of teeth or increased oral secretions, and have difficulty coordinating with the ventilator.40
Disposition, Triage, and Outpatient Treatment Protocol
A number of factors are used to determine the disposition of patients treated in the emergency department with an acute exacerbation of COPD. (See Table 6.) These include the patient’s overall respiratory status post treatment, as determined by the respiratory rate, respiratory effort, oxygen saturation, and pulmonary function. In addition, factors such as the patient’s home living conditions, mental status, and concomitant illnesses may play a role in the decision to admit or discharge a patient. It should be noted that there is a high rate of relapse, ranging from 15% to 30% following discharge from the emergency department.41,42 Interestingly, patients are at higher risk of relapse if they have nighttime ED visits, if they have a component of "asthma" as part of the chronic obstructive disease, or if they have weekend visits.641,42 The results of pulmonary function testing in association with patient assessment of respiratory distress may be useful in predicting the risk of relapse.
| Table 6. Factors Influencing Patient Disposition in AECOPD |
| • Age of patient |
| • Overall respiratory status |
| • Respiratory rate |
| • O2 saturation |
| • Degree of hypercarbia |
| • Patient's status compared to baseline |
| • Mental status |
| • Home environment |
| • Likelihood of acceptable medication compliance |
| • Nighttime emergency department visit |
| • Previous pattern of frequent relapse |
| • Pulmonary function tests |
| • FEV1 less than 40% of predicted normal |
| • Multiple ED courses of aerosolized b-agonists |
Unlike patients with asthma, who tend to have normal or near-normal pulmonary function between attacks, patients with COPD may have chronic airflow limitation. Therefore, the post-treatment pulmonary function compared to documented baseline function should be considered along with the patient’s self-assessment of respiratory distress.42 From a relapse perspective, patients with a post-treatment FEV1 less than 40% of predicted normal will have a significant relapse rate, even when the patient reports minimal respiratory distress. In contrast, patients with a post-treatment FEV1 greater than 40% of predicted normal can usually be treated successfully at home, especially when the patient has only mild residual respiratory distress.
The results of arterial blood gas testing are not particularly useful in predicting the risk of relapse, although patients with severe hypoxemia or respiratory acidosis will require admission. In addition, patients are more likely to relapse if they have had a shorter duration of dyspnea, have a lower FEV1, require a greater number of treatments with nebulized bronchodilators, require parenteral adrenergic drugs, or have a history of frequent relapses.42
Home-Based Treatment Plan
On discharge from the emergency department, several adjustments to the patient’s outpatient medical regimen may be considered.
Oxygen. First, patients with severe COPD may be eligible for home oxygen therapy. Although this is generally not initiated as part of the emergency department treatment, patients may benefit from a referral for subsequent consideration for home oxygen therapy. Patients with a PaO2 less than 55 mmHg at rest or PaO2 between 55-60 mmHg with evidence of cor pulmonale may meet Medicare criteria for reimbursable oxygen supplementation. It has been shown that home oxygen therapy prolongs survival, reduces polycythemia, decreases the risk of pulmonary hypertension, and reduces the risk of right ventricular failure. Accordingly, patients who meet these criteria should be referred to appropriate providers who can arrange for home oxygen supplementation
Bronchodilators. Long-term management of the patient with COPD almost always requires use of various bronchodilating agents. Studies have shown that most patients with COPD respond to bronchodilators.43,44 Significant improvements in pulmonary function may occur in response to inhaled beta-agonists, inhaled anticholinergic agents, and oral methylxanthines. Accordingly, patients should be discharged on bronchodilators, beginning with either inhaled beta-agonists or inhaled anticholinergics. Although the older, non-selective beta-agonists are effective in COPD, when used for long-term therapy, patients should be on one of the newer, longer acting, beta-2 selective agonists such as metaproterenol, albuterol, terbutaline, or bitolterol. For long-term maintenance, these agents are typically used in a dose of two puffs up to 4 times a day by metered dose inhaler. Some patients, however, may require larger doses, and studies in patients with chronic disease have found dose-related improvements up to 1600 mcg.45
In large studies, albuterol has been found to improve pulmonary function for stable patients with COPD.45 The effectiveness, however, decreases over time. Albuterol is safe for the long-term management of COPD, as the incidence of drug-related adverse events are low. Patients with COPD tend to be older, and as such, have decreased sensitivity to adrenergic compounds. Some authors have found that the response to anticholinergic compounds in chronic therapy may be superior to beta-agonists for routine use.
Anticholinergic Agents. Anticholinergics should probably be used for routine maintenance in most patients with COPD. Inhaled quaternary ammonium anticholinergic agents have been found in some studies to lead to greater bronchodilation than beta-agonists or theophylline. Since older patients have a decrease in responsiveness to the adrenergic receptors, the cholinergic receptors become even more important in the older patients with COPD. Ipratropium is the primary agent used by metered-dose inhaler in this country. It is relatively safe, with side effects generally limited to dry mouth or the sensation of a "metallic" taste in the mouth. Again, this agent leads to increasing bronchodilation as the dose increases up to 600 mcg. Ipratropium is available in 500 mcg doses by metered-dose inhaler.
A meta-analysis of seven long-term studies comparing ipratropium with beta-agonists demonstrated that ipratropium leads to greater improvement in FEV1 and even greater improvements in force vital capacity over the course of 90 days. Ipratropium leads to greater improvements in quality-of-life measurements. The improvements in pulmonary function are greatest in patients who have stopped smoking compared to current smokers. Furthermore, patients using ipratropium are less likely than patients using beta-agonists to develop a decreased response over time.46 Ipratropium has minimal side effects that primarily are related to dry mouth or leaving a bad taste in the mouth.
Inhalers. Prior to discharge, patients should be taught the proper means of using meter-dose inhalers. Many patients will benefit from the use of a spacer device. A typical discharge regimen will include albuterol by meter dose inhaler either on an as needed basis for rescue therapy or for chronic maintenance therapy.47,48 In addition, most patients with COPD should be using ipratropium by meter-dose inhaler for chronic maintenance therapy. These drugs are available as combination therapy in meter-dose inhalers. Patients who have prominent nighttime symptoms may benefit from a long-acting beta-agonist such as salmeterol. Patients should be counseled, however, that salmeterol should not be used for rescue therapy.
Theophylline. Theophylline does have dose-related effects on pulmonary function in patients with stable COPD. This drug may be used for patients who cannot or will not use meter-dose inhalers, patients who are not responding to otherwise maximal therapy, or patients who have prominent nighttime symptoms. Therapy is usually initiated at a dose of 300 mg twice a day with monitoring of the theophylline level. Therapeutic theophylline levels are considered to be between 10 and 20 micrograms per cc, although the FDA has changed labeling requirements for these drugs to suggest that consideration be given to maintain the level between 10 and 15 micrograms per cc. Theophylline metabolism is affected by a number of factors and patients should be cautioned not to increase their dose without seeking medical advice.
Corticosteroids. About 25% of patients with COPD will respond to oral steroids. Patients with a significant degree of reversibility of pulmonary function on baseline testing are most likely to respond to steroids.49 It seems reasonable to initiate a two-week trial of oral steroids for patients with COPD. Limited studies indicate that there may be a role for inhaled corticosteroids in patients with COPD. In this regard, one study found that the addition of inhaled corticosteroids over the course of two years decreased morbidity and improved airway obstruction when used in conjunction with an inhaled beta-2 agonist.50 A more recent study found a short-term improvement in lung function in smokers with COPD treated with inhaled steroids, but this then was followed by continued deterioration in lung function.51
Antibiotics. While many episodes of acute exacerbation of COPD are caused by viral infection, the weight of evidence seems to indicated that patients respond to oral antibiotics; especially, when the exacerbation is associated with signs and symptoms of acute, bacterial bronchitis that is superimposed on COPD with a presentation characterized by fever, dyspnea, increase in sputum production, or change in the color of sputum.52 (See Table 7.) Available antibiotics with evidence-based support for their efficacy and which have indications for ABE/COPD have been discussed in detail.
| Table 7. Role of Antibiotics: Potential Benefits of Antimicrobial Therapy |
| Short-Term Benefits |
| • Reduce cost of care |
| • Reduce duration of symptoms |
| • Avoid hospitalization and return to work |
| • Prevent progression to pneumonia |
| Long-Term Benefits |
| • Prevent progressive airway damage |
| • Prolong time between exacerbations |
| • Decrease bacterial load |
Patients with ABE/COPD who are deemed suitable for oral, outpatient therapy and who do not have IOTT criteria in the SERF pathway (See Table 4) that suggest the need for more extensive gram-negative coverage, should be discharged with a compliance-sensitive antibiotic that provides adequate coverage of S. pneumoniae, H. influenzae, and M. catarrhalis. (See Table 1.)
Based on evidence-based trials and pharmatectural criteria (duration of therapy, reduced dosing frequency, drug interaction profile, cost, and spectrum of coverage), azithromycin should be considered a first-line agent in patients with ABE/COPD who, on the basis of clinical judgement, are likely to be infected with S. pneumoniae, H. influenzae, or M. catarrhalis.3-4,12-15,53-55 Other advanced generation macrolides, as well as penicillin derivatives such amoxicillin-clavulanate, are also available and effective, although these agents require more frequent dosing and have a longer course of therapy.
It should be stressed that some of the advanced macrolides also have the advantage of a simplified dosing schedule, especially azithromycin, which is given once daily for only five days (500 mg po on day 1 and 250 mg po qd on days 2-5). Azithromycin (500 mg on day 1 and 250 mg on days 2-5) did not affect the plasma levels or pharmacokinetics of theophylline administered as a single intravenous dose. However, because the effect of azithromycin on plasma levels or pharmacokinetics of theophylline is not known, until further data are available, prudent medical practice dictates careful monitoring of plasma levels of theophylline in COPD patients receiving azithromycin and theophylline concomitantly. The same precaution should be applied to patients receiving warfarin and azithromycin concomitantly. Other macrolides generally require a similar monitoring strategy.
Clarithromycin, another advanced generation macrolide, requires a longer course of therapy and, as a 10-day course (500 mg bid) is more expensive ($58-$72 for a 10-day course) than a five-day course of azithromycin. Dirithromycin, a semi-synthetic macrolide is indicated for acute bacterial exacerbations of chronic bronchitis due to S. pneumoniae, H. influenzae, or M. catarrhalis. In general, the decision to use a macrolide such as azithromycin is based on consideration of its generally acceptable cost ($39-$44 for a five-day treatment regimen), as well as its real-world advantages, which include convenient, once-daily dosing, a correct spectrum of coverage, its favorable drug interaction profile, and toleration data (gastrointestinal side effects occur in about 3-5% of patients taking a five-day, multiple-dose regimen). The oral tablet formulation permits consumption of the antibiotic without regard to food ingestion.
Patients who are macrolide treatment failures, who are suspected of gram-negative infection with enterobacteria, and/or who present with multiple IOTT points on the SERF pathway may be effectively served by a fluoroquinolone such as levofloxacin or ciprofloxacin, the latter of which is not recommended when S. pneumoniae is the presumed causative agent. Levofloxacin is well-tolerated, with the most common side effects, including nausea, diarrhea, headache, and constipation. Food does not affect the absorption of the drug, but it should be taken at least two hours before or two hours after antacids containing magnesium or aluminum, as well as sucralfate, metal cations such as iron, and multivitamin preparations with zinc. Dosage adjustment for levofloxacin is recommended in patients with impaired renal function (clearance < 50 mL/min).
Although no significant effect of levofloxacin on plasma concentration of theophylline was detected in 14 health volunteers studied, because other quinolones have produced increases in patients taking concomitant theophylline, theophylline levels should be closely monitored in patients on levofloxacin and dosage adjustments made as necessary. Monitoring patients on warfarin also is recommended in patients on quinolones. All quinolones have been associated with cartilage damage in animal studies, and therefore, they are not recommended for use in children, adolescents, and pregnant and nursing women. Cephalosporins are also available and effective for treatment of ABE/COPD.
Patients with a greater risk of respiratory failure are more likely to benefit from antibiotic therapy. This would include patients of advanced age and patients with significant lung impairment, impairment due to other co-morbid conditions, frequent exacerbations, or steroid use. Accordingly, these patients may require intensification and amplification of antibiotic therapy (i.e., the movement from azithromycin to a fluoroquinolone) to cover gram-negative organisms in addition to the three common offenders cited above.
Less expensive and still widely used in certain institutions and health plans, many of the older agents (sulfa-derivatives, tetracyclines, and amoxicillin) are becoming resistant to S. pneumoniae or do not cover beta-lactamase-producing organisms and, as a result, may no longer represent the best choice for empiric therapy of ABE/COPD.3,4,11-13,55,56 The finding in one retrospective study that such antimicrobials as azithromycin, amoxicillin-clavulanate, or ciprofloxacin significantly reduced the failure rate and need for hospitalization, prolonged the time between AECOPD episodes, and were associated a lower total cost of management for AECOPD compared to the older agents is extremely provocative and requires further investigation.55
Even until clarification of outcome-effectiveness is forthcoming, clinicians should be aware that a number of newer antibiotic agents are available, including advanced generation macrolides and quinolones, which have the advantage of a broader spectrum of activity, simplified dosing regimens, and lower resistance rates.57 These agents, however, have not been demonstrated to have greater clinical efficacy than less expensive agents in controlled clinical trials. One such stratification scheme has been proposed although it has not been rigorously tested.58
Pneumonia in COPD. The development of pneumonia in a patient with COPD will frequently provide an indication for admission. However, there are younger patients with very mild COPD who have good ventilatory status and who do not have other concomitant medical diseases who, on the basis of clinical judgement, may be given a trial of outpatient antibiotic therapy. Protocols for treatment of CAP are widely published. (See Emergency Medicine Reports issue on Community-Acquired Pneumonia).59 However, most patients with COPD complicated by pneumonia will require admission.
The small percentage of patients who are discharged, and therefore judged appropriate for outpatient treatment, should be treated for the most common causative agents, which include S. pneumoniae, H. influenzae, M. catarrhalis, M. pneumoniae, and C. pneumoniae. Given the spectrum of organisms encountered, it is probably preferable to initiate therapy with either a macrolide such as azithromycin or a quinolone such as levofloxacin. If amoxicillin/clavulanic acid or a third-generation cephalosporin is used to treat CAP, the authors recommend mandatory co-treatment with an agent (usually an advanced generation macrolide such as azithromycin) providing coverage of atypical organisms.
Patient Counseling
Long-term studies have demonstrated that smoking cessation, even when undertaken in later years, leads to moderation of the decline in pulmonary function that occurs with chronic cigarette use. Patients who stop smoking do not return to predicted pulmonary function, however, their rate of decline in pulmonary function begins to mirror those of patients who have never smoked. In addition to the beneficial pulmonary effects of smoking cessation, within 3-4 years a decrease in the risk of cardiovascular disease also is observed. Prior to discharge, the patient’s ability to correctly use his or her metered-dose inhaler should be verified. Patients with COPD are at risk for streptococcal pneumonia. Patients should be counseled, therefore, about the need for anti-pneumococcal vaccinations and for annual influenza vaccination.
Summary
Assessment of the patients with acute exacerbation of COPD should include a systemic approach to distinguishing among many entities that may produce a similar clinical picture. These include congestive heart failure, pulmonary embolism, bacterial pneumonia, and pneumothorax. Once the diagnosis of ABE/COPD is verified, stabilization therapy should be initiated with oxygen and beta-agonists. Other pharmacologic intervention such as anticholinergic agents, theophylline, steroids, or magnesium should be considered only in patients with impending respiratory failure, those who have failed standard therapy, and those individuals considered for admission. Patients with unresponsive respiratory failure may be considered for a trial of nasal BiPAP before invasive ventilation.
Patients who on the basis of risk-stratification criteria are eligible for discharge may require modification of their outpatient regimen. When patients with COPD present with two or more of the following symptoms (increase in sputum production, increase in sputum purulence, increasing cough or dyspnea), outpatient antibiotic therapy has been shown improve clinical outcomes, including time to resolution, decrease in relapse rate, and improvement in functionality as measured by FEV1 and other respiratory parameters. The SERF pathway can be used to identify IOTT criteria to aid in antibiotic selection.
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Physician CME Questions
65. Patients with COPD may have colonization of the tracheal respiratory tract with:
A. Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.
B. E. coli.
C. ECHO virus.
D. all of the above.
E. none of the above.
66. When treating common, simple ABE/COPD, the azalide antibiotic azithromycin has the advantage of:
A. an appropriate spectrum of coverage.
B. an excellent safety profile.
C. reasonable cost.
D. a patient-dosing schedule that promotes patient compliance.
67. The goals of therapy for acute bacterial exacerbations of COPD include which of the following?
A. To resolve the infection expeditiously
B. Maintain an infection-free interval for as long as possible
C. Select an antibiotic with the fewest adverse effects
D. Select an antibiotic with a favorable compliance profile
E. All of the above
68. Invasive ventilation can be associated with significant complications including:
A. airway trauma.
B. cardiac arrhythmias.
C. transient hypoxemia.
D. aspiration of gastric contents.
E. all of the above.
69. Azithromycin should be considered a first-line agent in patients with ABE/COPD who, on the basis of clinical judgement, are likely to be infected with:
A. rhinovirus.
B. Klebsiella, E. coli, or Pseudomonas.
C. Enterococcus, Pseudomonas, or E. coli.
D. S. pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis.
E. none of the above.
70. Many of the "older" agents (sulfa-derivatives, tetracyclines, and amoxicillin) are becoming resistant to which organism that is commonly implicated in uncomplicated ABE/COPD?
A. Enterococcus
B. Listeria
C. S. pneumoniae
E. all of the above
D. none of the above
71. Which of the following factors are used to determine a patient’s disposition from the ED?
A. Respiratory rate
B. Respiratory effort
C. Oxygen saturation
D. Pulmonary function
E. All of the above
72. The majority of patients with COPD have airway obstruction that, to some degree, will show clinically significant reversibility in response to beta-agonist therapy.
A. True
B. False
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