COPD exacerbation resident survival guide
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
- Respiratory tract infections (~½)
- Unknown (~⅓)
- Air pollutants
Treatment Setting
Characterize the symptoms:
❑ Increased cough ❑ Increased Dyspnea ❑ Increased sputum production ❑ Wheezing | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Methylxanthines 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) Uncomplicated COPD (⌀ Risk Factors) 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
- Short-acting inhaled β2-agonists with or without short-acting anticholinergics are usually the preferred bronchodilators for treatment of an exacerbation.[7]
- 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.
- Intravenous methylxanthines (theophylline or aminophylline) are only to be used in selected cases when there is insufficient response to short-acting bronchodilators.[8][9][10][11][12][21]
Corticosteroids
- Systemic corticosteroids in COPD exacerbations shorten recovery time, improve FEV1 and PaO2,[22][14][23][24] and reduce the risk of early relapse, treatment failure, and length of hospital stay.[22][23][25]
- Consensus on optimal corticosteroids dose and duration for COPD exacerbations has not been reached.[26]
Antibiotics
- Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis are the most common bacterial pathogens involved in an exacerbation.[17] However, the choice of the antibiotic should be based on the local bacterial resistance pattern.
- Empirical coverage of Pseudomonas aeruginosa in GOLD 3 and GOLD 4 patients is important.[4]
- Procalcitonin may be of value in the decision to use antibiotics.[27]
Adjunct Therapies
- An appropriate fluid balance with special attention to the administration of diuretics, anticoagulants, treatment of comorbidities, and nutritional aspects should be considered.[4]
- Healthcare providers should strongly enforce stringent measures against active cigarette smoking.[4]
Respiratory Support
- Once oxygen is started, arterial blood gases should be checked 30 to 60 minutes later to ensure satisfactory oxygenation without carbon dioxide retention oracidosis.[4]
- Venturi masks offer more accurate and controlled delivery of oxygen than do nasal prongs but are less likely to be tolerated by the patient.[7]
- Noninvasive mechanical ventilation improves respiratory acidosis and decreases respiratory rate, severity of breathlessness, complications such as ventilator-associated pneumonia, length of hospital stay, mortality, and intubation rates.[28][29][30][31]
Hospital Discharge and Follow-up
- In the hospital prior to discharge, patients should start long-acting bronchodilators, either anticholinergics and/or β2-agonists with or without inhaled corticosteroids.[4]
- For patients who are hypoxemic during an exacerbation, arterial blood gases and/or pulse oximetry should be evaluated prior to hospital discharge and in the following 3 months. If the patient remains hypoxemic, long-term supplemental oxygen therapy may be required.[4]
Prevention of COPD Exacerbations
- Smoking cessation, influenza and pneumococcal vaccines, knowledge of current therapy including inhaler technique, and treatment with long-acting inhaled bronchodilators, with or without inhaled corticosteroids, and phosphodiesterase-4 inhibitors are all therapies that reduce the number of exacerbations and hospitalizations.[32][33][34][35][36][37]
- 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
- The use of mucolytics is not well-supported by evidence.[39]
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
- ↑ Burge, S.; Wedzicha, JA. (2003). "COPD exacerbations: definitions and classifications". Eur Respir J Suppl. 41: 46s–53s. PMID 12795331. Unknown parameter
|month=
ignored (help) - ↑ 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) - ↑ 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) - ↑ 4.0 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) - ↑ 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.
- ↑ 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) - ↑ 7.0 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) - ↑ 8.0 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) - ↑ 9.0 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) - ↑ 10.0 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) - ↑ 11.0 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) - ↑ 12.0 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) - ↑ "http://www.nice.org.uk/nicemedia/live/13029/49397/49397.pdf" (PDF). Retrieved 18 December 2013. External link in
|title=
(help) - ↑ 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) - ↑ 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) - ↑ 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.
- ↑ 17.0 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) - ↑ The Sanford Guide to Antimicrobial Therapy. ISBN 1-9308-0874-7.
- ↑ 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) - ↑ 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.
- ↑ "http://www.nice.org.uk/nicemedia/live/13029/49397/49397.pdf" (PDF). External link in
|title=
(help) - ↑ 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) - ↑ 23.0 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) - ↑ 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) - ↑ 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) - ↑ 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.
- ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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) - ↑ 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.
- ↑ 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) - ↑ 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) - ↑ "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)