Acute Exacerbations of COPD: Avoiding Danger and Death

Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are to COPD what heart attacks are to coronary artery disease: deadly events of a chronic disease.¹

AECOPD is responsible for making COPD the third leading cause of death among adults in the United States.² A more comprehensive and patient-centered approach to COPD care and management is essential in every clinical practice to recognize patients at higher risk for AECOPD and to protect patients from a more rapid decline to disability and death.

COPD is underdiagnosed and undertreated no matter where medicine is practiced. Clinicians are hurried and overworked and may not appreciate patients with COPD who hardly cough and who appear normal, without dyspnea, when sitting in a chair. Resting typically relieves dyspnea in COPD, which often improves quickly with inhaled albuterol. By the time COPD is diagnosed, lung function as measured by forced expiratory volume in the first second of expiration (FEV₁) can be reduced to 60% of predicted.³ When trouble with breathing strikes, as with AECOPD, patients who become more dyspneic than usual over a few days are not suddenly histrionic; they are in fear at home alone when their dyspnea is unrelieved by several rounds of albuterol. During AECOPDs, patients are exhausted with simple physical tasks such as walking, and they seldom sleep well at night, despite their fatigue. A common pitfall is to not put all the patient’s symptoms into the context of their living.

This article highlights the potential pitfalls during the clinical evaluation and treatment of AECOPD, including the missed opportunities to reduce risk factors at home and in hospitals and clinics, to empower patients and clinicians to better control COPD and promote patient safety.¹

AECOPD Background

Current evidence suggests that even a single AECOPD influences the natural course of COPD significantly, and that repeated AECOPDs are probably the most important cause of worsening COPD, manifesting as a steeper decline in FEV₁ over time rather than an effect of COPD and aging.⁴ Frequent AECOPDs are the rule in COPD patients, not the exception. AECOPDs beget more AECOPDs.

AECOPD triggers can be infectious (viruses, bacteria, or both), noninfectious (aspiration, air pollution, allergies, pulmonary embolism [PE], poor adherence and technique with inhalers), or both. The cause was infectious in the majority of cases in a recent study of 64 patients hospitalized for AECOPD—bacteria were indicted in 29.7% cases, viruses in 23.4%, and bacteria and viruses together in 25.0%, compared with 21.8% of cases where no infectious agent was detected.⁵

Patient safety is the highest priority in COPD. Few appreciate the real dangers of moderate to severe AECOPD, the risk of hospitalization and the risk of death from acute respiratory failure, and the simple measures patients and clinicians can implement immediately to reduce future AECOPDs.

Patients with COPD are a heterogeneous group with 3 to 4 identifiable phenotypes,⁶ which the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines do not fully recognize (Table 1).^6,7 In COPD type 2 and type 4, frequent exacerbations are the rule, not the exception. AECOPDs become more frequent, more severe, and more life-threatening as COPD progresses from moderate to very severe as defined by GOLD FEV₁ percent-predicted criteria.

However, AECOPDs are underreported by patients, and the rate at which AECOPDs occur appears to reflect independent phenotypes of COPD. Regardless of phenotypes, patients and their health care providers must jointly develop strategies to reduce the modifiable risks of AECOPDs.

AECOPD RISK FACTORS

The majority of patients with AECOPD are younger than 65 years and are women.^8,9 Women had greater increases in hospitalization for AECOPD than men from 1998 to 2009.⁹ Patients with COPD have their first exacerbation associated with FEV₁ that is between 40% and 60% of predicted.³ Often the acute exacerbation without evidence of pneumonia, PE, or heart failure is the clinical event that first raises suspicion of COPD and prompts spirometry evaluation for the first time.

Up to 50% of lung function as measured by FEV₁ may be lost when symptoms of COPD are noticed by clinicians or when exacerbations occur.¹⁰ The higher the severity or the worse the GOLD stage (GOLD stage 2 < 3 < 4), the more likely AECOPD and hospitalizations will occur and reoccur.¹¹

The frequency of AECOPD is a reliable indicator of future AECOPD risk.¹¹ Identifying patients with a prior history of AECOPD in the past year is the best predictor of another exacerbation occurring soon. In one study, patients who had an AECOPD in the previous year were more than 2 times more likely to have another in the following year, and patients who had 2 or more AECOPDs in the previous year were nearly 6 times more likely to have another exacerbation in the following year.¹¹

A major pitfall to avoid is to not take empathy a step further by not asking patients or their family exactly how many episodes of difficult breathing needing antibiotics and/or prednisone they have experienced in the past 12 months. It is our experience at UC Davis that patients generally have no idea what the meaning of an exacerbation is.

Smokers have more AECOPDs than do nonsmokers with COPD.¹² More women than men seek emergency department (ED) care for AECOPD (88.0 vs 54.5 per 10,000 US civilian population) and are hospitalized for AECOPD (33.4 vs 31.6 per 100,000).¹³ Other risk factors include gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), heart disease, depression, lower FEV₁, the absence of timely vaccinations against influenza and pneumococcal pneumonia, and a lack of daily exercise.⁷

DEFINING AECOPD

AECOPD is a clinical diagnosis. No single test can confirm the diagnosis. Plasma fibrinogen and osteopontin levels appear to be increased in patients with AECOPD and infrequent exacerbators, but they remain clinical research biomarkers. Elevated fibrinogen levels are a biomarker of increased risk for AECOPD and a sign of increased systemic inflammation.¹⁴ Osteopontin may be another useful biomarker of type 3 AECOPD (frequent exacerbators).¹⁵

AECOPD is an event characterized by an acute or subacute change in a patient’s baseline dyspnea (particularly with exertion), cough, and/or sputum production (volume [more phlegm or unexpectedly less], purulence) over 2 to 3 days, enough to warrant concern and a call for advice and help with a change in treatment and management.¹⁶

At UC Davis, we define and explain AECOPD to patients and their family, and we explain to all patients their responsibility to ask for help and a severity assessment by a registered respiratory therapist (RRT) whenever they feel that they are in trouble from AECOPD.

Exacerbations can be mild (type 1), moderate (type 2), or severe (type 3). Moderate AECOPDs often require administration of antibiotics and prednisone in addition to rescue albuterol. Severe exacerbations require ED evaluation and possibly hospitalization.¹⁷

A major pitfall is to evaluate a patient with suspected AECOPD without a disciplined strategy or checklist that can help stratify risk for further morbidity and mortality from AECOPD and acute respiratory failure.

The symptoms of AECOPD are not specific early on. To avoid danger and even death from AECOPD, the call for help must be interpreted specifically for the individual patient in the context of whether it is safe for the patient to remain at home. At UC Davis, we have RRTs employed as COPD case managers for patients during hospitalization and after discharge. The RRTs work under the supervision of a pulmonologist and are available by pager to address patients’ concerns from 7 am to 7 pm every day.

Each AECOPD can have deleterious effects on lung function. Loss of lung function often is greater than reported after AECOPDs, accelerating the patient’s decline to disability and even death. A significant increase in the rate of pre- and post-bronchodilator FEV₁ decline was observed before and after AECOPD in a select patient cohort in the UPLIFT trial.⁴ The mean age of patients with COPD was 64 years, and the data demonstrated a significant and surprising decline in FEV₁ after just one AECOPD. The mean rate of pre-bronchodilator FEV₁ decline was 27.5 mL/y before and 48.7 mL/y after one AECOPD. The mean rate of post-bronchodilator FEV₁ decline was 27.8 mL/y before and 59 mL/y after.⁴

TROUBLE BEGINS AT HOME

The decision to manage a patient with AECOPDs at home is a serious clinical decision that is not without risk and very often succeeds based on a knowledge of or familiarity with the patient (often subjective). Helpful objective criteria such as vital signs, oxygen saturation (Spo₂), arterial blood gas values, chest radiography results, and the patient’s overall physical appearance (diaphoresis; physical and mental exhaustion from increased work of breathing; paradoxical breathing) may not be available because the patient still is at home.

Checklists can be helpful in identifying patients who need to be treated in the ED or be hospitalized.

Patients at high-risk for frequent AECOPDs are those who have severe breathlessness; who have stage 2, 3, or 4 COPD; for whom albuterol (4 puffs) is ineffectual; who are unable to sleep; who live alone; who have major comorbidities (eg, GERD, OSA, cancer, diabetes mellitus, heart disease); and a history of AECOPD in the past 12 months.

It is a dangerous pitfall to presume that a sudden deterioration in a patient’s condition cannot or will not occur at home, in the clinic, or in the hospital. Physical and emotional exhaustion from increased work of breathing or altered mental status is an absolute indication for immediate hospitalization.

MISDIAGNOSIS IS DANGEROUS

Misdiagnosis of the severity of AECOPDs can be dangerous and costly. Patients with moderate AECOPDs often need empiric antibiotics and prednisone, and those with severe AECOPDs need hospitalization. Exhaustion from the increased work of breathing over 2 days during an AECOPD can result in acute hypoxemic and hypercapneic respiratory failure. The inability to sleep because of dyspnea from AECOPD is a tipping point for hospitalizing our patients at UC Davis.

Remembering the broad differential diagnosis of dyspnea, chest tightness, and cough in patients with COPD requires constant human vigilance, not an algorithm. AECOPD can be undertreated at home, and acute pneumonia or PEs can be missed, resulting in hospitalizations and even death. Overtreatment of baseline COPD and everyday symptoms as if they represent an AECOPD exposes patients to the potential dangers of the excessive use of albuterol (eg, tachyarrhythmia, hypokalemia, hyperglycemia, GERD), antibiotics (diarrhea, QT interval prolongation, arrhythmias), and prednisone (immunosuppression, GERD, aspiration), when all of these medications are unnecessary.

Dyspnea, or increased work of breathing, probably is the most important symptom to elicit. Increases in cough, sputum, fatigue, and failure of albuterol (4 puffs by metered-dose inhaler every 2 hours) to improve breathing promptly are other warning signs.

Chest tightness is common with AECOPD (“acute air constipation,” where air goes into the lungs but cannot come out), but chest pain, whether dull, sharp, or pleuritic, is not common. It is a dangerous pitfall to attribute chest pain to AECOPDs. With chest pain (sharp or dull), think acute coronary syndrome, acute pneumonia with pleurisy, pneumothorax, rib fracture, or acute PE. Chest tightness occurs from dynamic lung hyperinflation that is not relieved by albuterol. The presence of fever and decrease in Spo₂ (in patients with a pulse oximeter) may herald acute pneumonia, PE, or congestive heart failure (CHF) exacerbation in the correct clinical setting.

Productive cough of purulent sputum with or without hemoptysis (brown or blood-tinged sputum) may indicate bacterial pneumonia, whereas hemoptysis alone suggests PE. Remember the triad of chest pain, hemoptysis, and dyspnea occurs in only 20% of patients with PE. Hemoptysis requires evaluation with chest radiography and can be associated with acute pneumonia, bronchiectasis, lung abscess, lung cancer, and occasionally CHF.

DANGERS OF AECOPD

Patients and their families need to be empowered to recognize the dangers of AECOPD early enough to call for help from a health care provider. No longer can patients wait at home for others to recognize danger. Patients often refrain from seeking help, hoping to recover from AECOPD and return to baseline. Only 50% of AECOPDs are reported to health care providers, although patients with COPD experience exacerbations frequently, averaging from 1 to 3 moderate to severe exacerbations annually.¹⁸

The direct costs of COPD also are a concern of the Centers for Medicare and Medicaid Services and private health care insurers (Table 2).

(Treatment and Management of COPD and AECOPD on next page)

TREATMENT AND MANAGEMENT OF COPD

At UC Davis, we implemented evidence-based practices or bundles of patient-care services in our hospital and introduced them in our clinics to treat and manage patients during and after AECOPDs. Awareness of undertreatment of COPD can result in better symptom management and reduce the frequency and severity of acute exacerbations.¹⁹

Shockingly, nearly 60% of US patients with diagnosed COPD receive no drug therapy, according to one retrospective analysis.¹⁹ The majority of patients did not receive maintenance therapy for COPD or influenza vaccination, whether they were insured by Medicare or a private health insurer.

TREATMENT AND MANAGEMENT OF AECOPD

Remember the mnemonic ABC for AECOPD: antibiotics for moderate and severe AECOPDs (types 2 and 3),²⁰ bronchodilators,²¹ and corticosteroids.²²

The ABC approach in AECOPD is associated with improvement in FEV₁ lung function, shorter length of hospital stay, and fewer treatment failures. Antibiotics reduce both treatment failure and short-term mortality in moderate to severe AECOPD. Even mild AECOPD may benefit from antibiotics for 5 to 10 days if sputum is purulent and if the exacerbation is moderate or severe (or maybe even mild). The choice depends on community antibiotic resistance or susceptibility patterns. Macrolides, respiratory quinolones, and amoxicillin-clavulanate are all comparable in efficacy. Amoxicillin alone, doxycycline, and trimethoprim-sulfamethoxazole are associated with more treatment failures.^23,24

It is important to target Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis during AECOPDs. Remember the possibility for Pseudomonas species to cause AECOPDs in more severely affected patients and when patients do not experience clinical improvement after 2 days of treatment.

The inhalation of the short-acting β-agonist and short-acting muscarinic agonist bronchodilators by metered-dose inhaler (4 puffs of each) every 2 hours or by nebulizer can help relieve symptoms and identify patients with COPD who may need further escalation of treatment, such as with prednisone 30 to 40 mg for 5 to 10 days. The effects of both bronchodilators are additive.²¹

Other interventions may be necessary, including oxygen, if available, to keep Spo₂ at 90% to 92%; smoking cessation; and sputum culture when a patient fails to respond in 2 days (think Pseudomonas species). Gram stains are not helpful. Pseudomonas species can be a bacterial cause of AECOPD in patients with severe COPD or the prednisone and/or antibiotic use in the past 3 months.²⁵ If the patient does not immediately improve within 2 to 3 hours with bronchodilators, our patients are instructed to contact the RRT COPD case manager for advice.

If referral to the ED is needed, immediate, short-term treatment considerations include the following:

• Oxygen to keep Spo₂ at 90% to 92% or arterial partial pressure of oxygen (Pao₂) at 60 to 65 mm Hg
• Chest radiography in cases of severe AECOPD to rule out pneumonia, pneumothorax, or aspiration
• Electrocardiography to assess for cardiac ischemia (which is underdiagnosed in COPD), cardiac arrhythmias, and multifocal atrial tachycardia
• Arterial blood gas values to assess for hypoxemia, and hypercapnia, and acute respiratory acidosis
• A basic metabolic panel to rule out hypokalemia resulting from excess albuterol use
• Brain natriuretic peptide testing, given that 33% of patients with COPD have CHF exacerbation
• Noninvasive positive pressure ventilation (NIPPV) in AECOPD reduces the need for intubation for acute respiratory failure but can increase the time to recovery and hospital length of stay. Indications for NIPPV include worsening dyspnea, acute respiratory acidosis, and a Pao₂ to fraction of inspired oxygen ratio of less than 200. Do not apply NIPPV when respiratory failure is overt, when the patient is unable to protect the airway, or when an altered consciousness level is evident.
• Intubation for mechanical ventilation is needed when the respiratory rate is greater than 25/min, when dyspnea is profound with the use of accessory muscles with or without paradoxical breathing, when the blood pH is less than 7.3, when Pao₂ is 45 to 60 mm Hg, and when there is no evidence of improvement with NIPPV.

Prevention and Home Management

All patients with AECOPDs need patient education to reduce or prevent exacerbations. The authors of a study comparing patient self-management with usual care found that the number needed to treat to reduce one AECOPD hospitalization per patient per year was only 2.²⁶ A 39.8% reduction in hospitalization for COPD-related hospital admissions was accompanied by a 41% reduction in ED visits and a 58.9% reduction in unscheduled physician visits.

Long-term considerations include the following:

• Patient education about COPD with a written COPD action plan
• Smoking cessation
• Long-acting muscarinic receptor antagonists
• Inhaled corticosteroids
• Roflumilast^27,28
• Infection control, hand washing, and vaccines (pneumococcal conjugate, pneumococcal polyvalent, influenza, pertussis)
• Pulmonary rehabilitation and, if needed, palliative care²⁹
• Access to primary care providers and COPD case managers after hospital discharge.

Quality of Care Improvement

Significant differences in patient outcomes after AECOPD likely stem from  variations in the education, care, and aftercare services provided. All patients at UC Davis are given a written COPD action plan and an ABCDEF checklist (Table 3) that is easy to remember and necessary to begin more comprehensive COPD care, which may require palliative care.²⁹

Next to do:

• Make patient safety a priority at home and in the clinic and hospital
• Infection control
• Immunizations
• Provide services in the hospital and clinics that the patient needs
• Offer pulmonary rehabilitation²⁹
• Offer palliative care²⁹
• Improve patient access to care, including subspecialty referral to a pulmonologist
• Improve patient flow and consultations when needed
• Identify opportunities for quality of care improvement regularly.

Krystal M. Craddock, RRT-NPS, CCM; Carrie Lipe, BA, RRT; Claudia M. Vukovich, RRT, AE-C, CCM; Justin Griffiths, RRT; Alexandra Elliott, BSRT, RRT; Melissa Keo, RRT; and Jimmy Nguyen, RRT-NPS, ACCS, are American Association for Respiratory Care-certified COPD case managers at the Reversible Obstructive Airway Disease (ROAD) Center at UC Davis Medical Center (UCDMC) in Sacramento, California.

Brendy A. Avalos, BSRT, RRT, is manager of the Department of Respiratory Care at UCDMC.

Samuel Louie, MD, is a professor of medicine in the Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, and director of the ROAD Center at UCDMC.

REFERENCES:

1. Criner GJ, Bourbeau J, Diekemper RL, et al. Executive summary: prevention of acute exacerbation of COPD: American College of Chest Physicians and Canadian Thoracic Society Guideline. Chest. 2015;147(4):883-893.
2. How Serious Is COPD. American Lung Association. http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/copd/learn-about-copd/how-serious-is-copd.html. Accessed July 25, 2016.
3. Lindberg A, Bjerg-Bäcklund A, Rönmark E, Larsson L-G, Lundbäck B. Prevalence and underdiagnosis of COPD by disease severity and the attributable fraction of smoking: report from the Obstructive Lung Disease in Northern Sweden Studies. Respir Med. 2006;100(2):264-272.
4. Halpin D, Decramer M, Celli B, et al. Impact of single chronic obstructive pulmonary disease (COPD) exacerbation on lung function decline: analysis of UPLIFT®. Eur Respir J. 2012;​40(suppl 56):194. http://erj.ersjournals.com/content/40/Suppl_56/194. Accessed July 6, 2016.
5. Papi A, Bellettato CM, Braccioni F, et al. Infections and airway inflammation in chronic obstructive pulmonary disease severe exacerbations. Am J Respir Crit Care Med. 2006;173(10):​1114-1121.
6. Miravitlles M, Vogelmeier C, Roche N, et al. A review of national guidelines for management of COPD in Europe. Eur Respir J. 2016;47(2):625-637.
7. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive Lung Disease: Updated 2016. http://goldcopd.org/global-strategy-diagnosis-management-prevention-copd-2016/. Accessed July 7, 2016.
8. Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. 2012;(252):1-207.
9. Akinbami LJ, Liu X. Chronic obstructive pulmonary disease among adults aged 18 and over in the United States, 1998-2009. NCHS Data Brief. 2011;(63):1-8.
10. Doherty DE, Belfer MH, Brunton SA, Fromer L, Morris CM, Snader TC. Chronic obstructive pulmonary disease: consensus recommendations for early diagnosis and treatment. J Fam Pract. 2006;55(suppl 1):S1-S8.
11. Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;​363(12):​1128-1138.
12. Kanner RE, Anthonisen NR, Connett JE; Lung ealth tudy Research roup. Lower respiratory illnesses promote FEV₁ decline in current smokers but not ex-smokers with mild chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164(3):358-364.
13. Ford ES, Croft JB, Mannino DM, Wheaton AG, Zhang X, Giles WH. COPD Surveillance—United States, 1999-2011. Chest. 2013;144(1):284-305.
14. Groenewegen KH, Postma DS, Hop WC, Wielders PL, Schlösser NJ, Wouters EF; COSMIC Study Group. Increased systemic inflammation is a risk factor for COPD exacerbations. Chest. 2008;133(2):350-357.
15. Lee SJ, Kim SH, Kim W, et al. Increased plasma osteopontin in frequent exacerbator and acute exacerbation of COPD. Clin Respir J. 2014;8(3):​305-311.
16. Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl. 2003;21(suppl 41):46s-53s.
17. Celli BR, MacNee W, Agusti A, et al. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932-946.
18. Seemungal TAR, Donaldson GC, Bhowmik A, Jeffries DJ, Wedzicha JA. Time course and recovery of exacerbations in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2000;161(5):1608-1613.
19. Make B, Dutro MP, Paulose-Ram R, Marton JP, Mapel DW. Undertreatment of COPD: a retrospective analysis of US managed care and Medicare patients. Int J Chron Obstruct Pulmon Dis. 2012;7:1-9.
20. Stoller JK. Acute exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 2002;346(13):988-994.
21. Bach PB, Brown C, Gelfand SE, McCrory DC. Management of acute exacerbations of chronic obstructive pulmonary disease: a summary and appraisal of published evidence. Ann Intern Med. 2001;134(7):600-620.
22. Niewoehner DE, Erbland ML, Deupree RH, et al; Department of Veterans Affairs Cooperative Study Group. Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. N Engl J Med. 1999;340(25):​1941-1947.
23. Siempos II, Dimopoulos G, Korbila IP, Manta K, Falagas ME. Macrolides, quinolones and amoxicillin/clavulanate for chronic bronchitis: a meta-analysis. Eur Respir J. 2007;29(6):1127-1137.
24. Dimopoulos G. Siempos Il, Korbila IP, Manta KG, Falagas ME. Comparison of first-line with second-line antibiotics for acute exacerbations of chronic bronchitis: a metaanalysis of randomized controlled trials. Chest. 2007;132(2):447-455.
25. Lode H, Allewelt M, Balk S, et al. A prediction model for bacterial etiology in acute exacerbations of COPD. Infection. 2007;35(3):143-149.
26. Bourbeau J, Julien M, Maltais F, et al; Chronic Obstructive Pulmonary Disease axis of the Respiratory Network Fonds de la Recherche en Santé du Québec. Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern Med. 2003;​163(5):​585-591.
27. Calverley PMA, Rabe KF, Goehring U-M, Fabbri LM, Martinez FJ; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374(9691):685-694.
28. Martinez FJ, Calverley PMA, Goehring U-M, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015;385(9971):857-866.
29. Hardin KA, Meyers F, Louie S. Integrating palliative care in severe obstructive lung disease. COPD. 2008;5(4):207-220.
30. Louie S, Zeki AA, Schivo M, et al. The asthma-chronic obstructive pulmonary disease overlap syndrome: pharmacotherapeutic considerations. Expert Rev Clin Pharmacol. 2013;6(2):197-219.
31. Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease: the SUPPORT Investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;​154(4 pt 1):959-967.
32. Groenewegen KH, Schols AMWJ, Wouters EFM. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124(2):459-467.
33. Seneff MG, Wagner DP, Wagner RP, Zimmerman JE, Knaus WA. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA. 1995;274(23):1852-1857.
34. Ai-Ping C, Lee K-H, Lim T-K. In-hospital and 5-year mortality of patients treated in the ICU for acute exacerbation of COPD: a retrospective study. Chest. 2005;128(2):518-524.