Chronic Obstructive Pulmonary Disease in Hospitalized Patients: Managing Exacerbations
Deepali Dixit, PharmD, BCPS, is a Clinical Assistant Professor at Ernest Mario School of Pharmacy and a Clinical Critical Care Pharmacist in the Medical Intensive Care Unit at Robert Wood Johnson University Hospital. Dr. Dixit has been involved in multiple committees and in leadership positions in regional and national pharmacy and organizations. Dr. Dixit's research interests include sedation and delirium in the critically ill, infectious disease, alcohol withdrawal syndrome, chronic obstructive pulmonary disease, and patient safety.
According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, an exacerbation of chronic obstructive pulmonary disease (COPD) is defined as an event, in the natural course of the disease, that is characterized by a change in the patient’s baseline dyspnea, cough, or sputum that is beyond normal, day-to-day variations; is acute in onset; and may require an adjustment in medication regimen.1 The 3 major symptoms of COPD exacerbation are increased dyspnea, cough, and purulent sputum production.1 The frequency and severity of exacerbations are among the factors that determine the prognosis of COPD. Exacerbations become more frequent and severe as COPD severity increases. A recent report estimated that patients with moderate COPD experience an average of 1.3 exacerbations per year; those with severe COPD experience an average of 2 exacerbations per year.2
COPD is the third leading cause of death and a substantial cause of disability in the United States.3 The economic burden related to COPD continues to rise; approximately $50 billion was spent in 2010, including $20 billion in indirect costs and $30 billion in direct health care costs.4 A significant portion (50% to 70%) of the direct health care costs related to COPD are attributed to exacerbations.1,4 A recent report indicated an increase in cost with each COPD readmission, ranging from $8400 to $11,100, based on principal diagnosis and all-cause COPD readmissions, respectively.4
ETIOLOGY AND RISK FACTORS
Acute exacerbations of COPD (AECOPD) are often triggered by viral or bacterial illnesses, or by air pollution. These insults stimulate an increase in immune cells and their mediators, which produce the characteristic symptoms of AECOPD.5 Various risk factors that increase the likelihood of developing AECOPD include prior exacerbations, increasing grade of airflow limitation, female gender, smoking, noncompliance with medications, and the presence of serious comorbidities.6,7
GOALS OF TREATMENT
The main goals of treatment for patients with COPD are to optimize their pulmonary capacity, prevent further disease progression, and prevent exacerbations. If an exacerbation occurs, the goal is to reduce the impact of the exacerbation and to prevent recurrence.1
BETA-AGONISTS AND ANTICHOLINERGICS
Therapy with an inhaled short-acting beta-agonist (SABA), with or without a short-acting muscarinic antagonist (SAMA), continues to be the mainstay of therapy for an AE of COPD.1 No evidence exists that combination therapy is superior to SABA or SAMA monotherapy in an AE of COPD. However, the combination of albuterol and ipratropium has been shown to be superior to either agent alone in stable COPD patients, suggesting that a similar effect may be seen in AECOPD patients.8 Furthermore, the use of long-acting bronchodilators are not recommended in the acute exacerbation setting.1
The optimal method of bronchodilator delivery has been studied extensively, yet meta-analyses have not been able to show any consistent differences between metered-dose inhalers (MDIs) and nebulizers.9,10 A recent Cochrane systematic review analyzed 8 studies that compared the efficacy of an MDI with spacer with a nebulizer and found no sufficient evidence to suggest 1 delivery method over the other.10 The use of nebulized bronchodilators may be preferred in the inpatient setting because severely ill patients could have difficulty using MDI devices; however, factors like cost, need for rapid administration, and staff availability may favor the use of MDIs in certain circumstances.
Many AECOPD patients admitted to the intensive care unit (ICU) require mechanical ventilation and bronchodilator therapy. In this setting, MDI or nebulizer delivery methods can be employed; however, some MDI devices may not be compatible with all ventilators.10 Because of the turbulent airflow created by mechanical ventilation, drug delivery to the distal airway has been noted to be only 2.9% of the administered dose compared with 11.9% in the absence of ventilation.11 Multiple administration techniques can be used to increase drug delivery in these circumstances.12
The use of glucocorticoids for AECOPD has been shown to significantly improve lung function (FEV1), reduce treatment failure, and shorten hospital stays.13 Notably, however, there has been a lack of benefit in reducing the mortality rate related to COPD exacerbation. Due to potentially serious adverse events, such as hyperglycemia, the lowest effective dose and duration of a glucocorticoid should be employed. GOLD guidelines currently recommend the use of prednisone 40 mg by mouth daily for 5 days for AECOPD, but the guidelines do not differentiate among the outpatient, inpatient, and ICU settings.1
Studies comparing different doses of glucocorticoids for inpatient AECOPD patients have consistently shown that lower doses (20-80 mg per day of prednisone equivalent) have equal efficacy and cause fewer adverse effects than higher doses.14,15 Similarly, studies evaluating the duration of glucocorticoid treatment in hospital inpatients agree that shorter durations of therapy (as short as 5 days) have equal efficacy when compared with longer durations of therapy.16,17 Studies evaluating the optimal route in AECOPD indicate that oral administration is as efficacious as the intravenous route, and recent evidence suggests that nebulized glucocorticoids may have efficacy similar to that of oral glucocorticoids.18,19 The GOLD guidelines recommend nebulized budesonide as an alternative to oral corticosteroids for the treatment of AECOPD.1
Evidence for the use of glucocorticoids in the ICU setting is limited because most studies excluded these patients. Historically, physicians have employed higher doses of systemic glucocorticoids in these patients, but recent evidence shows that higher initial doses (>240 mg/day of methylprednisolone) have no added mortality benefit and, in fact, increase length of stay, hospital costs, length of invasive ventilation, need for insulin therapy, and fungal infections.20 In the absence of other evidence, the optimal dosage (beyond using <240 mg/day of of methylprednisolone) and duration of glucocorticoids for AECOPD in the ICU setting remain unknown.
The use of antibiotics in AECOPD is controversial; however, some data suggest benefit in patients admitted to the ICU.4,21 According to the GOLD guidelines, antibiotics are recommended for patients who exhibit characteristic symptoms of an infection. If patients exhibit an increase in dyspnea, sputum volume, and sputum purulence, or if they require mechanical ventilation, it is recommended that antibiotics be initiated. Patients who exhibit only 2 of these symptoms are also candidates for antibiotic therapy if 1 of the symptoms is sputum purulence.1,21
A study using ofloxacin demonstrated improvement in multiple outcomes in patients admitted to the ICU who were treated with ofloxacin versus placebo. Patients treated with ofloxacin had significantly decreased in-hospital mortality, treatment failure, duration of mechanical ventilation, and hospital length of stay.21 These benefits have not yet been demonstrated in patients admitted to the hospital who are not critically ill or part of the outpatient population. Antibiotics should only be initiated in patients who meet the criteria in order to reduce the risk of the development of antibiotic resistance.1,21 Common bacterial pathogens include Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae, and Staphylococcus aureus.1
No defined empiric antibiotic therapy recommendations exist for AECOPD. Antibiotic choice should be based on local susceptibility patterns and patient risk factors. If a patient has frequent exacerbations or multiple exacerbations that required mechanical ventilation, antibiotic coverage should be expanded to cover gram-negative and resistant bacteria. The choice between intravenous and oral antibiotics is based on patient factors and antibiotic availability. Antibiotics should be de-escalated to narrow-spectrum agents once culture and sensitivity results are obtained. The optimal length of antibiotic therapy is unknown, yet the GOLD guidelines recommend 5 to 10 days.1 Results of a meta-analysis done in 2008 compared the benefit of short-course with traditional-length antibiotic therapy. No benefit was observed in the inpatient population from the extended-length therapy; however, it is unknown whether these results can be applied to the critical care population.22
Procalcitonin is a biomarker that can be used to aid the decision to start antibiotics in AECOPD. It is specific for bacterial infections, so the use of this test can prevent overuse of antibiotics and help prevent the emergence of resistant pathogens.1
Smoking cessation can reduce the risk of COPD exacerbation by as much as 22%, according to the results of 1 study, and should be emphasized in all patients at risk for AECOPD.23 A subgroup analysis from this study implies that significant risk reductions may not occur until 5 years after smoking cessation.
The use of azithromycin for the prevention of AECOPD remains controversial. Historically used for its immunomodulatory and antimicrobial effects in cystic fibrosis, some evidence shows that it can reduce the number and frequency of COPD exacerbations.24 Although beneficial for the prevention of AECOPD, potentially life-threatening cardiovascular events and the emergence of macrolide-resistance patterns bring the safety of this prevention strategy into question.25,26 Decisions on the initiation of long-term azithromycin therapy should be made on a patient-specific basis, weighing the risks and benefits.
Patients who experience shortness of breath while walking during nonstrenuous activity should be offered pulmonary rehabilitation. The average length of a rehabilitation program is 4 to 10 weeks. The rehabilitation structure consists of exercise training, nutrition counseling, smoking cessation strategies, and education about overall wellness and medications. The goals of rehabilitation include symptom reduction, improved quality of life, and improved ability to complete activities of daily living. Clinical trials have shown that pulmonary rehabilitation programs can increase endurance time, peak workload, and oxygen consumption.1
It is critical for patients with COPD to stay up-to-date with their vaccinations. The yearly influenza and pneumococcal vaccines are important in order to avoid serious complications and hospitalizations for exacerbations. Patients aged 65 and older are encouraged to get both the pneumococcal conjugate vaccine (PCV13) and the pneumococcal polysaccharide vaccine (PPSV23). Patients younger than 65 with an FEV1 below 40% are also encouraged to get the PPSV23 because it has been shown to decrease the incidence of community-acquired pneumonia in this population. Health care providers should also ensure that patients have received a TDap vaccine and are up-to-date with the booster schedule, and they should urge patients older than 60 to receive a zoster vaccine, regardless of history of chickenpox.27
AEs of COPD are associated with a significant negative impact on pulmonary function, morbidity, and mortality and escalated health care costs. Prevention of COPD exacerbations should be a key component of management, with emphasis on preventive pharmacological and nonpharmacological strategies to reduce or prevent exacerbations of COPD.
DEEPALI DIXIT, PHARMD, BCPS, is a clinical assistant professor at Ernest Mario School of Pharmacy and a critical care pharmacist in the intensive care unit at Robert Wood Johnson University Hospital. At Robert Wood Johnson University Hospital, Dr Dixit is intricately involved in direct patient care activities and several interdisciplinary committees. She rounds with the multidisciplinary ICU team, promotes safe use of medications, and intervenes to ensure optimization of pharmacotherapy for her patients.
- Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the diagnosis, management, and prevention of COPD — 2016. GOLD website. goldcopd.org/global-strategy-diagnosis-management-prevention-copd-2016/. Published 2016. Accessed December 27, 2016.
- Johnston AK, Mannino DM. Epidemiology of COPD exacerbations. In: Wedzicha JA, Martinez FJ, eds. Chronic Obstructive Pulmonary Disease Exacerbation. New York, NY: Informa Healthcare; 2008:15-26.
- Ford ES, Croft JB, Mannino DM, Wheaton AG, Zhang X, Giles WH. COPD surveillance—United States, 1999-2011. Chest. 2013;144(1):284-305. doi: 10.1378/chest.13-0809.
- Guarascio AJ, Ray SM, Finch CK, Self TH. The clinical and economic burden of chronic obstructive pulmonary disease in the USA. Clinicoecon Outcomes Res. 2013;5:235-245. doi: 10.2147/CEOR.S34321.
- Papi A, Luppi F, Franco F, Fabbri LM. Pathophysiology of exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2006;3(3):245-251.
- Montserrat-Capdevila J, Godoy P, Marsal JR, Barbé F, Galván L. Risk factors for exacerbation in chronic obstructive pulmonary disease: a prospective study. Int J Tuberc Lung Dis. 2016;20(3):389-395. doi: 10.5588/ijtld.15.0441.
- Müllerová H, Shukla A, Hawkins A, Quint J. Risk factors for acute exacerbations of COPD in a primary care population: a retrospective observational cohort study. BMJ Open. 2014;4(12):e006171. doi: 10.1136/bmjopen-2014-006171.
- Routine nebulized ipratropium and albuterol together are better than either alone in COPD. the COMBIVENT Inhalation Solution Study Group. Chest. 1997;112(6):1514-1521.
- Turner MO, Patel A, Ginsburg S, FitzGerald JM. Bronchodilator delivery in acute airflow obstruction. a meta-analysis. Arch Intern Med. 1997;157(15):1736-1744.
- 10. van Geffen WH, Douma WR, Slebos DJ, Kerstjens HA. Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD. Cochrane Database Syst Rev. 2016;(8):CD011826. doi: 10.1002/14651858. CD011826.pub2.
- MacIntyre NR, Silver RM, Miller CW, Schuler F, Coleman RE. Aerosol deliv- ery in intubated, mechanically ventilated patients. Crit Care Med. 1985;13(2):81-84.
- Kallet RH. Adjunct therapies during mechanical ventilation: airway clearance techniques, therapeutic aerosols, and gases. Respir Care. 2013;58(6):1053-1073. doi: 10.4187/respcare.02217.
- Walters JA, Gibson PG, Wood-Baker R, Hannay M, Walters EH. Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2009;(1):CD001288. doi: 10.1002/14651858. CD001288.pub3.
- Lindenauer PK, Pekow PS, Lahti M, Lee Y, Benjamin EM, Rothberg MB. Association of corticosteroid dose and route of administration with risk of treat- ment failure in acute exacerbation of chronic obstructive pulmonary disease. JAMA. 2010;303(23):2359-2367. doi: 10.1001/jama.2010.796.
- Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet. 1999;354(9177):456-460.
- Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group. N Engl J Med. 1999;340(25):1941-1947.
- Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional gluco- corticoid therapy in acute exacerbations of chronic obstructive pulmonary disease: the REDUCE randomized clinical trial. JAMA. 2013;309(21):2223-2231. doi: 10.1001/jama.2013.5023.
- de Jong YP, Uil SM, Grotjohan HP, Postma DS, Kerstjens HA, van den Berg JW. Oral or IV prednisolone in the treatment of COPD exacerbations: a random- ized, controlled, double-blind study. Chest. 2007;132(6):1741-1747.
- Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Am J Respir Crit Care Med. 2002;165(5):698-703.
- Kiser TH, Allen RR, Valuck RJ, Moss M, Vandivier RW. Outcomes associated with corticosteroid dosage in critically ill patients with acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2014;189(9):1052-1064. doi: 10.1164/rccm.201401-0058OC.
- Nouira S, Marghil S, Beighith M, Besbes L, Elatrous, Abroug F. Once daily oral ofloxacin in chronic obstructive pulmonary disease exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet. 2001;358(9298):2020-2025.
- Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerba- tion of COPD: a systematic review and metaanalysis. Chest. 2008;133(3):756- 766. doi: 10.1378/chest.07-1207.
- Au DH, Bryson CL, Chien JW, et al. The effects of smoking cessation on the risk of chronic obstructive pulmonary disease exacerbations. J Gen Intern Med. 2009;24(4):457-463. doi: 10.1007/s11606-009-0907-y.
- Taylor SP, Sellers E, Taylor BT. Azithromycin for the prevention of COPD exacerbations: the good, bad, and ugly. Am J Med. 2015;128(12):1362.e1-6. doi: 10.1016/j.amjmed.2015.07.032.
- Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-698. doi: 10.1056/NEJMoa1104623.
- Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20):1881-1890. doi: 10.1056/NEJMoa1003833.
- Lung disease including asthma and adult vaccination. CDC website. cdc.gov/ vaccines/adults/rec-vac/health-conditions/lung-disease.html. Updated November 1, 2016. Accessed December 14, 2016.