Chronic bronchitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]

Overview

There main goal of chronic bronchitis treatment is to improve the lung function and slow down the loss of its function, in this regard the treatment plan is divided in to two main category:

  1. Reduce symptoms: by relief of dyspnea and improve exercise tolerance
  2. Reduce risks: by treating exacerbations, preventing disease progression and reducing mortality.

The details about medications and supportive measures are the same for COPD treatment.

General Therapy

  • Patient education session about the disease, a self-treatment plan for exacerbations, and a monthly follow-up call from hospital or nurse practitioner , is associated with a lower hospitalization rate and fewer emergency department visits[1] [2][3]
  • Treatment of COPD requires a careful and thorough evaluation by a physician.
  • The most important aspect of treatment is avoiding tobacco smoke and removing other air pollutants from the patient’s home or workplace.
  • Patients who have low blood oxygen levels in their blood are often given supplemental oxygen.
  • Oral and inhaled medications are used for patients with stable chronic obstructive pulmonary disease (COPD) to reduce dyspnea, improve exercise tolerance, and prevent complications. Symptoms such as coughing or wheezing can be treated with bronchodilators like subcutaneous medications, beta-adrenergics, methylxanthines, and anticholinergics. They act via decreasing muscle tone in small and large airways in the lungs.
  • Respiratory infections should be treated with antibiotics, if appropriate.
  • Nutritional support forms an integral part of management for COPD patients.

Pulmonary rehabilitation

  • Decreases the number of hospitalization and the exacerbations[4].
  • Helpful to alleviate symptoms and improve the lung capacities[5].

Oxygen Therapy

  • COPD patients commonly have hypoxemia {PaO2 (partial pressure of oxygen in arterial blood) of < 55 mm Hg or oxygen saturation of less than 90%}[6][1].
  • Oxygen administration reduces mortality rates in patients with advanced COPD because of the favorable effects on pulmonary hemodynamics[7].
  • Trials have shown long-term oxygen therapy (15-19 hours/day) to improves survival in advanced COPD patients and thus long term oxygen therapy for hypoxemic patients (paO2 < 55 mm Hg), patients with polycythemia and paO2 < 59mm Hg or cor pulmonale is recommended. These patients require re-evaluation in 1-3 months whether they require long term oxygen therapy or not.
  • Home oxygen supplementation are also recommended for patients who are well at rest but develop hypoxemia during exertion[8][9].
  • Oxygen therapy generally is safe. Oxygen toxicity from high inspired concentrations (>60%) is well recognized. Additionally, lot of concerns have been there on carbon dioxide retention caused as a result of decreased respiratory drive due to increased oxygen concentration. This complication can be best avoided by maintaining PaO2 at 60-65 mm Hg
  • The major physical hazards of oxygen therapy are fires or explosions thus patients, and others must be warned not to smoke[1].
  • Route - Nasal canula. Advantages of nasal canula are[1]:
    • It is simple and well tolerated
    • A liter of oxygen increases 3-4% of FiO2 (fraction of inspired oxygen)
    • Nasal oxygen delivery also is beneficial for most mouth-breathing patients.
    • Humidification generally is not necessary when the patient receives oxygen by nasal cannula at flows of less than 5 L/min.
  • Noninvasive positive-pressure ventilation (NIPPV) advantages
    • It allows the delivery of positive-pressure ventilation without the use of an endotracheal tube.
    • It has a tight-fitting nasal or facial mask that is attached to a continuous positive airway pressure (CPAP) or a bilevel positive airway pressure (BiPAP) machine.
    • The positive pressure is beneficial in hypercapneic respiratory failure by decreasing the work of breathing
    • NIPPV has been shown to decrease the need for endotracheal intubation, duration of hospital stay, morbidity and mortality.
    • Contraindication for use

Smoking Cessation

  • Smoking cessation the most important therapeutic intervention for COPD. It has been demonstrated that it is more effective than bronchodilators in the course of treatment[10][1].
  • Smoking cessation education and support should be offered to every patient with COPD, at every visit. Even temporary quit or cutting down the numbers will improve the outcomes in comparison with continued smokers[11].
  • Behavioral counseling (< 10 min) and pharmacotherapy are each effective alone. However, they have synergistic effect together.
  • Supervised use of pharmacologic agents is an important adjunct to self-help and group smoking cessation programs.
  • Nicotine addiction is quite strong and cessation at times is difficult. Withdrawal from nicotine may cause unpleasant adverse effects, like anxiety, irritability, difficulty concentrating, fatigue, drowsiness, depression, and sleep disruption.
  • If a smoker requires cigarette as an eye opener thing in the morning (within 30 minutes of waking), the individual is considered to be highly addicted and would benefit from nicotine replacement therapy.

Nicotine Replacement Therapies

Transdermal Nicotine Patches

  • Trade name - NicoDerm, Nicotrol, and Habitrol[12].
  • Success rates better compared with placebo.
  • Well tolerated, adverse effects are limited to local skin reactions.

Bupropion

  • Class - Antidepressant[13]
  • Trade name - Zyban
  • It enhances central nervous system nonadrenergic function.
  • Advantage - Better results compared to placebo
  • Bupropion may be effective in patients who failed to quit smoking with nicotine replacement therapy.

Varenicline

  • Trade name - Chantix[14]
  • It is a partial agonist selective for alpha4, beta2 nicotinic acetylcholine receptors.
  • Acts by binding to nicotinic acetylcholine receptors and produces agonist activity and preventing nicotine binding.

Vaccination

  • Pneumococcal vaccine should be given to all patients older than 65 years or to patients of any age with FEV1 of < 40% of predicted.
  • The influenza vaccine should be given annually to all COPD patients[15].

Medical treatment

Beta Adrenergic Receptor Agonists

Short Acting Selective B2 Agonist

  • Used for symptomatic relief during acute mild, exacerbation
  • Mechanism of action - Increases intracellular cyclic adenosine monophosphate via activation of B2 -adrenergic receptors on smooth muscle cells of airway and causes smooth muscle relaxation.
  • These agents are less effective in COPD compared to Asthma
  • Patients may not have increase in peak flows with treatment. However, it should be continued as it offers symptomatic relief.
  • The inhaled route is preferred as there is less systemic absorption thus less side-effects.
  • The adverse effects include tachycardia, tremors and cardiac arrhythmia.
  • Drugs available are:
Albuterol, Metaproterenol, Pirbuterol
  • Used for bronchospasm refractory to epinephrine.
  • Route - Inhaled
Levalbuterol
  • Albuterol is a racemic mixture containing both R and S enantiomer. The S enantiomer doesn't bind to Beta 2 receptor and maybe the cause of side-effects. On the other hand, levalbuterol has only active R enantiomer thus causes less side-effects.
  • It is used for both treatment and prevention of bronchospasm.

Long Acting Beta-2 Adrenergic Receptor Agonist

  • The long acting beta 2 receptor agonist are used to alleviate chronic persistent symptoms
  • They help to increase exercise tolerance, prevent nocturnal dyspnea, and improve quality of life.
  • Long-acting beta-agonists include salmeterol, formoterol, arformoterol, and indacaterol.
  • They all require twice-daily dosing, except for indacaterol. Bronchodilating effect lasts more than 12 hours. Indacaterol is administered once daily.
Salmeterol, Formoterol, Arformoterol
  • Facilitate expectoration, improve symptoms and morning peak flows.
Arformoterol
  • Higher potency than racemic formoterol.

Indacaterol

  • Indacaterol a long-acting beta2-agonist (LABA) is used for long-term, once-daily maintenance in patients with chronic obstructive pulmonary disease (COPD) [16].
  • It is not for use as initial therapy in patients with acute deteriorating COPD.

Anticholinergics

  • Anticholinergic drugs act as a competitive inhibitor of acetylcholine and block their action on postganglionic muscarinic receptors, thus inhibiting cholinergically mediated bronchspasm and resulting in bronchodilatation.
  • Reported adverse effects include dry mouth, metallic taste, and prostatic symptoms. Studies have found an increased incidence of acute urinary retention in patient above 66 years using inhaled anticholinergic medications than in nonusers [17].
Ipratropium
  • They have similar efficacy as beta 2 adrenergic receptor agonist.
  • They have a synergistic effect on broncho-dilatation when combined with beta 2 agonist.
  • They have a slower onset and longer duration of action. Thus, lesser helpful in use on an as-needed basis.
  • Dose - 2-4 puffs at 6-8 hour duration.

Tiotropium

  • It is the only long-acting muscarinic (once daily) anti-cholinergic agent available at this time
  • It has become a first-line therapy in patients with persistent symptoms.
  • It is more effective than salmeterol in preventing exacerbation [18]

Phosphodiesterase Inhibitor

Xanthine Derivatives (Theophylline) (Non Specific)

  • Causes inhibition of enzyme phosphodiesterase (non-specific) that in turn increases cyclic adenosine monophosphate (cAMP), causing the relaxation of bronchial smooth muscles.
  • It is mostly used as an adjunctive agent and reserved in non-responsive patients or patients having difficulty in using inhaled agents.
  • It has a narrow therapeutic index and adverse effects, like anxiety, tremors, insomnia, nausea, cardiac arrhythmia (multifocal atrial tachycardia), and seizures above the therapeutics range. Previously the recommended target range was 15-20 mg/dL. However, now it has been reduced to 8-13 mg/dL.
  • It is metabolized via cytochrome P 450 system. Thus, the plasma concentration of theophylline is affected by age, cardiac status, and liver abnormalities.

Phosphodiesterase Type 4 Inhibitors (Specific)

Cilomilast, Roflumilast

  • Second generation, selective phosphodiesterase-4 inhibitors.
  • Decreases inflammatory mediators like macrophages and CD8 lymphocytes.
  • Roflumilast helps in reducing exacerbations, improve dyspnea, and increase lung function in patients with severe COPD. However, Roflumilast has not gained FDA approval for clinical use, largely because of side effects including significant nausea.
  • Cilomilast another drug in this class is still in preliminary clinical trials. It is administered orally and is given in 15mg dose twice daily.

Steroid

  • Systemic (high doses intravenous) and inhaled corticosteroids act as anti-inflammatory agents and reduce the course of the disease, symptoms, treatment failure and need for additional therapy.
  • The use of systemic steroids in the treatment of acute exacerbation is widely done.
  • The 2011 ICSI guidelines conclude that inhaled steroids are appropriate in patients with recurrent exacerbation of COPD.
  • Studies have shown inhaled corticosteroids along with long acting beta agonist to be more beneficial than inhaled steroid alone.
  • Studies have shown an increased risk of pneumonia in patients treated with inhaled corticosteroids. The debate continues on the use of inhaled corticosteroids and the risk for pneumonia in patients with COPD [19], [20].
  • Use of oral steroids in stable COPD patients is not encouraged due to increased adverse effects due to steroid use (hypertension, glucose intolerance, osteoporosis, fractures, and cataracts).

Antibiotics

Anti Inflammatory

  • Macrolides like azithromycin have been occasionally used in treatment of COPD due to their anti-inflammatory properties [21], [22]. However, due to increased incidences of hearing loss and development of antibiotics resistance with azithromycin use, it has not been used on wide scales.

Infections

  • Common organism involved in acute exacerbation of COPD are S pneumonia, H. influenza, M catarrhalis and rarely P aeruginosa. Antibiotics are commonly used in the treatment of acute exacerbation or suggestive of infection. However, regular long term antibiotics used for prevention of COPD exacerbation is not encouraged.
  • Doxycycline has shown superior results for clinical cure, microbiological outcome, use of open label antibiotics, and symptoms.

Beta Adrenergic Receptor Blocker

COPD patients have increased risks of cardiovascular diseases. However, non-selective beta blockers have been found to increase the risks of bronchospasm and thus not recommended in these patients. Interestingly, a study has shown that addition of cardioselective beta-blocker along with standard inhaled COPD treatment with beta 2 selective agonist didn't affect the pulmonary function of the patients. Additionally, it reduce COPD exacerbation, hospital admission and all causes mortality during a follow up of 4.35 years with 5977 COPD patients [23]

Mucolytic

  • The efficacy of mucolytic agents in the treatment of COPD remains controversial.
  • The oral agent N -acetylcysteine has antioxidant and mucolytic properties (decreases sputum viscosity and secretion) and is used to treat patients with COPD
  • When used as an inhalational therapy, N -acetylcysteine should be administered along with a bronchodilator such as albuterol in order to counteract potential induction of bronchospasm.

Route of Therapy

  • Inhaled delivery is preferred over the oral route as there is less systemic absorption via inhaled route thus less adverse effects. However, some patients may have difficulty achieving effective delivery of the medication using a metered-dose inhaler. Use of spacer or nebulizer may be beneficial in them.

GOLD Recommendations for Management of COPD

GOLD recommendations for management of COPD
Stage Degree of airway obstruction Treatment
Stage I Mild
  • Influenza vaccine (decrease risk)
  • Short acting Beta 2 receptor agonist
Stage II Moderate
  • Influenza vaccine (decrease risk)
  • Short acting Beta 2 receptor agonist
  • Long-acting bronchodilator
  • Cardiopulmonary rehabilitation
Stage III Severe
  • Influenza vaccine (decrease risk)
  • Short acting Beta 2 receptor agonist
  • Long-acting bronchodilator
  • Cardiopulmonary rehabilitation
  • Inhaled steroids in case of frequent exacerbation
Stage IV

Very severe or moderate with evidence of chronic respiratory failure

  • Influenza vaccine (decrease risk)
  • Short acting Beta 2 receptor agonist
  • Long term oxygen therapy
  • Lung transplant can be considered



Chronic obstructive pulmonary disease treatment

  • Preferred regimen
  • Beta2-agonist
(1) Short acting: Fenoterol 100-200 mcg metered dose inhaler; 1 mg/ml solution for nebulizer ; 0.05 % syrup oral, duration of action 4-6 hrs OR Levalbuterol 45-90 mcg metered dose inhaler; 0.21 mg/ml -0.42 mg/ml solution for nebulizer ; duration of action 6-8 hrs OR Salbutamol 100-200 mcg metered dose inhaler and dry powder inhaler; 5 mg/ml solution for nebulizer ; 5 mg pill ; 0.024 % syrup oral; 0.1 mg, 0.5 mg vials for injection ; duration of action 4-6 hrs OR Terbutaline 400-500 mcg dry powder inhaler and 2.5 mg,5 mg pill oral, duration of action 4-6 hrs
(2) Long acting : Formoterol 4.5 mcg-12 mcg metered dose inhaler and dry powder inhaler ; 0.01 mg/ml solution for nebulizer ; duration of action 12 hrs OR Arformoterol 0.0075 mg/ml solution for nebulizer ; duration of action 12 hrs OR Indacaterol 75 mcg-300 mcg dry powder inhaler; duration of action 24 hrs OR Salmeterol 25 mcg-50 mcg metered dose inhaler and dry powder inhaler ; duration of action 12 hrs OR Tulobuterol 2 mg transdermal ; duration of action 24 hrs
  • Anticholinergics
(1) Short acting: Ipratropium bromide 20 mcg-40 mcg metered dose inhaler; duration of action 6-8 hrs OR Oxitropium bromide 100 mcg metered dose inhaler; duration of action 7-9 hrs
(2) Long acting: Aclidinium bromide 322 mcg dry powder inhaler; duration of action 12 hrs OR Glycopyrronium bromide 44 mcg dry powder inhaler; duration of action 24 hrs OR Tiotropium 18 mcg; 5 mcg soft mist inhaler; duration of action 24 hrs OR Umeclidinium 62.5 mcg dry powder inhaler; duration of action 24 hrs
  • Combination of short acting beta2 agonist and anticholinergics in one inhaler: Fenoterol/Ipratropium bromide 200-80 mcg metered dose inhaler; 0.25-0.5 solution for nebulizer; duration of action 6-8 hrs OR Salbutamol/Ipratropium bromide 100-20 mcg soft mist inhaler; 1.5 solution for nebulizer; duration of action 6-8 hrs
  • Methylxanthines: Aminophylline 200-600 mg pill oral; 240 mg injection OR Theophylline 100-600 mg pill oral; duration of action variable upto 24 hrs
  • Inhaled corticosteroids: Beclomethasone 50 mcg-400 mcg metered dose inhaler and dry powder inhaler; 0.2 mg/ml-0.4 mg/ml solution for nebulizer OR Budesonide 100 mcg,200 mcg,400 mcg dry powder inhaler; 0.20 mg/ml, 0.25mg/ml ,0.5 mg/ml solution for nebulizer OR Fluticasone 50 mcg-500 mcg metered dose inhaler and dry powder inhaler
  • Phosphodiesterase-4 inhibitors: Roflumilast 500 mcg pill oral; duration of action is 24 hrs.
Note: Formoterol nebulized solution is based on the unit dose containing 20 mcg in a volume of 2.0 ml.
  • Alternative regimen
  • Vaccination
(1) Influenza vaccination containing killed or live inactivated virus is more effective in elderly patients with chronic obstructive pulmonary disease.
(2) Pneumococcal polysaccharide vaccine is recommended for chronic obstructive pulmonary disease in elderly patients 65 years and older, and also in younger patient with significant comorbid conditions such as cardiac disease.This vaccine also shown to reduce the incidence of community acquired pneumonia in chronic obstructive pulmonary disease patients younger than age 65 years with an FEV1< 40 % predicted.
  • Alpha-1 antitrypsin augmentation therapy
Young patients with severe hereditary alpha-1 antitrypsin deficiency and established significant emphysema may be the candidates for alpha-1 antitrypsin augmentation therapy.
  • Antibiotics
The use of antibiotics, other than for treating infectious exacerbations of chronic obstructive pulmonary disease and other bacterial infections is currently not indicated.
  • Mucolytics (mucokinetic and mucoregulator) and antioxidant agents (ambroxol, erdosteine, carbocysteine, iodinated glycerol, N-acetylcysteine)
(1) Although a few patients with viscous sputum may benefit from mucolytics, the overall benefits seems to be very small; their wide spread use is not recommended.
(2) There is some evidence that in chronic obstructive pulmonary disease patients not receiving inhaled corticosteroids, treated with mucolytics and N-acetylcysteine may reduce exacerbations.
  • Immunoregulators (immunomodulators,immunostimulators): Studies using an immunoregulator in chronic obstructive pulmonary disease report a decrease in the severity and frequency of exacerbations.
  • Antitussives: has a significant protective role but the regular usage of antitussives is not recommended in stable chronic obstructive pulmonary disease patients.
  • Narcotics (morphine): Oral and parenteral opioids are effective for treating dyspnea in chronic obstructive pulmonary disease patients with very severe disease.
  • Others: Oxygen therapy, ventilation support.
  • Initial pharmacological management of chronic obstructive pulmonary disease
  • Group A patients: Have few symptoms and low risk of exacerbations.
  • Preferred regimen: Short acting anticholinergics OR short acting beta2 agonist
  • Alternative regimen (1): Long acting anticholinergics OR long acting beta2 agonist OR short acting beta2 agonist AND short acting anticholinergics
  • Alternative regimen (2): Theophylline
  • Group B patients: Have more significant symptoms but still low risk of exacerbations
  • Preferred regimen: Long acting anticholinergics OR long acting beta2 agonist
  • Alternative regimen (1): Long acting anticholinergics AND long acting beta2 agonist
  • Alternative regimen (2): short acting beta2 agonist AND/ OR short acting anticholinergics

Theophylline

  • Group C patients: Have few symptoms but high risk of exacerbations
  • Alternative regimen (1):
  • Alternative regimen (2):
  • Group D patients: Have many significant symptoms and high risk of exacerbations.
  • Alternative regimen (1):
  • Alternative regimen (2):

External Links

COPD CDC


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Joy M (2004). "Management of chronic obstructive pulmonary disease". N. Engl. J. Med. 351 (14): 1461–3, author reply 1461–3. PMID 15459997.
  2. ↑ Rice KL, Dewan N, Bloomfield HE, Grill J, Schult TM, Nelson DB, Kumari S, Thomas M, Geist LJ, Beaner C, Caldwell M, Niewoehner DE (2010). "Disease management program for chronic obstructive pulmonary disease: a randomized controlled trial". American Journal of Respiratory and Critical Care Medicine. 182 (7): 890–6. doi:10.1164/rccm.200910-1579OC. PMID 20075385. Retrieved 2012-03-20. Unknown parameter |month= ignored (help)
  3. ↑ Dewan NA, Rice KL, Caldwell M, Hilleman DE (2011). "Economic evaluation of a disease management program for chronic obstructive pulmonary disease". Copd. 8 (3): 153–9. doi:10.3109/15412555.2011.560129. PMID 21513435. Retrieved 2012-03-20. Unknown parameter |month= ignored (help)
  4. ↑ Lacasse Y, Brosseau L, Milne S, Martin S, Wong E, Guyatt GH, Goldstein RS (2002). "Pulmonary rehabilitation for chronic obstructive pulmonary disease". Cochrane Database Syst Rev (3): CD003793. doi:10.1002/14651858.CD003793. PMID 12137716.
  5. ↑ Griffiths TL, Burr ML, Campbell IA, Lewis-Jenkins V, Mullins J, Shiels K, Turner-Lawlor PJ, Payne N, Newcombe RG, Ionescu AA, Thomas J, Tunbridge J, Lonescu AA (2000). "Results at 1 year of outpatient multidisciplinary pulmonary rehabilitation: a randomised controlled trial". Lancet. 355 (9201): 362–8. PMID 10665556.
  6. ↑ "Long term domiciliary oxygen therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema. Report of the Medical Research Council Working Party". Lancet. 1 (8222): 681–6. 1981. PMID 6110912.
  7. ↑ Rennard SI (1998). "COPD: overview of definitions, epidemiology, and factors influencing its development". Chest. 113 (4 Suppl): 235S–241S. PMID 9552012.
  8. ↑ "Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease: a clinical trial. Nocturnal Oxygen Therapy Trial Group". Ann. Intern. Med. 93 (3): 391–8. 1980. PMID 6776858.
  9. ↑ Emtner M, Porszasz J, Burns M, Somfay A, Casaburi R (2003). "Benefits of supplemental oxygen in exercise training in nonhypoxemic chronic obstructive pulmonary disease patients". Am. J. Respir. Crit. Care Med. 168 (9): 1034–42. doi:10.1164/rccm.200212-1525OC. PMID 12869359.
  10. ↑ Anthonisen NR, Connett JE, Kiley JP, Altose MD, Bailey WC, Buist AS, Conway WA, Enright PL, Kanner RE, O'Hara P (1994). "Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study". JAMA. 272 (19): 1497–505. PMID 7966841.
  11. ↑ Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE, Connett JE (2005). "The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial". Ann. Intern. Med. 142 (4): 233–9. PMID 15710956.
  12. ↑ Schnoll RA, Patterson F, Wileyto EP, Heitjan DF, Shields AE, Asch DA, Lerman C (2010). "Effectiveness of extended-duration transdermal nicotine therapy: a randomized trial". Ann. Intern. Med. 152 (3): 144–51. doi:10.7326/0003-4819-152-3-201002020-00005. PMC 3782858. PMID 20124230.
  13. ↑ Hughes JR, Stead LF, Hartmann-Boyce J, Cahill K, Lancaster T (2014). "Antidepressants for smoking cessation". Cochrane Database Syst Rev (1): CD000031. doi:10.1002/14651858.CD000031.pub4. PMID 24402784.
  14. ↑ Hays JT, Ebbert JO (2008). "Varenicline for tobacco dependence". N. Engl. J. Med. 359 (19): 2018–24. doi:10.1056/NEJMct0800146. PMC 2959114. PMID 18987369.
  15. ↑ Wongsurakiat P, Maranetra KN, Wasi C, Kositanont U, Dejsomritrutai W, Charoenratanakul S (2004). "Acute respiratory illness in patients with COPD and the effectiveness of influenza vaccination: a randomized controlled study". Chest. 125 (6): 2011–20. PMID 15189916.
  16. ↑ Chapman KR, Rennard SI, Dogra A, Owen R, Lassen C, Kramer B (2011). "Long-term safety and efficacy of indacaterol, a long-acting β₂-agonist, in subjects with COPD: a randomized, placebo-controlled study". Chest. 140 (1): 68–75. doi:10.1378/chest.10-1830. PMID 21349928. Retrieved 2012-03-19. Unknown parameter |month= ignored (help)
  17. ↑ Singh S, Furberg CD (2011). "Inhaled anticholinergics for chronic obstructive pulmonary disease: comment on "Inhaled anticholinergic drug therapy and the risk of acute urinary retention in chronic obstructive pulmonary disease"". Archives of Internal Medicine. 171 (10): 920–2. doi:10.1001/archinternmed.2011.171. PMID 21606097. Retrieved 2012-03-21. Unknown parameter |month= ignored (help)
  18. ↑ Vogelmeier C, Hederer B, Glaab T, Schmidt H, Rutten-van Mölken MP, Beeh KM, Rabe KF, Fabbri LM (2011). "Tiotropium versus salmeterol for the prevention of exacerbations of COPD". The New England Journal of Medicine. 364 (12): 1093–1103. doi:10.1056/NEJMoa1008378. PMID 21428765. Retrieved 2012-03-19. Unknown parameter |month= ignored (help)
  19. ↑ Sin DD, Tashkin D, Zhang X, Radner F, Sjöbring U, Thorén A, Calverley PM, Rennard SI (2009). "Budesonide and the risk of pneumonia: a meta-analysis of individual patient data". Lancet. 374 (9691): 712–9. doi:10.1016/S0140-6736(09)61250-2. PMID 19716963. Retrieved 2012-03-21. Unknown parameter |month= ignored (help)
  20. ↑ 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". The New England Journal of Medicine. 356 (8): 775–89. doi:10.1056/NEJMoa063070. PMID 17314337. Retrieved 2012-03-21. Unknown parameter |month= ignored (help)
  21. ↑ Seemungal TA, Wilkinson TM, Hurst JR, Perera WR, Sapsford RJ, Wedzicha JA (2008). "Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations". American Journal of Respiratory and Critical Care Medicine. 178 (11): 1139–47. doi:10.1164/rccm.200801-145OC. PMID 18723437. Retrieved 2012-03-21. Unknown parameter |month= ignored (help)
  22. ↑ Albert RK, Connett J, Bailey WC, Casaburi R, Cooper JA, Criner GJ, Curtis JL, Dransfield MT, Han MK, Lazarus SC, Make B, Marchetti N, Martinez FJ, Madinger NE, McEvoy C, Niewoehner DE, Porsasz J, Price CS, Reilly J, Scanlon PD, Sciurba FC, Scharf SM, Washko GR, Woodruff PG, Anthonisen NR (2011). "Azithromycin for prevention of exacerbations of COPD". The New England Journal of Medicine. 365 (8): 689–98. doi:10.1056/NEJMoa1104623. PMC 3220999. PMID 21864166. Retrieved 2012-03-21. Unknown parameter |month= ignored (help)
  23. ↑ Short PM, Lipworth SI, Elder DH, Schembri S, Lipworth BJ (2011). "Effect of beta blockers in treatment of chronic obstructive pulmonary disease: a retrospective cohort study". BMJ (Clinical Research Ed.). 342: d2549. PMC 3091487. PMID 21558357. Retrieved 2012-03-21.

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