COPD exacerbation resident survival guide

Jump to navigation Jump to search

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Definition

  • Exacerbation of COPD is 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][2][3]
  • The diagnosis of an exacerbation relies exclusively on the clinical presentation of the patient complaining of an acute change of symptoms (baseline dyspnea, cough, and/or sputum production) that is beyond normal day-to-day variation.[4]

Causes

Life-Threatening Causes

Life-threatening causes include conditions which may result in death or permanent disability within 24 hours if left untreated.

Common Causes

Treatment Setting

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Characterize the symptoms:
❑ Increased cough
❑ Increased Dyspnea
❑ Increased sputum production
❑ Wheezing
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Examine the patient:
Pulse oximetry
Arterial blood gas
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consider alternative dagnosis:
Pulmonary embolism
Heart failure
Asthma exacerbation
Bronchiectasis
❑ Broncholitis obliterans
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Supplement Oxygen: (Urgent)
Maintain SaO2 ≥ 88-92% )[5]
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Need for ICU admission?
❑ Hemodynamic instability AND/OR
❑ Changes in mental status (confusion, lethargy, coma) AND/OR
❑ Severe dyspnea that responds inadequately to initial emergency therapy AND/OR
❑ Worsening hypoxemia (PaO2 <40 mm Hg) and/or respiratory acidosis (pH <7.25)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
No
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Indications for Hospitalization:

❑ Marked increase in intensity of symptoms (eg, sudden development of resting dyspnea)
❑ Presence of serious comorbidities (eg, heart failure or newly occurring arrhythmias)
❑ Failure of an exacerbation to respond to initial medical management
❑ Onset of new physical signs (eg, cyanosis, peripheral edema)
❑ Severe underlying COPD (GOLD 3—4 categories)
❑ Frequent exacerbations (≥2 events per year)
❑ Insufficient home support
❑ Older age (>65 years)
 
 
 
 
 
Assessment of Exacerbation:

❑ Cardinal symptoms (↑ dyspnea, ↑ sputum volume, and ↑ sputum purulence)
❑ ECG (identify coexisting cardiac problems)
❑ Chest radiograph (exclude alternative diagnoses)
❑ Whole-blood count (identify polycythemia, anemia, or leukocytosis)
❑ Electrolytes and glucose (identify electrolyte disturbances or hyperglycemia)
 
 
 
 
 
 
 
 
 
 
❑ Admit patient to ICU
❑ Classify as Life-threatening COPD exacerbation
❑ Assess patients need for mechanical ventilation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Indications for Noninvasive Mechanical Ventilation

❑ Respiratory acidosis (arterial pH < 7.35 or PaCO2 >45 mm Hg)
❑ Severe dyspnea with signs of respiratory muscle fatigue
❑ Increased work of breathing
 
 
 
Indications for Invasive Mechanical Ventilation

❑ Diminished consciousness, psychomotor agitation inadequately controlled by sedation
❑ Severe hemodynamic instability without response to fluids and vasoactive drugs
❑ Respiratory pauses with loss of consciousness or gasping for air
❑ Life-threatening hypoxemia in patients unable to tolerate NIV
❑ Persistent inability to remove respiratory secretions
❑ Heart rate <50/min with loss of alertness
❑ Severe ventricular arrhythmias
❑ Respiratory or cardiac arrest
❑ Failure of initial trial of NIV
❑ Massive aspiration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mild Exacerbation (⊕ 1 cardinal symptom)
❑ Consider outpatient management
❑ Require change of inhaled treatment by the patient
 
 
Moderate Exacerbation (⊕ 2 cardinal symptoms)
❑ Consider outpatient management
❑ Require a short course of antibiotics and/or oral corticosteroids
 
 
Severe Exacerbation (⊕ 3 cardinal symptoms)

❑ Consider inpatient management
❑ Assess symptoms, ABG, and CXR
❑ Monitor fluid balance and nutrition
❑ Identify and treat associated conditions
❑ Consider subcutaneous heparin or LMWH
❑ Controlled oxygen therapy (consider NIV if indicated)
❑ Antibiotics (if ↑ sputum purulence or ⊕ bacterial infection)
❑ Corticosteroids
❑ Bronchodilators
▸ Increase doses/frequency of short-acting bronchodilators
▸ Combine short-acting β2-agonists and anticholinergics
▸ Use spacers or air-driven nebulizers
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pharmacologic Treatment

β2-adrenergic agonists
Albuterol MDI 4—8 puffs IH q1—2h OR Nebulizer 2.5—5 mg IH q1—2h

Anticholinergics
Ipratropium MDI 4—8 puffs IH q1—2h OR Nebulizer 0.5 mg IH q1—2h


Methylxanthines
Aminophylline 0.9 mg/kg/hr IV
Theophylline 150—450 mg PO bid


Treatment Notes[6][7][8][9][10][11][12][13]
❑ Short-acting β2-agonists with or without short-acting anticholinergics are generally preferred
❑ Consider methylxanthine as an adjunct if inadequate response to bronchodilators


Corticosteroids
Prednisolone 30—40 mg PO q24h for 10—14 days (for mild/moderate exacerbation)
Methylprednisolone 125 mg IV q6h for 3 days (for severe exacerbation)
Treatment Notes[4][14][15][16]
Budesonide 400 mcg IH bid may be an alternative to oral corticosteroids
❑ Corticosteroids should be tapered over 2 weeks


Indications for Antibiotics
❑ Mechanical ventilation required
❑ Severe exacerbation (⊕ 3 cardinal symptoms)
❑ Moderate exacerbation with ↑ sputum purulence

Complicated COPD (⊕ Risk Factors)
❑ Age ≥65 years
❑ FEV1 ≤50% predicted
❑ ≥3 exacerbations per year
❑ Cardiac disease
Moxifloxacin 400 mg PO q24h
Gemifloxacin 320 mg PO q24h
Levofloxacin 500 mg PO q24h
Amoxicillin-Clavulanate 875/125 mg PO bid or 2000/125 mg PO bid or 500/125 mg PO q8h
Ciprofloxacin 750 mg PO q12h with sputum culture (if at risk for Pseudomonas)


Uncomplicated COPD (⌀ Risk Factors)
Azithromycin 500 mg PO q24h or 500 mg PO x1 dose followed by 250 mg PO q24h
Clarithromycinextended-release 1000 mg PO q24h
Cefuroxime axetil 250 or 500 mg PO q12h
Cefpodoxime 200 mg PO q12h
Cefdinir 300 mg PO q12h or 600 mg PO q24h
Doxycycline 100 mg PO bid
Trimethoprim-Sulfamethoxazole 160/800 mg PO bid


Treatment Notes[17][18]
❑ Antibiotic choice should reflect local resistance pattern
❑ Use alternative class if antibiotic exposure within 3 months
❑ Re-evaluate and consider sputum culture if failed to respond in 72 hours
❑ The recommended length of antibiotic therapy is usually 5—10 days

Checklist at Time of Discharge From Hospital

Action Items at Discharge
❑ Reinforce smoking cessation measures
❑ Assure effective home maintenance of pharmacotherapy regimen
❑ Reassess inhaler technique
❑ Educate about maintenance regimen
❑ Give instruction regarding completion of steroid therapy and antibiotics
❑ Assess need for long-term oxygen therapy
❑ Assure follow-up visit in 4—6 weeks
❑ Provide a management plan for comorbidities and their follow-up

Checklist at Follow-Up Visit 4—6 Weeks After Discharge

Action Items at Follow-Up Visit
❑ Smoking cessation measures
❑ Ability to cope in usual environment
❑ Reassess inhaler technique
❑ Measurement of FEV1
❑ Inhaler technique
❑ Understanding of recommended treatment regimen
❑ Need for long-term oxygen therapy and/or home nebulizer
❑ Capacity to do physical activity and activities of daily living
❑ Chronic Obstructive Pulmonary Disease Assessment Test (CAT)
❑ Modified British Medical Research Council questionnaire on breathlessness (mMRC)
❑ Status of comorbidities

Do's

Assessment

  • The presence of purulent sputum during an exacerbation can be sufficient indication for starting empirical antibiotic treatment.[19]

Treatment

Treatment Setting
  • When a patient comes to the ED, the first actions are to provide controlled oxygen therapy and to determine whether the exacerbation is life-threatening. If so, the patient should be admitted to the ICU immediately.[4]
Short-Acting Bronchodilators
  • A systematic review found no significant differences in FEV1 between MDI and nebulizers,[20] although the latter can be more convenient for sicker or frail patients.
Corticosteroids
  • Consensus on optimal corticosteroids dose and duration for COPD exacerbations has not been reached.[26]
Antibiotics
Adjunct Therapies
  • Healthcare providers should strongly enforce stringent measures against active cigarette smoking.[4]
Respiratory Support

Hospital Discharge and Follow-up

Prevention of COPD Exacerbations

  • Early outpatient pulmonary rehabilitation after hospitalization for an exacerbation is safe and results in clinically significant improvements in exercise capacity and health status at 3 months.[38]

Don'ts

Assessment

  • Spirometry is not recommended during an exacerbation because it can be difficult to perform and measurements are not accurate enough.[4]

Treatment

Adjunct Therapies
Respiratory Support
  • NIPPV is not considered in the following conditions:
Contraindications for NIPPV[40]
❑ Inability to cooperate/protect the airway
❑ Inability to clear respiratory secretions
❑ Facial surgery, trauma, or deformity
❑ Upper airway obstruction
❑ High risk for aspiration
❑ Cardiac or respiratory arrest
❑ Nonrespiratory organ failure
▸ Severe encephalopathy (e.g., GCS <10)
▸ Severe upper gastrointestinal bleeding
▸ Hemodynamic instability or unstable cardiac arrhythmia

References

  1. Burge, S.; Wedzicha, JA. (2003). "COPD exacerbations: definitions and classifications". Eur Respir J Suppl. 41: 46s–53s. PMID 12795331. Unknown parameter |month= ignored (help)
  2. Celli, BR.; Barnes, PJ. (2007). "Exacerbations of chronic obstructive pulmonary disease". Eur Respir J. 29 (6): 1224–38. doi:10.1183/09031936.00109906. PMID 17540785. Unknown parameter |month= ignored (help)
  3. Rodriguez-Roisin, R. (2000). "Toward a consensus definition for COPD exacerbations". Chest. 117 (5 Suppl 2): 398S–401S. PMID 10843984. Unknown parameter |month= ignored (help)
  4. 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 Vestbo, J.; Hurd, SS.; Agustí, AG.; Jones, PW.; Vogelmeier, C.; Anzueto, A.; Barnes, PJ.; Fabbri, LM.; Martinez, FJ. (2013). "Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary". Am J Respir Crit Care Med. 187 (4): 347–65. doi:10.1164/rccm.201204-0596PP. PMID 22878278. Unknown parameter |month= ignored (help)
  5. Austin, MA.; Wills, KE.; Blizzard, L.; Walters, EH.; Wood-Baker, R. (2010). "Effect of high flow oxygen on mortality in chronic obstructive pulmonary disease patients in prehospital setting: randomised controlled trial". BMJ. 341: c5462. PMID 20959284.
  6. Stoller, JK. (2002). "Clinical practice. Acute exacerbations of chronic obstructive pulmonary disease". N Engl J Med. 346 (13): 988–94. doi:10.1056/NEJMcp012477. PMID 11919309. Unknown parameter |month= ignored (help)
  7. 7.0 7.1 7.2 Celli, BR.; MacNee, W. (2004). "Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper". Eur Respir J. 23 (6): 932–46. PMID 15219010. Unknown parameter |month= ignored (help)
  8. 8.0 8.1 Barberá, JA.; Reyes, A.; Roca, J.; Montserrat, JM.; Wagner, PD.; Rodríguez-Roisin, R. (1992). "Effect of intravenously administered aminophylline on ventilation/perfusion inequality during recovery from exacerbations of chronic obstructive pulmonary disease". Am Rev Respir Dis. 145 (6): 1328–33. doi:10.1164/ajrccm/145.6.1328. PMID 1595998. Unknown parameter |month= ignored (help)
  9. 9.0 9.1 Emerman, CL.; Connors, AF.; Lukens, TW.; May, ME.; Effron, D. (1990). "Theophylline concentrations in patients with acute exacerbation of COPD". Am J Emerg Med. 8 (4): 289–92. PMID 2363749. Unknown parameter |month= ignored (help)
  10. 10.0 10.1 Lloberes, P.; Ramis, L.; Montserrat, JM.; Serra, J.; Campistol, J.; Picado, C.; Agusti-Vidal, A. (1988). "Effect of three different bronchodilators during an exacerbation of chronic obstructive pulmonary disease". Eur Respir J. 1 (6): 536–9. PMID 2971565. Unknown parameter |month= ignored (help)
  11. 11.0 11.1 Mahon, JL.; Laupacis, A.; Hodder, RV.; McKim, DA.; Paterson, NA.; Wood, TE.; Donner, A. (1999). "Theophylline for irreversible chronic airflow limitation: a randomized study comparing n of 1 trials to standard practice". Chest. 115 (1): 38–48. PMID 9925061. Unknown parameter |month= ignored (help)
  12. 12.0 12.1 Murciano, D.; Aubier, M.; Lecocguic, Y.; Pariente, R. (1984). "Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease". N Engl J Med. 311 (6): 349–53. doi:10.1056/NEJM198408093110601. PMID 6738652. Unknown parameter |month= ignored (help)
  13. "http://www.nice.org.uk/nicemedia/live/13029/49397/49397.pdf" (PDF). Retrieved 18 December 2013. External link in |title= (help)
  14. 14.0 14.1 Maltais, F.; Ostinelli, J.; Bourbeau, J.; Tonnel, AB.; Jacquemet, N.; Haddon, J.; Rouleau, M.; Boukhana, M.; Martinot, JB. (2002). "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. 165 (5): 698–703. doi:10.1164/ajrccm.165.5.2109093. PMID 11874817. Unknown parameter |month= ignored (help)
  15. Gunen, H.; Hacievliyagil, SS.; Yetkin, O.; Gulbas, G.; Mutlu, LC.; In, E. (2007). "The role of nebulised budesonide in the treatment of exacerbations of COPD". Eur Respir J. 29 (4): 660–7. doi:10.1183/09031936.00073506. PMID 17251232. Unknown parameter |month= ignored (help)
  16. Ställberg, B.; Selroos, O.; Vogelmeier, C.; Andersson, E.; Ekström, T.; Larsson, K. (2009). "Budesonide/formoterol as effective as prednisolone plus formoterol in acute exacerbations of COPD. A double-blind, randomised, non-inferiority, parallel-group, multicentre study". Respir Res. 10: 11. doi:10.1186/1465-9921-10-11. PMID 19228428.
  17. 17.0 17.1 Sethi, S.; Murphy, TF. (2008). "Infection in the pathogenesis and course of chronic obstructive pulmonary disease". N Engl J Med. 359 (22): 2355–65. doi:10.1056/NEJMra0800353. PMID 19038881. Unknown parameter |month= ignored (help)
  18. The Sanford Guide to Antimicrobial Therapy. ISBN 1-9308-0874-7.
  19. Stockley, RA.; O'Brien, C.; Pye, A.; Hill, SL. (2000). "Relationship of sputum color to nature and outpatient management of acute exacerbations of COPD". Chest. 117 (6): 1638–45. PMID 10858396. Unknown parameter |month= ignored (help)
  20. Turner, MO.; Patel, A.; Ginsburg, S.; FitzGerald, JM. "Bronchodilator delivery in acute airflow obstruction. A meta-analysis". Arch Intern Med. 157 (15): 1736–44. PMID 9250235.
  21. "http://www.nice.org.uk/nicemedia/live/13029/49397/49397.pdf" (PDF). External link in |title= (help)
  22. 22.0 22.1 Davies, L.; Angus, RM.; Calverley, PM. (1999). "Oral corticosteroids in patients admitted to hospital with exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial". Lancet. 354 (9177): 456–60. PMID 10465169. Unknown parameter |month= ignored (help)
  23. 23.0 23.1 Niewoehner, DE.; Erbland, ML.; Deupree, RH.; Collins, D.; Gross, NJ.; Light, RW.; Anderson, P.; Morgan, NA. (1999). "Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group". N Engl J Med. 340 (25): 1941–7. doi:10.1056/NEJM199906243402502. PMID 10379017. Unknown parameter |month= ignored (help)
  24. Thompson, WH.; Nielson, CP.; Carvalho, P.; Charan, NB.; Crowley, JJ. (1996). "Controlled trial of oral prednisone in outpatients with acute COPD exacerbation". Am J Respir Crit Care Med. 154 (2 Pt 1): 407–12. doi:10.1164/ajrccm.154.2.8756814. PMID 8756814. Unknown parameter |month= ignored (help)
  25. Aaron, SD.; Vandemheen, KL.; Hebert, P.; Dales, R.; Stiell, IG.; Ahuja, J.; Dickinson, G.; Brison, R.; Rowe, BH. (2003). "Outpatient oral prednisone after emergency treatment of chronic obstructive pulmonary disease". N Engl J Med. 348 (26): 2618–25. doi:10.1056/NEJMoa023161. PMID 12826636. Unknown parameter |month= ignored (help)
  26. Walters, JA.; Gibson, PG.; Wood-Baker, R.; Hannay, M.; Walters, EH. (2009). "Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease". Cochrane Database Syst Rev (1): CD001288. doi:10.1002/14651858.CD001288.pub3. PMID 19160195.
  27. Christ-Crain, M.; Jaccard-Stolz, D.; Bingisser, R.; Gencay, MM.; Huber, PR.; Tamm, M.; Müller, B. (2004). "Effect of procalcitonin-guided treatment on antibiotic use and outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial". Lancet. 363 (9409): 600–7. doi:10.1016/S0140-6736(04)15591-8. PMID 14987884. Unknown parameter |month= ignored (help)
  28. Brochard, L.; Mancebo, J.; Wysocki, M.; Lofaso, F.; Conti, G.; Rauss, A.; Simonneau, G.; Benito, S.; Gasparetto, A. (1995). "Noninvasive ventilation for acute exacerbations of chronic obstructive pulmonary disease". N Engl J Med. 333 (13): 817–22. doi:10.1056/NEJM199509283331301. PMID 7651472. Unknown parameter |month= ignored (help)
  29. Bott, J.; Carroll, MP.; Conway, JH.; Keilty, SE.; Ward, EM.; Brown, AM.; Paul, EA.; Elliott, MW.; Godfrey, RC. (1993). "Randomised controlled trial of nasal ventilation in acute ventilatory failure due to chronic obstructive airways disease". Lancet. 341 (8860): 1555–7. PMID 8099639. Unknown parameter |month= ignored (help)
  30. Kramer, N.; Meyer, TJ.; Meharg, J.; Cece, RD.; Hill, NS. (1995). "Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure". Am J Respir Crit Care Med. 151 (6): 1799–806. doi:10.1164/ajrccm.151.6.7767523. PMID 7767523. Unknown parameter |month= ignored (help)
  31. Plant, PK.; Owen, JL.; Elliott, MW. (2000). "Early use of non-invasive ventilation for acute exacerbations of chronic obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial". Lancet. 355 (9219): 1931–5. PMID 10859037. Unknown parameter |month= ignored (help)
  32. Calverley, PM.; Anderson, JA.; Celli, B.; Ferguson, GT.; Jenkins, C.; Jones, PW.; Yates, JC.; Vestbo, J. (2007). "Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease". N Engl J Med. 356 (8): 775–89. doi:10.1056/NEJMoa063070. PMID 17314337. Unknown parameter |month= ignored (help)
  33. Tashkin, DP.; Celli, B.; Senn, S.; Burkhart, D.; Kesten, S.; Menjoge, S.; Decramer, M.; Schiavi, E.; Figueroa Casas, JC. (2008). "A 4-year trial of tiotropium in chronic obstructive pulmonary disease". N Engl J Med. 359 (15): 1543–54. doi:10.1056/NEJMoa0805800. PMID 18836213. Unknown parameter |month= ignored (help)
  34. Calverley, PM.; Rabe, KF.; Goehring, UM.; Kristiansen, S.; Fabbri, LM.; Martinez, FJ.; Abdool-Gaffar, MS.; Abdullah, IA.; Abdullah, I. (2009). "Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials". Lancet. 374 (9691): 685–94. doi:10.1016/S0140-6736(09)61255-1. PMID 19716960. Unknown parameter |month= ignored (help)
  35. Fabbri, LM.; Calverley, PM.; Izquierdo-Alonso, JL.; Bundschuh, DS.; Brose, M.; Martinez, FJ.; Rabe, KF.; Abdulla, R.; Abdullah, I. (2009). "Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials". Lancet. 374 (9691): 695–703. doi:10.1016/S0140-6736(09)61252-6. PMID 19716961. Unknown parameter |month= ignored (help)
  36. Decramer, M.; Celli, B.; Kesten, S.; Lystig, T.; Mehra, S.; Tashkin, DP.; Schiavi, E.; Casas, JC.; Rhodius, E. (2009). "Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial". Lancet. 374 (9696): 1171–8. doi:10.1016/S0140-6736(09)61298-8. PMID 19716598. Unknown parameter |month= ignored (help)
  37. Jenkins, CR.; Jones, PW.; Calverley, PM.; Celli, B.; Anderson, JA.; Ferguson, GT.; Yates, JC.; Willits, LR.; Vestbo, J. (2009). "Efficacy of salmeterol/fluticasone propionate by GOLD stage of chronic obstructive pulmonary disease: analysis from the randomised, placebo-controlled TORCH study". Respir Res. 10: 59. doi:10.1186/1465-9921-10-59. PMID 19566934.
  38. Man, WD.; Polkey, MI.; Donaldson, N.; Gray, BJ.; Moxham, J. (2004). "Community pulmonary rehabilitation after hospitalisation for acute exacerbations of chronic obstructive pulmonary disease: randomised controlled study". BMJ. 329 (7476): 1209. doi:10.1136/bmj.38258.662720.3A. PMID 15504763. Unknown parameter |month= ignored (help)
  39. McCrory, DC.; Brown, C.; Gelfand, SE.; Bach, PB. (2001). "Management of acute exacerbations of COPD: a summary and appraisal of published evidence". Chest. 119 (4): 1190–209. PMID 11296189. Unknown parameter |month= ignored (help)
  40. "International Consensus Conferences in Intensive Care Medicine: noninvasive positive pressure ventilation in acute Respiratory failure". Am J Respir Crit Care Med. 163 (1): 283–91. 2001. doi:10.1164/ajrccm.163.1.ats1000. PMID 11208659. Unknown parameter |month= ignored (help)