Managing and preventing acute exacerbation of COPD (AECOPD) is an important component in reducing hospital readmission rates for chronic lung disease. Proper diagnosis, classification of severity, and proper treatment for AECOPD through pharmacological and nonpharmacological therapies can improve disease management and prevent excess financial penalties for hospitals from Medicare due to readmissions.
By Timothy Op’t Holt, EdD, RRT, AE-C, FAARC
The Centers for Medicare and Medicaid Services (CMS) has begun financially penalizing hospitals if their 30-day readmission rates are higher than expected. In FY 2014, readmission for COPD will be added to those diagnoses already on the list: heart attack, heart failure, and pneumonia. Respiratory therapists must play an active role in reducing acute exacerbation of COPD (AECOPD) and readmission, to decrease the number of so-called “frequent flyers.”
Part One of this two-part article will define and discuss the causes of AECOPD, how COPD is diagnosed and classified, and how pharmacological therapies, if administered appropriately, have been shown to prevent exacerbation.
Exacerbation of COPD
AECOPD is defined in the Global Initiative for Obstructive Lung Disease (GOLD 2013) as “an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day to day variations and leads to a change in medication.”1 Initially, the patient may notice one or more of the following signs:
- An increase in shortness of breath, to where it is difficult to speak in complete sentences;
- Change in color and quantity of sputum; or
If the patient recognizes these symptoms, a physician should be contacted immediately. It is important that patients be made aware of the urgency, as failure to notify the provider in a timely manner allows the exacerbation to worsen unabated, leading to hospitalization. The most common causes of AECOPD are bacterial or viral respiratory tract infections, followed by air pollution, and unidentified reasons, which account for up to one-third of AECOPD.
Patients with more severe underlying COPD tend to have more AECOPD. Effects of AECOPD include a poorer quality of life, increased risk of hospitalization, greater mortality, peripheral muscle weakness, and an increased likelihood of comorbidities (ischemic heart disease, pneumonia, and diabetes).2
Preventing AECOPD is complex, involving a combination of pharmacologic and nonpharmacologic actions. An emerging role of the respiratory therapist is to become a coordinator of these actions in order to prevent AECOPD, or, in the event of exacerbation, to help the patient stabilize and prevent an admission or readmission.
Diagnosis and Classification of Severity in COPD
An excellent start in preventing AECOPD with pharmacologic actions is to follow the 2013 GOLD guidelines. According to GOLD, one begins by diagnosing COPD, followed by classifying the severity, then managing stable COPD.1 Diagnosis is the responsibility of the physician. However, respiratory therapists are normally charged with gathering pulmonary function and arterial blood gas data that contribute to diagnosis and staging of severity. Once the diagnosis is made, determining the severity of the disease is based on spirometry and symptom scoring. The classification of COPD using spirometry is based on postbronchodilator FEV1 as follows:
In patients with FEV1/FVC% < 70%:
- GOLD stage 1: Mild (FEV1 > 80% predicted)
- GOLD stage 2: Moderate (50% < FEV1 < 80% predicted)
- GOLD stage 3: Severe (30% < FEV1 < 50% predicted)
- GOLD stage 4: Very Severe (FEV1 < 30% predicted)
In addition to spirometry, the patient’s symptoms, exacerbation risk, and comorbidities are assessed. Symptoms are assessed by using either the COPD Assessment Test (CAT test)3 or the Modified British Medical Research Council Questionnaire (mMRC).4 The CAT or mMRC should be administered at the time that COPD is diagnosed. Exacerbation risk is higher as airflow limitation worsens. Patients with a higher GOLD classification level are more likely to have more frequent exacerbations. The best predictor of having frequent exacerbations (defined as two or more exacerbations per year) is a history of previously treated events. Hospitalizations per year and 3-year mortality also correlate with severity of COPD.5 Lastly, comorbidities are assessed, which include cardiovascular disease, skeletal muscle dysfunction, metabolic syndrome, diabetes, osteoporosis, depression, and lung cancer. These assessments are combined to account for spirometry, symptom score, and exacerbation history as shown in the GOLD document, “Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease, Updated 2013.”6
To use this classification scheme, refer to the figure in the GOLD report.6 First, use either the CAT or mMRC to determine if the patient falls into the right or left side of the box. Next, determine exacerbation risk, using either the GOLD spirometry classification or exacerbation history. Two or more exacerbations in the previous year represent a high risk (upper part of the box). This results in the ability to classify the patient into one of the four groups, A, B, C, or D.
- Group A are patients with low risk and less symptoms; these are typically GOLD 1 or GOLD 2 and/or 0 to 1 exacerbations per year and mMRC grade 0 to 1, or CAT score < 10.
- Group B patients are low risk and more symptoms; these are typically GOLD 1 or GOLD 2 and/or 0 to 1 exacerbations per year and mMRC grade > 2, or CAT score > 10.
- Group C patients are high risk, less symptoms; these are typically GOLD 3 or GOLD 4 and/or > 2 exacerbations per year and mMRC grade 0 to 1, or CAT score < 10.
- Group D patients are high risk, more symptoms; typically GOLD 3 or GOLD 4 and/or > 2 exacerbations per year and mMRC grade > 2, or CAT score > 10.7
Additional investigations may be considered useful as part of the diagnosis and assessment of COPD, to include a chest radiograph, lung volumes and diffusing capacity, oximetry and arterial blood gas measurement, alpha-1 antitrypsin deficiency screening, and exercise testing, but a complete discussion is outside the realm of this article, as is differential diagnosis. However, there are mimics of COPD, which should be excluded: asthma, heart failure, bronchiectasis, tuberculosis, obliterative bronchiolitis, and diffuse panbronchiolitis.
Therapy for Stable COPD to Prevent Exacerbations
Once the diagnosis is made and the severity classified, a plan of care is made based on severity, a process that will be detailed in Part Two of this article. Nonpharmacologic therapy, also to be discussed in Part Two, includes smoking cessation counseling, noninvasive ventilation, and comprehensive pulmonary rehabilitation, including patient education.
Meanwhile, the cornerstone of pharmacologic therapy for COPD is the appropriate use of bronchodilators, both beta-adrenergic and anticholinergic. Bronchodilators may be supplemented with corticosteroids, methylxanthines, phosphodiesterase-4 inhibitors, antibiotics, vaccines, home oxygen, and pharmacotherapy for smoking cessation.
Pharmacologic therapy in COPD does not treat the underlying disease. However, it is effective in treating symptoms, reducing frequency and severity of exacerbations, and improving quality of life.
All patients with COPD (groups A to D) should always have a short-acting ?-2 adrenergic bronchodilator available. This is usually albuterol in the form of a metered dose inhaler (MDI) or as a nebulizer solution, in which patients use their inhaler or nebulizer up to every 4 hours for symptom relief. Levalbuterol, or the anticholinergic bronchodilator ipratropium bromide, can be used for patients who may become tachycardic or have tremor with racemic albuterol. A combination product of albuterol and ipratropium is also available in a Respimat inhaler (Combivent Respimat) and as a nebulizer solution. Gardenhire et al offer a complete discussion of the use of metered dose inhalers, nebulizers, and all other aerosol delivery devices.8
In addition, long-acting ?-2 adrenergics—salmeterol, formoterol, arformoterol (12-hour duration), and indacaterol (24-hour duration)—are effective treatment options. Salmeterol, formoterol, and indacaterol are available as dry powder inhalers. Arformoterol is available as a nebulizer solution. Formoterol and salmeterol significantly improve FEV1 and lung volumes, dyspnea, health-related quality of life, and exacerbation rate. Salmeterol also reduces the rate of hospitalization. Indacaterol significantly improves FEV1, dyspnea, and health-related quality of life. Long-acting ?-2 adrenergics are introduced in GOLD stage 2 (moderate COPD/group B).9
Anticholinergic bronchodilators include the aforementioned ipratropium, and tiotropium, a long-acting anticholinergic (24-hour duration). The bronchodilating effects of short-acting anticholinergic bronchodilators last longer than those of short-acting ?-2 adrenergics, by 2 to 4 hours. In one 6-month study of tiotropium, patients had a decrease in exacerbations, hospitalizations, unscheduled medical visits, and days of antibiotic treatments.10 In other tiotropium studies, frequency of exacerbation decreased,11 and time to first exacerbation and time to first hospitalization were delayed.12 In one large study, Voglemeier et al found that tiotropium was more effective than salmeterol in preventing exacerbations.13 Clearly, the addition of tiotropium makes a difference for many patients. Tiotropium is administered with a single-dose dry powder inhaler and is introduced at GOLD stage 2, group B.
Inhaled corticosteroids (ICS) are added to the care plan in GOLD stage 3, Group C, in the event that the patient has frequent AECOPD. ICS are usually added to the plan alone or in the form of a combination product, such as fluticasone plus salmeterol, mometasone plus formoterol, or budesonide plus formoterol. In a study of fluticasone alone with albuterol or ipratropium as needed, versus no fluticasone, Burge and colleagues found that exacerbation rate decreased and health status deteriorated less (as measured by the St. George’s Respiratory Questionnaire, SGRQ) in the fluticasone group.14 Likewise in a fluticasone alone trial, Spencer and colleagues found that frequency of exacerbations decreased in their group of patients with moderate to severe COPD.15 While these results are promising, there is no universal agreement that ICS are beneficial, as a later systematic review by Agarwal finds that the perceived benefit of ICS in severe to very severe COPD (GOLD 3 and 4 or groups C and D) may be overstated. There was a modest benefit of ICS preventing AECOPD in patients with FEV1 < 50%.16
An ICS combined with a long-acting beta agonist (LABA) is more effective in improving lung function and health status and reducing exacerbations in patients with moderate to very severe COPD.17 It was determined in a review of the “Towards a Revolution in COPD Health” (TORCH) data that a combination product (salmeterol plus fluticasone) led to a reduced rate of exacerbations, improved health status, and reduced risk of death. However, the incidence of pneumonia was higher in the combination product group.18 These combination products are available as MDIs and DPIs. A steroid (budesonide) and LABA (arformoterol) also may be nebulized.
Theophylline is less effective and less well tolerated than the LABAs; it is only recommended if the first-line drugs are not available. Low-dose theophylline reduces exacerbations but does not improve postbronchodilator lung function.19 In addition, theophylline has cardiovascular and gastrointestinal side effects and its absorption varies with age and smoking habit. Serum levels must be monitored and it has a narrow therapeutic window. Theophylline is only included in GOLD as an alternative (groups B to D).
The phosphodiesterase-4 inhibitor roflumilast is now available in the United States. Roflumilast is an oral anti-inflammatory that acts by inhibiting the breakdown of intracellular cyclic AMP. In a study by Claverley, patients with severe COPD who took roflumilast had an increased prebronchodilator FEV1 and fewer exacerbations per year than those in the placebo group.20 These findings were similar to those in the Fabbri study, where it was found that prebronchodilator FEV1 was higher in the roflumilast plus salmeterol, or tiotropium groups.21 Side effects including nausea, diarrhea, weight loss, and headache were more common in the roflumilast groups. Roflumilast is included as a second-choice drug in patients with severe COPD in GOLD C and D.
Chronic antibiotic therapy is uncommon in COPD, but a recent trial of chronic moxifloxacin resulted in decreased odds of exacerbation (OR=0.75, a 19% reduction). In patients with baseline purulent sputum, OR was 0.55, a 45% reduction.22 Moxifloxacin was administered once daily for 5 days, in eight courses over 8 weeks. There were no significant differences in hospital or mortality rates, lung function, or changes in the SGRQ. The authors concluded that “treatment with intermittent pulsed moxifloxacin could be indicated [in patients with] baseline purulent/mucopurulent sputum who are not colonized with P. aeruginosa and who have an unacceptable frequency of exacerbations in spite of maximal therapy with inhaled agents.”22
In a similar yearlong study, azithromycin was administered to a group of patients with COPD.23 Results showed a decrease in AECOPD frequency and improved SGRQ scores. Some in the azithromycin group had hearing decrements. Authors concluded that adding azithromycin to the treatment regimen of patients who have had AECOPD within the previous year or who require supplemental oxygen may be an option. Patients should be screened for presence or risk of QTc prolongation and hearing should be monitored.24 While these outcomes are positive, GOLD guidelines state that the use of antibiotics, other than to treat infectious AECOPD and other bacterial infections, is currently not indicated.24
Other Therapeutic Options
Significant health benefits for COPD patients are associated with influenza vaccination: fewer outpatient visits and hospitalizations and reduced mortality.25 In a recent systematic review in Canada of the use of the influenza vaccine, in all patients:
- Vaccine group (total of 4 cases) averaged 6.8 episodes per 100 person-years;
- Placebo group (total of 17 cases) averaged 28.1 episodes per 100 person-years (relative risk [RR]: 0.2; 95% confidence interval [CI], 0.06 to 0.70; P = 0.005).26
In patients with severe airflow obstruction (FEV1 < 50%):
- Vaccine group (total of 1 case) averaged 4.6 episodes per 100 person-years;
- Placebo group (total of 7 cases) averaged 31.2 episodes per 100 person-years (RR: 0.1; 95% CI, 0.003 to 1.1; P = 0.04).26
The influenza vaccine is adjusted each year and is administered annually. The pneumococcal polysaccharide vaccine is recommended for patients 65 and older and in patients with significant comorbid conditions, such as cardiac disease.
In the same Canadian study, the Kaplan-Meier survival analysis showed no significant differences between the group receiving the pneumoccocal vaccination and the control group for time to the first episode of community-acquired pneumonia due to pneumococcus or of unknown etiology (log-rank test 1.15; P = 0.28).26 Overall, vaccine efficacy was 24% (95% CI, ?24 to 54; P = 0.33). With respect to the incidence of pneumococcal pneumonia, the Kaplan-Meier survival analysis showed a significant difference between the two groups (vaccine: 0/298; control: 5/298; log-rank test 5.03; P = 0.03).26 Hospital admission rates and median length of hospital stays were lower in the vaccine group, but the difference was not statistically significant. The mortality rate was not different between the two groups.26 GOLD recommends that the administration of vaccines be dependent upon local guidelines.27
Long-term oxygen therapy (LTOT, > 15 hours per day) is indicated for patients with COPD who have chronic hypoxemia.28 This condition is defined as: PaO2 < 55 mm Hg or SaO2 < 88% with or without hypercapnia, confirmed twice over a 3-week period; or a PaO2 between 55 and 60 mm Hg with evidence of pulmonary hypertension, peripheral edema suggesting congestive heart failure, or polycythemia (HCT > 55%). LTOT increases survival in patients with hypoxemia, as defined above, and includes other positive outcomes such as reduction in anxiety, depression, and hospital admission rate.28
Smoking cessation is the only intervention that has an effect on the natural history of the disease, in that it slows the deterioration of lung function (loss of FEV1). Smoking cessation drugs include nicotine replacement therapy (NRT), varenicline, bupropion, and nortriptyline. Nicotine replacement, as the name implies, replaces the nicotine normally inhaled when smoking. NRT is available as a patch, gum, lozenges, inhaler, and nasal spray. Varenicline (Chantix) blocks the ability of nicotine to activate ?4?2 receptors and thus to stimulate the central nervous mesolimbic dopamine system, believed to be the neuronal mechanism underlying reinforcement and reward experienced upon smoking.29
Bupropion and nortriptyline are antidepressants. It is not clear which of these effects accounts for the antismoking activity of the drug, but inhibition of the reductions in levels of dopamine and noradrenaline levels in the central nervous system that occur in nicotine withdrawal is likely to be important.30 The smoking cessation effect of these drugs varies and any drug therapy should be accompanied by qualified smoking cessation counseling to optimize the chance of quitting.31
Preventing AECOPD is a complex task but one that respiratory therapists can be successful at by understanding the existing pharmacologic treatment options and by following the 2013 GOLD guidelines for diagnosis, classification, and management. Again, pharmacologic therapy in COPD does not treat the underlying disease, but it is effective in treating symptoms, reducing frequency and severity of exacerbations, and improving quality of life.
RTs must be aware of the potential benefits and shortcomings of pharmacologic treatment options, which include:
- Short-acting ?-2 adrenergic bronchodilators;
- Long-acting ?-2 adrenergics;
- Anticholinergic bronchodilators;
- Inhaled corticosteroids (ICS), alone or with a combination LABA;
- Low-dose theophylline;
- Phosphodiesterase-4 inhibitors, such as roflumilast
- Antibiotic therapies, such as azithromycin or moxifloxacin;
- Influenza vaccination;
- Long-term oxygen therapy; and
- Smoking cessation drugs, such as varenicline, bupropion, and nortriptyline.
Part Two of this article will discuss nonpharmacologic therapy for stable COPD, therapy for COPD by GOLD group classification, prevention of exacerbation, current problems with exacerbation and readmission, and recommendations on how hospitals can avoid readmissions. RT
Timothy Op’t Holt, EdD, RRT, AE-C, FAARC, is a professor in the department of cardiorespiratory care at the University of South Alabama. He will be contributing a subsequent article on AECOPD. For further information, contact [email protected].
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf.:40. Accessed June 14, 2013.
- Wedzicha JA, Seemungal TAR. COPD exacerbations: defining their cause and prevention. The Lancet. 2007;370:786-796.
- http://www.catestonline.org. Accessed June 7, 2013.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf:13. Accessed June 14, 2013.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 14. Accessed June 14, 2013.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 33. Accessed June 14, 2013.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 15-16. Accessed June 14, 2013.
- Gardenhire DS, Hess D, Myers TR, Rau JL. A Guide to Aerosol Delivery Devices for Respiratory Therapists, 3rd ed. American Association for Respiratory Care. 2013. http://www.aarc.org/resources/aerosol_resources/aerosol_guide_rt.pdf. Accessed June 7, 2013.
- GOLD 2011, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 23. Accessed June 14, 2013.
- Niewoehner DE, Rice K, Cote C, et.al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once daily inhaled anticholinergic bronchodilator. Ann Internal Med 2005;143:317-326.
- Dusser D, Bravo M-L, Iacono P. The effect of tiotropium on exacerbations and airflow in patients with COPD. Eur Respir J 2006;27:547-555.
- Tashkin DP, Chelli B, Senn S, et. al. A 4-year trila of tiotropium in chronic obstructive pulmonary disease. N Engl J Med 2008;359:1543-1554.
- Voglemeier C, Hederer B, Glaab T, Schmidt H, Rutten van-Molken MPMH, Beeh KM, Rabe KF, Fabbri LM. Tiotropum versus salmeterol for the prevention of exacerbations of COPD. New Engl J Med 2011;364(12):1093-1103.
- Burge PS, Calverley PMA, Jones PW, Spence S, Anderson JA, Maslen TK. Randomised, double blind, placebo controlled study of fluticasone propionate in patients with moderate to severe chronic obstructive pulmonary disease: the ISOLDE trial. BMJ 2000;320:1297-1303.
- Spencer S, Calverley PMA, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Resp J 2004;23:698-702.
- Agarwal R, Aggarwal AN, Gupta D, Jindal SK. Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized clinical trials. Chest 2010;137:318-325.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 25. Accessed June 14, 2013.
- Jenkins CR, Jones PW, Calverely PMA, Celli B, Anderson JA, Ferguson GT, Yates JC, Willits LR, Vestbo J. Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomized, placebo-controlled TORCH study. Resp Research 2009;10:59.
- Zhou Y, Wang X, Zeng X, et. al. Positive benefits of theophylline in a randomized, double-blind, parallel group, placebo-controlled study of low-dose, slow-release theophylline in the treatment of COPD for 1 year. Respirology 2006;11;603-610.
- Claverley PMA, Rabe KF, Goehring U-M, Kristiansen S, Fabbri LM, Martinez FJ. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomized clinical trials. The Lancet 2009;374:685-94.
- Fabbri LM, Claverley, PMA, Izquierdo-Alonso JL, Bundschuh DS, Brose M, Martinez FJ, Rabe KF. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with long-acting bronchodilators: two randomized clinical trials. The Lancet 2009;374:695-703.
- Sethi S, Jones PW, Theron MS, Miravitlles M, Rubenstein E, Wedzicha JA, Wilson R. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructinve pulmonary disease: a randomized controlled trial. Resp Research. 2010;11:10.
- Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, Curtis JL. et al. Azithromycin for prevention of exacerbations of COPD. NEJM 2011;365(8):689-698.
- GOLD 2013, http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf: 25. Accessed June 14, 2013.
- Nichol KL, Baken L, Nelson A. Relation between influenza vaccination and outpatient visits, hospitalization and mortality in elderly patients with chronic lung disease. Ann Intern Med 1999;130:397-403.
- Sehatzadeh S. Influenza and pneumococcal vaccinations for patients with chronic obstructive pulmonary disease (COPD): an evidence-based analysis. Ont Health Technol Assess Ser [Internet]. 2012 Mar; 12(3) 1-64. Available from: www.hqontario.ca/en/mas/tech/pdfs/2012/rev_COPD_Vaccinations_March.pdf. Accessed June 11, 2013.
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- Description and clinical pharmacology of varenicline. http://www.druglib.com/druginfo/chantix/description_pharmacology/ Accessed June 11, 2013.
- Roddy E. Bupropion and other non-nicotine pharmacotherapies. BMJ 2004; 328(7438): 509–511.
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